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A strict permit system is in place for all flights arriving in NSW from microzide best price Victoria and passengers undergo comprehensive police and health checks upon arrival. Health Minister Brad Hazzard said all flights are met by NSW Health staff and police officers to ensure anyone entering NSW complies with the current health orders. “There are only limited reasons anyone from Victoria should be entering NSW and people have been turned back despite being allowed on the plane in Melbourne,” microzide best price Mr Hazzard said.

€œVictorian residents are not permitted into NSW at all unless they are needed for specific purposes and even then have to apply for and get a permit. €œWe are constantly reviewing the situation in Victoria and will adjust the health orders as necessary to protect the people of NSW.” Anyone who flies into NSW from Victoria must either be a NSW resident or have a relevant permit that allows entry into NSW – that can include:defence officialsdoctors and nursescritical workers in energy, mining and constructionchild protection workersdisability workers.All travellers are provided with a pack of two masks and hand sanitiser microzide best price by the airlines. Upon arrival into NSW all passengers from Victoria are.

given masks if they left them on the planetemperature checkedasked relevant questions about their health. And their permit is checked to ensure it complies with the strict permit system.Anyone without a valid permit is referred to NSW Police and microzide best price taken to the Special Health Accommodation to complete 14 days of quarantine. Strict instructions and rules are in place for those going into ‘Home Isolation’ including.

Recommended they be collected in a private car by family or friendsnot to use public transport to get hometo only sit in the back seat of a car with the windows open and air conditioning not on recirculationtold to microzide best price wear their face masks and observe hand hygiene recommendations, andcalled to make sure they arrive home.NSW Health is provided the contact details of everyone who enters NSW from Victoria. NSW Police is conducting regular compliance checks for people told to go into ‘Home Isolation’ as well as responding to reports from the community in relation to suspected breaches. Over microzide best price the weekend, NSW Police visited almost 600 homes to check that those that were meant to be self-isolating were doing so.

In addition to that, over the same period NSW Police received 374 calls to Crime Stoppers reporting suspected breaches of the health orders, the majority of which were for people suspected of not following self-isolation rules. ​Seven cutting-edge NSW research projects have been awarded almost $15 million in NSW Government grants to improve the health of people with spinal cord injuries (SCI).Treasurer Dominic Perrottet and Minister for Health and Medical Research Brad Hazzard today announced the grants at the opening of the Neuroscience Research Australia (NeuRA) Spinal Cord Injury Research Centre at Randwick where three of the projects will be carried out. €œThe investment microzide best price of close to $15 million over four years was a centrepiece of our last Budget and it’s exciting to see the range of research projects now underway,” Mr Perrottet said.

€œThis is about improving the health and wellbeing of people with spinal cord injuries, and these projects could help people not just in NSW but right around the world.” Minister Hazzard said every one of the innovative projects holds tremendous promise to improve treatment for people living with spinal cord injuries, giving back muscle function, sense of touch and other abilities that most of us take for granted. €œA spinal injury brings very substantial life challenges, but advances in research now mean survivors can have a better quality of life – and even the hope of a cure,” Mr Hazzard microzide best price said. €œThese projects have great scope, from investigating ways to restore touch sensation through immersive virtual reality through to using electrical stimulation to improve breathing for people affected by the most severe form of paralysis.” The following grant recipients will conduct their research at the new NeuRA centre.

Associate Professor Sylvia Gustin, The University of NSW, Neuroscience Research Australia – received $2.5 million for her research project on using virtual reality training to microzide best price restore touch sensation. Professor Jane Butler – Neuroscience Research Australia, The University of NSW, received $1.5 million to develop a treatment to restore voluntary function after spinal cord injury. And Dr Euan McCaughey, Neuroscience Research Australia, The University of NSW, received $2.4 million for his research into using muscle stimulation to improve respiratory function for people with tetraplegia.

The projects have been awarded through the NSW Government’s Spinal Cord Injury Research Grants program, microzide best price launched in November 2019, with guidance from an advisory committee of spinal cord injury experts. NeuRA CEO, Professor Peter Schofield, said the range and scope of the funded research projects held exciting promise for health related outcomes. €œNeuroscience Research Australia is at the forefront microzide best price of spinal cord injury research in Australia.

Our new Spinal Cord Injury Research Centre and these research projects will dramatically improve Australia’s understanding of how to best treat people with these life-long injuries,” Professor Schofield said. €œNeuRA thanks the NSW Government for funding the Spinal Cord Injury Research Grants Program, and SpinalCure Australia for its tireless efforts in campaigning for more research funding to improve the quality of life for people with a spinal cord injury.” Information on grant recipients and their research projects is available on the OHMR Funded Research Directory​​.​​​.

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IntroductionThe lymphatic system is a network of vessels important for whole body fluid homeostasis, lipid absorption and immune cell trafficking.1 2 Lymphoedema is caused by lymphatic dysfunction, which leads to a build-up of interstitial fluid get microzide online within the tissues. This manifests with swelling of the extremities, usually of the legs but may involve other regions or segments of the body such as the upper limbs, face, trunk or genital area. There is an increased risk of infection due to disturbances in immune cell trafficking within the segment of compromised lymph drainage.3 Lymphatic dysfunction within the thorax and abdomen, here referred to as systemic/internal involvement (but can be referred to as visceral or central involