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One of the priority actions in the New Zealand Healthy Ageing Strategy (2016) cialis 5mg cost walgreens was to improve models of care for Home and community Support Services (HCSS) in response to the multiple and growing demands on HCSS. The National Framework for HCSS provides guidance for district health boards for future commissioning, developing, delivering and evaluating HCSS to improve national consistency and quality of care. The National Framework for HCSS was developed in collaboration cialis 5mg cost walgreens with key stakeholders in the HCSS sector, including older people and their whānau. It includes. a vision and principles to guide service design core (essential) components of services that could be expected anywhere in the country a draft outcomes framework describing the outcomes sought from HCSS at individual, population and system levels.

The National Framework for HCSS covers cialis 5mg cost walgreens DHB-funded services for. people aged 65 years and over who have an assessed need in response to an interRAI assessment and meet criteria for funding people considered to be alike in age and interest – for example, Pacific peoples and Māori, aged over 55 years, and others aged over 60 years, with age-related disabilities older people receiving HCSS who require increased support following an acute health episode who have required hospitalisation HCSS that may continue concurrently with short-term Accident Compensation Corporation (ACC) services. Three additional initiatives are linked with developing the National Framework to help achieve consistency in service commissioning, provision and resource allocation. First, a cialis 5mg cost walgreens National Service Specification for HCSS. This service specification will become the nationally mandated specification describing in detail the services and service approaches required of DHBs and providers.

This National Service Specification will be implemented by July 2022, in line with DHB service commissioning timetables. This approach aims to achieve the best balance between national cialis 5mg cost walgreens consistency and flexibility for DHBs in meeting the needs of their populations. Second, a nationally consistent case-mix methodology will be developed for all DHBs to use as a way of improving targeting of resources according to need. Some DHBs are already applying case-mix methods to resource allocation or use. However, different versions of the methodology are being used, resulting in some inconsistency in resource allocation and lack of cialis 5mg cost walgreens transparency across DHBs.

This indicates the need for a single, nationally consistent case-mix method which will also be implemented across all DHBs by July 2022. Third, a nationally consistent outcomes and measurement framework will be developed for use in HCSS and is expected to be completed by July 2021.The Historical mortality web tool presents mortality data (numbers and age-standardised rates) by sex for certain causes of death from 1948 to 2016. Mortality data cialis 5mg cost walgreens by sex, age group and ethnicity (Māori and non-Māori) is presented from 1996 to 2016.The web tool enables you to explore trends over time using interactive graphs and tables. Filtered results and the full data set can be downloaded from within the web tool. The causes of death included are.

All cancer Ischaemic heart disease Cerebrovascular disease Chronic lower respiratory diseases Other forms of heart disease Influenza and Pneumonia Diabetes mellitus cialis 5mg cost walgreens Motor vehicle accidents Intentional self-harm Assault All deaths. The full data set presented in the web tool is available for you to download in text file format. A technical document accompanies the web tool. This document contains information about the data source and analytical methods used to produce summary data, cialis 5mg cost walgreens and a data dictionary for variables used in the web tool. About the data used in this edition Data from 1948 to 1995 presented in these tables was sourced from publications in the Ministry of Health Mortality data and stats series.

Data from 1996 to 2016 was extracted from the New Zealand Mortality Collection records on 07 June 2019. At the time of extraction, there were 606,450 deaths registered from 1996 to 2016 cialis 5mg cost walgreens. Included in this data were 641 deaths provisionally coded awaiting coroners’ findings and 41 deaths awaiting coroners’ findings with no known cause. Ethnic breakdowns of mortality data are only shown from 1996 onwards because there was a significant change in the way ethnicity was defined, and in the way ethnicity data was collected in 1995. For more information please cialis 5mg cost walgreens refer to the Ministry of Health report, Mortality and Demographic Data 1996.

Disclaimer In this edition, data for causes of death was extracted and recalculated for the years 1996–2016 to reflect ongoing updates to data in the New Zealand Mortality Collection (for example, following the release of coroners’ findings) and the revision of population estimates and projections following each census. For this reason there may be small changes to some numbers and rates from those presented in previous publications and tables. We have quality checked the collection, extraction, and reporting of the data presented here. However errors can occur. Contact the Ministry of Health if you have any concerns regarding any of the data or analyses presented here, at data-enquires@health.govt.nz.

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Date published cialis 5 mg. August 26, 2020On this page BackgroundCOVID-19 is an infectious disease caused by the SARS-CoV-2 coronavirus. The World Health Organization declared a global pandemic in March 2020, and cialis 5 mg the Minister of Health signed the Interim Order Respecting the Importation and Sale of Medical Devices for Use in Relation to COVID-19 on March 18, 2020. The Interim Order (IO) allows us to quickly address large-scale public health emergencies.This IO allows for faster authorization of Class I-IV medical devices for COVID-19.This document presents the criteria for safety and effectiveness that apply to test swabs used for COVID-19 sampling.

It also provides guidance on how to meet these criteria in an application under the IO pathway. Diagnostic testing is a key element cialis 5 mg in both. identifying cases of infection preventing the spread of the coronavirus A test swab may be used to collect a sample for either Polymerase Chain Reaction (PCR) laboratory testing or point-of-care testing. Point-of-care testing can be done directly in a hospital or doctor’s office.

Once the sample has been taken, the swab is cialis 5 mg either placed in a preserving liquid and sent to a laboratory for testing, or placed directly in a testing device (point-of-care).Swabs may be packaged in a variety of virus transport media (VTM). Specifications for individual VTMs are beyond the scope of this document. Swabs play a role in the accuracy of COVID-19 diagnostic testing. For example, false negatives cialis 5 mg can occur in PCR tests if.

the swab material inhibits the test reaction or the swab design doesn’t provide enough surface area to obtain a sufficient sample Test swabs that are not safe and effective may cause or lead to harm. For example. A swab that breaks during sample collection can cause cialis 5 mg physical injury a non-sterile swab that produces an incorrect test result can lead to harmHealth Canada has published a guidance document to support the preparation of applications submitted under the IO. It should be read in conjunction with this document.

We are processing applications as quickly as possible. To avoid delays, please ensure you have completed your application properly.Medical Devices Regulations (MDR) classification In the Canadian regulatory framework, Class I devices present the cialis 5 mg lowest potential risk and Class IV the highest. Swabs are classified according to their labelling and intended use. For example, if a swab is labelled for nasopharyngeal (NP) or oropharyngeal (OP) use only, it will be classified as a Class I medical device according to Classification Rule 2(2) of the MDR.

If a swab is not exclusively for use in oral or nasal cavities, or its use is not explicitly stated, it will be classified as a cialis 5 mg Class II device by Rule 2(1). These swabs belong to a higher risk class because their use in other body orifices for the collection of tissue samples (for example, to test for chlamydia or ureaplasma) is associated with greater risk. Rule 2 Subject to subrules (2) to (4), all invasive devices that penetrate cialis 5 mg the body through a body orifice or that come into contact with the surface of the eye are classified as Class II. A device described in subrule (1) that is intended to be placed in the oral or nasal cavities as far as the pharynx or in the ear canal up to the ear drum is classified as Class I.Regulatory pathways for COVID-19 devicesManufacturers of Class I swabs may seek authorization to import and sell their products under either.

A Medical Device Establishment Licence (MDEL) MDEL is an establishment oversight framework that is not product-specific and not designed to assess safety and effectiveness an IO authorization information on safety and effectiveness are required as part of the application Health Canada is encouraging a sub-group of swab manufacturers to use the IO authorization pathway for Class I swabs, especially if they are. New to the manufacturing of swabs and manufacturing in Canada (such as a company that has re-tooled to manufacture), or using a new manufacturing process or design for swabs (such as 3D printing or honeycomb design)IO applications for swabs should include the following information.Device cialis 5 mg description The device description should include. A picture and/or engineering drawing identification of all materials used in the production of the swab the intended use(s) (for example, NP swabs)Quality manufacturingManufacturers must either. demonstrate compliance with Quality Manufacturing Systems (for example, ISO 13485 certificate) applicable to the swab, or provide a clear description of the planned quality manufacturing systems that are consistent with similar existing manufacturing systemsDesign verificationProvide swab design verification (bench testing) data in a summary report.

It should show that the essential minimum design cialis 5 mg characteristics are met. These data should be based on test samples representative of finished swabs that have undergone sterilization prior to bench testing.Dimensions Swabs should have minimum length specifications and minimum and maximum head diameter specifications in order to be safe and effective. Minimum length specification for example, adult NP swabs require ≥14 cm to reach the posterior nasopharynx minimum and maximum head diameter specification for example, adult NP swabs require 1–4 mm to pass into the mid-inferior portion of the inferior turbinate and maneuver well FlexibilitySwab flexibility is assessed through. Durability for example, tolerate 20 rough repeated insertions into a 4 mm inner diameter clear plastic tube curved back on itself with a curve radius of 3 cm bendability for example, bend tip and neck 90º without breaking ability to maintain initial form for example, restore to initial form following 45º bending Manufacturers may describe the test performed, the number of samples, and cialis 5 mg a summary of the results.Strength/Breakpoint (failure) To limit the potential for patient harm, the minimum breakpoint distance should be approximately 8 to 9 cm from the nasopharynx.

However, no breaks or fractures should occur following reasonable manipulation. Applicants should submit a rationale for the design of the breakpoint distance from the swab tip. It should cialis 5 mg demonstrate that the breakpoint length can be accommodated by commercially available swab/media tubes.Surface propertiesThe swab surface should be free of. processing aids (such as disinfectants) foreign materials degreasers mold release agents For injection molded swabs, no burrs, flashing, or sharp edges should be present.

Design validationProvide swab validation (performance) data in a summary report that demonstrates that the swab. can acquire samples comparable to a commercially available swab control, and will not inhibit the PCR reactionThese data should be based on test samples representative cialis 5 mg of finished swabs that have undergone sterilization prior to testing.Comparable sample acquisition to a control, and PCR compatibilityThe manufacturer should demonstrate test swab cycle threshold (Ct) recovery values (RT-PCR) that are statistically comparable to those obtained from a commercially available swab control using SARS-CoV-2 (or a scientifically justified surrogate).Pass/Fail criteria. Values ≥ 2Cts indicate significantly less efficient ribonucleic acid collection and/or elution.Clinical feasibility/suitability simulationManufacturers should submit either. A clinical test report or previous clinical data Clinical cialis 5 mg test reportThe clinical test report should describe the use of the proposed finished swab (sterilized) in a sufficient number of individuals by trained healthcare professionals in a minimum of 30 patients that have tested positive for SARS-CoV-2, or a scientifically justified surrogate virus.

Include comparisons of the proposed swab against a flocked swab commercially available in Canada with respect to. flexibility fit ability to navigate to the nasopharynx (or other areas specified in the indications) ability to collect a specimen/respiratory epithelial cells for example, using the RNase P housekeeping gene test results agreement for example, ≥ 90% positive % agreement using a composite control (positive % agreement calculation that includes all positive findings from control and test swabs) Clinical testing considerations A scientifically justified surrogate virus may be used if COVID-positive patients are not available. Positive % agreement should not be determined using high Ct samples cialis 5 mg. One-half (1/2) to two-thirds (2/3) of COVID-positive samples should have a high viral loads (Cts <.

30). Report agreement between control and test swabs in terms cialis 5 mg of quantitative (Ct) and qualitative (+/- test) values with appropriate descriptive statistics. Include patient symptomatology for samples. For example, days from symptom onset, known vs.

Suspected COVID cialis 5 mg status. Use of different VTM/universal transport media (V/UTM) across COVID-positive samples may contribute to Ct variability. Ensure consistency by using the same media/tubes for each specimen within a clinical evaluation. Validate the chosen V/UTM media/tubes to show they cialis 5 mg will not interfere with the PCR test results.

For example, allowing 7 days of swab positive specimen incubation with the chosen media/vial is considered a worst-case transportation scenario to evaluate maximal leaching/interaction potential). Use a single PCR test platform throughout each clinical evaluation. The platform should have been cialis 5 mg previously authorized by HC or another jurisdiction. Location (for example, left vs right nostril) and order of sampling (for example, control vs.

Test swab) can affect specimen quality and results variability. Location and swab sampling order should be randomized.For additional information on collecting, handling, and testing COVID-19 specimens, please refer to the cialis 5 mg Centers for Disease Control and Prevention (CDC) Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens for COVID-19.Previous clinical dataPreviously obtained clinical data may be submitted in lieu of clinical testing. Those data should demonstrate the safe and effective use of a swab of identical design and materials in human subjects. The proposed swab should be compared against a flocked cialis 5 mg swab commercially available in Canada with respect to.

flexibility fit ability to navigate to the nasopharynx (or other areas specified in the indications) ability to collect a specimen/respiratory epithelial cells for example, using the RNase P housekeeping gene test results agreement for example, ≥ 90% positive % agreement) using a composite control (positive % agreement calculation that includes all positive findings from control and test swabs) Sterility Provide sterilization validation data in a summary report. It should demonstrate that the chosen sterilization method will achieve a minimum Sterility Assurance Level (SAL) of 10-6 for the proposed swab, using an appropriate biological indicator (BI) organism (see below). If the swab will be sterilized using an ethylene oxide (EtO) method, you should demonstrate that EtO and ethylene chlorohydrin (ECH) residuals meet the tolerable contact limits cialis 5 mg (TCL) specified in ISO 10993-7. Commonly used swab materials, compatible sterilization methods, and appropriate biological indicators are described below.

Sterilization Method Swab Materials EtO(for example, ISO 11135) Gamma Irradiation(ISO 11137) Polystyrene handle, polyester bicomponent fiber tipFootnote * X(for example, Puritan 25-3316-H/U) Not applicable Polystyrene handle, nylon flocked fiber tipFootnote * X(for example, Copan 503CS01) X(for example, BD 220252) Footnote * The CDC provides guidance on the types of swabs that should be used for optimal specimen collection for PCR testing. They include cialis 5 mg swabs that are made of polyester (for example, Dacron), rayon, or nylon-flocked. Cotton-tipped or calcium alginate swabs are not acceptable because residues present in those materials inhibit the PCR reaction. Return to footnote * referrer Appropriate BIIf ionizing radiation will be used to sterilize the swab.

Bacillus pumilus spores are recommended for doses of 25 kGy Bacillus cereus or Bacillus sphaericus spores cialis 5 mg are recommended for doses of >. 25 kGy (World Health Organization, The International Pharmacopoeia, 9th Ed., 2019) Sterilization Process Spore (Indicator Organism) Steam Geobacillus stearothermophilus(formerly Bacillus stearothermophilus) Dry Heat Bacillus atrophaeus (formerly Bacillus subtilis var. Niger) Ethlylene Oxide Bacillus atrophaeus (formerly Bacillus subtilis var. Niger) cialis 5 mg Hydrogen Peroxide Geobacillus stearothermophilus(formerly Bacillus stearothermophilus) Source.

US Food and Drug Administration, "Biological Indicator (BI) Premarket Notification [510(k)] Submissions," October 2007. [Online].Packaging validation Provide packaging validation data in a summary report. It should cialis 5 mg demonstrate that the swab packaging system will maintain a sterile environment across the labelled shelf life (for example, ASTM F1980). without leakage (for example, ASTM D3078-02) with adequate seal strength (for example, ASTM F88/EN 868-5)Test packaging samples should be representative of finished swab packages that have undergone sterilization prior to testing.Biocompatibility Provide biocompatibility data in a summary report.

It should demonstrate compliance with biocompatibility tests recommended for devices in limited contact (≤24 hrs) with mucosal membranes, as per ISO 10993-1. These include cialis 5 mg. cytotoxicity sensitization irritation/intracutaneous reactivityThese data should be based on test samples representative of finished swabs that have undergone sterilization prior to testing.LabellingSwabs should be individually packaged and labelled. The application must include the swab label, which must include cialis 5 mg.

The name and model number of the device the term ‘sterile’, along with the sterilization method (EtO = ethylene oxide. R = gamma irradiation), if the swab is intended to be sold in a sterile condition the name and address of the manufacturer manufacturing and expiry datesIf swabs are not sterile but must be sterilized at the user facility, then the sterilization parameters and method should be clearly described in accompanying instructions for use documentation.Post-market requirementsAs stated in Section 12 of the IO, within 10 days of becoming aware of an incident in Canada, all IO authorization holders must. report the incident specify the nature of the incident specify the cialis 5 mg circumstances surrounding the incidentOn this page About face shields Personal protective equipment (PPE) can help prevent potential exposure to infectious disease. They are considered medical devices in Canada and therefore must follow the requirements outlined in the Medical Devices Regulations.

Medical devices are classified into 4 groups (Class I, II, III and IV) based on their risk to health and safety. Class I devices, such as cialis 5 mg gauze bandages, pose the lowest potential risk, while Class IV devices, such as pacemakers, pose the greatest potential risk. In Canada, face shields are Class I medical devices. A face shield has a transparent window or visor that shields the face and associated mucous membranes (eyes, nose and mouth).

It protects the wearer against exposure from splashes and sprays cialis 5 mg of body fluids. Face shields are made of shatterproof plastic, fit over the face and are held in place by head straps or caps. They may be made of polycarbonate, propionate, acetate, polyvinyl chloride, or polyethylene terephthalate. They are cialis 5 mg usually worn with other PPE, such as a medical mask, respirator or eyewear.

Health Canada strongly advises against the use of plastic bags as an alternative to face shields. Standards and requirements for face shields Organizations that are manufacturing face shields are advised to consult some or all of the following standards throughout the design and testing stages. ANSI/ISEA Z.87.1 (2015), American National Standard for Occupational and Educational Personal Eye and Face Protection Devices CSA Z94.3 (2020), Eye and Face Protectors CSA Z94.3.1 (2016), Guideline for Selection, Use, and Care of Eye and Face Protectors BS EN 166 (2002), Personal Eye Protection cialis 5 mg. Specifications.

Minimum specifications must be incorporated into the design and verification stages to ensure safe and effective face shields. Provide adequate coverage (CSA Z94.3 cialis 5 mg Sections 0.2.1/10.2.2/10.3/10.4). The size of the face shield is important because it must protect the face and front part of the head. This includes the eyes, forehead, cheeks, nose, mouth, and chin.

Protection may also need to extend to the front of the neck in situations with flying particles and sprays cialis 5 mg of hazardous liquids. Fit snugly to afford a good seal to the forehead area and to prevent slippage of the device Footnote 1. Be made of optically clear, cialis 5 mg distortion-free, lightweight materials (CSA Z94.3.1-16 and Footnote 1). Be free of visible defects or flaws that would impede vision (ANSI Z87.1 Section 9.4).

Be comfortable and easy to assemble, use and remove by health care professionals. Provide adequate space between the wearer’s face cialis 5 mg and the inner surface of the visor to allow for the use of ancillary equipment (for example, medical mask, respirator, eyewear) Footnote 1. The characteristics and performance requirements of face shields must not be altered when attaching shields to other protective equipment, such as hats or caps. Display anti-fog characteristics on inside and outside of shield (CSA Z94.3.1-16).

For face shields that are not fog resistant, anti-fog cialis 5 mg spray must be provided. Provide user-contacting materials that have adequate material biocompatibility (skin sensitivity and cytotoxic testing) (ISO 10993-5, 10). Other items to take note of include. Face shields used cialis 5 mg for protection in hospital settings do not have to be impact- or flame- resistant.

If the device is specifically designed to withstand impact from sharp or fast projectiles, it must comply with set-out standards (ANSI Z87.1, sections 9.2 and 9.3, CSA Z94.3, section 10.1). For reuse, manufacturers must provide validated cleaning instructions. Sterilization procedures must not compromise the shield in any way, such as deformation or cialis 5 mg cracking. Regulatory authorization Most PPE, including face shields, are Class I medical devices if they are manufactured, sold or represented for use for reducing the risk of or preventing the user from infection.

This includes COVID-19. Face shields may be authorized for sale cialis 5 mg or import into Canada through the following regulatory pathways. Pathway 1. Interim order authorization to import and sell medical devices related to COVID-19.

Pathway 2 cialis 5 mg. Expedited review and issuance of Medical Device Establishment Licences (MDEL) related to COVID-19. MDEL holders that import and cialis 5 mg sell face shields should take measures to ensure they are safe and effective. Pathway 3.

Exceptional importation and sale of certain non-compliant medical devices related to COVID-19. Note that a sale generally requires the transfer of ownership of a device from one cialis 5 mg party to another and does not necessitate any transfer of money. Applicants should carefully review the pathways and select the most appropriate authorization route for their product. For more information, see Personal protective equipment (COVID-19).

How to cialis 5 mg get authorization. If you intend to manufacture 3D print face shields in response to the COVID-19 crisis, see. 3D printing and other manufacturing of personal protective equipment in response to COVID-19 Feedback If you have any questions or comments about this notice, contact the Medical Devices Directorate at hc.meddevices-instrumentsmed.sc@canada.ca R. J.

Roberge, "Face shields for infection control. A review," Journal of Occupational and Environmental Hygiene, pp. 235-242, 2016. Related links FootnotesFootnote 1 R.

J. Roberge, "Face shields for infection control. A review," Journal of Occupational and Environmental Hygiene, pp. 235-242, 2016.Return to footnote 1 referrer.

Date published cialis 5mg cost walgreens. August 26, 2020On this page BackgroundCOVID-19 is an infectious disease caused by the SARS-CoV-2 coronavirus. The World Health Organization declared a global pandemic in March 2020, and cialis 5mg cost walgreens the Minister of Health signed the Interim Order Respecting the Importation and Sale of Medical Devices for Use in Relation to COVID-19 on March 18, 2020.

The Interim Order (IO) allows us to quickly address large-scale public health emergencies.This IO allows for faster authorization of Class I-IV medical devices for COVID-19.This document presents the criteria for safety and effectiveness that apply to test swabs used for COVID-19 sampling. It also provides guidance on how to meet these criteria in an application under the IO pathway. Diagnostic testing cialis 5mg cost walgreens is a key element in both.

identifying cases of infection preventing the spread of the coronavirus A test swab may be used to collect a sample for either Polymerase Chain Reaction (PCR) laboratory testing or point-of-care testing. Point-of-care testing can be done directly in a hospital or doctor’s office. Once the sample has been taken, the swab is either placed in a preserving liquid and sent to a laboratory for testing, or placed directly in a testing device (point-of-care).Swabs may be packaged in cialis 5mg cost walgreens a variety of virus transport media (VTM).

Specifications for individual VTMs are beyond the scope of this document. Swabs play a role in the accuracy of COVID-19 diagnostic testing. For example, false cialis 5mg cost walgreens negatives can occur in PCR tests if.

the swab material inhibits the test reaction or the swab design doesn’t provide enough surface area to obtain a sufficient sample Test swabs that are not safe and effective may cause or lead to harm. For example. A swab that breaks during sample collection can cause physical injury a non-sterile swab that produces an incorrect test result can lead to cialis 5mg cost walgreens harmHealth Canada has published a guidance document to support the preparation of applications submitted under the IO.

It should be read in conjunction with this document. We are processing applications as quickly as possible. To avoid delays, please ensure you have completed your application properly.Medical Devices Regulations (MDR) classification In the Canadian regulatory framework, Class I devices present the lowest potential cialis 5mg cost walgreens risk and Class IV the highest.

Swabs are classified according to their labelling and intended use. For example, if a swab is labelled for nasopharyngeal (NP) or oropharyngeal (OP) use only, it will be classified as a Class I medical device according to Classification Rule 2(2) of the MDR. If a swab is not exclusively for use in oral or nasal cavities, or its cialis 5mg cost walgreens use is not explicitly stated, it will be classified as a Class II device by Rule 2(1).

These swabs belong to a higher risk class because their use in other body orifices for the collection of tissue samples (for example, to test for chlamydia or ureaplasma) is associated with greater risk. Rule 2 Subject to subrules (2) to (4), all invasive devices that penetrate the body cialis 5mg cost walgreens through a body orifice or that come into contact with the surface of the eye are classified as Class II. A device described in subrule (1) that is intended to be placed in the oral or nasal cavities as far as the pharynx or in the ear canal up to the ear drum is classified as Class I.Regulatory pathways for COVID-19 devicesManufacturers of Class I swabs may seek authorization to import and sell their products under either.

A Medical Device Establishment Licence (MDEL) MDEL is an establishment oversight framework that is not product-specific and not designed to assess safety and effectiveness an IO authorization information on safety and effectiveness are required as part of the application Health Canada is encouraging a sub-group of swab manufacturers to use the IO authorization pathway for Class I swabs, especially if they are. New to the manufacturing of swabs and manufacturing in Canada (such as a company that has re-tooled to manufacture), or using a new manufacturing process cialis 5mg cost walgreens or design for swabs (such as 3D printing or honeycomb design)IO applications for swabs should include the following information.Device description The device description should include. A picture and/or engineering drawing identification of all materials used in the production of the swab the intended use(s) (for example, NP swabs)Quality manufacturingManufacturers must either.

demonstrate compliance with Quality Manufacturing Systems (for example, ISO 13485 certificate) applicable to the swab, or provide a clear description of the planned quality manufacturing systems that are consistent with similar existing manufacturing systemsDesign verificationProvide swab design verification (bench testing) data in a summary report. It should show that the essential cialis 5mg cost walgreens minimum design characteristics are met. These data should be based on test samples representative of finished swabs that have undergone sterilization prior to bench testing.Dimensions Swabs should have minimum length specifications and minimum and maximum head diameter specifications in order to be safe and effective.

Minimum length specification for example, adult NP swabs require ≥14 cm to reach the posterior nasopharynx minimum and maximum head diameter specification for example, adult NP swabs require 1–4 mm to pass into the mid-inferior portion of the inferior turbinate and maneuver well FlexibilitySwab flexibility is assessed through. Durability for example, tolerate 20 rough repeated insertions into a 4 mm inner diameter clear plastic tube curved back on itself with a curve radius of 3 cm bendability for example, bend tip and neck 90º without breaking ability to cialis 5mg cost walgreens maintain initial form for example, restore to initial form following 45º bending Manufacturers may describe the test performed, the number of samples, and a summary of the results.Strength/Breakpoint (failure) To limit the potential for patient harm, the minimum breakpoint distance should be approximately 8 to 9 cm from the nasopharynx. However, no breaks or fractures should occur following reasonable manipulation.

Applicants should submit a rationale for the design of the breakpoint distance from the swab tip. It should demonstrate that the breakpoint length can be accommodated by commercially available swab/media tubes.Surface propertiesThe cialis 5mg cost walgreens swab surface should be free of. processing aids (such as disinfectants) foreign materials degreasers mold release agents For injection molded swabs, no burrs, flashing, or sharp edges should be present.

Design validationProvide swab validation (performance) data in a summary report that demonstrates that the swab. can acquire samples comparable to a commercially available swab control, and will not inhibit the PCR reactionThese data should be based on test samples representative of finished swabs that have cialis 5mg cost walgreens undergone sterilization prior to testing.Comparable sample acquisition to a control, and PCR compatibilityThe manufacturer should demonstrate test swab cycle threshold (Ct) recovery values (RT-PCR) that are statistically comparable to those obtained from a commercially available swab control using SARS-CoV-2 (or a scientifically justified surrogate).Pass/Fail criteria. Values ≥ 2Cts indicate significantly less efficient ribonucleic acid collection and/or elution.Clinical feasibility/suitability simulationManufacturers should submit either.

A clinical test report or previous clinical data Clinical test reportThe clinical test report should describe the use of the proposed finished swab (sterilized) in a sufficient number of individuals by cialis 5mg cost walgreens trained healthcare professionals in a minimum of 30 patients that have tested positive for SARS-CoV-2, or a scientifically justified surrogate virus. Include comparisons of the proposed swab against a flocked swab commercially available in Canada with respect to. flexibility fit ability to navigate to the nasopharynx (or other areas specified in the indications) ability to collect a specimen/respiratory epithelial cells for example, using the RNase P housekeeping gene test results agreement for example, ≥ 90% positive % agreement using a composite control (positive % agreement calculation that includes all positive findings from control and test swabs) Clinical testing considerations A scientifically justified surrogate virus may be used if COVID-positive patients are not available.

Positive % agreement should not be determined cialis 5mg cost walgreens using high Ct samples. One-half (1/2) to two-thirds (2/3) of COVID-positive samples should have a high viral loads (Cts <. 30).

Report agreement between control and test swabs in terms of quantitative (Ct) cialis 5mg cost walgreens and qualitative (+/- test) values with appropriate descriptive statistics. Include patient symptomatology for samples. For example, days from symptom onset, known vs.

Suspected COVID status cialis 5mg cost walgreens. Use of different VTM/universal transport media (V/UTM) across COVID-positive samples may contribute to Ct variability. Ensure consistency by using the same media/tubes for each specimen within a clinical evaluation.

Validate the chosen V/UTM media/tubes to show they will cialis 5mg cost walgreens not interfere with the PCR test results. For example, allowing 7 days of swab positive specimen incubation with the chosen media/vial is considered a worst-case transportation scenario to evaluate maximal leaching/interaction potential). Use a single PCR test platform throughout each clinical evaluation.

The platform cialis 5mg cost walgreens should have been previously authorized by HC or another jurisdiction. Location (for example, left vs right nostril) and order of sampling (for example, control vs. Test swab) can affect specimen quality and results variability.

Location and swab sampling order should be randomized.For additional information on collecting, handling, and testing COVID-19 specimens, please refer to the Centers for Disease Control and Prevention (CDC) Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens for COVID-19.Previous clinical dataPreviously obtained clinical data cialis 5mg cost walgreens may be submitted in lieu of clinical testing. Those data should demonstrate the safe and effective use of a swab of identical design and materials in human subjects. The proposed swab should be compared against a flocked swab commercially available in Canada cialis 5mg cost walgreens with respect to.

flexibility fit ability to navigate to the nasopharynx (or other areas specified in the indications) ability to collect a specimen/respiratory epithelial cells for example, using the RNase P housekeeping gene test results agreement for example, ≥ 90% positive % agreement) using a composite control (positive % agreement calculation that includes all positive findings from control and test swabs) Sterility Provide sterilization validation data in a summary report. It should demonstrate that the chosen sterilization method will achieve a minimum Sterility Assurance Level (SAL) of 10-6 for the proposed swab, using an appropriate biological indicator (BI) organism (see below). If the swab will be sterilized using an ethylene oxide (EtO) method, you should demonstrate that EtO and ethylene chlorohydrin (ECH) residuals meet the tolerable contact limits cialis 5mg cost walgreens (TCL) specified in ISO 10993-7.

Commonly used swab materials, compatible sterilization methods, and appropriate biological indicators are described below. Sterilization Method Swab Materials EtO(for example, ISO 11135) Gamma Irradiation(ISO 11137) Polystyrene handle, polyester bicomponent fiber tipFootnote * X(for example, Puritan 25-3316-H/U) Not applicable Polystyrene handle, nylon flocked fiber tipFootnote * X(for example, Copan 503CS01) X(for example, BD 220252) Footnote * The CDC provides guidance on the types of swabs that should be used for optimal specimen collection for PCR testing. They include swabs that are made of polyester (for example, cialis 5mg cost walgreens Dacron), rayon, or nylon-flocked.

Cotton-tipped or calcium alginate swabs are not acceptable because residues present in those materials inhibit the PCR reaction. Return to footnote * referrer Appropriate BIIf ionizing radiation will be used to sterilize the swab. Bacillus pumilus cialis 5mg cost walgreens spores are recommended for doses of 25 kGy Bacillus cereus or Bacillus sphaericus spores are recommended for doses of >.

25 kGy (World Health Organization, The International Pharmacopoeia, 9th Ed., 2019) Sterilization Process Spore (Indicator Organism) Steam Geobacillus stearothermophilus(formerly Bacillus stearothermophilus) Dry Heat Bacillus atrophaeus (formerly Bacillus subtilis var. Niger) Ethlylene Oxide Bacillus atrophaeus (formerly Bacillus subtilis var. Niger) Hydrogen Peroxide Geobacillus stearothermophilus(formerly cialis 5mg cost walgreens Bacillus stearothermophilus) Source.

US Food and Drug Administration, "Biological Indicator (BI) Premarket Notification [510(k)] Submissions," October 2007. [Online].Packaging validation Provide packaging validation data in a summary report. It should demonstrate cialis 5mg cost walgreens that the swab packaging system will maintain a sterile environment across the labelled shelf life (for example, ASTM F1980).

without leakage (for example, ASTM D3078-02) with adequate seal strength (for example, ASTM F88/EN 868-5)Test packaging samples should be representative of finished swab packages that have undergone sterilization prior to testing.Biocompatibility Provide biocompatibility data in a summary report. It should demonstrate compliance with biocompatibility tests recommended for devices in limited contact (≤24 hrs) with mucosal membranes, as per ISO 10993-1. These include cialis 5mg cost walgreens.

cytotoxicity sensitization irritation/intracutaneous reactivityThese data should be based on test samples representative of finished swabs that have undergone sterilization prior to testing.LabellingSwabs should be individually packaged and labelled. The application must include the swab label, cialis 5mg cost walgreens which must include. The name and model number of the device the term ‘sterile’, along with the sterilization method (EtO = ethylene oxide.

R = gamma irradiation), if the swab is intended to be sold in a sterile condition the name and address of the manufacturer manufacturing and expiry datesIf swabs are not sterile but must be sterilized at the user facility, then the sterilization parameters and method should be clearly described in accompanying instructions for use documentation.Post-market requirementsAs stated in Section 12 of the IO, within 10 days of becoming aware of an incident in Canada, all IO authorization holders must. report the incident specify the nature of the incident specify the circumstances surrounding the incidentOn this page About face shields Personal protective equipment (PPE) can help prevent cialis 5mg cost walgreens potential exposure to infectious disease. They are considered medical devices in Canada and therefore must follow the requirements outlined in the Medical Devices Regulations.

Medical devices are classified into 4 groups (Class I, II, III and IV) based on their risk to health and safety. Class I devices, cialis 5mg cost walgreens such as gauze bandages, pose the lowest potential risk, while Class IV devices, such as pacemakers, pose the greatest potential risk. In Canada, face shields are Class I medical devices.

A face shield has a transparent window or visor that shields the face and associated mucous membranes (eyes, nose and mouth). It protects the wearer against exposure from splashes and sprays of body fluids cialis 5mg cost walgreens. Face shields are made of shatterproof plastic, fit over the face and are held in place by head straps or caps.

They may be made of polycarbonate, propionate, acetate, polyvinyl chloride, or polyethylene terephthalate. They are usually worn with other PPE, cialis 5mg cost walgreens such as a medical mask, respirator or eyewear. Health Canada strongly advises against the use of plastic bags as an alternative to face shields.

Standards and requirements for face shields Organizations that are manufacturing face shields are advised to consult some or all of the following standards throughout the design and testing stages. ANSI/ISEA Z.87.1 (2015), American National Standard for Occupational and Educational Personal Eye and cialis 5mg cost walgreens Face Protection Devices CSA Z94.3 (2020), Eye and Face Protectors CSA Z94.3.1 (2016), Guideline for Selection, Use, and Care of Eye and Face Protectors BS EN 166 (2002), Personal Eye Protection. Specifications.

Minimum specifications must be incorporated into the design and verification stages to ensure safe and effective face shields. Provide adequate coverage (CSA cialis 5mg cost walgreens Z94.3 Sections 0.2.1/10.2.2/10.3/10.4). The size of the face shield is important because it must protect the face and front part of the head.

This includes the eyes, forehead, cheeks, nose, mouth, and chin. Protection may also need to cialis 5mg cost walgreens extend to the front of the neck in situations with flying particles and sprays of hazardous liquids. Fit snugly to afford a good seal to the forehead area and to prevent slippage of the device Footnote 1.

Be made cialis 5mg cost walgreens of optically clear, distortion-free, lightweight materials (CSA Z94.3.1-16 and Footnote 1). Be free of visible defects or flaws that would impede vision (ANSI Z87.1 Section 9.4). Be comfortable and easy to assemble, use and remove by health care professionals.

Provide adequate space between the wearer’s face and the inner cialis 5mg cost walgreens surface of the visor to allow for the use of ancillary equipment (for example, medical mask, respirator, eyewear) Footnote 1. The characteristics and performance requirements of face shields must not be altered when attaching shields to other protective equipment, such as hats or caps. Display anti-fog characteristics on inside and outside of shield (CSA Z94.3.1-16).

For face shields that are not fog resistant, anti-fog cialis 5mg cost walgreens spray must be provided. Provide user-contacting materials that have adequate material biocompatibility (skin sensitivity and cytotoxic testing) (ISO 10993-5, 10). Other items to take note of include.

Face shields used for protection in hospital settings cialis 5mg cost walgreens do not have to be impact- or flame- resistant. If the device is specifically designed to withstand impact from sharp or fast projectiles, it must comply with set-out standards (ANSI Z87.1, sections 9.2 and 9.3, CSA Z94.3, section 10.1). For reuse, manufacturers must provide validated cleaning instructions.

Sterilization procedures must not compromise the shield in any way, such as deformation cialis 5mg cost walgreens or cracking. Regulatory authorization Most PPE, including face shields, are Class I medical devices if they are manufactured, sold or represented for use for reducing the risk of or preventing the user from infection. This includes COVID-19.

Face shields may cialis 5mg cost walgreens be authorized for sale or import into Canada through the following regulatory pathways. Pathway 1. Interim order authorization to import and sell medical devices related to COVID-19.

Pathway 2 cialis 5mg cost walgreens. Expedited review and issuance of Medical Device Establishment Licences (MDEL) related to COVID-19. MDEL holders that import and sell face shields should take cialis 5mg cost walgreens measures to ensure they are safe and effective.

Pathway 3. Exceptional importation and sale of certain non-compliant medical devices related to COVID-19. Note that a sale generally requires the transfer of ownership of a device from one party cialis 5mg cost walgreens to another and does not necessitate any transfer of money.

Applicants should carefully review the pathways and select the most appropriate authorization route for their product. For more information, see Personal protective equipment (COVID-19). How to get cialis 5mg cost walgreens authorization.

If you intend to manufacture 3D print face shields in response to the COVID-19 crisis, see. 3D printing and other manufacturing of personal protective equipment in response to COVID-19 Feedback If you have any questions or comments about this notice, contact the Medical Devices Directorate at hc.meddevices-instrumentsmed.sc@canada.ca R. J.

Roberge, "Face shields for infection control. A review," Journal of Occupational and Environmental Hygiene, pp. 235-242, 2016.

Related links FootnotesFootnote 1 R. J. Roberge, "Face shields for infection control.

A review," Journal of Occupational and Environmental Hygiene, pp. 235-242, 2016.Return to footnote 1 referrer.

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Added newly established codes that capture COVID-related treatments delivered in the hospital setting walgreens cialis 10mg price. As COVID-19 disrupts people’s lives and livelihoods and threatens institutions around the world, the need for fast, data-driven solutions to combat the crisis is growing. This primer is designed to help researchers, data scientists, and others who analyze health care claims or administrative data (herein referred to as “claims”) quickly join the effort to better understand, track, and contain COVID-19.

Readers can use this guidance to help them assess data on health care use and costs linked to COVID-19, create models for risk identification, and pinpoint complications that may follow a COVID-19 diagnosis. Related News.

Mathematica Aug 27, 2020 Authors Alex Bohl and Michelle Roozeboom-Baker Updates to the sixth edition include information on. Added newly established codes that capture COVID-related treatments delivered in the hospital setting. As COVID-19 disrupts people’s lives and livelihoods and threatens institutions around the world, the need for fast, data-driven solutions to combat the crisis is growing. This primer is designed to help researchers, data scientists, and others who analyze health care claims or administrative data (herein referred to as “claims”) quickly join the effort to better understand, track, and contain COVID-19.

Readers can use this guidance to help them assess data on health care use and costs linked to COVID-19, create models for risk identification, and pinpoint complications that may follow a COVID-19 diagnosis.

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4 pro cialis 20mg. FOUR Special Benefits of MSP Programs. Back Door to Extra Help with Part D MSPs Automatically Waive Late Enrollment Penalties for Part B - and allow enrollment in Part B year-round outside of the short Annual Enrollment Period No Medicaid Lien on Estate to Recover Payment of Expenses Paid by MSP Food Stamps/SNAP not reduced by Decreased Medical Expenses when Enroll in MSP - at least temporarily 5. Enrolling in an MSP - Automatic Enrollment & pro cialis 20mg. Applications for People who Have Medicare What is Application Process?.

6. Enrolling in an MSP for People age 65+ who Do Not Qualify for Free pro cialis 20mg Medicare Part A - the "Part A Buy-In Program" 7. What Happens After MSP Approved - How Part B Premium is Paid 8 Special Rules for QMBs - How Medicare Cost-Sharing Works 1. NO ASSET LIMIT!. Since April 1, 2008, none of the three MSP programs have pro cialis 20mg resource limits in New York -- which means many Medicare beneficiaries who might not qualify for Medicaid because of excess resources can qualify for an MSP.

1.A. SUMMARY CHART OF MSP BENEFITS QMB SLIMB QI-1 Eligibility ASSET LIMIT NO LIMIT IN NEW YORK STATE INCOME LIMIT (2020) Single Couple Single Couple Single Couple $1,064 $1,437 $1,276 $1,724 $1,436 $1,940 Federal Poverty Level 100% FPL 100 – 120% FPL 120 – 135% FPL Benefits Pays Monthly Part B premium?. YES, and also Part A premium if did pro cialis 20mg not have enough work quarters and meets citizenship requirement. See “Part A Buy-In” YES YES Pays Part A &. B deductibles &.

Co-insurance YES pro cialis 20mg - with limitations NO NO Retroactive to Filing of Application?. Yes - Benefits begin the month after the month of the MSP application. 18 NYCRR §360-7.8(b)(5) Yes – Retroactive to 3rd month before month of application, if eligible in prior months Yes – may be retroactive to 3rd month before month of applica-tion, but only within the current calendar year. (No pro cialis 20mg retro for January application). See GIS 07 MA 027.

Can Enroll in MSP and Medicaid at Same Time?. YES pro cialis 20mg YES NO!. Must choose between QI-1 and Medicaid. Cannot have both, not even Medicaid with a spend-down. 2 pro cialis 20mg.

INCOME LIMITS and RULES Each of the three MSP programs has different income eligibility requirements and provides different benefits. The income limits are tied to the Federal Poverty Level (FPL). 2019 FPL levels were released by NYS DOH in GIS 20 MA/02 - 2020 Federal Poverty Levels pro cialis 20mg -- Attachment II and have been posted by Medicaid.gov and the National Council on Aging and are in the chart below. NOTE. There is usually a lag in time of several weeks, or even months, from January 1st of each year until the new FPLs are release, and then before the new MSP income limits are officially implemented.

During this lag period, local Medicaid offices should continue to use the previous year's FPLs AND count the person's Social Security benefit amount from the previous year - do NOT factor in the Social Security COLA (cost of living adjustment) pro cialis 20mg. Once the updated guidelines are released, districts will use the new FPLs and go ahead and factor in any COLA. See 2019 Fact Sheet on MSP in NYS by Medicare Rights Center ENGLISH SPANISH Income is determined by the same methodology as is used for determining in eligibility for SSI The rules for counting income for SSI-related (Aged 65+, Blind, or Disabled) Medicaid recipients, borrowed from the SSI program, apply to the MSP program, except for the new rules about counting household size for married couples. N.Y pro cialis 20mg. Soc.

Serv. L. 367-a(3)(c)(2), NYS DOH 2000-ADM-7, 89-ADM-7 p.7. Gross income is counted, although there are certain types of income that are disregarded. The most common income disregards, also known as deductions, include.

(a) The first $20 of your &. Your spouse's monthly income, earned or unearned ($20 per couple max). (b) SSI EARNED INCOME DISREGARDS. * The first $65 of monthly wages of you and your spouse, * One-half of the remaining monthly wages (after the $65 is deducted). * Other work incentives including PASS plans, impairment related work expenses (IRWEs), blind work expenses, etc.

For information on these deductions, see The Medicaid Buy-In for Working People with Disabilities (MBI-WPD) and other guides in this article -- though written for the MBI-WPD, the work incentives apply to all Medicaid programs, including MSP, for people age 65+, disabled or blind. (c) monthly cost of any health insurance premiums but NOT the Part B premium, since Medicaid will now pay this premium (may deduct Medigap supplemental policies, vision, dental, or long term care insurance premiums, and the Part D premium but only to the extent the premium exceeds the Extra Help benchmark amount) (d) Food stamps not counted. You can get a more comprehensive listing of the SSI-related income disregards on the Medicaid income disregards chart. As for all benefit programs based on financial need, it is usually advantageous to be considered a larger household, because the income limit is higher. The above chart shows that Households of TWO have a higher income limit than households of ONE.

The MSP programs use the same rules as Medicaid does for the Disabled, Aged and Blind (DAB) which are borrowed from the SSI program for Medicaid recipients in the “SSI-related category.” Under these rules, a household can be only ONE or TWO. 18 NYCRR 360-4.2. See DAB Household Size Chart. Married persons can sometimes be ONE or TWO depending on arcane rules, which can force a Medicare beneficiary to be limited to the income limit for ONE person even though his spouse who is under 65 and not disabled has no income, and is supported by the client applying for an MSP. EXAMPLE.

Bob's Social Security is $1300/month. He is age 67 and has Medicare. His wife, Nancy, is age 62 and is not disabled and does not work. Under the old rule, Bob was not eligible for an MSP because his income was above the Income limit for One, even though it was well under the Couple limit. In 2010, NYS DOH modified its rules so that all married individuals will be considered a household size of TWO.

DOH GIS 10 MA 10 Medicare Savings Program Household Size, June 4, 2010. This rule for household size is an exception to the rule applying SSI budgeting rules to the MSP program. Under these rules, Bob is now eligible for an MSP. When is One Better than Two?. Of course, there may be couples where the non-applying spouse's income is too high, and disqualifies the applying spouse from an MSP.

In such cases, "spousal refusal" may be used SSL 366.3(a). (Link is to NYC HRA form, can be adapted for other counties). 3. The Three Medicare Savings Programs - what are they and how are they different?. 1.

Qualified Medicare Beneficiary (QMB). The QMB program provides the most comprehensive benefits. Available to those with incomes at or below 100% of the Federal Poverty Level (FPL), the QMB program covers virtually all Medicare cost-sharing obligations. Part B premiums, Part A premiums, if there are any, and any and all deductibles and co-insurance. QMB coverage is not retroactive.

The program’s benefits will begin the month after the month in which your client is found eligible. ** See special rules about cost-sharing for QMBs below - updated with new CMS directive issued January 2012 ** See NYC HRA QMB Recertification form ** Even if you do not have Part A automatically, because you did not have enough wages, you may be able to enroll in the Part A Buy-In Program, in which people eligible for QMB who do not otherwise have Medicare Part A may enroll, with Medicaid paying the Part A premium (Materials by the Medicare Rights Center). 2. Specifiedl Low-Income Medicare Beneficiary (SLMB). For those with incomes between 100% and 120% FPL, the SLMB program will cover Part B premiums only.

SLMB is retroactive, however, providing coverage for three months prior to the month of application, as long as your client was eligible during those months. 3. Qualified Individual (QI-1). For those with incomes between 120% and 135% FPL, and not receiving Medicaid, the QI-1 program will cover Medicare Part B premiums only. QI-1 is also retroactive, providing coverage for three months prior to the month of application, as long as your client was eligible during those months.

However, QI-1 retroactive coverage can only be provided within the current calendar year. (GIS 07 MA 027) So if you apply in January, you get no retroactive coverage. Q-I-1 recipients would be eligible for Medicaid with a spend-down, but if they want the Part B premium paid, they must choose between enrolling in QI-1 or Medicaid. They cannot be in both. It is their choice.

DOH MRG p. 19. In contrast, one may receive Medicaid and either QMB or SLIMB. 4. Four Special Benefits of MSPs (in addition to NO ASSET TEST).

Benefit 1. Back Door to Medicare Part D "Extra Help" or Low Income Subsidy -- All MSP recipients are automatically enrolled in Extra Help, the subsidy that makes Part D affordable. They have no Part D deductible or doughnut hole, the premium is subsidized, and they pay very low copayments. Once they are enrolled in Extra Help by virtue of enrollment in an MSP, they retain Extra Help for the entire calendar year, even if they lose MSP eligibility during that year. The "Full" Extra Help subsidy has the same income limit as QI-1 - 135% FPL.

However, many people may be eligible for QI-1 but not Extra Help because QI-1 and the other MSPs have no asset limit. People applying to the Social Security Administration for Extra Help might be rejected for this reason. Recent (2009-10) changes to federal law called "MIPPA" requires the Social Security Administration (SSA) to share eligibility data with NYSDOH on all persons who apply for Extra Help/ the Low Income Subsidy. Data sent to NYSDOH from SSA will enable NYSDOH to open MSP cases on many clients. The effective date of the MSP application must be the same date as the Extra Help application.

Signatures will not be required from clients. In cases where the SSA data is incomplete, NYSDOH will forward what is collected to the local district for completion of an MSP application. The State implementing procedures are in DOH 2010 ADM-03. Also see CMS "Dear State Medicaid Director" letter dated Feb. 18, 2010 Benefit 2.

MSPs Automatically Waive Late Enrollment Penalties for Part B Generally one must enroll in Part B within the strict enrollment periods after turning age 65 or after 24 months of Social Security Disability. An exception is if you or your spouse are still working and insured under an employer sponsored group health plan, or if you have End Stage Renal Disease, and other factors, see this from Medicare Rights Center. If you fail to enroll within those short periods, you might have to pay higher Part B premiums for life as a Late Enrollment Penalty (LEP). Also, you may only enroll in Part B during the Annual Enrollment Period from January 1 - March 31st each year, with Part B not effective until the following July. Enrollment in an MSP automatically eliminates such penalties...

For life.. Even if one later ceases to be eligible for the MSP. AND enrolling in an MSP will automatically result in becoming enrolled in Part B if you didn't already have it and only had Part A. See Medicare Rights Center flyer. Benefit 3.

No Medicaid Lien on Estate to Recover MSP Benefits Paid Generally speaking, states may place liens on the Estates of deceased Medicaid recipients to recover the cost of Medicaid services that were provided after the recipient reached the age of 55. Since 2002, states have not been allowed to recover the cost of Medicare premiums paid under MSPs. In 2010, Congress expanded protection for MSP benefits. Beginning on January 1, 2010, states may not place liens on the Estates of Medicaid recipients who died after January 1, 2010 to recover costs for co-insurance paid under the QMB MSP program for services rendered after January 1, 2010. The federal government made this change in order to eliminate barriers to enrollment in MSPs.

See NYS DOH GIS 10-MA-008 - Medicare Savings Program Changes in Estate Recovery The GIS clarifies that a client who receives both QMB and full Medicaid is exempt from estate recovery for these Medicare cost-sharing expenses. Benefit 4. SNAP (Food Stamp) benefits not reduced despite increased income from MSP - at least temporarily Many people receive both SNAP (Food Stamp) benefits and MSP. Income for purposes of SNAP/Food Stamps is reduced by a deduction for medical expenses, which includes payment of the Part B premium. Since approval for an MSP means that the client no longer pays for the Part B premium, his/her SNAP/Food Stamps income goes up, so their SNAP/Food Stamps go down.

Here are some protections. Do these individuals have to report to their SNAP worker that their out of pocket medical costs have decreased?. And will the household see a reduction in their SNAP benefits, since the decrease in medical expenses will increase their countable income?. The good news is that MSP households do NOT have to report the decrease in their medical expenses to the SNAP/Food Stamp office until their next SNAP/Food Stamp recertification. Even if they do report the change, or the local district finds out because the same worker is handling both the MSP and SNAP case, there should be no reduction in the household’s benefit until the next recertification.

New York’s SNAP policy per administrative directive 02 ADM-07 is to “freeze” the deduction for medical expenses between certification periods. Increases in medical expenses can be budgeted at the household’s request, but NYS never decreases a household’s medical expense deduction until the next recertification. Most elderly and disabled households have 24-month SNAP certification periods. Eventually, though, the decrease in medical expenses will need to be reported when the household recertifies for SNAP, and the household should expect to see a decrease in their monthly SNAP benefit. It is really important to stress that the loss in SNAP benefits is NOT dollar for dollar.

A $100 decrease in out of pocket medical expenses would translate roughly into a $30 drop in SNAP benefits. See more info on SNAP/Food Stamp benefits by the Empire Justice Center, and on the State OTDA website. Some clients will be automatically enrolled in an MSP by the New York State Department of Health (NYSDOH) shortly after attaining eligibility for Medicare. Others need to apply. The 2010 "MIPPA" law introduced some improvements to increase MSP enrollment.

See 3rd bullet below. Also, some people who had Medicaid through the Affordable Care Act before they became eligible for Medicare have special procedures to have their Part B premium paid before they enroll in an MSP. See below. WHO IS AUTOMATICALLY ENROLLED IN AN MSP. Clients receiving even $1.00 of Supplemental Security Income should be automatically enrolled into a Medicare Savings Program (most often QMB) under New York State’s Medicare Savings Program Buy-in Agreement with the federal government once they become eligible for Medicare.

They should receive Medicare Parts A and B. Clients who are already eligible for Medicare when they apply for Medicaid should be automatically assessed for MSP eligibility when they apply for Medicaid. (NYS DOH 2000-ADM-7 and GIS 05 MA 033). Clients who apply to the Social Security Administration for Extra Help, but are rejected, should be contacted &. Enrolled into an MSP by the Medicaid program directly under new MIPPA procedures that require data sharing.

Strategy TIP. Since the Extra Help filing date will be assigned to the MSP application, it may help the client to apply online for Extra Help with the SSA, even knowing that this application will be rejected because of excess assets or other reason. SSA processes these requests quickly, and it will be routed to the State for MSP processing. Since MSP applications take a while, at least the filing date will be retroactive. Note.

The above strategy does not work as well for QMB, because the effective date of QMB is the month after the month of application. As a result, the retroactive effective date of Extra Help will be the month after the failed Extra Help application for those with QMB rather than SLMB/QI-1. Applying for MSP Directly with Local Medicaid Program. Those who do not have Medicaid already must apply for an MSP through their local social services district. (See more in Section D.

Below re those who already have Medicaid through the Affordable Care Act before they became eligible for Medicare. If you are applying for MSP only (not also Medicaid), you can use the simplified MSP application form (theDOH-4328(Rev. 8/2017-- English) (2017 Spanish version not yet available). Either application form can be mailed in -- there is no interview requirement anymore for MSP or Medicaid. See 10 ADM-04.

Applicants will need to submit proof of income, a copy of their Medicare card (front &. Back), and proof of residency/address. See the application form for other instructions. One who is only eligible for QI-1 because of higher income may ONLY apply for an MSP, not for Medicaid too. One may not receive Medicaid and QI-1 at the same time.

If someone only eligible for QI-1 wants Medicaid, s/he may enroll in and deposit excess income into a pooled Supplemental Needs Trust, to bring her countable income down to the Medicaid level, which also qualifies him or her for SLIMB or QMB instead of QI-1. Advocates in NYC can sign up for a half-day "Deputization Training" conducted by the Medicare Rights Center, at which you'll be trained and authorized to complete an MSP application and to submit it via the Medicare Rights Center, which submits it to HRA without the client having to apply in person. Enrolling in an MSP if you already have Medicaid, but just become eligible for Medicare Those who, prior to becoming enrolled in Medicare, had Medicaid through Affordable Care Act are eligible to have their Part B premiums paid by Medicaid (or the cost reimbursed) during the time it takes for them to transition to a Medicare Savings Program. In 2018, DOH clarified that reimbursement of the Part B premium will be made regardless of whether the individual is still in a Medicaid managed care (MMC) plan. GIS 18 MA/001 Medicaid Managed Care Transition for Enrollees Gaining Medicare ( PDF) provides, "Due to efforts to transition individuals who gain Medicare eligibility and who require LTSS, individuals may not be disenrolled from MMC upon receipt of Medicare.

To facilitate the transition and not disadvantage the recipient, the Medicaid program is approving reimbursement of Part B premiums for enrollees in MMC." The procedure for getting the Part B premium paid is different for those whose Medicaid was administered by the NYS of Health Exchange (Marketplace), as opposed to their local social services district. The procedure is also different for those who obtain Medicare because they turn 65, as opposed to obtaining Medicare based on disability. Either way, Medicaid recipients who transition onto Medicare should be automatically evaluated for MSP eligibility at their next Medicaid recertification. NYS DOH 2000-ADM-7 Individuals can also affirmatively ask to be enrolled in MSP in between recertification periods. IF CLIENT HAD MEDICAID ON THE MARKETPLACE (NYS of Health Exchange) before obtaining Medicare.

IF they obtain Medicare because they turn age 65, they will receive a letter from their local district asking them to "renew" Medicaid through their local district. See 2014 LCM-02. Now, their Medicaid income limit will be lower than the MAGI limits ($842/ mo reduced from $1387/month) and they now will have an asset test. For this reason, some individuals may lose full Medicaid eligibility when they begin receiving Medicare. People over age 65 who obtain Medicare do NOT keep "Marketplace Medicaid" for 12 months (continuous eligibility) See GIS 15 MA/022 - Continuous Coverage for MAGI Individuals.

Since MSP has NO ASSET limit. Some individuals may be enrolled in the MSP even if they lose Medicaid, or if they now have a Medicaid spend-down. If a Medicare/Medicaid recipient reports income that exceeds the Medicaid level, districts must evaluate the person’s eligibility for MSP. 08 OHIP/ADM-4 ​If you became eligible for Medicare based on disability and you are UNDER AGE 65, you are entitled to keep MAGI Medicaid for 12 months from the month it was last authorized, even if you now have income normally above the MAGI limit, and even though you now have Medicare. This is called Continuous Eligibility.

EXAMPLE. Sam, age 60, was last authorized for Medicaid on the Marketplace in June 2016. He became enrolled in Medicare based on disability in August 2016, and started receiving Social Security in the same month (he won a hearing approving Social Security disability benefits retroactively, after first being denied disability). Even though his Social Security is too high, he can keep Medicaid for 12 months beginning June 2016. Sam has to pay for his Part B premium - it is deducted from his Social Security check.

He may call the Marketplace and request a refund. This will continue until the end of his 12 months of continues MAGI Medicaid eligibility. He will be reimbursed regardless of whether he is in a Medicaid managed care plan. See GIS 18 MA/001 Medicaid Managed Care Transition for Enrollees Gaining Medicare (PDF) When that ends, he will renew Medicaid and apply for MSP with his local district. Individuals who are eligible for Medicaid with a spenddown can opt whether or not to receive MSP.

(Medicaid Reference Guide (MRG) p. 19). Obtaining MSP may increase their spenddown. MIPPA - Outreach by Social Security Administration -- Under MIPPA, the SSA sends a form letter to people who may be eligible for a Medicare Savings Program or Extra Help (Low Income Subsidy - LIS) that they may apply. The letters are.

· Beneficiary has Extra Help (LIS), but not MSP · Beneficiary has no Extra Help (LIS) or MSP 6. Enrolling in MSP for People Age 65+ who do Not have Free Medicare Part A - the "Part A Buy-In Program" Seniors WITHOUT MEDICARE PART A or B -- They may be able to enroll in the Part A Buy-In program, in which people eligible for QMB who are age 65+ who do not otherwise have Medicare Part A may enroll in Part A, with Medicaid paying the Part A premium. See Step-by-Step Guide by the Medicare Rights Center). This guide explains the various steps in "conditionally enrolling" in Part A at the SSA office, which must be done before applying for QMB at the Medicaid office, which will then pay the Part A premium. See also GIS 04 MA/013.

In June, 2018, the SSA revised the POMS manual procedures for the Part A Buy-In to to address inconsistencies and confusion in SSA field offices and help smooth the path for QMB enrollment. The procedures are in the POMS Section HI 00801.140 "Premium-Free Part A Enrollments for Qualified Medicare BenefiIaries." It includes important clarifications, such as. SSA Field Offices should explain the QMB program and conditional enrollment process if an individual lacks premium-free Part A and appears to meet QMB requirements. SSA field offices can add notes to the “Remarks” section of the application and provide a screen shot to the individual so the individual can provide proof of conditional Part A enrollment when applying for QMB through the state Medicaid program. Beneficiaries are allowed to complete the conditional application even if they owe Medicare premiums.

In Part A Buy-in states like NYS, SSA should process conditional applications on a rolling basis (without regard to enrollment periods), even if the application coincides with the General Enrollment Period. (The General Enrollment Period is from Jan 1 to March 31st every year, in which anyone eligible may enroll in Medicare Part A or Part B to be effective on July 1st). 7. What happens after the MSP approval - How is Part B premium paid For all three MSP programs, the Medicaid program is now responsible for paying the Part B premiums, even though the MSP enrollee is not necessarily a recipient of Medicaid. The local Medicaid office (DSS/HRA) transmits the MSP approval to the NYS Department of Health – that information gets shared w/ SSA and CMS SSA stops deducting the Part B premiums out of the beneficiary’s Social Security check.

SSA also refunds any amounts owed to the recipient. (Note. This process can take awhile!. !. !.

) CMS “deems” the MSP recipient eligible for Part D Extra Help/ Low Income Subsidy (LIS). ​Can the MSP be retroactive like Medicaid, back to 3 months before the application?. ​The answer is different for the 3 MSP programs. QMB -No Retroactive Eligibility – Benefits begin the month after the month of the MSP application. 18 NYCRR § 360-7.8(b)(5) SLIMB - YES - Retroactive Eligibility up to 3 months before the application, if was eligible This means applicant may be reimbursed for the 3 months of Part B benefits prior to the month of application.

QI-1 - YES up to 3 months but only in the same calendar year. No retroactive eligibility to the previous year. 7. QMBs -Special Rules on Cost-Sharing. QMB is the only MSP program which pays not only the Part B premium, but also the Medicare co-insurance.

However, there are limitations. First, co-insurance will only be paid if the provide accepts Medicaid. Not all Medicare provides accept Medicaid. Second, under recent changes in New York law, Medicaid will not always pay the Medicare co-insurance, even to a Medicaid provider. But even if the provider does not accept Medicaid, or if Medicaid does not pay the full co-insurance, the provider is banned from "balance billing" the QMB beneficiary for the co-insurance.

Click here for an article that explains all of these rules. This article was authored by the Empire Justice Center.THE PROBLEM. Meet Joe, whose Doctor has Billed him for the Medicare Coinsurance Joe Client is disabled and has SSD, Medicaid and Qualified Medicare Beneficiary (QMB). His health care is covered by Medicare, and Medicaid and the QMB program pick up his Medicare cost-sharing obligations. Under Medicare Part B, his co-insurance is 20% of the Medicare-approved charge for most outpatient services.

He went to the doctor recently and, as with any other Medicare beneficiary, the doctor handed him a bill for his co-pay. Now Joe has a bill that he can’t pay. Read below to find out -- SHORT ANSWER. QMB or Medicaid will pay the Medicare coinsurance only in limited situations. First, the provider must be a Medicaid provider.

Second, even if the provider accepts Medicaid, under recent legislation in New York enacted in 2015 and 2016, QMB or Medicaid may pay only part of the coinsurance, or none at all. This depends in part on whether the beneficiary has Original Medicare or is in a Medicare Advantage plan, and in part on the type of service. However, the bottom line is that the provider is barred from "balance billing" a QMB beneficiary for the Medicare coinsurance. Unfortunately, this creates tension between an individual and her doctors, pharmacies dispensing Part B medications, and other providers. Providers may not know they are not allowed to bill a QMB beneficiary for Medicare coinsurance, since they bill other Medicare beneficiaries.

Even those who know may pressure their patients to pay, or simply decline to serve them. These rights and the ramifications of these QMB rules are explained in this article. CMS is doing more education about QMB Rights. The Medicare Handbook, since 2017, gives information about QMB Protections. Download the 2020 Medicare Handbook here.

See pp. 53, 86. 1. To Which Providers will QMB or Medicaid Pay the Medicare Co-Insurance?. "Providers must enroll as Medicaid providers in order to bill Medicaid for the Medicare coinsurance." CMS Informational Bulletin issued January 6, 2012, titled "Billing for Services Provided to Qualified Medicare Beneficiaries (QMBs).

The CMS bulletin states, "If the provider wants Medicaid to pay the coinsurance, then the provider must register as a Medicaid provider under the state rules." If the provider chooses not to enroll as a Medicaid provider, they still may not "balance bill" the QMB recipient for the coinsurance. 2. How Does a Provider that DOES accept Medicaid Bill for a QMB Beneficiary?. If beneficiary has Original Medicare -- The provider bills Medicaid - even if the QMB Beneficiary does not also have Medicaid. Medicaid is required to pay the provider for all Medicare Part A and B cost-sharing charges, even if the service is normally not covered by Medicaid (ie, chiropractic, podiatry and clinical social work care).

Whatever reimbursement Medicaid pays the provider constitutes by law payment in full, and the provider cannot bill the beneficiary for any difference remaining. 42 U.S.C. § 1396a(n)(3)(A), NYS DOH 2000-ADM-7 If the QMB beneficiary is in a Medicare Advantage plan - The provider bills the Medicare Advantage plan, then bills Medicaid for the balance using a “16” code to get paid. The provider must include the amount it received from Medicare Advantage plan. 3.

For a Provider who accepts Medicaid, How Much of the Medicare Coinsurance will be Paid for a QMB or Medicaid Beneficiary in NYS?. The answer to this question has changed by laws enacted in 2015 and 2016. In the proposed 2019 State Budget, Gov. Cuomo has proposed to reduce how much Medicaid pays for the Medicare costs even further. The amount Medicaid pays is different depending on whether the individual has Original Medicare or is a Medicare Advantage plan, with better payment for those in Medicare Advantage plans.

The answer also differs based on the type of service. Part A Deductibles and Coinsurance - Medicaid pays the full Part A hospital deductible ($1,408 in 2020) and Skilled Nursing Facility coinsurance ($176/day) for days 20 - 100 of a rehab stay. Full payment is made for QMB beneficiaries and Medicaid recipients who have no spend-down. Payments are reduced if the beneficiary has a Medicaid spend-down. For in-patient hospital deductible, Medicaid will pay only if six times the monthly spend-down has been met.

For example, if Mary has a $200/month spend down which has not been met otherwise, Medicaid will pay only $164 of the hospital deductible (the amount exceeding 6 x $200). See more on spend-down here. Medicare Part B - Deductible - Currently, Medicaid pays the full Medicare approved charges until the beneficiary has met the annual deductible, which is $198 in 2020. For example, Dr. John charges $500 for a visit, for which the Medicare approved charge is $198.

Medicaid pays the entire $198, meeting the deductible. If the beneficiary has a spend-down, then the Medicaid payment would be subject to the spend-down. In the 2019 proposed state budget, Gov. Cuomo proposed to reduce the amount Medicaid pays toward the deductible to the same amount paid for coinsurance during the year, described below. This proposal was REJECTED by the state legislature.

Co-Insurance - The amount medicaid pays in NYS is different for Original Medicare and Medicare Advantage. If individual has Original Medicare, QMB/Medicaid will pay the 20% Part B coinsurance only to the extent the total combined payment the provider receives from Medicare and Medicaid is the lesser of the Medicaid or Medicare rate for the service. For example, if the Medicare rate for a service is $100, the coinsurance is $20. If the Medicaid rate for the same service is only $80 or less, Medicaid would pay nothing, as it would consider the doctor fully paid = the provider has received the full Medicaid rate, which is lesser than the Medicare rate. Exceptions - Medicaid/QMB wil pay the full coinsurance for the following services, regardless of the Medicaid rate.

ambulance and psychologists - The Gov's 2019 proposal to eliminate these exceptions was rejected. hospital outpatient clinic, certain facilities operating under certificates issued under the Mental Hygiene Law for people with developmental disabilities, psychiatric disability, and chemical dependence (Mental Hygiene Law Articles 16, 31 or 32). SSL 367-a, subd. 1(d)(iii)-(v) , as amended 2015 If individual is in a Medicare Advantage plan, 85% of the copayment will be paid to the provider (must be a Medicaid provider), regardless of how low the Medicaid rate is. This limit was enacted in the 2016 State Budget, and is better than what the Governor proposed - which was the same rule used in Original Medicare -- NONE of the copayment or coinsurance would be paid if the Medicaid rate was lower than the Medicare rate for the service, which is usually the case.

This would have deterred doctors and other providers from being willing to treat them. SSL 367-a, subd. 1(d)(iv), added 2016. EXCEPTIONS. The Medicare Advantage plan must pay the full coinsurance for the following services, regardless of the Medicaid rate.

ambulance ) psychologist ) The Gov's proposal in the 2019 budget to eliminate these exceptions was rejected by the legislature Example to illustrate the current rules. The Medicare rate for Mary's specialist visit is $185. The Medicaid rate for the same service is $120. Current rules (since 2016). Medicare Advantage -- Medicare Advantage plan pays $135 and Mary is charged a copayment of $50 (amount varies by plan).

Medicaid pays the specialist 85% of the $50 copayment, which is $42.50. The doctor is prohibited by federal law from "balance billing" QMB beneficiaries for the balance of that copayment. Since provider is getting $177.50 of the $185 approved rate, provider will hopefully not be deterred from serving Mary or other QMBs/Medicaid recipients. Original Medicare - The 20% coinsurance is $37. Medicaid pays none of the coinsurance because the Medicaid rate ($120) is lower than the amount the provider already received from Medicare ($148).

For both Medicare Advantage and Original Medicare, if the bill was for a ambulance or psychologist, Medicaid would pay the full 20% coinsurance regardless of the Medicaid rate. The proposal to eliminate this exception was rejected by the legislature in 2019 budget. . 4. May the Provider 'Balance Bill" a QMB Benficiary for the Coinsurance if Provider Does Not Accept Medicaid, or if Neither the Patient or Medicaid/QMB pays any coinsurance?.

No. Balance billing is banned by the Balanced Budget Act of 1997. 42 U.S.C. § 1396a(n)(3)(A). In an Informational Bulletin issued January 6, 2012, titled "Billing for Services Provided to Qualified Medicare Beneficiaries (QMBs)," the federal Medicare agency - CMS - clarified that providers MAY NOT BILL QMB recipients for the Medicare coinsurance.

This is true whether or not the provider is registered as a Medicaid provider. If the provider wants Medicaid to pay the coinsurance, then the provider must register as a Medicaid provider under the state rules. This is a change in policy in implementing Section 1902(n)(3)(B) of the Social Security Act (the Act), as modified by section 4714 of the Balanced Budget Act of 1997, which prohibits Medicare providers from balance-billing QMBs for Medicare cost-sharing. The CMS letter states, "All Medicare physicians, providers, and suppliers who offer services and supplies to QMBs are prohibited from billing QMBs for Medicare cost-sharing, including deductible, coinsurance, and copayments. This section of the Act is available at.

CMCS Informational Bulletin http://www.ssa.gov/OP_Home/ssact/title19/1902.htm. QMBs have no legal obligation to make further payment to a provider or Medicare managed care plan for Part A or Part B cost sharing. Providers who inappropriately bill QMBs for Medicare cost-sharing are subject to sanctions. Please note that the statute referenced above supersedes CMS State Medicaid Manual, Chapter 3, Eligibility, 3490.14 (b), which is no longer in effect, but may be causing confusion about QMB billing." The same information was sent to providers in this Medicare Learning Network bulletin, last revised in June 26, 2018. CMS reminded Medicare Advantage plans of the rule against Balance Billing in the 2017 Call Letter for plan renewals.

See this excerpt of the 2017 call letter by Justice in Aging - Prohibition on Billing Medicare-Medicaid Enrollees for Medicare Cost Sharing 5. How do QMB Beneficiaries Show a Provider that they have QMB and cannot be Billed for the Coinsurance?. It can be difficult to show a provider that one is a QMB. It is especially difficult for providers who are not Medicaid providers to identify QMB's, since they do not have access to online Medicaid eligibility systems Consumers can now call 1-800-MEDICARE to verify their QMB Status and report a billing issue. If a consumer reports a balance billng problem to this number, the Customer Service Rep can escalate the complaint to the Medicare Administrative Contractor (MAC), which will send a compliance letter to the provider with a copy to the consumer.

See CMS Medicare Learning Network Bulletin effective Dec. 16, 2016. Medicare Summary Notices (MSNs) that Medicare beneficiaries receive every three months state that QMBs have no financial liability for co-insurance for each Medicare-covered service listed on the MSN. The Remittance Advice (RA) that Medicare sends to providers shows the same information. By spelling out billing protections on a service-by-service basis, the MSNs provide clarity for both the QMB beneficiary and the provider.

Justice in Aging has posted samples of what the new MSNs look like here. They have also updated Justice in Aging’s Improper Billing Toolkit to incorporate references to the MSNs in its model letters that you can use to advocate for clients who have been improperly billed for Medicare-covered services. CMS is implementing systems changes that will notify providers when they process a Medicare claim that the patient is QMB and has no cost-sharing liability. The Medicare Summary Notice sent to the beneficiary will also state that the beneficiary has QMB and no liability. These changes were scheduled to go into effect in October 2017, but have been delayed.

Read more about them in this Justice in Aging Issue Brief on New Strategies in Fighting Improper Billing for QMBs (Feb. 2017). QMBs are issued a Medicaid benefit card (by mail), even if they do not also receive Medicaid. The card is the mechanism for health care providers to bill the QMB program for the Medicare deductibles and co-pays. Unfortunately, the Medicaid card dos not indicate QMB eligibility.

Not all people who have Medicaid also have QMB (they may have higher incomes and "spend down" to the Medicaid limits. Advocates have asked for a special QMB card, or a notation on the Medicaid card to show that the individual has QMB. See this Report - a National Survey on QMB Identification Practices published by Justice in Aging, authored by Peter Travitsky, NYLAG EFLRP staff attorney. The Report, published in March 2017, documents how QMB beneficiaries could be better identified in order to ensure providers do not bill them improperly. 6.

If you are Billed -​ Strategies Consumers can now call 1-800-MEDICARE to report a billing issue. If a consumer reports a balance billng problem to this number, the Customer Service Rep can escalate the complaint to the Medicare Administrative Contractor (MAC), which will send a compliance letter to the provider with a copy to the consumer. See CMS Medicare Learning Network Bulletin effective Dec. 16, 2016. Send a letter to the provider, using the Justice In Aging Model model letters to providers to explain QMB rights.​​​ both for Original Medicare (Letters 1-2) and Medicare Advantage (Letters 3-5) - see Overview of model letters.

Include a link to the CMS Medicare Learning Network Notice. Prohibition on Balance Billing Dually Eligible Individuals Enrolled in the Qualified Medicare Beneficiary (QMB) Program (revised June 26. 2018) In January 2017, the Consumer Finance Protection Bureau issued this guide to QMB billing. A consumer who has a problem with debt collection, may also submit a complaint online or call the CFPB at 1-855-411-2372. TTY/TDD users can call 1-855-729-2372.

Medicare Advantage members should complain to their Medicare Advantage plan. In its 2017 Call Letter, CMS stressed to Medicare Advantage contractors that federal regulations at 42 C.F.R. § 422.504 (g)(1)(iii), require that provider contracts must prohibit collection of deductibles and co-payments from dual eligibles and QMBs. Toolkit to Help Protect QMB Rights ​​In July 2015, CMS issued a report, "Access to Care Issues Among Qualified Medicare Beneficiaries (QMB's)" documenting how pervasive illegal attempts to bill QMBs for the Medicare coinsurance, including those who are members of managed care plans. Justice in Aging, a national advocacy organization, has a project to educate beneficiaries about balance billing and to advocate for stronger protections for QMBs.

N.Y cialis 5mg cost walgreens. Soc. Serv.

L. § 367-a(3)(a), (b), and (d). 2020 Medicare 101 Basics for New York State - 1.5 hour webinar by Eric Hausman, sponsored by NYS Office of the Aging TOPICS COVERED IN THIS ARTICLE 1.

No Asset Limit 1A. Summary Chart of MSP Programs 2. Income Limits &.

Rules and Household Size 3. The Three MSP Programs - What are they and how are they Different?. 4.

FOUR Special Benefits of MSP Programs. Back Door to Extra Help with Part D MSPs Automatically Waive Late Enrollment Penalties for Part B - and allow enrollment in Part B year-round outside of the short Annual Enrollment Period No Medicaid Lien on Estate to Recover Payment of Expenses Paid by MSP Food Stamps/SNAP not reduced by Decreased Medical Expenses when Enroll in MSP - at least temporarily 5. Enrolling in an MSP - Automatic Enrollment &.

Applications for People who Have Medicare What is Application Process?. 6. Enrolling in an MSP for People age 65+ who Do Not Qualify for Free Medicare Part A - the "Part A Buy-In Program" 7.

What Happens After MSP Approved - How Part B Premium is Paid 8 Special Rules for QMBs - How Medicare Cost-Sharing Works 1. NO ASSET LIMIT!. Since April 1, 2008, none of the three MSP programs have resource limits in New York -- which means many Medicare beneficiaries who might not qualify for Medicaid because of excess resources can qualify for an MSP.

1.A. SUMMARY CHART OF MSP BENEFITS QMB SLIMB QI-1 Eligibility ASSET LIMIT NO LIMIT IN NEW YORK STATE INCOME LIMIT (2020) Single Couple Single Couple Single Couple $1,064 $1,437 $1,276 $1,724 $1,436 $1,940 Federal Poverty Level 100% FPL 100 – 120% FPL 120 – 135% FPL Benefits Pays Monthly Part B premium?. YES, and also Part A premium if did not have enough work quarters and meets citizenship requirement.

See “Part A Buy-In” YES YES Pays Part A &. B deductibles &. Co-insurance YES - with limitations NO NO Retroactive to Filing of Application?.

Yes - Benefits begin the month after the month of the MSP application. 18 NYCRR §360-7.8(b)(5) Yes – Retroactive to 3rd month before month of application, if eligible in prior months Yes – may be retroactive to 3rd month before month of applica-tion, but only within the current calendar year. (No retro for January application).

See GIS 07 MA 027. Can Enroll in MSP and Medicaid at Same Time?. YES YES NO!.

Must choose between QI-1 and Medicaid. Cannot have both, not even Medicaid with a spend-down. 2.

INCOME LIMITS and RULES Each of the three MSP programs has different income eligibility requirements and provides different benefits. The income limits are tied to the Federal Poverty Level (FPL). 2019 FPL levels were released by NYS DOH in GIS 20 MA/02 - 2020 Federal Poverty Levels -- Attachment II and have been posted by Medicaid.gov and the National Council on Aging and are in the chart below.

NOTE. There is usually a lag in time of several weeks, or even months, from January 1st of each year until the new FPLs are release, and then before the new MSP income limits are officially implemented. During this lag period, local Medicaid offices should continue to use the previous year's FPLs AND count the person's Social Security benefit amount from the previous year - do NOT factor in the Social Security COLA (cost of living adjustment).

Once the updated guidelines are released, districts will use the new FPLs and go ahead and factor in any COLA. See 2019 Fact Sheet on MSP in NYS by Medicare Rights Center ENGLISH SPANISH Income is determined by the same methodology as is used for determining in eligibility for SSI The rules for counting income for SSI-related (Aged 65+, Blind, or Disabled) Medicaid recipients, borrowed from the SSI program, apply to the MSP program, except for the new rules about counting household size for married couples. N.Y.

367-a(3)(c)(2), NYS DOH 2000-ADM-7, 89-ADM-7 p.7. Gross income is counted, although there are certain types of income that are disregarded. The most common income disregards, also known as deductions, include.

(a) The first $20 of your &. Your spouse's monthly income, earned or unearned ($20 per couple max). (b) SSI EARNED INCOME DISREGARDS.

* The first $65 of monthly wages of you and your spouse, * One-half of the remaining monthly wages (after the $65 is deducted). * Other work incentives including PASS plans, impairment related work expenses (IRWEs), blind work expenses, etc. For information on these deductions, see The Medicaid Buy-In for Working People with Disabilities (MBI-WPD) and other guides in this article -- though written for the MBI-WPD, the work incentives apply to all Medicaid programs, including MSP, for people age 65+, disabled or blind.

(c) monthly cost of any health insurance premiums but NOT the Part B premium, since Medicaid will now pay this premium (may deduct Medigap supplemental policies, vision, dental, or long term care insurance premiums, and the Part D premium but only to the extent the premium exceeds the Extra Help benchmark amount) (d) Food stamps not counted. You can get a more comprehensive listing of the SSI-related income disregards on the Medicaid income disregards chart. As for all benefit programs based on financial need, it is usually advantageous to be considered a larger household, because the income limit is higher.

The above chart shows that Households of TWO have a higher income limit than households of ONE. The MSP programs use the same rules as Medicaid does for the Disabled, Aged and Blind (DAB) which are borrowed from the SSI program for Medicaid recipients in the “SSI-related category.” Under these rules, a household can be only ONE or TWO. 18 NYCRR 360-4.2.

See DAB Household Size Chart. Married persons can sometimes be ONE or TWO depending on arcane rules, which can force a Medicare beneficiary to be limited to the income limit for ONE person even though his spouse who is under 65 and not disabled has no income, and is supported by the client applying for an MSP. EXAMPLE.

Bob's Social Security is $1300/month. He is age 67 and has Medicare. His wife, Nancy, is age 62 and is not disabled and does not work.

Under the old rule, Bob was not eligible for an MSP because his income was above the Income limit for One, even though it was well under the Couple limit. In 2010, NYS DOH modified its rules so that all married individuals will be considered a household size of TWO. DOH GIS 10 MA 10 Medicare Savings Program Household Size, June 4, 2010.

This rule for household size is an exception to the rule applying SSI budgeting rules to the MSP program. Under these rules, Bob is now eligible for an MSP. When is One Better than Two?.

Of course, there may be couples where the non-applying spouse's income is too high, and disqualifies the applying spouse from an MSP. In such cases, "spousal refusal" may be used SSL 366.3(a). (Link is to NYC HRA form, can be adapted for other counties).

3. The Three Medicare Savings Programs - what are they and how are they different?. 1.

Qualified Medicare Beneficiary (QMB). The QMB program provides the most comprehensive benefits. Available to those with incomes at or below 100% of the Federal Poverty Level (FPL), the QMB program covers virtually all Medicare cost-sharing obligations.

Part B premiums, Part A premiums, if there are any, and any and all deductibles and co-insurance. QMB coverage is not retroactive. The program’s benefits will begin the month after the month in which your client is found eligible.

** See special rules about cost-sharing for QMBs below - updated with new CMS directive issued January 2012 ** See NYC HRA QMB Recertification form ** Even if you do not have Part A automatically, because you did not have enough wages, you may be able to enroll in the Part A Buy-In Program, in which people eligible for QMB who do not otherwise have Medicare Part A may enroll, with Medicaid paying the Part A premium (Materials by the Medicare Rights Center). 2. Specifiedl Low-Income Medicare Beneficiary (SLMB).

For those with incomes between 100% and 120% FPL, the SLMB program will cover Part B premiums only. SLMB is retroactive, however, providing coverage for three months prior to the month of application, as long as your client was eligible during those months. 3.

Qualified Individual (QI-1). For those with incomes between 120% and 135% FPL, and not receiving Medicaid, the QI-1 program will cover Medicare Part B premiums only. QI-1 is also retroactive, providing coverage for three months prior to the month of application, as long as your client was eligible during those months.

However, QI-1 retroactive coverage can only be provided within the current calendar year. (GIS 07 MA 027) So if you apply in January, you get no retroactive coverage. Q-I-1 recipients would be eligible for Medicaid with a spend-down, but if they want the Part B premium paid, they must choose between enrolling in QI-1 or Medicaid.

They cannot be in both. It is their choice. DOH MRG p.

19. In contrast, one may receive Medicaid and either QMB or SLIMB. 4.

Four Special Benefits of MSPs (in addition to NO ASSET TEST). Benefit 1. Back Door to Medicare Part D "Extra Help" or Low Income Subsidy -- All MSP recipients are automatically enrolled in Extra Help, the subsidy that makes Part D affordable.

They have no Part D deductible or doughnut hole, the premium is subsidized, and they pay very low copayments. Once they are enrolled in Extra Help by virtue of enrollment in an MSP, they retain Extra Help for the entire calendar year, even if they lose MSP eligibility during that year. The "Full" Extra Help subsidy has the same income limit as QI-1 - 135% FPL.

However, many people may be eligible for QI-1 but not Extra Help because QI-1 and the other MSPs have no asset limit. People applying to the Social Security Administration for Extra Help might be rejected for this reason. Recent (2009-10) changes to federal law called "MIPPA" requires the Social Security Administration (SSA) to share eligibility data with NYSDOH on all persons who apply for Extra Help/ the Low Income Subsidy.

Data sent to NYSDOH from SSA will enable NYSDOH to open MSP cases on many clients. The effective date of the MSP application must be the same date as the Extra Help application. Signatures will not be required from clients.

In cases where the SSA data is incomplete, NYSDOH will forward what is collected to the local district for completion of an MSP application. The State implementing procedures are in DOH 2010 ADM-03. Also see CMS "Dear State Medicaid Director" letter dated Feb.

18, 2010 Benefit 2. MSPs Automatically Waive Late Enrollment Penalties for Part B Generally one must enroll in Part B within the strict enrollment periods after turning age 65 or after 24 months of Social Security Disability. An exception is if you or your spouse are still working and insured under an employer sponsored group health plan, or if you have End Stage Renal Disease, and other factors, see this from Medicare Rights Center.

If you fail to enroll within those short periods, you might have to pay higher Part B premiums for life as a Late Enrollment Penalty (LEP). Also, you may only enroll in Part B during the Annual Enrollment Period from January 1 - March 31st each year, with Part B not effective until the following July. Enrollment in an MSP automatically eliminates such penalties...

For life.. Even if one later ceases to be eligible for the MSP. AND enrolling in an MSP will automatically result in becoming enrolled in Part B if you didn't already have it and only had Part A.

See Medicare Rights Center flyer. Benefit 3. No Medicaid Lien on Estate to Recover MSP Benefits Paid Generally speaking, states may place liens on the Estates of deceased Medicaid recipients to recover the cost of Medicaid services that were provided after the recipient reached the age of 55.

Since 2002, states have not been allowed to recover the cost of Medicare premiums paid under MSPs. In 2010, Congress expanded protection for MSP benefits. Beginning on January 1, 2010, states may not place liens on the Estates of Medicaid recipients who died after January 1, 2010 to recover costs for co-insurance paid under the QMB MSP program for services rendered after January 1, 2010.

The federal government made this change in order to eliminate barriers to enrollment in MSPs. See NYS DOH GIS 10-MA-008 - Medicare Savings Program Changes in Estate Recovery The GIS clarifies that a client who receives both QMB and full Medicaid is exempt from estate recovery for these Medicare cost-sharing expenses. Benefit 4.

SNAP (Food Stamp) benefits not reduced despite increased income from MSP - at least temporarily Many people receive both SNAP (Food Stamp) benefits and MSP. Income for purposes of SNAP/Food Stamps is reduced by a deduction for medical expenses, which includes payment of the Part B premium. Since approval for an MSP means that the client no longer pays for the Part B premium, his/her SNAP/Food Stamps income goes up, so their SNAP/Food Stamps go down.

Here are some protections. Do these individuals have to report to their SNAP worker that their out of pocket medical costs have decreased?. And will the household see a reduction in their SNAP benefits, since the decrease in medical expenses will increase their countable income?.

The good news is that MSP households do NOT have to report the decrease in their medical expenses to the SNAP/Food Stamp office until their next SNAP/Food Stamp recertification. Even if they do report the change, or the local district finds out because the same worker is handling both the MSP and SNAP case, there should be no reduction in the household’s benefit until the next recertification. New York’s SNAP policy per administrative directive 02 ADM-07 is to “freeze” the deduction for medical expenses between certification periods.

Increases in medical expenses can be budgeted at the household’s request, but NYS never decreases a household’s medical expense deduction until the next recertification. Most elderly and disabled households have 24-month SNAP certification periods. Eventually, though, the decrease in medical expenses will need to be reported when the household recertifies for SNAP, and the household should expect to see a decrease in their monthly SNAP benefit.

It is really important to stress that the loss in SNAP benefits is NOT dollar for dollar. A $100 decrease in out of pocket medical expenses would translate roughly into a $30 drop in SNAP benefits. See more info on SNAP/Food Stamp benefits by the Empire Justice Center, and on the State OTDA website.

Some clients will be automatically enrolled in an MSP by the New York State Department of Health (NYSDOH) shortly after attaining eligibility for Medicare. Others need to apply. The 2010 "MIPPA" law introduced some improvements to increase MSP enrollment.

See 3rd bullet below. Also, some people who had Medicaid through the Affordable Care Act before they became eligible for Medicare have special procedures to have their Part B premium paid before they enroll in an MSP. See below.

WHO IS AUTOMATICALLY ENROLLED IN AN MSP. Clients receiving even $1.00 of Supplemental Security Income should be automatically enrolled into a Medicare Savings Program (most often QMB) under New York State’s Medicare Savings Program Buy-in Agreement with the federal government once they become eligible for Medicare. They should receive Medicare Parts A and B.

Clients who are already eligible for Medicare when they apply for Medicaid should be automatically assessed for MSP eligibility when they apply for Medicaid. (NYS DOH 2000-ADM-7 and GIS 05 MA 033). Clients who apply to the Social Security Administration for Extra Help, but are rejected, should be contacted &.

Enrolled into an MSP by the Medicaid program directly under new MIPPA procedures that require data sharing. Strategy TIP. Since the Extra Help filing date will be assigned to the MSP application, it may help the client to apply online for Extra Help with the SSA, even knowing that this application will be rejected because of excess assets or other reason.

SSA processes these requests quickly, and it will be routed to the State for MSP processing. Since MSP applications take a while, at least the filing date will be retroactive. Note.

The above strategy does not work as well for QMB, because the effective date of QMB is the month after the month of application. As a result, the retroactive effective date of Extra Help will be the month after the failed Extra Help application for those with QMB rather than SLMB/QI-1. Applying for MSP Directly with Local Medicaid Program.

Those who do not have Medicaid already must apply for an MSP through their local social services district. (See more in Section D. Below re those who already have Medicaid through the Affordable Care Act before they became eligible for Medicare.

If you are applying for MSP only (not also Medicaid), you can use the simplified MSP application form (theDOH-4328(Rev. 8/2017-- English) (2017 Spanish version not yet available). Either application form can be mailed in -- there is no interview requirement anymore for MSP or Medicaid.

See 10 ADM-04. Applicants will need to submit proof of income, a copy of their Medicare card (front &. Back), and proof of residency/address.

See the application form for other instructions. One who is only eligible for QI-1 because of higher income may ONLY apply for an MSP, not for Medicaid too. One may not receive Medicaid and QI-1 at the same time.

If someone only eligible for QI-1 wants Medicaid, s/he may enroll in and deposit excess income into a pooled Supplemental Needs Trust, to bring her countable income down to the Medicaid level, which also qualifies him or her for SLIMB or QMB instead of QI-1. Advocates in NYC can sign up for a half-day "Deputization Training" conducted by the Medicare Rights Center, at which you'll be trained and authorized to complete an MSP application and to submit it via the Medicare Rights Center, which submits it to HRA without the client having to apply in person. Enrolling in an MSP if you already have Medicaid, but just become eligible for Medicare Those who, prior to becoming enrolled in Medicare, had Medicaid through Affordable Care Act are eligible to have their Part B premiums paid by Medicaid (or the cost reimbursed) during the time it takes for them to transition to a Medicare Savings Program.

In 2018, DOH clarified that reimbursement of the Part B premium will be made regardless of whether the individual is still in a Medicaid managed care (MMC) plan. GIS 18 MA/001 Medicaid Managed Care Transition for Enrollees Gaining Medicare ( PDF) provides, "Due to efforts to transition individuals who gain Medicare eligibility and who require LTSS, individuals may not be disenrolled from MMC upon receipt of Medicare. To facilitate the transition and not disadvantage the recipient, the Medicaid program is approving reimbursement of Part B premiums for enrollees in MMC." The procedure for getting the Part B premium paid is different for those whose Medicaid was administered by the NYS of Health Exchange (Marketplace), as opposed to their local social services district.

The procedure is also different for those who obtain Medicare because they turn 65, as opposed to obtaining Medicare based on disability. Either way, Medicaid recipients who transition onto Medicare should be automatically evaluated for MSP eligibility at their next Medicaid recertification. NYS DOH 2000-ADM-7 Individuals can also affirmatively ask to be enrolled in MSP in between recertification periods.

IF CLIENT HAD MEDICAID ON THE MARKETPLACE (NYS of Health Exchange) before obtaining Medicare. IF they obtain Medicare because they turn age 65, they will receive a letter from their local district asking them to "renew" Medicaid through their local district. See 2014 LCM-02.

Now, their Medicaid income limit will be lower than the MAGI limits ($842/ mo reduced from $1387/month) and they now will have an asset test. For this reason, some individuals may lose full Medicaid eligibility when they begin receiving Medicare. People over age 65 who obtain Medicare do NOT keep "Marketplace Medicaid" for 12 months (continuous eligibility) See GIS 15 MA/022 - Continuous Coverage for MAGI Individuals.

Since MSP has NO ASSET limit. Some individuals may be enrolled in the MSP even if they lose Medicaid, or if they now have a Medicaid spend-down. If a Medicare/Medicaid recipient reports income that exceeds the Medicaid level, districts must evaluate the person’s eligibility for MSP.

08 OHIP/ADM-4 ​If you became eligible for Medicare based on disability and you are UNDER AGE 65, you are entitled to keep MAGI Medicaid for 12 months from the month it was last authorized, even if you now have income normally above the MAGI limit, and even though you now have Medicare. This is called Continuous Eligibility. EXAMPLE.

Sam, age 60, was last authorized for Medicaid on the Marketplace in June 2016. He became enrolled in Medicare based on disability in August 2016, and started receiving Social Security in the same month (he won a hearing approving Social Security disability benefits retroactively, after first being denied disability). Even though his Social Security is too high, he can keep Medicaid for 12 months beginning June 2016.

Sam has to pay for his Part B premium - it is deducted from his Social Security check. He may call the Marketplace and request a refund. This will continue until the end of his 12 months of continues MAGI Medicaid eligibility.

He will be reimbursed regardless of whether he is in a Medicaid managed care plan. See GIS 18 MA/001 Medicaid Managed Care Transition for Enrollees Gaining Medicare (PDF) When that ends, he will renew Medicaid and apply for MSP with his local district. Individuals who are eligible for Medicaid with a spenddown can opt whether or not to receive MSP.

(Medicaid Reference Guide (MRG) p. 19). Obtaining MSP may increase their spenddown.

MIPPA - Outreach by Social Security Administration -- Under MIPPA, the SSA sends a form letter to people who may be eligible for a Medicare Savings Program or Extra Help (Low Income Subsidy - LIS) that they may apply. The letters are. · Beneficiary has Extra Help (LIS), but not MSP · Beneficiary has no Extra Help (LIS) or MSP 6.

Enrolling in MSP for People Age 65+ who do Not have Free Medicare Part A - the "Part A Buy-In Program" Seniors WITHOUT MEDICARE PART A or B -- They may be able to enroll in the Part A Buy-In program, in which people eligible for QMB who are age 65+ who do not otherwise have Medicare Part A may enroll in Part A, with Medicaid paying the Part A premium. See Step-by-Step Guide by the Medicare Rights Center). This guide explains the various steps in "conditionally enrolling" in Part A at the SSA office, which must be done before applying for QMB at the Medicaid office, which will then pay the Part A premium.

See also GIS 04 MA/013. In June, 2018, the SSA revised the POMS manual procedures for the Part A Buy-In to to address inconsistencies and confusion in SSA field offices and help smooth the path for QMB enrollment. The procedures are in the POMS Section HI 00801.140 "Premium-Free Part A Enrollments for Qualified Medicare BenefiIaries." It includes important clarifications, such as.

SSA Field Offices should explain the QMB program and conditional enrollment process if an individual lacks premium-free Part A and appears to meet QMB requirements. SSA field offices can add notes to the “Remarks” section of the application and provide a screen shot to the individual so the individual can provide proof of conditional Part A enrollment when applying for QMB through the state Medicaid program. Beneficiaries are allowed to complete the conditional application even if they owe Medicare premiums.

In Part A Buy-in states like NYS, SSA should process conditional applications on a rolling basis (without regard to enrollment periods), even if the application coincides with the General Enrollment Period. (The General Enrollment Period is from Jan 1 to March 31st every year, in which anyone eligible may enroll in Medicare Part A or Part B to be effective on July 1st). 7.

What happens after the MSP approval - How is Part B premium paid For all three MSP programs, the Medicaid program is now responsible for paying the Part B premiums, even though the MSP enrollee is not necessarily a recipient of Medicaid. The local Medicaid office (DSS/HRA) transmits the MSP approval to the NYS Department of Health – that information gets shared w/ SSA and CMS SSA stops deducting the Part B premiums out of the beneficiary’s Social Security check. SSA also refunds any amounts owed to the recipient.

!. ) CMS “deems” the MSP recipient eligible for Part D Extra Help/ Low Income Subsidy (LIS). ​Can the MSP be retroactive like Medicaid, back to 3 months before the application?.

​The answer is different for the 3 MSP programs. QMB -No Retroactive Eligibility – Benefits begin the month after the month of the MSP application. 18 NYCRR § 360-7.8(b)(5) SLIMB - YES - Retroactive Eligibility up to 3 months before the application, if was eligible This means applicant may be reimbursed for the 3 months of Part B benefits prior to the month of application.

QI-1 - YES up to 3 months but only in the same calendar year. No retroactive eligibility to the previous year. 7.

QMBs -Special Rules on Cost-Sharing. QMB is the only MSP program which pays not only the Part B premium, but also the Medicare co-insurance. However, there are limitations.

First, co-insurance will only be paid if the provide accepts Medicaid. Not all Medicare provides accept Medicaid. Second, under recent changes in New York law, Medicaid will not always pay the Medicare co-insurance, even to a Medicaid provider.

But even if the provider does not accept Medicaid, or if Medicaid does not pay the full co-insurance, the provider is banned from "balance billing" the QMB beneficiary for the co-insurance. Click here for an article that explains all of these rules. This article was authored by the Empire Justice Center.THE PROBLEM.

Meet Joe, whose Doctor has Billed him for the Medicare Coinsurance Joe Client is disabled and has SSD, Medicaid and Qualified Medicare Beneficiary (QMB). His health care is covered by Medicare, and Medicaid and the QMB program pick up his Medicare cost-sharing obligations. Under Medicare Part B, his co-insurance is 20% of the Medicare-approved charge for most outpatient services.

He went to the doctor recently and, as with any other Medicare beneficiary, the doctor handed him a bill for his co-pay. Now Joe has a bill that he can’t pay. Read below to find out -- SHORT ANSWER.

QMB or Medicaid will pay the Medicare coinsurance only in limited situations. First, the provider must be a Medicaid provider. Second, even if the provider accepts Medicaid, under recent legislation in New York enacted in 2015 and 2016, QMB or Medicaid may pay only part of the coinsurance, or none at all.

This depends in part on whether the beneficiary has Original Medicare or is in a Medicare Advantage plan, and in part on the type of service. However, the bottom line is that the provider is barred from "balance billing" a QMB beneficiary for the Medicare coinsurance. Unfortunately, this creates tension between an individual and her doctors, pharmacies dispensing Part B medications, and other providers.

Providers may not know they are not allowed to bill a QMB beneficiary for Medicare coinsurance, since they bill other Medicare beneficiaries. Even those who know may pressure their patients to pay, or simply decline to serve them. These rights and the ramifications of these QMB rules are explained in this article.

CMS is doing more education about QMB Rights. The Medicare Handbook, since 2017, gives information about QMB Protections. Download the 2020 Medicare Handbook here.

To Which Providers will QMB or Medicaid Pay the Medicare Co-Insurance?. "Providers must enroll as Medicaid providers in order to bill Medicaid for the Medicare coinsurance." CMS Informational Bulletin issued January 6, 2012, titled "Billing for Services Provided to Qualified Medicare Beneficiaries (QMBs). The CMS bulletin states, "If the provider wants Medicaid to pay the coinsurance, then the provider must register as a Medicaid provider under the state rules." If the provider chooses not to enroll as a Medicaid provider, they still may not "balance bill" the QMB recipient for the coinsurance.

2. How Does a Provider that DOES accept Medicaid Bill for a QMB Beneficiary?. If beneficiary has Original Medicare -- The provider bills Medicaid - even if the QMB Beneficiary does not also have Medicaid.

Medicaid is required to pay the provider for all Medicare Part A and B cost-sharing charges, even if the service is normally not covered by Medicaid (ie, chiropractic, podiatry and clinical social work care). Whatever reimbursement Medicaid pays the provider constitutes by law payment in full, and the provider cannot bill the beneficiary for any difference remaining. 42 U.S.C.

§ 1396a(n)(3)(A), NYS DOH 2000-ADM-7 If the QMB beneficiary is in a Medicare Advantage plan - The provider bills the Medicare Advantage plan, then bills Medicaid for the balance using a “16” code to get paid. The provider must include the amount it received from Medicare Advantage plan. 3.

For a Provider who accepts Medicaid, How Much of the Medicare Coinsurance will be Paid for a QMB or Medicaid Beneficiary in NYS?. The answer to this question has changed by laws enacted in 2015 and 2016. In the proposed 2019 State Budget, Gov.

Cuomo has proposed to reduce how much Medicaid pays for the Medicare costs even further. The amount Medicaid pays is different depending on whether the individual has Original Medicare or is a Medicare Advantage plan, with better payment for those in Medicare Advantage plans. The answer also differs based on the type of service.

Part A Deductibles and Coinsurance - Medicaid pays the full Part A hospital deductible ($1,408 in 2020) and Skilled Nursing Facility coinsurance ($176/day) for days 20 - 100 of a rehab stay. Full payment is made for QMB beneficiaries and Medicaid recipients who have no spend-down. Payments are reduced if the beneficiary has a Medicaid spend-down.

For in-patient hospital deductible, Medicaid will pay only if six times the monthly spend-down has been met. For example, if Mary has a $200/month spend down which has not been met otherwise, Medicaid will pay only $164 of the hospital deductible (the amount exceeding 6 x $200). See more on spend-down here.

Medicare Part B - Deductible - Currently, Medicaid pays the full Medicare approved charges until the beneficiary has met the annual deductible, which is $198 in 2020. For example, Dr. John charges $500 for a visit, for which the Medicare approved charge is $198.

Medicaid pays the entire $198, meeting the deductible. If the beneficiary has a spend-down, then the Medicaid payment would be subject to the spend-down. In the 2019 proposed state budget, Gov.

Cuomo proposed to reduce the amount Medicaid pays toward the deductible to the same amount paid for coinsurance during the year, described below. This proposal was REJECTED by the state legislature. Co-Insurance - The amount medicaid pays in NYS is different for Original Medicare and Medicare Advantage.

If individual has Original Medicare, QMB/Medicaid will pay the 20% Part B coinsurance only to the extent the total combined payment the provider receives from Medicare and Medicaid is the lesser of the Medicaid or Medicare rate for the service. For example, if the Medicare rate for a service is $100, the coinsurance is $20. If the Medicaid rate for the same service is only $80 or less, Medicaid would pay nothing, as it would consider the doctor fully paid = the provider has received the full Medicaid rate, which is lesser than the Medicare rate.

Exceptions - Medicaid/QMB wil pay the full coinsurance for the following services, regardless of the Medicaid rate. ambulance and psychologists - The Gov's 2019 proposal to eliminate these exceptions was rejected. hospital outpatient clinic, certain facilities operating under certificates issued under the Mental Hygiene Law for people with developmental disabilities, psychiatric disability, and chemical dependence (Mental Hygiene Law Articles 16, 31 or 32).

SSL 367-a, subd. 1(d)(iii)-(v) , as amended 2015 If individual is in a Medicare Advantage plan, 85% of the copayment will be paid to the provider (must be a Medicaid provider), regardless of how low the Medicaid rate is. This limit was enacted in the 2016 State Budget, and is better than what the Governor proposed - which was the same rule used in Original Medicare -- NONE of the copayment or coinsurance would be paid if the Medicaid rate was lower than the Medicare rate for the service, which is usually the case.

This would have deterred doctors and other providers from being willing to treat them. SSL 367-a, subd. 1(d)(iv), added 2016.

EXCEPTIONS. The Medicare Advantage plan must pay the full coinsurance for the following services, regardless of the Medicaid rate. ambulance ) psychologist ) The Gov's proposal in the 2019 budget to eliminate these exceptions was rejected by the legislature Example to illustrate the current rules.

The Medicare rate for Mary's specialist visit is $185. The Medicaid rate for the same service is $120. Current rules (since 2016).

Medicare Advantage -- Medicare Advantage plan pays $135 and Mary is charged a copayment of $50 (amount varies by plan). Medicaid pays the specialist 85% of the $50 copayment, which is $42.50. The doctor is prohibited by federal law from "balance billing" QMB beneficiaries for the balance of that copayment.

Since provider is getting $177.50 of the $185 approved rate, provider will hopefully not be deterred from serving Mary or other QMBs/Medicaid recipients. Original Medicare - The 20% coinsurance is $37. Medicaid pays none of the coinsurance because the Medicaid rate ($120) is lower than the amount the provider already received from Medicare ($148).

For both Medicare Advantage and Original Medicare, if the bill was for a ambulance or psychologist, Medicaid would pay the full 20% coinsurance regardless of the Medicaid rate. The proposal to eliminate this exception was rejected by the legislature in 2019 budget. .

4. May the Provider 'Balance Bill" a QMB Benficiary for the Coinsurance if Provider Does Not Accept Medicaid, or if Neither the Patient or Medicaid/QMB pays any coinsurance?. No.

Balance billing is banned by the Balanced Budget Act of 1997. 42 U.S.C. § 1396a(n)(3)(A).

In an Informational Bulletin issued January 6, 2012, titled "Billing for Services Provided to Qualified Medicare Beneficiaries (QMBs)," the federal Medicare agency - CMS - clarified that providers MAY NOT BILL QMB recipients for the Medicare coinsurance. This is true whether or not the provider is registered as a Medicaid provider. If the provider wants Medicaid to pay the coinsurance, then the provider must register as a Medicaid provider under the state rules.

This is a change in policy in implementing Section 1902(n)(3)(B) of the Social Security Act (the Act), as modified by section 4714 of the Balanced Budget Act of 1997, which prohibits Medicare providers from balance-billing QMBs for Medicare cost-sharing. The CMS letter states, "All Medicare physicians, providers, and suppliers who offer services and supplies to QMBs are prohibited from billing QMBs for Medicare cost-sharing, including deductible, coinsurance, and copayments. This section of the Act is available at.

CMCS Informational Bulletin http://www.ssa.gov/OP_Home/ssact/title19/1902.htm. QMBs have no legal obligation to make further payment to a provider or Medicare managed care plan for Part A or Part B cost sharing. Providers who inappropriately bill QMBs for Medicare cost-sharing are subject to sanctions.

Please note that the statute referenced above supersedes CMS State Medicaid Manual, Chapter 3, Eligibility, 3490.14 (b), which is no longer in effect, but may be causing confusion about QMB billing." The same information was sent to providers in this Medicare Learning Network bulletin, last revised in June 26, 2018. CMS reminded Medicare Advantage plans of the rule against Balance Billing in the 2017 Call Letter for plan renewals. See this excerpt of the 2017 call letter by Justice in Aging - Prohibition on Billing Medicare-Medicaid Enrollees for Medicare Cost Sharing 5.

How do QMB Beneficiaries Show a Provider that they have QMB and cannot be Billed for the Coinsurance?. It can be difficult to show a provider that one is a QMB. It is especially difficult for providers who are not Medicaid providers to identify QMB's, since they do not have access to online Medicaid eligibility systems Consumers can now call 1-800-MEDICARE to verify their QMB Status and report a billing issue.

If a consumer reports a balance billng problem to this number, the Customer Service Rep can escalate the complaint to the Medicare Administrative Contractor (MAC), which will send a compliance letter to the provider with a copy to the consumer. See CMS Medicare Learning Network Bulletin effective Dec. 16, 2016.

Medicare Summary Notices (MSNs) that Medicare beneficiaries receive every three months state that QMBs have no financial liability for co-insurance for each Medicare-covered service listed on the MSN. The Remittance Advice (RA) that Medicare sends to providers shows the same information. By spelling out billing protections on a service-by-service basis, the MSNs provide clarity for both the QMB beneficiary and the provider.

Justice in Aging has posted samples of what the new MSNs look like here. They have also updated Justice in Aging’s Improper Billing Toolkit to incorporate references to the MSNs in its model letters that you can use to advocate for clients who have been improperly billed for Medicare-covered services. CMS is implementing systems changes that will notify providers when they process a Medicare claim that the patient is QMB and has no cost-sharing liability.

The Medicare Summary Notice sent to the beneficiary will also state that the beneficiary has QMB and no liability. These changes were scheduled to go into effect in October 2017, but have been delayed. Read more about them in this Justice in Aging Issue Brief on New Strategies in Fighting Improper Billing for QMBs (Feb.

2017). QMBs are issued a Medicaid benefit card (by mail), even if they do not also receive Medicaid. The card is the mechanism for health care providers to bill the QMB program for the Medicare deductibles and co-pays.

Unfortunately, the Medicaid card dos not indicate QMB eligibility. Not all people who have Medicaid also have QMB (they may have higher incomes and "spend down" to the Medicaid limits. Advocates have asked for a special QMB card, or a notation on the Medicaid card to show that the individual has QMB.

See this Report - a National Survey on QMB Identification Practices published by Justice in Aging, authored by Peter Travitsky, NYLAG EFLRP staff attorney. The Report, published in March 2017, documents how QMB beneficiaries could be better identified in order to ensure providers do not bill them improperly. 6.

If you are Billed -​ Strategies Consumers can now call 1-800-MEDICARE to report a billing issue. If a consumer reports a balance billng problem to this number, the Customer Service Rep can escalate the complaint to the Medicare Administrative Contractor (MAC), which will send a compliance letter to the provider with a copy to the consumer. See CMS Medicare Learning Network Bulletin effective Dec.

My wife took cialis

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To help cialis 5mg cost walgreens stop the spread of COVID-19. If you are unwell, stay in, get tested and isolate. Wash your hands regularly. Take hand sanitiser cialis 5mg cost walgreens with you when you go out.Keep your distance.

Leave 1.5 metres between yourself and others.Wear a mask in situations where you cannot physically distance. A full cialis 5mg cost walgreens list of COVID-19 testing clinics is available or people can visit their GP. Confirmed cases to date Overseas2,067Interstate acquired89Locally acquired – contact of a confirmed case and/or in a known cluster1,296Locally acquired – contact not identified391Under investigation​1 Counts reported for a particular day may vary over time with ongoing enhanced surveillance activities. Returned travellers in hotel quarantine to date​​ Symptomatic travellers tested4,765Found positive122 As​ymptomatic travellers screened at a day 217,750Found positive88 Asymptomatic travellers screened at a day 1030,788​Found positive119​Video update​​NSW Health is investigating new cases of COVID-19 in relation to City Tattersalls Fitness Centre on Pitt Street.These cases attended the centre during the past few days, while unknowingly infectious and after being exposed to infections in the gym.Anyone who attended this venue on the following dates and times are considered to be close contacts and must immediately get tested for COVID-19, and self-isolate for 14 days since their last visit.

Wednesday 19 August between 8am - 2pm Friday cialis 5mg cost walgreens 21 August between 8am - 2pm, including. Aqua Aerobics from 10am-10:45am Stretch Class from 11am – 11:50am Pump Class from 12:15pm - 1pm Sunday 23 August between 8am - 2pm Monday 24 August between 8am - 2pm Tuesday 25 August between 8am - 2pm Members who attended the gym on the above dates but outside those times should be on the alert for symptoms and get tested and self-isolate if symptoms do develop.A previously reported case attended one of the gaming areas of City Tattersalls on 24 August. Others who were in the gaming areas on this day must monitor for symptoms and get tested immediately if even the mildest symptoms develop. NSW Health is investigating whether the CBD cluster originated in the City Tattersalls Club and then spread to workplaces in the city and to households across Sydney and the cialis 5mg cost walgreens Central Coast.

To assist in identifying undiagnosed earlier COVID cases, NSW Health is asking anyone who attended the Club between 4 August 2020 – 18 August 2020 to get tested for COVID-19 and isolate until a negative test result is received. A full list of COVID-19 testing clinics is available or people can visit their GP..

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We must enhance the ability of the Federal Government, as well as its State, local, and Tribal partners, to what happens if you overdose on cialis appropriately address these ongoing mental- and behavioral-health concerns. Sec. 2.

Policy. It is the policy of the United States to prevent suicides, drug-related deaths, and poor behavioral-health outcomes, particularly those that are induced or made worse by prolonged State and local COVID-19 shutdown orders. I am therefore issuing a national call to action to.

(a) Engage the resources of the Federal Government to address the mental- and behavioral-health needs of vulnerable Americans, including by. (i) providing crisis-intervention services to treat those in immediate life-threatening situations. And (ii) increasing the availability of and access to quality continuing care following initial crisis resolution to improve behavioral-health outcomes.

(b) Permit and encourage safe in-person mentorship programs. Support-group participation. And attendance at communal facilities, including schools, civic centers, and houses of worship.

(c) Increase the availability of telehealth and online mental-health and substance-use tools and services. And (d) Marshal public and private resources to address deteriorating mental health, such as factors that contribute to prolonged unemployment and social isolation. Sec.

3. Establishment of a Coronavirus Mental Health Working Group. The Coronavirus Mental Health Working Group (Working Group) is hereby established to facilitate an “all-of-government” response to the mental-health conditions induced or exacerbated by the pandemic, including issues related to suicide prevention.

The Working Group will be co-chaired by the Secretary of Health and Human Services, or his designee, and the Assistant to the Start Printed Page 63978President for Domestic Policy, or her designee. The Working Group shall be composed of representatives from the Department of Defense, the Department of Justice, the Department of Agriculture, the Department of Labor, the Department of Housing and Urban Development, the Department of Education, the Department of Veterans Affairs, the Small Business Administration, the Office of National Drug Control Policy, the Office of Management and Budget (OMB), and such representatives of other executive departments, agencies, and offices as the Co-Chairs may, from time to time, designate with the concurrence of the head of the department, agency, or office concerned. All members of the Working Group shall be full-time, or permanent part-time, officers or employees of the Federal Government.

Sec. 4. Responsibilities of the Coronavirus Mental Health Working Group.

(a) As part of the Working Group's efforts, it shall consider the mental- and behavioral-health conditions of those vulnerable populations affected by the pandemic, including. Minorities, seniors, veterans, small business owners, children, and individuals potentially affected by domestic violence or physical abuse. Those living with disabilities.

And those with a substance use disorder. The Working Group shall examine existing protocols and evidence-based programs that may serve as models to better support these at-risk groups, including implementation and broader application of the PREVENTS, and the Department of Labor's Employer Assistance and Resource Network on Disability Inclusion's Mental Health Toolkit and Centralized Accommodation Programs. (b) Within 45 days of the date of this order, the Working Group shall develop and submit to the President a report that outlines a plan for improved service coordination between all relevant public and private stakeholders and executive departments and agencies (agencies) to assist individuals in crisis so that they receive effective treatment and recovery services.

Sec. 5. Grant Funding for States and Organizations that Permit In-Person Treatment and Recovery Support Activities for Mental and Behavioral Health.

The heads of agencies, in consultation with the Director of OMB, shall. (a) Examine their existing grant programs that fund mental-health, medical, or related services and, consistent with applicable law, take steps to encourage grantees to consider adopting policies, where appropriate, that have been shown to improve mental health and reduce suicide risk, including the following. (i) Safe in-person and telehealth participation in support groups for people in recovery from substance use disorders, mental-health issues, or other ailments that benefit from communal support.

And peer-to-peer services that support underserved communities. (ii) Safe face-to-face therapeutic services, including group therapy, to remediate poor behavioral health. And (iii) Safe participation in communal support—both faith-based and secular—including educational programs, civic activities, and in-person religious services.

(b) Maximize use of existing agency authorities to award contracts or grants to community organizations or other local entities to enhance mental-health and suicide-prevention services, such as outreach, education, and case management, to vulnerable Americans. Sec.

The pandemic has also exacerbated mental- cialis 5mg cost walgreens and behavioral-health conditions as a result of stress from prolonged lockdown orders, lost employment, and social isolation. Survey data from the Centers for Disease Control and Prevention show that during the last week of June, 40.9 percent of Americans struggled with mental-health or substance-abuse issues and 10.7 percent reported seriously considering suicide. We must enhance the ability of the Federal Government, as well as its State, local, and Tribal partners, to appropriately address these ongoing mental- and behavioral-health concerns. Sec cialis 5mg cost walgreens. 2.

Policy. It is the policy of the United States to prevent suicides, cialis 5mg cost walgreens drug-related deaths, and poor behavioral-health outcomes, particularly those that are induced or made worse by prolonged State and local COVID-19 shutdown orders. I am therefore issuing a national call to action to. (a) Engage the resources of the Federal Government to address the mental- and behavioral-health needs of vulnerable Americans, including by. (i) providing crisis-intervention cialis 5mg cost walgreens services to treat those in immediate life-threatening situations.

And (ii) increasing the availability of and access to quality continuing care following initial crisis resolution to improve behavioral-health outcomes. (b) Permit and encourage safe in-person mentorship programs. Support-group participation cialis 5mg cost walgreens. And attendance at communal facilities, including schools, civic centers, and houses of worship. (c) Increase the availability of telehealth and online mental-health and substance-use tools and services.

And (d) Marshal public and private resources to address deteriorating mental health, such as factors cialis 5mg cost walgreens that contribute to prolonged unemployment and social isolation. Sec. 3. Establishment of a Coronavirus Mental Health cialis 5mg cost walgreens Working Group. The Coronavirus Mental Health Working Group (Working Group) is hereby established to facilitate an “all-of-government” response to the mental-health conditions induced or exacerbated by the pandemic, including issues related to suicide prevention.

The Working Group will be co-chaired by the Secretary of Health and Human Services, or his designee, and the Assistant to the Start Printed Page 63978President for Domestic Policy, or her designee. The Working Group shall be composed of representatives from the Department of Defense, the Department of Justice, the Department of Agriculture, the Department of Labor, the Department of Housing and Urban Development, the Department of Education, the Department of Veterans Affairs, the Small Business Administration, the Office of National Drug Control Policy, the Office of Management and Budget (OMB), and such representatives of other executive departments, agencies, and offices as the Co-Chairs may, from time to time, designate with the concurrence of the head of the department, agency, or office concerned. All members of the Working Group shall be full-time, or permanent part-time, officers or employees of the Federal Government cialis 5mg cost walgreens. Sec. 4.

Responsibilities of the Coronavirus cialis 5mg cost walgreens Mental Health Working Group. (a) As part of the Working Group's efforts, it shall consider the mental- and behavioral-health conditions of those vulnerable populations affected by the pandemic, including. Minorities, seniors, veterans, small business owners, children, and individuals potentially affected by domestic violence or physical abuse. Those living with cialis 5mg cost walgreens disabilities. And those with a substance use disorder.

The Working Group shall examine existing protocols and evidence-based programs that may serve as models to better support these at-risk groups, including implementation and broader application of the PREVENTS, and the Department of Labor's Employer Assistance and Resource Network on Disability Inclusion's Mental Health Toolkit and Centralized Accommodation Programs. (b) Within 45 days of the date of this order, the Working Group shall develop and submit to the President a report that outlines a plan for improved service coordination between all relevant public and private stakeholders and executive departments and agencies (agencies) cialis 5mg cost walgreens to assist individuals in crisis so that they receive effective treatment and recovery services. Sec. 5. Grant Funding for States and Organizations that cialis 5mg cost walgreens Permit In-Person Treatment and Recovery Support Activities for Mental and Behavioral Health.

The heads of agencies, in consultation with the Director of OMB, shall. (a) Examine their existing grant programs that fund mental-health, medical, or related services and, consistent with applicable law, take steps to encourage grantees to consider adopting policies, where appropriate, that have been shown to improve mental health and reduce suicide risk, including the following. (i) Safe in-person and cialis 5mg cost walgreens telehealth participation in support groups for people in recovery from substance use disorders, mental-health issues, or other ailments that benefit from communal support. And peer-to-peer services that support underserved communities. (ii) Safe face-to-face therapeutic services, including group therapy, to remediate poor behavioral health.

And (iii) Safe participation in communal support—both faith-based and secular—including educational programs, civic activities, and in-person religious services.

Cialis tablet description

7 September 2020 The four day digital event will feature content aimed at all IBMS members and will be free to attend SAVE THE DATE - 16-19th NovemberOur new, virtual cialis tablet description CPD event, The Biomedical Scientist Live, will feature a packed line up of knowledge sharing sessions including. Workshops, seminars, discussions and demonstrations. The dedicated event website will be live soon and will include more information on how to sign up, cialis tablet description free for IBMS members, and the programme of talks. Members will be notified once live.1 September 2020 This September we're asking you to send us your best laboratory bloopers Our members work long hours and everything they do has to be 100% correct - so sometimes the slack falls out of their mouths.

We got the idea for this competition courtesy of Gayatri Chohan who overheard the line in the image when one of her colleagues answered the phone (and was overdue a holiday). What has come out of your mouth in the lab? cialis tablet description. Keep it family-friendly scientists!. The rules of the competition are simple:One entry per person (we will add your blooper to a randomly selected photo from our Biomedical Science Day archives - unless you want to send us your own photo)Use the #IBMSCompetition or #LaboratoryLaughs hashtag on Facebook, Twitter or Instagram along with your entry or email to website@ibms.orgThe competition starts Tuesday 1st September and closes at 12pm on Friday 18th SeptemberTwo entries will be chosen for the semi-finals and presented to our members in a social media poll on the week cialis tablet description of 21th - 25th SeptemberThe winner will be announced at the end of the month and sent some goodies when we return to our officesOnce we get some entries, we will start a Facebook gallery so that you can see the all the bloopers in one place by clicking here.Black nurses – as well as Black patients – need strong allies and advocates who understand their backgrounds and experiences.

That’s just one of the factors that inspired UC Davis Health nurse Carter Todd to establish the Capitol City Black Nurses Association.Now with 40 members and growing, the group continues to develop the skills of its members and grow its network in the state and across the country.Learn more as Carter shares his story, in his own words.In celebration of Florence Nightingale's 200th birthday, 2020 is the Year of the Nurse. Beginning on National Nurses Week (May 6-12) and continuing throughout the year, a special blog will feature the stories, memories and motivations of UC Davis Health nurses.Hear their words, and get to know why and how they invest such heart, passion, expertise and commitment in their life-changing work.Bedwetting, also known as nocturnal enuresis, is common in childhood and most children will grow out of it as they age. We asked UC Davis pediatrician Lena cialis tablet description van der List about causes, strategies and solutions that can help families beat the bedwetting blues. Kids can experience dry mornings with these strategies to prevent bedwetting.What causes bedwetting?.

In the majority of young children who experience bedwetting, the main issue is sleep arousal. The brain is not signaling to awaken when the bladder is full, and, cialis tablet description at times, doesn’t even signal the child to wake up when wet. Frequently, these kids are extremely heavy sleepers. Kids may also produce more cialis tablet description urine than expected at night (which is called nocturnal polyuria) or have small bladder capacity (with frequent small urinations throughout the day and night), which may increase their risk for bedwetting.Other causes for bedwetting:Constipation, which, if appropriately treated, can alleviate the problem.

Constipation causes bedwetting because a large amount of stool may actually push up against the bladder and prevent the bladder from expanding all the way. Doctors may prescribe a medication to help “clean out” the stool and keep your child more regular. The most commonly used medication is a laxative, polyethylene glycol, with the brand cialis tablet description name Miralax.Urinary tract infectionsGenetic predisposition. If one parent experienced problems with nocturnal enuresis, on average, half of their children also will.

If both parents did, then three-quarters of their children will.Sleep disorders like obstructive cialis tablet description sleep apnea. It is estimated that 30% of kids with sleep apnea will also have nocturnal enuresis. A child with symptoms of sleep apnea may snore at night, have periods where they seem like they pause breathing or be excessively sleepy during the day - although some kids may exhibit more hyperactivity. Sleep apnea can be diagnosed with cialis tablet description a sleep study (these are frequently performed by pulmonologists).

If a child is found to have sleep apnea, the most common treatment is removing the tonsils and adenoids (tonsillectomy/adenoidectomy). This allows for a more open airway at night and resolves the apnea. One study from 2016 looked cialis tablet description at kids with bedwetting before and after tonsillectomy/adenoidectomy were performed for obstructive sleep apnea. After the surgery, 76% showed complete resolution of bedwetting, however the studies have been mixed on this.There are other more serious conditions including diabetes, spinal cord issues that prevent a normal functioning bladder, and metabolic issues.

While these are extremely rare, they should be considered in older kids with persistent enuresis that does not respond to typical treatment.How can pediatricians help with bedwetting kids? cialis tablet description. When you visit your doctor with a bedwetting concern, they may ask you questions like how long has it been going on?. What time does it occur most nights?. How much fluid and what types cialis tablet description of fluid does your child drink in a day?.

Has your child had any previous “dry” periods?. How cialis tablet description often do they stool and what is it like?. Do they ever have continence issues during the day?. Your child’s physician will perform an exam, which may include a genital exam and a neurologic exam.

He or she may perform a urinalysis (where they ask your child to pee in a cup) to make sure there isn’t an infection or signs of diabetes, or extremely diluted urine.Some physicians may ask you to cialis tablet description keep a diary documenting all elimination (stools, day and night-time urination), fluids consumed, or even at times the volume of urine to help pinpoint the problem.If the doctor doesn’t find a medical problem, how can parents help stop bedwetting?. Well, the first criteria is that the child is motivated for it to stop. If the child is not bothered by the bedwetting, each of these proven methods is much less likely to work:Limit their nighttime fluid intake. A good rule of thumb is for the child to consume two-thirds of their fluid goal before the end of the school day and then one-third of the fluid after school with no more cialis tablet description drinking in the last one to two hours before bed.Have a stable bedtime routine.

Going pee before bed and first thing upon awakening should always be encouraged.Consider stopping pull ups or diapers at night once they are reliably potty trained during the day. For some kids, these may be used as a crutch and could continue to trick their brains into thinking they don’t have to wake up to urinate.Do bedwetting cialis tablet description alarms work?. Bedwetting alarms are recommended by the International Children’s Continence Society. It is worn attached to the pajamas or underwear and will alert the child as soon as wetness or moisture is detected.

At first, the alarm may not wake cialis tablet description the child so parents need to play active roles in waking up their kid, walking him or her to the bathroom. Their child should help change the sheets before going back to bed.The alarm needs to be used nightly and may take two to three months to work, but it has been shown to be very successful in up to two-thirds of children. It also costs about $60 and is typically not covered by insurance so this can be a barrier cialis tablet description for some families. It is recommended that parents and kids continue to use the alarm until two weeks of consecutive dry nights!.

Are there medications that can help?. The most commonly used medication for bedwetting cialis tablet description is called desmopressin. It reduces the amount of urine produced overnight so it may be more beneficial in those kids that produce more urine at night. Studies have shown a 20-30% response.

One side effect of the medication can be low sodium, so parents need to be aware of the signs, including confusion, weakness and even seizures.One other cialis tablet description bedwetting medication that is occasionally used is called imipramine. It belongs to a class of medications called tricyclics and is also used to treat depression. It is less frequently prescribed these days because if too cialis tablet description much is taken, an overdose may occur. Before starting on this medication, the heart needs to be monitored with an EKG.There are a few other medications that have been used, but they have a higher likelihood of side effects and are therefore not routinely recommended as a first line of treatment in kids.What is dry bed training, and how do I do it?.

Dry bed training is a more hands-on, parent-led approach.On the first night, awaken the child once every hour until 1 a.m., asking if he or she has to use the bathroom. At the cialis tablet description 1 a.m. Awakening, tell the child to try using the bathroom, even if he or she is dry.The second night, wake him or her only once, three hours after falling asleep.The third through fifth nights, wake the child once each night. Start at two-and-a-half hours after falling asleep, and keep diminishing the interval each night, so that on the fifth night, the child is awakened one hour after cialis tablet description falling asleep.On the sixth night, tell the child to self-awaken from then on.One older study reported a great than 90% success rate with this method.What do you recommend when a child has had a dry period for more than six months and then begins to wet the bed again?.

This is referred to as secondary nocturnal enuresis. This is often related to a psychological stressor like a divorce or the birth of a new sibling. Exploring what may be bothering your child is a good cialis tablet description idea. But the above other medical diagnoses should also be considered.What’s the best way for parents to respond to bedwetting while still making sure they are being sensitive toward the child?.

As kids get older, typically closer to around 6-8 years old, they begin to get self-conscious and embarrassed by bedwetting. They may resist sleepovers cialis tablet description. This can affect their self-esteem and friendships. It’s important that the child doesn’t cialis tablet description feel like it’s their fault or something is wrong with them.They should not be shamed.

For example, never say “I can’t believe you did this again” or “You are costing us a lot of money having to wash your dirty sheets every night.” It’s important that bedwetting is not discussed in front of the child’s siblings or friends. Parents should reassure the child that it’s normal for his or her age. Act as an ally to the child and show that you’re going to tackle this as a team.Parents cialis tablet description may want to teach the child to do the laundry so they can wash their sheets and pajamas on their own. This should not be treated like a punishment.

It is an opportunity for the child cialis tablet description to have control over it and limit who knows about it. This also helps develop responsibility. If you approach it in this supportive and collaborative way, most kids will outgrow it.ResourcesHealthy Children BedwettingHealthy Children Bedwetting in Children &. Teens.

Nocturnal Enuresis Healthy Children Radio. Bedwetting International Children’s Continence Society Enuresis alarms on Amazon Kids Considered podcast episode. Bedwetting Basics7 September 2020 The four day digital event will feature content aimed at all IBMS members and will be free to attend SAVE THE DATE - 16-19th NovemberOur new, virtual CPD event, The Biomedical Scientist Live, will feature a packed line up of knowledge sharing sessions including. Workshops, seminars, discussions and demonstrations.

The dedicated event website will be live soon and will include more information on how to sign up, free for IBMS members, and the programme of talks. Members will be notified once live.1 September 2020 This September we're asking you to send us your best laboratory bloopers Our members work long hours and everything they do has to be 100% correct - so sometimes the slack falls out of their mouths. We got the idea for this competition courtesy of Gayatri Chohan who overheard the line in the image when one of her colleagues answered the phone (and was overdue a holiday). What has come out of your mouth in the lab?.

Keep it family-friendly scientists!. The rules of the competition are simple:One entry per person (we will add your blooper to a randomly selected photo from our Biomedical Science Day archives - unless you want to send us your own photo)Use the #IBMSCompetition or #LaboratoryLaughs hashtag on Facebook, Twitter or Instagram along with your entry or email to website@ibms.orgThe competition starts Tuesday 1st September and closes at 12pm on Friday 18th SeptemberTwo entries will be chosen for the semi-finals and presented to our members in a social media poll on the week of 21th - 25th SeptemberThe winner will be announced at the end of the month and sent some goodies when we return to our officesOnce we get some entries, we will start a Facebook gallery so that you can see the all the bloopers in one place by clicking here..

7 September cialis 5mg cost walgreens 2020 The four day digital event will feature content aimed at all IBMS members and will be free to attend SAVE THE DATE - 16-19th NovemberOur new, virtual CPD event, The Biomedical Scientist Live, will feature a packed line up of knowledge sharing sessions including. Workshops, seminars, discussions and demonstrations. The dedicated event website will be live soon and will include more information on how to sign up, free for IBMS members, and the programme of cialis 5mg cost walgreens talks.

Members will be notified once live.1 September 2020 This September we're asking you to send us your best laboratory bloopers Our members work long hours and everything they do has to be 100% correct - so sometimes the slack falls out of their mouths. We got the idea for this competition courtesy of Gayatri Chohan who overheard the line in the image when one of her colleagues answered the phone (and was overdue a holiday). What has come out of your mouth in cialis 5mg cost walgreens the lab?.

Keep it family-friendly scientists!. The rules of the competition are simple:One entry per person (we will add your blooper to a randomly selected photo from our Biomedical Science Day archives - unless you want to send us your own photo)Use the #IBMSCompetition or #LaboratoryLaughs hashtag on Facebook, Twitter or Instagram along with your entry or email to website@ibms.orgThe competition starts Tuesday 1st September and closes at 12pm on Friday 18th SeptemberTwo entries will be chosen cialis 5mg cost walgreens for the semi-finals and presented to our members in a social media poll on the week of 21th - 25th SeptemberThe winner will be announced at the end of the month and sent some goodies when we return to our officesOnce we get some entries, we will start a Facebook gallery so that you can see the all the bloopers in one place by clicking here.Black nurses – as well as Black patients – need strong allies and advocates who understand their backgrounds and experiences. That’s just one of the factors that inspired UC Davis Health nurse Carter Todd to establish the Capitol City Black Nurses Association.Now with 40 members and growing, the group continues to develop the skills of its members and grow its network in the state and across the country.Learn more as Carter shares his story, in his own words.In celebration of Florence Nightingale's 200th birthday, 2020 is the Year of the Nurse.

Beginning on National Nurses Week (May 6-12) and continuing throughout the year, a special blog will feature the stories, memories and motivations of UC Davis Health nurses.Hear their words, and get to know why and how they invest such heart, passion, expertise and commitment in their life-changing work.Bedwetting, also known as nocturnal enuresis, is common in childhood and most children will grow out of it as they age. We asked UC Davis pediatrician Lena van der List about causes, strategies and solutions that can help families cialis 5mg cost walgreens beat the bedwetting blues. Kids can experience dry mornings with these strategies to prevent bedwetting.What causes bedwetting?.

In the majority of young children who experience bedwetting, the main issue is sleep arousal. The brain is not signaling cialis 5mg cost walgreens to awaken when the bladder is full, and, at times, doesn’t even signal the child to wake up when wet. Frequently, these kids are extremely heavy sleepers.

Kids may also produce more urine than expected at night (which is called nocturnal polyuria) or have small bladder capacity (with frequent small urinations throughout the day and night), which cialis 5mg cost walgreens may increase their risk for bedwetting.Other causes for bedwetting:Constipation, which, if appropriately treated, can alleviate the problem. Constipation causes bedwetting because a large amount of stool may actually push up against the bladder and prevent the bladder from expanding all the way. Doctors may prescribe a medication to help “clean out” the stool and keep your child more regular.

The most commonly used medication is a cialis 5mg cost walgreens laxative, polyethylene glycol, with the brand name Miralax.Urinary tract infectionsGenetic predisposition. If one parent experienced problems with nocturnal enuresis, on average, half of their children also will. If both parents did, then three-quarters of their children will.Sleep disorders like obstructive cialis 5mg cost walgreens sleep apnea.

It is estimated that 30% of kids with sleep apnea will also have nocturnal enuresis. A child with symptoms of sleep apnea may snore at night, have periods where they seem like they pause breathing or be excessively sleepy during the day - although some kids may exhibit more hyperactivity. Sleep apnea can be diagnosed with a sleep study (these cialis 5mg cost walgreens are frequently performed by pulmonologists).

If a child is found to have sleep apnea, the most common treatment is removing the tonsils and adenoids (tonsillectomy/adenoidectomy). This allows for a more open airway at night and resolves the apnea. One study from 2016 looked at kids with bedwetting before and cialis 5mg cost walgreens after tonsillectomy/adenoidectomy were performed for obstructive sleep apnea.

After the surgery, 76% showed complete resolution of bedwetting, however the studies have been mixed on this.There are other more serious conditions including diabetes, spinal cord issues that prevent a normal functioning bladder, and metabolic issues. While these are extremely rare, they should be considered in older kids with cialis 5mg cost walgreens persistent enuresis that does not respond to typical treatment.How can pediatricians help with bedwetting kids?. When you visit your doctor with a bedwetting concern, they may ask you questions like how long has it been going on?.

What time does it occur most nights?. How much cialis 5mg cost walgreens fluid and what types of fluid does your child drink in a day?. Has your child had any previous “dry” periods?.

How cialis 5mg cost walgreens often do they stool and what is it like?. Do they ever have continence issues during the day?. Your child’s physician will perform an exam, which may include a genital exam and a neurologic exam.

He or she may perform a urinalysis (where they ask your child to pee in a cup) to make sure there isn’t an infection or signs of diabetes, or extremely diluted urine.Some physicians may ask you to keep a diary documenting all elimination (stools, day and night-time urination), fluids consumed, cialis 5mg cost walgreens or even at times the volume of urine to help pinpoint the problem.If the doctor doesn’t find a medical problem, how can parents help stop bedwetting?. Well, the first criteria is that the child is motivated for it to stop. If the child is not bothered by the bedwetting, each of these proven methods is much less likely to work:Limit their nighttime fluid intake.

A good rule of thumb is for the child to consume two-thirds of their fluid goal before the end of the school day and then one-third of the fluid after school with no more drinking in the last one to two hours before bed.Have a stable cialis 5mg cost walgreens bedtime routine. Going pee before bed and first thing upon awakening should always be encouraged.Consider stopping pull ups or diapers at night once they are reliably potty trained during the day. For some kids, these may be used as a crutch and could continue to trick their brains into thinking they cialis 5mg cost walgreens don’t have to wake up to urinate.Do bedwetting alarms work?.

Bedwetting alarms are recommended by the International Children’s Continence Society. It is worn attached to the pajamas or underwear and will alert the child as soon as wetness or moisture is detected. At first, the alarm may not wake the child so parents need to play active roles in waking up their kid, walking him or her to cialis 5mg cost walgreens the bathroom.

Their child should help change the sheets before going back to bed.The alarm needs to be used nightly and may take two to three months to work, but it has been shown to be very successful in up to two-thirds of children. It also costs about $60 and is typically not covered by insurance so this can be a barrier cialis 5mg cost walgreens for some families. It is recommended that parents and kids continue to use the alarm until two weeks of consecutive dry nights!.

Are there medications that can help?. The most commonly used medication for bedwetting is called desmopressin cialis 5mg cost walgreens. It reduces the amount of urine produced overnight so it may be more beneficial in those kids that produce more urine at night.

Studies have shown a 20-30% response. One side effect of the medication can be low sodium, so parents need to be aware of the signs, including confusion, weakness and even seizures.One other bedwetting medication that is occasionally used cialis 5mg cost walgreens is called imipramine. It belongs to a class of medications called tricyclics and is also used to treat depression.

It is less frequently prescribed these days because if too much cialis 5mg cost walgreens is taken, an overdose may occur. Before starting on this medication, the heart needs to be monitored with an EKG.There are a few other medications that have been used, but they have a higher likelihood of side effects and are therefore not routinely recommended as a first line of treatment in kids.What is dry bed training, and how do I do it?. Dry bed training is a more hands-on, parent-led approach.On the first night, awaken the child once every hour until 1 a.m., asking if he or she has to use the bathroom.

At the cialis 5mg cost walgreens 1 a.m. Awakening, tell the child to try using the bathroom, even if he or she is dry.The second night, wake him or her only once, three hours after falling asleep.The third through fifth nights, wake the child once each night. Start at two-and-a-half hours after falling asleep, and keep diminishing the interval each night, so that on the fifth night, the child is awakened one hour after falling asleep.On the sixth night, tell the child to self-awaken from then on.One older study reported a great than 90% cialis 5mg cost walgreens success rate with this method.What do you recommend when a child has had a dry period for more than six months and then begins to wet the bed again?.

This is referred to as secondary nocturnal enuresis. This is often related to a psychological stressor like a divorce or the birth of a new sibling. Exploring what may be bothering your child is cialis 5mg cost walgreens a good idea.

But the above other medical diagnoses should also be considered.What’s the best way for parents to respond to bedwetting while still making sure they are being sensitive toward the child?. As kids get older, typically closer to around 6-8 years old, they begin to get self-conscious and embarrassed by bedwetting. They may resist cialis 5mg cost walgreens sleepovers.

This can affect their self-esteem and friendships. It’s important that the child doesn’t feel like it’s their fault or something is wrong cialis 5mg cost walgreens with them.They should not be shamed. For example, never say “I can’t believe you did this again” or “You are costing us a lot of money having to wash your dirty sheets every night.” It’s important that bedwetting is not discussed in front of the child’s siblings or friends.

Parents should reassure the child that it’s normal for his or her age. Act as an ally to the child and show that you’re going to tackle this as a team.Parents may want to teach the child to do the laundry so they can wash their sheets and pajamas cialis 5mg cost walgreens on their own. This should not be treated like a punishment.

It is cialis 5mg cost walgreens an opportunity for the child to have control over it and limit who knows about it. This also helps develop responsibility. If you approach it in this supportive and collaborative way, most kids will outgrow it.ResourcesHealthy Children BedwettingHealthy Children Bedwetting in Children &.

Teens. Nocturnal Enuresis Healthy Children Radio. Bedwetting International Children’s Continence Society Enuresis alarms on Amazon Kids Considered podcast episode.

Bedwetting Basics7 September 2020 The four day digital event will feature content aimed at all IBMS members and will be free to attend SAVE THE DATE - 16-19th NovemberOur new, virtual CPD event, The Biomedical Scientist Live, will feature a packed line up of knowledge sharing sessions including. Workshops, seminars, discussions and demonstrations. The dedicated event website will be live soon and will include more information on how to sign up, free for IBMS members, and the programme of talks.

Members will be notified once live.1 September 2020 This September we're asking you to send us your best laboratory bloopers Our members work long hours and everything they do has to be 100% correct - so sometimes the slack falls out of their mouths. We got the idea for this competition courtesy of Gayatri Chohan who overheard the line in the image when one of her colleagues answered the phone (and was overdue a holiday). What has come out of your mouth in the lab?.

Keep it family-friendly scientists!. The rules of the competition are simple:One entry per person (we will add your blooper to a randomly selected photo from our Biomedical Science Day archives - unless you want to send us your own photo)Use the #IBMSCompetition or #LaboratoryLaughs hashtag on Facebook, Twitter or Instagram along with your entry or email to website@ibms.orgThe competition starts Tuesday 1st September and closes at 12pm on Friday 18th SeptemberTwo entries will be chosen for the semi-finals and presented to our members in a social media poll on the week of 21th - 25th SeptemberThe winner will be announced at the end of the month and sent some goodies when we return to our officesOnce we get some entries, we will start a Facebook gallery so that you can see the all the bloopers in one place by clicking here..

Cialis 20mg price

IntroductionIn recent years, many studies have been published on new diagnostic possibilities and management approaches in cohorts of patients suspected to have a disorder/difference of sex development (DSD).1–13 Based on cialis 20mg price these studies, it has become clear that services and institutions still differ in the composition of the multidisciplinary teams that provide care for patients who have a DSD.11 14 Several projects have now worked to resolve this variability in care. The European Cooperation in Science and Technology (EU COST) action BM1303 ‘A systematic elucidation of differences of sex development’ has been a platform to achieve European agreement on harmonisation of clinical management and laboratory practices.15–17 Another such cialis 20mg price initiative involved an update of the 2006 DSD consensus document by an international group of professionals and patient representatives.18 These initiatives have highlighted how cultural and financial aspects and the availability of resources differ significantly between countries and societies, a situation that hampers supranational agreement on common diagnostic protocols. As only a few national guidelines have been published in international journals, comparison of these guidelines is difficult even though such a comparison is necessary to capture the differences and initiate actions to overcome them. Nonetheless, four DSD (expert) centres located in the Netherlands and Flanders (the Dutch-speaking Northern part of Belgium) have collaborated to produce a detailed guideline on diagnostics in DSD.19 This shows that cialis 20mg price a supranational guideline can be a reasonable approach for countries with similarly structured healthcare systems and similar resources. Within the guideline there is agreement that optimisation of expertise and care can be achieved through centralisation, for example, by limiting analysis of next-generation sequencing (NGS)-based diagnostic panels to only a few centres and by centralising pathological review of gonadal tissues.

International networks such as the European Reference Network for rare endocrine conditions (EndoERN), in which cialis 20mg price DSD is embedded, may facilitate the expansion of this kind of collaboration across Europe.This paper highlights key discussion points in the Dutch-Flemish guideline that have been insufficiently addressed in the literature thus far because they reflect evolving technologies or less visible stakeholders. For example, prenatal observation of an atypical aspect of the genitalia indicating a possible DSD is becoming increasingly common, and we discuss appropriate counselling and a diagnostic approach for these cases, including the option of using NGS-based genetic testing. So far, little attention has been paid to this process.20 21 Furthermore, informing patients and/or their parents about atypical cialis 20mg price sex development and why this may warrant referral to a specialised team may be challenging, especially for professionals with limited experience in DSD.22 23 Therefore, a section of the Dutch-Flemish guideline was written for these healthcare providers. Moreover, this enables DSD specialists to refer to the guideline when advising a referral. Transition from the prenatal to the postnatal team and from the paediatric to the adult team requires optimal communication between cialis 20mg price the specialists involved.

Application of NGS-based techniques may lead to a higher diagnostic yield, providing a molecular genetic diagnosis in previously unsolved cases.16 We address the timing of this testing and the problems associated with this technique such as the interpretation of variants of unknown clinical significance (VUS). Similarly, histopathological interpretation and classification of removed gonadal tissue is challenging and would benefit from international collaboration and centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary cialis 20mg price multicentre group was formed with all members responsible for updating the literature for a specific part of the guideline. Literature search in PubMed was not systematic, but rather intended to be broad in order to cover all areas and follow expert opinions. This approach is more in line with the Clinical Practice Advisory Document method described by Burke et al24 for guidelines involving genetic practice because it is often troublesome to substantiate such guidelines with sufficient evidence due to cialis 20mg price the rapid changes in testing methods, for example, gene panels. All input provided by the group was synthesised by the chairperson (YvB), who also reviewed abstracts of papers on DSD published between 2010 and September 2017 for the guideline and up to October 2019 for this paper.

Abstracts had to be written in English and were identified using a broad range of Medical Subject Headings terms (eg, DSD, genetic, review, diagnosis, diagnostics, cialis 20mg price 46,XX DSD, 46,XY DSD, guideline, multidisciplinary care). Next, potentially relevant papers on diagnostic procedures in DSD were selected. Case reports were cialis 20mg price excluded, as were articles that were not open access or retrievable through institutional access. Based on this, a draft guideline was produced that was in line with the international principles of good diagnostic care in DSD. This draft was discussed by cialis 20mg price the writing committee and, after having obtained agreement on remaining points of discussion, revised into a final draft.

This version was sent to a broad group of professionals from academic centres and DSD teams whose members had volunteered to review the draft guideline. After receiving and incorporating their input, the final version was presented to cialis 20mg price the paediatric and genetic associations for approval. After approval by the members of the paediatric (NVK), clinical genetic (VKGN) and genetic laboratory (VKGL) associations, the guideline was published on their respective websites.19 Although Turner syndrome and Klinefelter syndrome are considered to be part of the DSD spectrum, they are not extensively discussed in this diagnostic guideline as guidelines dedicated to these syndromes already exist.25 26 However, some individuals with Turner syndrome or Klinefelter syndrome may present with ambiguous or atypical genitalia and may therefore initially follow the DSD diagnostic process.Guideline highlightsPrenatal settingPresentationThe most frequent prenatal presentation of a DSD condition is atypical genitalia found on prenatal ultrasound as an isolated finding or in combination with other structural anomalies. This usually occurs after the 20-week routine medical ultrasound for screening of congenital anomalies, but may also occur earlier, for example, when a commercial ultrasound is performed cialis 20mg price at the request of the parents.Another way DSD can be diagnosed before birth is when invasive prenatal genetic testing carried out for a different reason, for example, due to suspicion of other structural anomalies, reveals a discrepancy between the genotypic sex and the phenotypic sex seen by ultrasound. In certified laboratories, the possibility of a sample switch is extremely low but should be ruled out immediately.

More often, the discrepancy will be due to sex-chromosome mosaicism or a true form of DSD.A situation now occurring with increasing frequency is a discrepancy between the genotypic sex revealed by non-invasive prenatal testing (NIPT), which is now available to high-risk pregnant women in cialis 20mg price the Netherlands and to all pregnant women in Belgium, and later ultrasound findings. NIPT screens for CNVs in the fetus. However, depending cialis 20mg price on legal restrictions and/or ethical considerations, the X and Y chromosomes are not always included in NIPT analysis and reports. If the X and Y chromosomes are included, it is important to realise that the presence of a Y-chromosome does not necessarily imply male fetal development. At the time that NIPT is performed (usually 11–13 weeks), cialis 20mg price genital development cannot be reliably appreciated by ultrasound, so any discrepancy or atypical aspect of the genitalia will only be noticed later in pregnancy and should prompt further evaluation.Counselling and diagnosticsIf a DSD is suspected, first-line sonographers and obstetricians should refer the couple to their colleague prenatal specialists working with or in a DSD team.

After confirming an atypical genital on ultrasound, the specialist team should offer the couple a referral for genetic counselling to discuss the possibility of performing invasive prenatal testing (usually an amniocentesis) to identify an underlying cause that fits the ultrasound findings.22 23 To enable the parents to make a well-informed decision, prenatal counselling should, in our opinion, include. Information on cialis 20mg price the ultrasound findings and the limitations of this technique. The procedure(s) that can be followed, including the risks associated with an amniocentesis. And the type of information genetic testing can and cialis 20mg price cannot provide. Knowing which information has been provided and what words have been used by the prenatal specialist is very helpful for those involved in postnatal care.It is important that parents understand that the biological sex of a baby is determined by a complex interplay of chromosomes, genes and hormones, and thus that assessment of the presence or absence of a Y-chromosome alone is insufficient to assign the sex of their unborn child or, as in any unborn child, say anything about the child’s future gender identity.Expecting parents can be counselled by the clinical geneticist and the psychologist from the DSD team, although other DSD specialists can also be involved.

The clinical geneticist should be experienced in prenatal counselling and well informed about the diagnostic possibilities given the limited time span in which test results need to be available to allow parents to make a well-informed decision about whether or not to continue cialis 20mg price the pregnancy. Termination of pregnancy can be considered, for instance, in a syndromic form of DSD with multiple malformations, but when the DSD occurs as an apparently isolated condition, expecting parents may also consider termination of pregnancy, which, although considered controversial by some, is legal in Belgium and the cialis 20mg price Netherlands. The psychologist of the DSD team can support parents during and after pregnancy and help them cope with feelings of uncertainty and eventual considerations of a termination of pregnancy, as well as with practical issues, for example, how to inform others. The stress of not knowing exactly what the child’s genitalia will look like and uncertainty about the diagnosis, treatment and prognosis cannot be cialis 20mg price avoided completely. Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images.

In our experience, parents appreciate having already cialis 20mg price spoken to some members of the DSD team during pregnancy and having a contact person before birth.After expert prenatal counselling, a significant number of pregnant couples decline prenatal testing (personal experience IALG, MK, ABD, YvB, MC and HC-vdG). At birth, umbilical cord blood is a good source for (molecular) karyotyping and storage of DNA and can be obtained by the obstetrician, midwife or neonatologist. The terminology used in communication with parents should be carefully chosen,22 23 and midwives and staff of neonatal and cialis 20mg price delivery units should be clearly instructed to use gender-neutral and non-stigmatising vocabulary (eg, ‘your baby’) as long as sex assignment is pending.An algorithm for diagnostic evaluation of a suspected DSD in the prenatal situation is proposed in figure 1. When couples opt for invasive prenatal diagnosis, the genetic analysis usually involves an (SNP)-array. It was recently estimated that >30% of individuals who have a DSD have additional structural anomalies, with cardiac and neurological anomalies and fetal growth restriction being particularly common.27 cialis 20mg price 28 If additional anomalies are seen, the geneticist can consider specific gene defects that may underlie a known genetic syndrome or carry out NGS.

NGS-based techniques have also now made their appearance in prenatal diagnosis of congenital anomalies.29 30 Panels using these techniques can be specific for genes involved in DSD, or be larger panels covering multiple congenital anomalies, and are usually employed with trio-analysis to compare variants identified in the child with the parents’ genetics.29–31 Finding a genetic cause before delivery can help reduce parental stress in the neonatal period and speed up decisions regarding gender assignment. In such cases there is no tight time limit, and we propose cialis 20mg price completing the analysis well before the expected delivery.Disorders/differences of sex development (DSD) in the prenatal setting. A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!.

Conventional karyotyping can be useful. NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 1 Disorders/differences of sex development (DSD) in the prenatal setting. A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!.

Conventional karyotyping can be useful. NGS, next-generation sequencing.First contact by a professional less experienced in DSDWhereas most current guidelines start from the point when an individual has been referred to the DSD team,1 15 the Dutch-Flemish guideline dedicates a chapter to healthcare professionals less experienced in DSD as they are often the first to suspect or identify such a condition. Apart from the paper of Indyk,7 little guidance is available for these professionals about how to act in such a situation. The chapter in the Dutch-Flemish guideline summarises the various clinical presentations that a DSD can have and provides information on how to communicate with parents and/or patients about the findings of the physical examination, the first-line investigations and the need for prompt referral to a specialised centre for further evaluation. Clinical examples are offered to illustrate some of these recurring situations.

The medical issues in DSD can be very challenging, and the social and psychological impact is high. For neonates with ambiguous genitalia, sex assignment is an urgent and crucial issue, and it is mandatory that parents are informed that it is possible to postpone registration of their child’s sex. In cases where sex assignment has already taken place, the message that the development of the gonads or genitalia is still atypical is complicated and distressing for patients and parents or carers. A list of contact details for DSD centres and patient organisations in the Netherlands and Flanders is attached to the Dutch-Flemish guideline. Publishing such a list, either in guidelines or online, can help healthcare professionals find the nearest centres for consultations and provide patients and patient organisations with an overview of the centres where expertise is available.Timing and place of genetic testing using NGS-based gene panelsThe diagnostic workup that is proposed for 46,XX and 46,XY DSD is shown in figures 2 and 3, respectively.

Even with the rapidly expanding molecular possibilities, a (family) history and a physical examination remain the essential first steps in the diagnostic process. Biochemical and hormonal screening aim at investigating serum electrolytes, renal function and the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes. Ultrasound screening of kidneys and internal genitalia, as well as establishing genotypic sex, should be accomplished within 48 hours and complete the baseline diagnostic work-up of a child born with ambiguous genitalia.1 16 32 3346,XX disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. NGS, next-generation sequencing.

CAH, Congenital adrenal hyperplasia. AMH, Anti-Müllerian Hormone." data-icon-position data-hide-link-title="0">Figure 2 46,XX disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. NGS, next-generation sequencing. CAH, Congenital adrenal hyperplasia.

AMH, Anti-Müllerian Hormone.46,XY disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. * SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful.

NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 3 46,XY disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful.

NGS, next-generation sequencing.Very recently, a European position paper has been published focusing on the genetic workup of DSD.16 It highlights the limitations and drawbacks of NGS-based tests, which include the chance of missing subtle structural variants such as CNVs and mosaicism and the fact that NGS cannot detect methylation defects or other epigenetic changes.16 28 31 Targeted DNA analysis is preferred in cases where hormonal investigations suggest a block in steroidogenesis (eg, 11-β-hydroxylase deficiency, 21-hydroxylase deficiency), or in the context of a specific clinical constellation such as the often coincidental finding of Müllerian structures in a boy with normal external genitalia or cryptorchidism, that is, persistent Müllerian duct syndrome.33 34 Alternative tests should also be considered depending on the available information. Sometimes, a simple mouth swab for FISH analysis can detect mosaic XY/X in a male with hypospadias or asymmetric gonadal development or in a female with little or no Turner syndrome stigmata and a normal male molecular karyotyping profile or peripheral blood karyotype. Such targeted testing avoids incidental findings and is cheaper and faster than analysis of a large NGS-based panel, although the cost difference is rapidly declining.However, due to the genetic and phenotypic heterogeneity of DSD conditions, the most cost-effective next steps in the majority of cases are whole exome sequencing followed by panel analysis of genes involved in genital development and function or trio-analysis of a large gene panel (such as a Mendeliome).16 35–38 Pretest genetic counselling involves discussing what kind of information will be reported to patients or parents and the chance of detecting VUS, and the small risk of incidental findings when analysing a DSD panel should be mentioned. Laboratories also differ in what class of variants they report.39 In our experience, the fear of incidental findings is a major reason why some parents refrain from genetic testing.Timing of the DSD gene panel analysis is also important. While some patients or parents prefer that all diagnostic procedures be performed as soon as possible, others need time to reflect on the complex information related to more extensive genetic testing and on its possible consequences.

If parents or patients do not consent to panel-based genetic testing, analysis of specific genes, such as WT1, should be considered when appropriate in view of the clinical consequences if a mutation is present (eg, clinical surveillance of renal function and screening for Wilms’ tumour in the case of WT1 mutations). Genes that are more frequently involved in DSD (eg, SRY, NR5A1) and that match the specific clinical and hormonal features in a given patient could also be considered for sequencing. Targeted gene analysis may also be preferred in centres located in countries that do not have the resources or technical requirements to perform NGS panel-based genetic testing. Alternatively, participation by these centres in international collaborative networks may allow them to outsource the molecular genetic workup abroad.Gene panels differ between centres and are regularly updated based on scientific progress. A comparison of DSD gene panels used in recent studies can be found at https://www.nature.com/articles/s41574-018-0010-8%23Sec46.15 The panels currently used at the coauthors’ institutions can be found on their respective websites.

Given the pace of change, it is important to regularly consider repeating analysis in patients with an unexplained DSD, for example, when they transition into adult care or when they move from one centre to another. This also applies to patients in whom a clinical diagnosis has never been genetically confirmed. Confusion may arise when the diagnosis cannot be confirmed or when a mutation is identified in a different gene, for example, NR5A1 in someone with a clinical diagnosis of CAIS that has other consequences for relatives. Hence, new genetic counselling should always accompany new diagnostic endeavours.Class 3 variants and histopathological examinationsThe rapidly evolving diagnostic possibilities raise new questions. What do laboratories report?.

How should we deal with the frequent findings of mainly unique VUS or class 3 variants (ACMG recommendation) in the many different DSD-related genes in the diagnostic setting?. Reporting VUS can be a source of uncertainty for parents, but not reporting these variants precludes further investigations to determine their possible pathogenicity. It can also be difficult to prove variant pathogenicity, both on gene-level and variant-level.39 Moreover, given the gonad-specific expression of some genes and the variable phenotypic spectrum and reduced penetrance, segregation analysis is not always informative. A class 3 variant that does not fit the clinical presentation may be unrelated to the observed phenotype, but it could also represent a newly emerging phenotype. This was recently demonstrated by the identification of the NR5A1 mutation, R92W, in individuals with 46,XX testicular and ovotesticular DSD.40 This gene had previously been associated with 46,XY DSD.

In diagnostic laboratories, there is usually no capacity or expertise to conduct large-scale functional studies to determine pathogenicity of these unique class 3 VUS in the different genes involved in DSD. Functional validation of variants identified in novel genes may be more attractive in a research context. However, for individual families with VUS in well-established DSD genes such as AR or HSD17B3, functional analysis may provide a confirmed diagnosis that implies for relatives the option of undergoing their own DNA analysis and estimating the genetic risk of their own future offspring. This makes genetic follow-up important in these cases and demonstrates the usefulness of international databases and networks and the centralisation of functional studies of genetic variants in order to reduce costs and maximise expertise.The same is true for histopathological description, germ-cell tumour risk assessment in specific forms of DSD and classification of gonadal samples. Germ-cell tumour risk is related to the type of DSD (among other factors), but it is impossible to make risk estimates in individual cases.41–44 Gonadectomy may be indicated in cases with high-risk dysgenetic abdominal gonads that cannot be brought into a stable superficial (ie, inguinal, labioscrotal) position that allows clinical or radiological surveillance, or to avoid virilisation due to 5-alpha reductase deficiency in a 46,XY girl with a stable female gender identity.45 Pathological examination of DSD gonads requires specific expertise.

For example, the differentiation between benign germ cell abnormalities, such as delayed maturation and (pre)malignant development of germ cells, is crucial for clinical management but can be very troublesome.46 Centralised pathological examination of gonadal biopsy and gonadectomy samples in one centre, or a restricted number of centres, on a national scale can help to overcome the problem of non-uniform classification and has proven feasible in the Netherlands and Belgium. We therefore believe that uniform assessment and classification of gonadal differentiation patterns should also be addressed in guidelines on DSD management.International databases of gonadal tissues are crucial for learning more about the risk of malignancy in different forms of DSD, but they are only reliable if uniform criteria for histological classification are strictly applied.46 These criteria could be incorporated in many existing networks such as the I-DSD consortium, the Disorders of Sex Development Translational Research Network, the European Reference Network on Urogenital Diseases (eUROGEN), the EndoERN and COST actions.15–17 47Communication at the transition from paediatric to adult carePaediatric and adult teams need to collaborate closely to facilitate a well-organised transition from paediatric to adult specialist care.15 48–50 Both teams need to exchange information optimally and should consider transition as a longitudinal process rather than a fixed moment in time. Age-appropriate information is key at all ages, and an overview of topics to be discussed at each stage is described by Cools et al.15 Table 1 shows an example of how transition can be organised.View this table:Table 1 Example of transition table as used in the DSD clinic of the Erasmus Medical CenterPsychological support and the continued provision of information remains important for individuals with a DSD at all ages.15 22 In addition to the information given by the DSD team members, families and patients can benefit from resources such as support groups and information available on the internet.47 Information available online should be checked for accuracy and completeness when referring patients and parents to internet sites.Recommendations for future actionsMost guidelines and articles on the diagnosis and management of DSD are aimed at specialists and are only published in specialist journals or on websites for endocrinologists, urologists or geneticists. Yet there is a need for guidelines directed towards first-line and second-line healthcare workers that summarise the recommendations about the first crucial steps in the management of DSD. These should be published in widely available general medical journals and online, along with a national list of DSD centres.

Furthermore, DSD (expert) centres should provide continuous education to all those who may be involved in the identification of individuals with a DSD in order to enable these healthcare professionals to recognise atypical genitalia, to promptly refer individuals who have a DSD and to inform the patient and parents about this and subsequent diagnostic procedures.As DSD continues to be a rare condition, it will take time to evaluate the effects of having such a guideline on the preparedness of first-line and second-line healthcare workers to recognise DSD conditions. One way to evaluate this might be the development and use of questionnaires asking patients, carers and families and referring physicians how satisfied they were with the initial medical consultation and referral and what could be improved. A helpful addition to existing international databases that collect information on genetic variations would be a list of centres that offer suitable functional studies for certain genes, ideally covering the most frequently mutated genes (at minimum).Patient organisations can also play an important role in informing patients about newly available diagnostic or therapeutic strategies and options, and their influence and specific role has now been recognised and discussed in several publications.17 47 However, it should be kept in mind that these organisations do not represent all patients, as a substantial number of patients and parents are not member of such an organisation.Professionals have to provide optimal medical care based on well-established evidence, or at least on broad consensus. Yet not everything can be regulated by recommendations and guidelines. Options, ideas and wishes should be openly discussed between professionals, patients and families within their confidential relationship.

This will enable highly individualised holistic care tailored to the patient’s needs and expectations. Once they are well-informed of all available options, parents and/or patients can choose what they consider the optimal care for their children or themselves.15 16ConclusionThe Dutch-Flemish guideline uniquely addresses some topics that are under-represented in the literature, thus adding some key aspects to those addressed in recent consensus papers and guidelines.15–17 33 47As more children with a DSD are now being identified prenatally, and the literature on prenatal diagnosis of DSD remains scarce,20 21 we propose a prenatal diagnostic algorithm and emphasise the importance of having a prenatal specialist involved in or collaborating with DSD (expert) centres.We also stress that good communication between all involved parties is essential. Professionals should be well informed about protocols and communication. Collaboration between centres is necessary to optimise aspects of care such as uniform interpretation of gonadal pathology and functional testing of class 3 variants found by genetic testing. Guidelines can provide a framework within which individualised patient care should be discussed with all stakeholders.AcknowledgmentsThe authors would like to thank the colleagues of the DSD teams for their input in and critical reading of the Dutch-Flemish guideline.

Amsterdam University Center (AMC and VU), Maastricht University Medical Center, Erasmus Medical Center Rotterdam, Radboud University Medical Center Nijmegen, University Medical Center Groningen, University Medical Center Utrecht, Ghent University Hospital. The authors would like to thank Kate McIntyre for editing the revised manuscript and Tom de Vries Lentsch for providing the figures as a PDF. Three of the authors of this publication are members of the European Reference Network for rare endocrine diseases—Project ID 739543.IntroductionEndometrial cancer is the most common gynaecological malignancy in the developed world.1 Its incidence has risen over the last two decades as a consequence of the ageing population, fewer hysterectomies for benign disease and the obesity epidemic. In the USA, it is estimated that women have a 1 in 35 lifetime risk of endometrial cancer, and in contrast to cancers of most other sites, cancer-specific mortality has risen by approximately 2% every year since 2008 related to the rapidly rising incidence.2Endometrial cancer has traditionally been classified into type I and type II based on morphology.3 The more common subtype, type I, is mostly comprised of endometrioid tumours and is oestrogen-driven, arises from a hyperplastic endometrium, presents at an early stage and has an excellent 5 year survival rate.4 By contrast, type II includes non-endometrioid tumours, specifically serous, carcinosarcoma and clear cell subtypes, which are biologically aggressive tumours with a poor prognosis that are often diagnosed at an advanced stage.5 Recent efforts have focused on a molecular classification system for more accurate categorisation of endometrial tumours into four groups with distinct prognostic profiles.6 7The majority of endometrial cancers arise through the interplay of familial, genetic and lifestyle factors. Two inherited cancer predisposition syndromes, Lynch syndrome and the much rarer Cowden syndrome, substantially increase the lifetime risk of endometrial cancer, but these only account for around 3–5% of cases.8–10 Having first or second degree relative(s) with endometrial or colorectal cancer increases endometrial cancer risk, although a large European twin study failed to demonstrate a strong heritable link.11 The authors failed to show that there was greater concordance in monozygotic than dizygotic twins, but the study was based on relatively small numbers of endometrial cancers.

Lu and colleagues reported an association between common single nucleotide polymorphisms (SNPs) and endometrial cancer risk, revealing the potential role of SNPs in explaining part of the risk in both the familial and general populations.12 Thus far, many SNPs have been reported to modify susceptibility to endometrial cancer. However, much of this work predated genome wide association studies and is of variable quality. Understanding genetic predisposition to endometrial cancer could facilitate personalised risk assessment with a view to targeted prevention and screening interventions.13 This emerged as the most important unanswered research question in endometrial cancer according to patients, carers and healthcare professionals in our recently completed James Lind Womb Cancer Alliance Priority Setting Partnership.14 It would be particularly useful for non-endometrioid endometrial cancers, for which advancing age is so far the only predictor.15We therefore conducted a comprehensive systematic review of the literature to provide an overview of the relationship between SNPs and endometrial cancer risk. We compiled a list of the most robust endometrial cancer-associated SNPs. We assessed the applicability of this panel of SNPs with a theoretical polygenic risk score (PRS) calculation.

We also critically appraised the meta-analyses investigating the most frequently reported SNPs in MDM2. Finally, we described all SNPs reported within genes and pathways that are likely involved in endometrial carcinogenesis and metastasis.MethodsOur systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) collaboration 2009 recommendations. The registered protocol is available through PROSPERO (CRD42018091907).16Search strategyWe searched Embase, MEDLINE and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases via the Healthcare Databases Advanced Search (HDAS) platform, from 2007 to 2018, to identify studies reporting associations between polymorphisms and endometrial cancer risk. Key words including MeSH (Medical Subject Heading) terms and free-text words were searched in both titles and abstracts. The following terms were used.

€œendomet*”,“uter*”, “womb”, “cancer(s)”, “neoplasm(s)”, “endometrium tumour”, “carcinoma”, “adenosarcoma”, “clear cell carcinoma”, “carcinosarcoma”, “SNP”, “single nucleotide polymorphism”, “GWAS”, and “genome-wide association study/ies”. No other restrictions were applied. The search was repeated with time restrictions between 2018 and June 2019 to capture any recent publications.Eligibility criteriaStudies were selected for full-text evaluation if they were primary articles investigating a relationship between endometrial cancer and SNPs. Study outcome was either the increased or decreased risk of endometrial cancer relative to controls reported as an odds ratio (OR) with corresponding 95% confidence intervals (95% CIs).Study selectionThree independent reviewers screened all articles uploaded to a screening spreadsheet developed by Helena VonVille.17 Disagreements were resolved by discussion. Chronbach’s α score was calculated between reviewers and indicated high consistency at 0.92.

Case–control, prospective and retrospective studies, genome-wide association studies (GWAS), and both discovery and validation studies were selected for full-text evaluation. Non-English articles, editorials, conference abstracts and proceedings, letters and correspondence, case reports and review articles were excluded.Candidate-gene studies with at least 100 women and GWAS with at least 1000 women in the case arm were selected to ensure reliability of the results, as explained by Spencer et al.18 To construct a panel of up to 30 SNPs with the strongest evidence of association, those with the strongest p values were selected. For the purpose of an SNP panel, articles utilising broad European or multi-ethnic cohorts were selected. Where overlapping populations were identified, the most comprehensive study was included.Data extraction and synthesisFor each study, the following data were extracted. SNP ID, nearby gene(s)/chromosome location, OR (95% CI), p value, minor or effect allele frequency (MAF/EAF), EA (effect allele) and OA (other allele), adjustment, ethnicity and ancestry, number of cases and controls, endometrial cancer type, and study type including discovery or validation study and meta-analysis.

For risk estimates, a preference towards most adjusted results was applied. For candidate-gene studies, a standard p value of<0.05 was applied and for GWAS a p value of <5×10-8, indicating genome-wide significance, was accepted as statistically significant. However, due to the limited number of SNPs with p values reaching genome-wide significance, this threshold was then lowered to <1×10-5, allowing for marginally significant SNPs to be included. As shown by Mavaddat et al, for breast cancer, SNPs that fall below genome-wide significance may still be useful for generating a PRS and improving the models.19We estimated the potential value of a PRS based on the most significant SNPs by comparing the predicted risk for a woman with a risk score in the top 1% of the distribution to the mean predicted risk. Per-allele ORs and MAFs were taken from the publications and standard errors (SEs) for the lnORs were derived from published 95% CIs.

The PRS was assumed to have a Normal distribution, with mean 2∑βipI and SE, σ, equal to √2∑βi2pI(1−pi), according to the binomial distribution, where the summation is over all SNPs in the risk score. Hence the relative risk (RR) comparing the top 1% of the distribution to the mean is given by exp(Z0.01σ), where Z is the inverse of the standard normal cumulative distribution.ResultsThe flow chart of study selection is illustrated in figure 1. In total, 453 text articles were evaluated and, of those, 149 articles met our inclusion criteria. One study was excluded from table 1, for having an Asian-only population, as this would make it harder to compare with the rest of the results which were all either multi-ethnic or Caucasian cohorts, as stated in our inclusion criteria for the SNP panel.20 Any SNPs without 95% CIs were also excluded from any downstream analysis. Additionally, SNPs in linkage disequilibrium (r2 >0.2) with each other were examined, and of those in linkage disequilibrium, the SNP with strongest association was reported.

Per allele ORs were used unless stated otherwise.View this table:Table 1 List of top SNPs most likely to contribute to endometrial cancer risk identified through systematic review of recent literature21–25Study selection flow diagram. *Reasons. Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study. Adapted from.

Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The PRISMA Statement. PLoS Med 6(6). E1000097.

Doi:10.1371/journal.pmed1000097." data-icon-position data-hide-link-title="0">Figure 1 Study selection flow diagram. *Reasons. Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study. Adapted from.

Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The PRISMA Statement. PLoS Med 6(6). E1000097.

Doi:10.1371/journal.pmed1000097.Top SNPs associated with endometrial cancer riskFollowing careful interpretation of the data, 24 independent SNPs with the lowest p values that showed the strongest association with endometrial cancer were obtained (table 1).21–25 These SNPs are located in or around genes coding for transcription factors, cell growth and apoptosis regulators, and enzymes involved in the steroidogenesis pathway. All the SNPs presented here were reported on the basis of a GWAS or in one case, an exome-wide association study, and hence no SNPs from candidate-gene studies made it to the list. This is partly due to the nature of larger GWAS providing more comprehensive and powered results as opposed to candidate gene studies. Additionally, a vast majority of SNPs reported by candidate-gene studies were later refuted by large-scale GWAS such as in the case of TERT and MDM2 variants.26 27 The exception to this is the CYP19 gene, where candidate-gene studies reported an association between variants in this gene with endometrial cancer in both Asian and broad European populations, and this association was more recently confirmed by large-scale GWAS.21 28–30 Moreover, a recent article authored by O’Mara and colleagues reviewed the GWAS that identified most of the currently known SNPs associated with endometrial cancer.31Most of the studies represented in table 1 are GWAS and the majority of these involved broad European populations. Those having a multi-ethnic cohort also consisted primarily of broad European populations.

Only four of the variants in table 1 are located in coding regions of a gene, or in regulatory flanking regions around the gene. Thus, most of these variants would not be expected to cause any functional effects on the gene or the resulting protein. An eQTL search using GTEx Portal showed that some of the SNPs are significantly associated (p<0.05) with modified transcription levels of the respective genes in various tissues such as prostate (rs11263761), thyroid (rs9668337), pituitary (rs2747716), breast mammary (rs882380) and testicular (rs2498794) tissue, as summarised in table 2.View this table:Table 2 List of eQTL hits for the selected panel of SNPsThe only variant for which there was an indication of a specific association with non-endometrioid endometrial cancer was rs148261157 near the BCL11A gene. The A allele of this SNP had a moderately higher association in the non-endometrioid arm (OR 1.64, 95% CI 1.32 to 2.04. P=9.6×10-6) compared with the endometrioid arm (OR 1.25, 95% CI 1.14 to 1.38.

P=4.7×10-6).21Oestrogen receptors α and β encoded by ESR1 and ESR2, respectively, have been extensively studied due to the assumed role of oestrogens in the development of endometrial cancer. O’Mara et al reported a lead SNP (rs79575945) in the ESR1 region that was associated with endometrial cancer (p=1.86×10-5).24 However, this SNP did not reach genome-wide significance in a more recent larger GWAS.21 No statistically significant associations have been reported between endometrial cancer and SNPs in the ESR2 gene region.AKT is an oncogene linked to endometrial carcinogenesis. It is involved in the PI3K/AKT/mTOR pro-proliferative signalling pathway to inactivate apoptosis and allow cell survival. The A allele of rs2494737 and G allele of rs2498796 were reported to be associated with increased and decreased risk of endometrial cancer in 2016, respectively.22 30 However, this association was not replicated in a larger GWAS in 2018.21 Nevertheless, given the previous strong indications, and biological basis that could explain endometrial carcinogenesis, we decided to include an AKT1 variant (rs2498794) in our results.PTEN is a multi-functional tumour suppressor gene that regulates the AKT/PKB signalling pathway and is commonly mutated in many cancers including endometrial cancer.32 Loss-of-function germline mutations in PTEN are responsible for Cowden syndrome, which exerts a lifetime risk of endometrial cancer of up to 28%.9 Lacey and colleagues studied SNPs in the PTEN gene region. However, none showed significant differences in frequency between 447 endometrial cancer cases and 439 controls of European ancestry.33KRAS mutations are known to be present in endometrial cancer.

These can be activated by high levels of KLF5 (transcriptional activator). Three SNPs have been identified in or around KLF5 that are associated with endometrial cancer. The G allele of rs11841589 (OR 1.15, 95% CI 1.11 to 1.21. P=4.83×10-11), the A allele of rs9600103 (OR 1.23, 95% CI 1.16 to 1.30. P=3.76×10-12) and C allele of rs7981863 (OR 1.16, 95% CI 1.12 to 1.20.

P=2.70×10-17) have all been found to be associated with an increased likelihood of endometrial cancer in large European cohorts.21 30 34 It is worth noting that these SNPs are not independent, and hence they quite possibly tag the same causal variant.The MYC family of proto-oncogenes encode transcription factors that regulate cell proliferation, which can contribute to cancer development if dysregulated. The recent GWAS by O’Mara et al reported three SNPs within the MYC region that reached genome-wide significance with conditional p values reaching at least 5×10–8.35To test the utility of these SNPs as predictive markers, we devised a theoretical PRS calculation using the log ORs and EAFs per SNP from the published data. The results were very encouraging with an RR of 3.16 for the top 1% versus the mean, using all the top SNPs presented in table 1 and 2.09 when using only the SNPs that reached genome-wide significance (including AKT1).Controversy surrounding MDM2 variant SNP309MDM2 negatively regulates tumour suppressor gene TP53, and as such, has been extensively studied in relation to its potential role in predisposition to endometrial cancer. Our search identified six original studies of the association between MDM2 SNP rs2279744 (also referred to as SNP309) and endometrial cancer, all of which found a statistically significant increased risk per copy of the G allele. Two more original studies were identified through our full-text evaluation.

However, these were not included here as they did not meet our inclusion criteria—one due to small sample size, the other due to studying rs2279744 status dependent on another SNP.36 37 Even so, the two studies were described in multiple meta-analyses that are listed in table 3. Different permutations of these eight original studies appear in at least eight published meta-analyses. However, even the largest meta-analysis contained <2000 cases (table 3)38View this table:Table 3 Characteristics of studies that examined MDM2 SNP rs2279744In comparison, a GWAS including nearly 13 000 cases found no evidence of an association with OR and corresponding 95% CI of 1.00 (0.97 to 1.03) and a p value of 0.93 (personal communication).21 Nevertheless, we cannot completely rule out a role for MDM2 variants in endometrial cancer predisposition as the candidate-gene studies reported larger effects in Asians, whereas the GWAS primarily contained participants of European ancestry. There is also some suggestion that the SNP309 variant is in linkage disequilibrium with another variant, SNP285, which confers an opposite effect.It is worth noting that the SNP285C/SNP309G haplotype frequency was observed in up to 8% of Europeans, thus requiring correction for the confounding effect of SNP285C in European studies.39 However, aside from one study conducted by Knappskog et al, no other study including the meta-analyses corrected for the confounding effect of SNP285.40 Among the studies presented in table 3, Knappskog et al (2012) reported that after correcting for SNP285, the OR for association of this haplotype with endometrial cancer was much lower, though still significant. Unfortunately, the meta-analyses which synthesised Knappskog et al (2012), as part of their analysis, did not correct for SNP285C in the European-based studies they included.38 41 42 It is also concerning that two meta-analyses using the same primary articles failed to report the same result, in two instances.38 42–44DiscussionThis article represents the most comprehensive systematic review to date, regarding critical appraisal of the available evidence of common low-penetrance variants implicated in predisposition to endometrial cancer.

We have identified the most robust SNPs in the context of endometrial cancer risk. Of those, only 19 were significant at genome-wide level and a further five were considered marginally significant. The largest GWAS conducted in this field was the discovery- and meta-GWAS by O’Mara et al, which utilised 12 096 cases and 108 979 controls.21 Despite the inclusion of all published GWAS and around 5000 newly genotyped cases, the total number did not reach anywhere near what is currently available for other common cancers such as breast cancer. For instance, BCAC (Breast Cancer Association Consortium) stands at well over 200 000 individuals with more than half being cases, and resulted in identification of ~170 SNPs in relation to breast cancer.19 45 A total of 313 SNPs including imputations were then used to derive a PRS for breast cancer.19 Therefore, further efforts should be directed to recruit more patients, with deep phenotypic clinical data to allow for relevant adjustments and subgroup analyses to be conducted for better precision.A recent pre-print study by Zhang and colleagues examined the polygenicity and potential for SNP-based risk prediction for 14 common cancers, including endometrial cancer, using available summary-level data from European-ancestry datasets.46 They estimated that there are just over 1000 independent endometrial cancer susceptibility SNPs, and that a PRS comprising all such SNPs would have an area under the receiver-operator curve of 0.64, similar to that predicted for ovarian cancer, but lower than that for the other cancers in the study. The modelling in the paper suggests that an endometrial cancer GWAS double the size of the current largest study would be able to identify susceptibility SNPs together explaining 40% of the genetic variance, but that in order to explain 75% of the genetic variance it would be necessary to have a GWAS comprising close to 150 000 cases and controls, far in excess of what is currently feasible.We found that the literature consists mainly of candidate-gene studies with small sample sizes, meta-analyses reporting conflicting results despite using the same set of primary articles, and multiple reports of significant SNPs that have not been validated by any larger GWAS.

The candidate-gene studies were indeed the most useful and cheaper technique available until the mid to late 2000s. However, a lack of reproducibility (particularly due to population stratification and reporting bias), uncertainty of reported associations, and considerably high false discovery rates make these studies much less appropriate in the post-GWAS era. Unlike the candidate-gene approach, GWAS do not require prior knowledge, selection of genes or SNPs, and provide vast amounts of data. Furthermore, both the genotyping process and data analysis phases have become cheaper, the latter particularly due to faster and open-access pre-phasing and imputation tools being made available.It is clear from table 1 that some SNPs were reported with wide 95% CI, which can be directly attributed to small sample sizes particularly when restricting the cases to non-endometrioid histology only, low EAF or poor imputation quality. Thus, these should be interpreted with caution.

Additionally, most of the SNPs reported by candidate-gene studies were not detected by the largest GWAS to date conducted by O’Mara et al.21 However, this does not necessarily mean that the possibility of those SNPs being relevant should be completely dismissed. Moreover, meta-analyses were attempted for other variants. However, these showed no statistically significant association and many presented with high heterogeneity between the respective studies (data not shown). Furthermore, as many studies utilised the same set of cases and/or controls, conducting a meta-analysis was not possible for a good number of SNPs. It is therefore unequivocal that the literature is crowded with numerous small candidate-gene studies and conflicting data.

This makes it particularly hard to detect novel SNPs and conduct meaningful meta-analyses.We found convincing evidence for 19 variants that indicated the strongest association with endometrial cancer, as shown in table 1. The associations between endometrial cancer and variants in or around HNF1B, CYP19A1, SOX4, MYC, KLF and EIF2AK found in earlier GWAS were then replicated in the latest and largest GWAS. These SNPs showed promising potential in a theoretical PRS we devised based on published data. Using all 24 or genome-wide significant SNPs only, women with a PRS in the top 1% of the distribution would be predicted to have a risk of endometrial cancer 3.16 and 2.09 times higher than the mean risk, respectively.However, the importance of these variants and relevance of the proximate genes in a functional or biological context is challenging to evaluate. Long distance promoter regulation by enhancers may disguise the genuine target gene.

In addition, enhancers often do not loop to the nearest gene, further complicating the relevance of nearby gene(s) to a GWAS hit. In order to elucidate biologically relevant candidate target genes in endometrial cancer, O’Mara et al looked into promoter-associated chromatin looping using a modern HiChIP approach.47 The authors utilised normal and tumoural endometrial cell lines for this analysis which showed significant enrichment for endometrial cancer heritability, with 103 candidate target genes identified across the 13 risk loci identified by the largest ECAC GWAS. Notable genes identified here were CDKN2A and WT1, and their antisense counterparts. The former was reported to be nearby of rs1679014 and the latter of rs10835920, as shown in table 1. Moreover, of the 36 candidate target genes, 17 were found to be downregulated while 19 were upregulated in endometrial tumours.The authors also investigated overlap between the 13 endometrial cancer risk loci and top eQTL variants for each target gene.47 In whole blood, of the two particular lead SNPs, rs8822380 at 17q21.32 was a top eQTL for SNX11 and HOXB2, whereas rs937213 at 15q15.1 was a top eQTL for SRP14.

In endometrial tumour, rs7579014 at 2p16.1 was found to be a top eQTL for BCL11A. This is particularly interesting because BCL11A was the only nearby/candidate gene that had a GWAS association reported in both endometrioid and non-endometrioid subtypes. The study looked at protein–protein interactions between endometrial cancer drivers and candidate target gene products. Significant interactions were observed with TP53 (most significant), AKT, PTEN, ESR1 and KRAS, among others. Finally, when 103 target candidate genes and 387 proteins were combined together, 462 pathways were found to be significantly enriched.

Many of these are related to gene regulation, cancer, obesity, insulinaemia and oestrogen exposure. This study clearly showed a potential biological relevance for some of the SNPs reported by ECAC GWAS in 2018.Most of the larger included studies used cohorts primarily composed of women of broad European descent. Hence, there are negligible data available for other ethnicities, particularly African women. This is compounded by the lack of reference genotype data available for comparative analysis, making it harder for research to be conducted in ethnicities other than Europeans. This poses a problem for developing risk prediction models that are equally valuable and predictive across populations.

Thus, our results also are of limited applicability to non-European populations.Furthermore, considering that non-endometrioid cases comprise a small proportion (~20%) of all endometrial cancer cases, much larger cohort sizes are needed to detect any genuine signals for non-endometrioid tumours. Most of the evaluated studies looked at either overall/mixed endometrial cancer subtypes or endometrioid histology, and those that looked at variant associations with non-endometrioid histology were unlikely to have enough power to detect any signal with statistical significance. This is particularly concerning because non-endometrioid subtypes are biologically aggressive tumours with a much poorer prognosis that contribute disproportionately to mortality from endometrial cancer. It is particularly important that attempts to improve early detection and prevention of endometrial cancer focus primarily on improving outcomes from these subtypes. It is also worth noting that, despite the current shift towards a molecular classification of endometrial cancer, most studies used the overarching classical Bokhman’s classification system, type I versus type II, or no histological classification system at all.

Therefore, it is important to create and follow a standardised and comprehensive classification system for reporting tumour subtypes for future studies.This study compiled and presented available information for an extensively studied, yet unproven in large datasets, SNP309 variant in MDM2. Currently, there is no convincing evidence for an association between this variant and endometrial cancer risk. Additionally, of all the studies, only one accounted for the opposing effect of a nearby variant SNP285 in their analyses. Thus, we conclude that until confirmed by a sufficiently large GWAS, this variant should not be considered significant in influencing the risk of endometrial cancer and therefore not included in a PRS. This is also true for the majority of the SNPs reported in candidate-gene studies, as the numbers fall far short of being able to detect genuine signals.This systematic review presents the most up-to-date evidence for endometrial cancer susceptibility variants, emphasising the need for further large-scale studies to identify more variants of importance, and validation of these associations.

Until data from larger and more diverse cohorts are available, the top 24 SNPs presented here are the most robust common genetic variants that affect endometrial cancer risk. The multiplicative effects of these SNPs could be used in a PRS to allow personalised risk prediction models to be developed for targeted screening and prevention interventions for women at greatest risk of endometrial cancer..

IntroductionIn recent years, many studies have been published on new diagnostic possibilities and management approaches in cohorts of patients suspected to have a disorder/difference of sex development (DSD).1–13 Based on these studies, cialis 5mg cost walgreens it has become clear that services and institutions still differ in the composition of the multidisciplinary teams that provide care for patients who have a DSD.11 14 Several projects have now worked to resolve this variability in care. The European Cooperation in Science and Technology (EU COST) action BM1303 ‘A systematic elucidation of differences of sex development’ has been a platform to achieve European agreement on harmonisation of clinical management and laboratory practices.15–17 Another such initiative involved an cialis 5mg cost walgreens update of the 2006 DSD consensus document by an international group of professionals and patient representatives.18 These initiatives have highlighted how cultural and financial aspects and the availability of resources differ significantly between countries and societies, a situation that hampers supranational agreement on common diagnostic protocols. As only a few national guidelines have been published in international journals, comparison of these guidelines is difficult even though such a comparison is necessary to capture the differences and initiate actions to overcome them. Nonetheless, four cialis 5mg cost walgreens DSD (expert) centres located in the Netherlands and Flanders (the Dutch-speaking Northern part of Belgium) have collaborated to produce a detailed guideline on diagnostics in DSD.19 This shows that a supranational guideline can be a reasonable approach for countries with similarly structured healthcare systems and similar resources.

Within the guideline there is agreement that optimisation of expertise and care can be achieved through centralisation, for example, by limiting analysis of next-generation sequencing (NGS)-based diagnostic panels to only a few centres and by centralising pathological review of gonadal tissues. International networks such as the European Reference Network for rare endocrine conditions (EndoERN), in which DSD is embedded, may facilitate the expansion of this kind of collaboration across Europe.This paper highlights key discussion points in the Dutch-Flemish guideline that have been insufficiently addressed in the literature thus far cialis 5mg cost walgreens because they reflect evolving technologies or less visible stakeholders. For example, prenatal observation of an atypical aspect of the genitalia indicating a possible DSD is becoming increasingly common, and we discuss appropriate counselling and a diagnostic approach for these cases, including the option of using NGS-based genetic testing. So far, little attention has been paid to this process.20 21 Furthermore, informing patients and/or their parents about atypical sex development and why this may warrant referral to a specialised team may be challenging, especially for professionals with limited experience in DSD.22 23 Therefore, a section of the Dutch-Flemish guideline was written for these healthcare providers cialis 5mg cost walgreens.

Moreover, this enables DSD specialists to refer to the guideline when advising a referral. Transition from the prenatal to the postnatal team and from the paediatric to cialis 5mg cost walgreens the adult team requires optimal communication between the specialists involved. Application of NGS-based techniques may lead to a higher diagnostic yield, providing a molecular genetic diagnosis in previously unsolved cases.16 We address the timing of this testing and the problems associated with this technique such as the interpretation of variants of unknown clinical significance (VUS). Similarly, histopathological interpretation and classification of removed gonadal tissue is challenging and would benefit from international cialis 5mg cost walgreens collaboration and centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary multicentre group was formed with all members responsible for updating the literature for a specific part of the guideline.

Literature search in PubMed was not systematic, but rather intended to be broad in order to cover all areas and follow expert opinions. This approach is more in line with the Clinical Practice Advisory Document method described by Burke et al24 for guidelines involving genetic practice because it is cialis 5mg cost walgreens often troublesome to substantiate such guidelines with sufficient evidence due to the rapid changes in testing methods, for example, gene panels. All input provided by the group was synthesised by the chairperson (YvB), who also reviewed abstracts of papers on DSD published between 2010 and September 2017 for the guideline and up to October 2019 for this paper. Abstracts had to be written in English and were identified using a broad range of Medical Subject Headings terms cialis 5mg cost walgreens (eg, DSD, genetic, review, diagnosis, diagnostics, 46,XX DSD, 46,XY DSD, guideline, multidisciplinary care).

Next, potentially relevant papers on diagnostic procedures in DSD were selected. Case reports were excluded, as were articles that were not open access or retrievable through institutional cialis 5mg cost walgreens access. Based on this, a draft guideline was produced that was in line with the international principles of good diagnostic care in DSD. This draft was discussed by the writing committee and, after having obtained agreement on remaining points of discussion, revised into a final draft cialis 5mg cost walgreens.

This version was sent to a broad group of professionals from academic centres and DSD teams whose members had volunteered to review the draft guideline. After receiving and incorporating their input, the final version was presented to cialis 5mg cost walgreens the paediatric and genetic associations for approval. After approval by the members of the paediatric (NVK), clinical genetic (VKGN) and genetic laboratory (VKGL) associations, the guideline was published on their respective websites.19 Although Turner syndrome and Klinefelter syndrome are considered to be part of the DSD spectrum, they are not extensively discussed in this diagnostic guideline as guidelines dedicated to these syndromes already exist.25 26 However, some individuals with Turner syndrome or Klinefelter syndrome may present with ambiguous or atypical genitalia and may therefore initially follow the DSD diagnostic process.Guideline highlightsPrenatal settingPresentationThe most frequent prenatal presentation of a DSD condition is atypical genitalia found on prenatal ultrasound as an isolated finding or in combination with other structural anomalies. This usually occurs after the 20-week routine medical ultrasound for screening of congenital anomalies, but may also occur earlier, for example, when a commercial ultrasound is performed at the request of the parents.Another way DSD can be diagnosed before birth is when invasive prenatal genetic testing carried out for a different reason, for example, due cialis 5mg cost walgreens to suspicion of other structural anomalies, reveals a discrepancy between the genotypic sex and the phenotypic sex seen by ultrasound.

In certified laboratories, the possibility of a sample switch is extremely low but should be ruled out immediately. More often, the discrepancy will be due to sex-chromosome mosaicism or a true form of DSD.A situation now occurring with increasing frequency is a discrepancy cialis 5mg cost walgreens between the genotypic sex revealed by non-invasive prenatal testing (NIPT), which is now available to high-risk pregnant women in the Netherlands and to all pregnant women in Belgium, and later ultrasound findings. NIPT screens for CNVs in the fetus. However, depending on legal restrictions and/or ethical considerations, the X and Y chromosomes are not always included in NIPT analysis cialis 5mg cost walgreens and reports.

If the X and Y chromosomes are included, it is important to realise that the presence of a Y-chromosome does not necessarily imply male fetal development. At the time that NIPT is performed (usually 11–13 weeks), genital development cannot be reliably appreciated by ultrasound, so any discrepancy or atypical aspect of the genitalia will only be noticed later in pregnancy and should prompt further evaluation.Counselling and diagnosticsIf a DSD cialis 5mg cost walgreens is suspected, first-line sonographers and obstetricians should refer the couple to their colleague prenatal specialists working with or in a DSD team. After confirming an atypical genital on ultrasound, the specialist team should offer the couple a referral for genetic counselling to discuss the possibility of performing invasive prenatal testing (usually an amniocentesis) to identify an underlying cause that fits the ultrasound findings.22 23 To enable the parents to make a well-informed decision, prenatal counselling should, in our opinion, include. Information on the ultrasound findings and the cialis 5mg cost walgreens limitations of this technique.

The procedure(s) that can be followed, including the risks associated with an amniocentesis. And the type of information genetic testing can cialis 5mg cost walgreens and cannot provide. Knowing which information has been provided and what words have been used by the prenatal specialist is very helpful for those involved in postnatal care.It is important that parents understand that the biological sex of a baby is determined by a complex interplay of chromosomes, genes and hormones, and thus that assessment of the presence or absence of a Y-chromosome alone is insufficient to assign the sex of their unborn child or, as in any unborn child, say anything about the child’s future gender identity.Expecting parents can be counselled by the clinical geneticist and the psychologist from the DSD team, although other DSD specialists can also be involved. The clinical geneticist should be experienced in prenatal counselling and well informed about the cialis 5mg cost walgreens diagnostic possibilities given the limited time span in which test results need to be available to allow parents to make a well-informed decision about whether or not to continue the pregnancy.

Termination of pregnancy can be considered, for instance, in a syndromic form of DSD with multiple malformations, but when the DSD occurs as an apparently isolated condition, expecting parents may also consider termination of pregnancy, which, although considered controversial by some, is cialis 5mg cost walgreens legal in Belgium and the Netherlands. The psychologist of the DSD team can support parents during and after pregnancy and help them cope with feelings of uncertainty and eventual considerations of a termination of pregnancy, as well as with practical issues, for example, how to inform others. The stress of not knowing exactly what the child’s genitalia will cialis 5mg cost walgreens look like and uncertainty about the diagnosis, treatment and prognosis cannot be avoided completely. Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images.

In our experience, parents appreciate having already spoken to some members of the DSD team during pregnancy and having a contact person before birth.After expert cialis 5mg cost walgreens prenatal counselling, a significant number of pregnant couples decline prenatal testing (personal experience IALG, MK, ABD, YvB, MC and HC-vdG). At birth, umbilical cord blood is a good source for (molecular) karyotyping and storage of DNA and can be obtained by the obstetrician, midwife or neonatologist. The terminology used in communication with parents should be carefully cialis 5mg cost walgreens chosen,22 23 and midwives and staff of neonatal and delivery units should be clearly instructed to use gender-neutral and non-stigmatising vocabulary (eg, ‘your baby’) as long as sex assignment is pending.An algorithm for diagnostic evaluation of a suspected DSD in the prenatal situation is proposed in figure 1. When couples opt for invasive prenatal diagnosis, the genetic analysis usually involves an (SNP)-array.

It was recently estimated that >30% of individuals who have a DSD have additional structural cialis 5mg cost walgreens anomalies, with cardiac and neurological anomalies and fetal growth restriction being particularly common.27 28 If additional anomalies are seen, the geneticist can consider specific gene defects that may underlie a known genetic syndrome or carry out NGS. NGS-based techniques have also now made their appearance in prenatal diagnosis of congenital anomalies.29 30 Panels using these techniques can be specific for genes involved in DSD, or be larger panels covering multiple congenital anomalies, and are usually employed with trio-analysis to compare variants identified in the child with the parents’ genetics.29–31 Finding a genetic cause before delivery can help reduce parental stress in the neonatal period and speed up decisions regarding gender assignment. In such cases cialis 5mg cost walgreens there is no tight time limit, and we propose completing the analysis well before the expected delivery.Disorders/differences of sex development (DSD) in the prenatal setting. A diagnostic algorithm.

*SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful. NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 1 Disorders/differences of sex development (DSD) in the prenatal setting.

A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful.

NGS, next-generation sequencing.First contact by a professional less experienced in DSDWhereas most current guidelines start from the point when an individual has been referred to the DSD team,1 15 the Dutch-Flemish guideline dedicates a chapter to healthcare professionals less experienced in DSD as they are often the first to suspect or identify such a condition. Apart from the paper of Indyk,7 little guidance is available for these professionals about how to act in such a situation. The chapter in the Dutch-Flemish guideline summarises the various clinical presentations that a DSD can have and provides information on how to communicate with parents and/or patients about the findings of the physical examination, the first-line investigations and the need for prompt referral to a specialised centre for further evaluation. Clinical examples are offered to illustrate some of these recurring situations.

The medical issues in DSD can be very challenging, and the social and psychological impact is high. For neonates with ambiguous genitalia, sex assignment is an urgent and crucial issue, and it is mandatory that parents are informed that it is possible to postpone registration of their child’s sex. In cases where sex assignment has already taken place, the message that the development of the gonads or genitalia is still atypical is complicated and distressing for patients and parents or carers. A list of contact details for DSD centres and patient organisations in the Netherlands and Flanders is attached to the Dutch-Flemish guideline.

Publishing such a list, either in guidelines or online, can help healthcare professionals find the nearest centres for consultations and provide patients and patient organisations with an overview of the centres where expertise is available.Timing and place of genetic testing using NGS-based gene panelsThe diagnostic workup that is proposed for 46,XX and 46,XY DSD is shown in figures 2 and 3, respectively. Even with the rapidly expanding molecular possibilities, a (family) history and a physical examination remain the essential first steps in the diagnostic process. Biochemical and hormonal screening aim at investigating serum electrolytes, renal function and the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes. Ultrasound screening of kidneys and internal genitalia, as well as establishing genotypic sex, should be accomplished within 48 hours and complete the baseline diagnostic work-up of a child born with ambiguous genitalia.1 16 32 3346,XX disorders/differences of sex development (DSD) in the postnatal setting.

A diagnostic algorithm. NGS, next-generation sequencing. CAH, Congenital adrenal hyperplasia. AMH, Anti-Müllerian Hormone." data-icon-position data-hide-link-title="0">Figure 2 46,XX disorders/differences of sex development (DSD) in the postnatal setting.

A diagnostic algorithm. NGS, next-generation sequencing. CAH, Congenital adrenal hyperplasia. AMH, Anti-Müllerian Hormone.46,XY disorders/differences of sex development (DSD) in the postnatal setting.

A diagnostic algorithm. * SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful.

NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 3 46,XY disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!.

Conventional karyotyping can be useful. NGS, next-generation sequencing.Very recently, a European position paper has been published focusing on the genetic workup of DSD.16 It highlights the limitations and drawbacks of NGS-based tests, which include the chance of missing subtle structural variants such as CNVs and mosaicism and the fact that NGS cannot detect methylation defects or other epigenetic changes.16 28 31 Targeted DNA analysis is preferred in cases where hormonal investigations suggest a block in steroidogenesis (eg, 11-β-hydroxylase deficiency, 21-hydroxylase deficiency), or in the context of a specific clinical constellation such as the often coincidental finding of Müllerian structures in a boy with normal external genitalia or cryptorchidism, that is, persistent Müllerian duct syndrome.33 34 Alternative tests should also be considered depending on the available information. Sometimes, a simple mouth swab for FISH analysis can detect mosaic XY/X in a male with hypospadias or asymmetric gonadal development or in a female with little or no Turner syndrome stigmata and a normal male molecular karyotyping profile or peripheral blood karyotype. Such targeted testing avoids incidental findings and is cheaper and faster than analysis of a large NGS-based panel, although the cost difference is rapidly declining.However, due to the genetic and phenotypic heterogeneity of DSD conditions, the most cost-effective next steps in the majority of cases are whole exome sequencing followed by panel analysis of genes involved in genital development and function or trio-analysis of a large gene panel (such as a Mendeliome).16 35–38 Pretest genetic counselling involves discussing what kind of information will be reported to patients or parents and the chance of detecting VUS, and the small risk of incidental findings when analysing a DSD panel should be mentioned.

Laboratories also differ in what class of variants they report.39 In our experience, the fear of incidental findings is a major reason why some parents refrain from genetic testing.Timing of the DSD gene panel analysis is also important. While some patients or parents prefer that all diagnostic procedures be performed as soon as possible, others need time to reflect on the complex information related to more extensive genetic testing and on its possible consequences. If parents or patients do not consent to panel-based genetic testing, analysis of specific genes, such as WT1, should be considered when appropriate in view of the clinical consequences if a mutation is present (eg, clinical surveillance of renal function and screening for Wilms’ tumour in the case of WT1 mutations). Genes that are more frequently involved in DSD (eg, SRY, NR5A1) and that match the specific clinical and hormonal features in a given patient could also be considered for sequencing.

Targeted gene analysis may also be preferred in centres located in countries that do not have the resources or technical requirements to perform NGS panel-based genetic testing. Alternatively, participation by these centres in international collaborative networks may allow them to outsource the molecular genetic workup abroad.Gene panels differ between centres and are regularly updated based on scientific progress. A comparison of DSD gene panels used in recent studies can be found at https://www.nature.com/articles/s41574-018-0010-8%23Sec46.15 The panels currently used at the coauthors’ institutions can be found on their respective websites. Given the pace of change, it is important to regularly consider repeating analysis in patients with an unexplained DSD, for example, when they transition into adult care or when they move from one centre to another.

This also applies to patients in whom a clinical diagnosis has never been genetically confirmed. Confusion may arise when the diagnosis cannot be confirmed or when a mutation is identified in a different gene, for example, NR5A1 in someone with a clinical diagnosis of CAIS that has other consequences for relatives. Hence, new genetic counselling should always accompany new diagnostic endeavours.Class 3 variants and histopathological examinationsThe rapidly evolving diagnostic possibilities raise new questions. What do laboratories report?.

How should we deal with the frequent findings of mainly unique VUS or class 3 variants (ACMG recommendation) in the many different DSD-related genes in the diagnostic setting?. Reporting VUS can be a source of uncertainty for parents, but not reporting these variants precludes further investigations to determine their possible pathogenicity. It can also be difficult to prove variant pathogenicity, both on gene-level and variant-level.39 Moreover, given the gonad-specific expression of some genes and the variable phenotypic spectrum and reduced penetrance, segregation analysis is not always informative. A class 3 variant that does not fit the clinical presentation may be unrelated to the observed phenotype, but it could also represent a newly emerging phenotype.

This was recently demonstrated by the identification of the NR5A1 mutation, R92W, in individuals with 46,XX testicular and ovotesticular DSD.40 This gene had previously been associated with 46,XY DSD. In diagnostic laboratories, there is usually no capacity or expertise to conduct large-scale functional studies to determine pathogenicity of these unique class 3 VUS in the different genes involved in DSD. Functional validation of variants identified in novel genes may be more attractive in a research context. However, for individual families with VUS in well-established DSD genes such as AR or HSD17B3, functional analysis may provide a confirmed diagnosis that implies for relatives the option of undergoing their own DNA analysis and estimating the genetic risk of their own future offspring.

This makes genetic follow-up important in these cases and demonstrates the usefulness of international databases and networks and the centralisation of functional studies of genetic variants in order to reduce costs and maximise expertise.The same is true for histopathological description, germ-cell tumour risk assessment in specific forms of DSD and classification of gonadal samples. Germ-cell tumour risk is related to the type of DSD (among other factors), but it is impossible to make risk estimates in individual cases.41–44 Gonadectomy may be indicated in cases with high-risk dysgenetic abdominal gonads that cannot be brought into a stable superficial (ie, inguinal, labioscrotal) position that allows clinical or radiological surveillance, or to avoid virilisation due to 5-alpha reductase deficiency in a 46,XY girl with a stable female gender identity.45 Pathological examination of DSD gonads requires specific expertise. For example, the differentiation between benign germ cell abnormalities, such as delayed maturation and (pre)malignant development of germ cells, is crucial for clinical management but can be very troublesome.46 Centralised pathological examination of gonadal biopsy and gonadectomy samples in one centre, or a restricted number of centres, on a national scale can help to overcome the problem of non-uniform classification and has proven feasible in the Netherlands and Belgium. We therefore believe that uniform assessment and classification of gonadal differentiation patterns should also be addressed in guidelines on DSD management.International databases of gonadal tissues are crucial for learning more about the risk of malignancy in different forms of DSD, but they are only reliable if uniform criteria for histological classification are strictly applied.46 These criteria could be incorporated in many existing networks such as the I-DSD consortium, the Disorders of Sex Development Translational Research Network, the European Reference Network on Urogenital Diseases (eUROGEN), the EndoERN and COST actions.15–17 47Communication at the transition from paediatric to adult carePaediatric and adult teams need to collaborate closely to facilitate a well-organised transition from paediatric to adult specialist care.15 48–50 Both teams need to exchange information optimally and should consider transition as a longitudinal process rather than a fixed moment in time.

Age-appropriate information is key at all ages, and an overview of topics to be discussed at each stage is described by Cools et al.15 Table 1 shows an example of how transition can be organised.View this table:Table 1 Example of transition table as used in the DSD clinic of the Erasmus Medical CenterPsychological support and the continued provision of information remains important for individuals with a DSD at all ages.15 22 In addition to the information given by the DSD team members, families and patients can benefit from resources such as support groups and information available on the internet.47 Information available online should be checked for accuracy and completeness when referring patients and parents to internet sites.Recommendations for future actionsMost guidelines and articles on the diagnosis and management of DSD are aimed at specialists and are only published in specialist journals or on websites for endocrinologists, urologists or geneticists. Yet there is a need for guidelines directed towards first-line and second-line healthcare workers that summarise the recommendations about the first crucial steps in the management of DSD. These should be published in widely available general medical journals and online, along with a national list of DSD centres. Furthermore, DSD (expert) centres should provide continuous education to all those who may be involved in the identification of individuals with a DSD in order to enable these healthcare professionals to recognise atypical genitalia, to promptly refer individuals who have a DSD and to inform the patient and parents about this and subsequent diagnostic procedures.As DSD continues to be a rare condition, it will take time to evaluate the effects of having such a guideline on the preparedness of first-line and second-line healthcare workers to recognise DSD conditions.

One way to evaluate this might be the development and use of questionnaires asking patients, carers and families and referring physicians how satisfied they were with the initial medical consultation and referral and what could be improved. A helpful addition to existing international databases that collect information on genetic variations would be a list of centres that offer suitable functional studies for certain genes, ideally covering the most frequently mutated genes (at minimum).Patient organisations can also play an important role in informing patients about newly available diagnostic or therapeutic strategies and options, and their influence and specific role has now been recognised and discussed in several publications.17 47 However, it should be kept in mind that these organisations do not represent all patients, as a substantial number of patients and parents are not member of such an organisation.Professionals have to provide optimal medical care based on well-established evidence, or at least on broad consensus. Yet not everything can be regulated by recommendations and guidelines. Options, ideas and wishes should be openly discussed between professionals, patients and families within their confidential relationship.

This will enable highly individualised holistic care tailored to the patient’s needs and expectations. Once they are well-informed of all available options, parents and/or patients can choose what they consider the optimal care for their children or themselves.15 16ConclusionThe Dutch-Flemish guideline uniquely addresses some topics that are under-represented in the literature, thus adding some key aspects to those addressed in recent consensus papers and guidelines.15–17 33 47As more children with a DSD are now being identified prenatally, and the literature on prenatal diagnosis of DSD remains scarce,20 21 we propose a prenatal diagnostic algorithm and emphasise the importance of having a prenatal specialist involved in or collaborating with DSD (expert) centres.We also stress that good communication between all involved parties is essential. Professionals should be well informed about protocols and communication. Collaboration between centres is necessary to optimise aspects of care such as uniform interpretation of gonadal pathology and functional testing of class 3 variants found by genetic testing.

Guidelines can provide a framework within which individualised patient care should be discussed with all stakeholders.AcknowledgmentsThe authors would like to thank the colleagues of the DSD teams for their input in and critical reading of the Dutch-Flemish guideline. Amsterdam University Center (AMC and VU), Maastricht University Medical Center, Erasmus Medical Center Rotterdam, Radboud University Medical Center Nijmegen, University Medical Center Groningen, University Medical Center Utrecht, Ghent University Hospital. The authors would like to thank Kate McIntyre for editing the revised manuscript and Tom de Vries Lentsch for providing the figures as a PDF. Three of the authors of this publication are members of the European Reference Network for rare endocrine diseases—Project ID 739543.IntroductionEndometrial cancer is the most common gynaecological malignancy in the developed world.1 Its incidence has risen over the last two decades as a consequence of the ageing population, fewer hysterectomies for benign disease and the obesity epidemic.

In the USA, it is estimated that women have a 1 in 35 lifetime risk of endometrial cancer, and in contrast to cancers of most other sites, cancer-specific mortality has risen by approximately 2% every year since 2008 related to the rapidly rising incidence.2Endometrial cancer has traditionally been classified into type I and type II based on morphology.3 The more common subtype, type I, is mostly comprised of endometrioid tumours and is oestrogen-driven, arises from a hyperplastic endometrium, presents at an early stage and has an excellent 5 year survival rate.4 By contrast, type II includes non-endometrioid tumours, specifically serous, carcinosarcoma and clear cell subtypes, which are biologically aggressive tumours with a poor prognosis that are often diagnosed at an advanced stage.5 Recent efforts have focused on a molecular classification system for more accurate categorisation of endometrial tumours into four groups with distinct prognostic profiles.6 7The majority of endometrial cancers arise through the interplay of familial, genetic and lifestyle factors. Two inherited cancer predisposition syndromes, Lynch syndrome and the much rarer Cowden syndrome, substantially increase the lifetime risk of endometrial cancer, but these only account for around 3–5% of cases.8–10 Having first or second degree relative(s) with endometrial or colorectal cancer increases endometrial cancer risk, although a large European twin study failed to demonstrate a strong heritable link.11 The authors failed to show that there was greater concordance in monozygotic than dizygotic twins, but the study was based on relatively small numbers of endometrial cancers. Lu and colleagues reported an association between common single nucleotide polymorphisms (SNPs) and endometrial cancer risk, revealing the potential role of SNPs in explaining part of the risk in both the familial and general populations.12 Thus far, many SNPs have been reported to modify susceptibility to endometrial cancer. However, much of this work predated genome wide association studies and is of variable quality.

Understanding genetic predisposition to endometrial cancer could facilitate personalised risk assessment with a view to targeted prevention and screening interventions.13 This emerged as the most important unanswered research question in endometrial cancer according to patients, carers and healthcare professionals in our recently completed James Lind Womb Cancer Alliance Priority Setting Partnership.14 It would be particularly useful for non-endometrioid endometrial cancers, for which advancing age is so far the only predictor.15We therefore conducted a comprehensive systematic review of the literature to provide an overview of the relationship between SNPs and endometrial cancer risk. We compiled a list of the most robust endometrial cancer-associated SNPs. We assessed the applicability of this panel of SNPs with a theoretical polygenic risk score (PRS) calculation. We also critically appraised the meta-analyses investigating the most frequently reported SNPs in MDM2.

Finally, we described all SNPs reported within genes and pathways that are likely involved in endometrial carcinogenesis and metastasis.MethodsOur systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) collaboration 2009 recommendations. The registered protocol is available through PROSPERO (CRD42018091907).16Search strategyWe searched Embase, MEDLINE and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases via the Healthcare Databases Advanced Search (HDAS) platform, from 2007 to 2018, to identify studies reporting associations between polymorphisms and endometrial cancer risk. Key words including MeSH (Medical Subject Heading) terms and free-text words were searched in both titles and abstracts. The following terms were used.

€œendomet*”,“uter*”, “womb”, “cancer(s)”, “neoplasm(s)”, “endometrium tumour”, “carcinoma”, “adenosarcoma”, “clear cell carcinoma”, “carcinosarcoma”, “SNP”, “single nucleotide polymorphism”, “GWAS”, and “genome-wide association study/ies”. No other restrictions were applied. The search was repeated with time restrictions between 2018 and June 2019 to capture any recent publications.Eligibility criteriaStudies were selected for full-text evaluation if they were primary articles investigating a relationship between endometrial cancer and SNPs. Study outcome was either the increased or decreased risk of endometrial cancer relative to controls reported as an odds ratio (OR) with corresponding 95% confidence intervals (95% CIs).Study selectionThree independent reviewers screened all articles uploaded to a screening spreadsheet developed by Helena VonVille.17 Disagreements were resolved by discussion.

Chronbach’s α score was calculated between reviewers and indicated high consistency at 0.92. Case–control, prospective and retrospective studies, genome-wide association studies (GWAS), and both discovery and validation studies were selected for full-text evaluation. Non-English articles, editorials, conference abstracts and proceedings, letters and correspondence, case reports and review articles were excluded.Candidate-gene studies with at least 100 women and GWAS with at least 1000 women in the case arm were selected to ensure reliability of the results, as explained by Spencer et al.18 To construct a panel of up to 30 SNPs with the strongest evidence of association, those with the strongest p values were selected. For the purpose of an SNP panel, articles utilising broad European or multi-ethnic cohorts were selected.

Where overlapping populations were identified, the most comprehensive study was included.Data extraction and synthesisFor each study, the following data were extracted. SNP ID, nearby gene(s)/chromosome location, OR (95% CI), p value, minor or effect allele frequency (MAF/EAF), EA (effect allele) and OA (other allele), adjustment, ethnicity and ancestry, number of cases and controls, endometrial cancer type, and study type including discovery or validation study and meta-analysis. For risk estimates, a preference towards most adjusted results was applied. For candidate-gene studies, a standard p value of<0.05 was applied and for GWAS a p value of <5×10-8, indicating genome-wide significance, was accepted as statistically significant.

However, due to the limited number of SNPs with p values reaching genome-wide significance, this threshold was then lowered to <1×10-5, allowing for marginally significant SNPs to be included. As shown by Mavaddat et al, for breast cancer, SNPs that fall below genome-wide significance may still be useful for generating a PRS and improving the models.19We estimated the potential value of a PRS based on the most significant SNPs by comparing the predicted risk for a woman with a risk score in the top 1% of the distribution to the mean predicted risk. Per-allele ORs and MAFs were taken from the publications and standard errors (SEs) for the lnORs were derived from published 95% CIs. The PRS was assumed to have a Normal distribution, with mean 2∑βipI and SE, σ, equal to √2∑βi2pI(1−pi), according to the binomial distribution, where the summation is over all SNPs in the risk score.

Hence the relative risk (RR) comparing the top 1% of the distribution to the mean is given by exp(Z0.01σ), where Z is the inverse of the standard normal cumulative distribution.ResultsThe flow chart of study selection is illustrated in figure 1. In total, 453 text articles were evaluated and, of those, 149 articles met our inclusion criteria. One study was excluded from table 1, for having an Asian-only population, as this would make it harder to compare with the rest of the results which were all either multi-ethnic or Caucasian cohorts, as stated in our inclusion criteria for the SNP panel.20 Any SNPs without 95% CIs were also excluded from any downstream analysis. Additionally, SNPs in linkage disequilibrium (r2 >0.2) with each other were examined, and of those in linkage disequilibrium, the SNP with strongest association was reported.

Per allele ORs were used unless stated otherwise.View this table:Table 1 List of top SNPs most likely to contribute to endometrial cancer risk identified through systematic review of recent literature21–25Study selection flow diagram. *Reasons. Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study.

Adapted from. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The PRISMA Statement.

PLoS Med 6(6). E1000097. Doi:10.1371/journal.pmed1000097." data-icon-position data-hide-link-title="0">Figure 1 Study selection flow diagram. *Reasons.

Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study. Adapted from. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009).

Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The PRISMA Statement. PLoS Med 6(6). E1000097.

Doi:10.1371/journal.pmed1000097.Top SNPs associated with endometrial cancer riskFollowing careful interpretation of the data, 24 independent SNPs with the lowest p values that showed the strongest association with endometrial cancer were obtained (table 1).21–25 These SNPs are located in or around genes coding for transcription factors, cell growth and apoptosis regulators, and enzymes involved in the steroidogenesis pathway. All the SNPs presented here were reported on the basis of a GWAS or in one case, an exome-wide association study, and hence no SNPs from candidate-gene studies made it to the list. This is partly due to the nature of larger GWAS providing more comprehensive and powered results as opposed to candidate gene studies. Additionally, a vast majority of SNPs reported by candidate-gene studies were later refuted by large-scale GWAS such as in the case of TERT and MDM2 variants.26 27 The exception to this is the CYP19 gene, where candidate-gene studies reported an association between variants in this gene with endometrial cancer in both Asian and broad European populations, and this association was more recently confirmed by large-scale GWAS.21 28–30 Moreover, a recent article authored by O’Mara and colleagues reviewed the GWAS that identified most of the currently known SNPs associated with endometrial cancer.31Most of the studies represented in table 1 are GWAS and the majority of these involved broad European populations.

Those having a multi-ethnic cohort also consisted primarily of broad European populations. Only four of the variants in table 1 are located in coding regions of a gene, or in regulatory flanking regions around the gene. Thus, most of these variants would not be expected to cause any functional effects on the gene or the resulting protein. An eQTL search using GTEx Portal showed that some of the SNPs are significantly associated (p<0.05) with modified transcription levels of the respective genes in various tissues such as prostate (rs11263761), thyroid (rs9668337), pituitary (rs2747716), breast mammary (rs882380) and testicular (rs2498794) tissue, as summarised in table 2.View this table:Table 2 List of eQTL hits for the selected panel of SNPsThe only variant for which there was an indication of a specific association with non-endometrioid endometrial cancer was rs148261157 near the BCL11A gene.

The A allele of this SNP had a moderately higher association in the non-endometrioid arm (OR 1.64, 95% CI 1.32 to 2.04. P=9.6×10-6) compared with the endometrioid arm (OR 1.25, 95% CI 1.14 to 1.38. P=4.7×10-6).21Oestrogen receptors α and β encoded by ESR1 and ESR2, respectively, have been extensively studied due to the assumed role of oestrogens in the development of endometrial cancer. O’Mara et al reported a lead SNP (rs79575945) in the ESR1 region that was associated with endometrial cancer (p=1.86×10-5).24 However, this SNP did not reach genome-wide significance in a more recent larger GWAS.21 No statistically significant associations have been reported between endometrial cancer and SNPs in the ESR2 gene region.AKT is an oncogene linked to endometrial carcinogenesis.

It is involved in the PI3K/AKT/mTOR pro-proliferative signalling pathway to inactivate apoptosis and allow cell survival. The A allele of rs2494737 and G allele of rs2498796 were reported to be associated with increased and decreased risk of endometrial cancer in 2016, respectively.22 30 However, this association was not replicated in a larger GWAS in 2018.21 Nevertheless, given the previous strong indications, and biological basis that could explain endometrial carcinogenesis, we decided to include an AKT1 variant (rs2498794) in our results.PTEN is a multi-functional tumour suppressor gene that regulates the AKT/PKB signalling pathway and is commonly mutated in many cancers including endometrial cancer.32 Loss-of-function germline mutations in PTEN are responsible for Cowden syndrome, which exerts a lifetime risk of endometrial cancer of up to 28%.9 Lacey and colleagues studied SNPs in the PTEN gene region. However, none showed significant differences in frequency between 447 endometrial cancer cases and 439 controls of European ancestry.33KRAS mutations are known to be present in endometrial cancer. These can be activated by high levels of KLF5 (transcriptional activator).

Three SNPs have been identified in or around KLF5 that are associated with endometrial cancer. The G allele of rs11841589 (OR 1.15, 95% CI 1.11 to 1.21. P=4.83×10-11), the A allele of rs9600103 (OR 1.23, 95% CI 1.16 to 1.30. P=3.76×10-12) and C allele of rs7981863 (OR 1.16, 95% CI 1.12 to 1.20.

P=2.70×10-17) have all been found to be associated with an increased likelihood of endometrial cancer in large European cohorts.21 30 34 It is worth noting that these SNPs are not independent, and hence they quite possibly tag the same causal variant.The MYC family of proto-oncogenes encode transcription factors that regulate cell proliferation, which can contribute to cancer development if dysregulated. The recent GWAS by O’Mara et al reported three SNPs within the MYC region that reached genome-wide significance with conditional p values reaching at least 5×10–8.35To test the utility of these SNPs as predictive markers, we devised a theoretical PRS calculation using the log ORs and EAFs per SNP from the published data. The results were very encouraging with an RR of 3.16 for the top 1% versus the mean, using all the top SNPs presented in table 1 and 2.09 when using only the SNPs that reached genome-wide significance (including AKT1).Controversy surrounding MDM2 variant SNP309MDM2 negatively regulates tumour suppressor gene TP53, and as such, has been extensively studied in relation to its potential role in predisposition to endometrial cancer. Our search identified six original studies of the association between MDM2 SNP rs2279744 (also referred to as SNP309) and endometrial cancer, all of which found a statistically significant increased risk per copy of the G allele.

Two more original studies were identified through our full-text evaluation. However, these were not included here as they did not meet our inclusion criteria—one due to small sample size, the other due to studying rs2279744 status dependent on another SNP.36 37 Even so, the two studies were described in multiple meta-analyses that are listed in table 3. Different permutations of these eight original studies appear in at least eight published meta-analyses. However, even the largest meta-analysis contained <2000 cases (table 3)38View this table:Table 3 Characteristics of studies that examined MDM2 SNP rs2279744In comparison, a GWAS including nearly 13 000 cases found no evidence of an association with OR and corresponding 95% CI of 1.00 (0.97 to 1.03) and a p value of 0.93 (personal communication).21 Nevertheless, we cannot completely rule out a role for MDM2 variants in endometrial cancer predisposition as the candidate-gene studies reported larger effects in Asians, whereas the GWAS primarily contained participants of European ancestry.

There is also some suggestion that the SNP309 variant is in linkage disequilibrium with another variant, SNP285, which confers an opposite effect.It is worth noting that the SNP285C/SNP309G haplotype frequency was observed in up to 8% of Europeans, thus requiring correction for the confounding effect of SNP285C in European studies.39 However, aside from one study conducted by Knappskog et al, no other study including the meta-analyses corrected for the confounding effect of SNP285.40 Among the studies presented in table 3, Knappskog et al (2012) reported that after correcting for SNP285, the OR for association of this haplotype with endometrial cancer was much lower, though still significant. Unfortunately, the meta-analyses which synthesised Knappskog et al (2012), as part of their analysis, did not correct for SNP285C in the European-based studies they included.38 41 42 It is also concerning that two meta-analyses using the same primary articles failed to report the same result, in two instances.38 42–44DiscussionThis article represents the most comprehensive systematic review to date, regarding critical appraisal of the available evidence of common low-penetrance variants implicated in predisposition to endometrial cancer. We have identified the most robust SNPs in the context of endometrial cancer risk. Of those, only 19 were significant at genome-wide level and a further five were considered marginally significant.

The largest GWAS conducted in this field was the discovery- and meta-GWAS by O’Mara et al, which utilised 12 096 cases and 108 979 controls.21 Despite the inclusion of all published GWAS and around 5000 newly genotyped cases, the total number did not reach anywhere near what is currently available for other common cancers such as breast cancer. For instance, BCAC (Breast Cancer Association Consortium) stands at well over 200 000 individuals with more than half being cases, and resulted in identification of ~170 SNPs in relation to breast cancer.19 45 A total of 313 SNPs including imputations were then used to derive a PRS for breast cancer.19 Therefore, further efforts should be directed to recruit more patients, with deep phenotypic clinical data to allow for relevant adjustments and subgroup analyses to be conducted for better precision.A recent pre-print study by Zhang and colleagues examined the polygenicity and potential for SNP-based risk prediction for 14 common cancers, including endometrial cancer, using available summary-level data from European-ancestry datasets.46 They estimated that there are just over 1000 independent endometrial cancer susceptibility SNPs, and that a PRS comprising all such SNPs would have an area under the receiver-operator curve of 0.64, similar to that predicted for ovarian cancer, but lower than that for the other cancers in the study. The modelling in the paper suggests that an endometrial cancer GWAS double the size of the current largest study would be able to identify susceptibility SNPs together explaining 40% of the genetic variance, but that in order to explain 75% of the genetic variance it would be necessary to have a GWAS comprising close to 150 000 cases and controls, far in excess of what is currently feasible.We found that the literature consists mainly of candidate-gene studies with small sample sizes, meta-analyses reporting conflicting results despite using the same set of primary articles, and multiple reports of significant SNPs that have not been validated by any larger GWAS. The candidate-gene studies were indeed the most useful and cheaper technique available until the mid to late 2000s.

However, a lack of reproducibility (particularly due to population stratification and reporting bias), uncertainty of reported associations, and considerably high false discovery rates make these studies much less appropriate in the post-GWAS era. Unlike the candidate-gene approach, GWAS do not require prior knowledge, selection of genes or SNPs, and provide vast amounts of data. Furthermore, both the genotyping process and data analysis phases have become cheaper, the latter particularly due to faster and open-access pre-phasing and imputation tools being made available.It is clear from table 1 that some SNPs were reported with wide 95% CI, which can be directly attributed to small sample sizes particularly when restricting the cases to non-endometrioid histology only, low EAF or poor imputation quality. Thus, these should be interpreted with caution.

Additionally, most of the SNPs reported by candidate-gene studies were not detected by the largest GWAS to date conducted by O’Mara et al.21 However, this does not necessarily mean that the possibility of those SNPs being relevant should be completely dismissed. Moreover, meta-analyses were attempted for other variants. However, these showed no statistically significant association and many presented with high heterogeneity between the respective studies (data not shown). Furthermore, as many studies utilised the same set of cases and/or controls, conducting a meta-analysis was not possible for a good number of SNPs.

It is therefore unequivocal that the literature is crowded with numerous small candidate-gene studies and conflicting data. This makes it particularly hard to detect novel SNPs and conduct meaningful meta-analyses.We found convincing evidence for 19 variants that indicated the strongest association with endometrial cancer, as shown in table 1. The associations between endometrial cancer and variants in or around HNF1B, CYP19A1, SOX4, MYC, KLF and EIF2AK found in earlier GWAS were then replicated in the latest and largest GWAS. These SNPs showed promising potential in a theoretical PRS we devised based on published data.

Using all 24 or genome-wide significant SNPs only, women with a PRS in the top 1% of the distribution would be predicted to have a risk of endometrial cancer 3.16 and 2.09 times higher than the mean risk, respectively.However, the importance of these variants and relevance of the proximate genes in a functional or biological context is challenging to evaluate. Long distance promoter regulation by enhancers may disguise the genuine target gene. In addition, enhancers often do not loop to the nearest gene, further complicating the relevance of nearby gene(s) to a GWAS hit. In order to elucidate biologically relevant candidate target genes in endometrial cancer, O’Mara et al looked into promoter-associated chromatin looping using a modern HiChIP approach.47 The authors utilised normal and tumoural endometrial cell lines for this analysis which showed significant enrichment for endometrial cancer heritability, with 103 candidate target genes identified across the 13 risk loci identified by the largest ECAC GWAS.

Notable genes identified here were CDKN2A and WT1, and their antisense counterparts. The former was reported to be nearby of rs1679014 and the latter of rs10835920, as shown in table 1. Moreover, of the 36 candidate target genes, 17 were found to be downregulated while 19 were upregulated in endometrial tumours.The authors also investigated overlap between the 13 endometrial cancer risk loci and top eQTL variants for each target gene.47 In whole blood, of the two particular lead SNPs, rs8822380 at 17q21.32 was a top eQTL for SNX11 and HOXB2, whereas rs937213 at 15q15.1 was a top eQTL for SRP14. In endometrial tumour, rs7579014 at 2p16.1 was found to be a top eQTL for BCL11A.

This is particularly interesting because BCL11A was the only nearby/candidate gene that had a GWAS association reported in both endometrioid and non-endometrioid subtypes. The study looked at protein–protein interactions between endometrial cancer drivers and candidate target gene products. Significant interactions were observed with TP53 (most significant), AKT, PTEN, ESR1 and KRAS, among others. Finally, when 103 target candidate genes and 387 proteins were combined together, 462 pathways were found to be significantly enriched.

Many of these are related to gene regulation, cancer, obesity, insulinaemia and oestrogen exposure. This study clearly showed a potential biological relevance for some of the SNPs reported by ECAC GWAS in 2018.Most of the larger included studies used cohorts primarily composed of women of broad European descent. Hence, there are negligible data available for other ethnicities, particularly African women. This is compounded by the lack of reference genotype data available for comparative analysis, making it harder for research to be conducted in ethnicities other than Europeans.

This poses a problem for developing risk prediction models that are equally valuable and predictive across populations. Thus, our results also are of limited applicability to non-European populations.Furthermore, considering that non-endometrioid cases comprise a small proportion (~20%) of all endometrial cancer cases, much larger cohort sizes are needed to detect any genuine signals for non-endometrioid tumours. Most of the evaluated studies looked at either overall/mixed endometrial cancer subtypes or endometrioid histology, and those that looked at variant associations with non-endometrioid histology were unlikely to have enough power to detect any signal with statistical significance. This is particularly concerning because non-endometrioid subtypes are biologically aggressive tumours with a much poorer prognosis that contribute disproportionately to mortality from endometrial cancer.

It is particularly important that attempts to improve early detection and prevention of endometrial cancer focus primarily on improving outcomes from these subtypes. It is also worth noting that, despite the current shift towards a molecular classification of endometrial cancer, most studies used the overarching classical Bokhman’s classification system, type I versus type II, or no histological classification system at all. Therefore, it is important to create and follow a standardised and comprehensive classification system for reporting tumour subtypes for future studies.This study compiled and presented available information for an extensively studied, yet unproven in large datasets, SNP309 variant in MDM2. Currently, there is no convincing evidence for an association between this variant and endometrial cancer risk.

Additionally, of all the studies, only one accounted for the opposing effect of a nearby variant SNP285 in their analyses. Thus, we conclude that until confirmed by a sufficiently large GWAS, this variant should not be considered significant in influencing the risk of endometrial cancer and therefore not included in a PRS. This is also true for the majority of the SNPs reported in candidate-gene studies, as the numbers fall far short of being able to detect genuine signals.This systematic review presents the most up-to-date evidence for endometrial cancer susceptibility variants, emphasising the need for further large-scale studies to identify more variants of importance, and validation of these associations. Until data from larger and more diverse cohorts are available, the top 24 SNPs presented here are the most robust common genetic variants that affect endometrial cancer risk.

The multiplicative effects of these SNPs could be used in a PRS to allow personalised risk prediction models to be developed for targeted screening and prevention interventions for women at greatest risk of endometrial cancer..

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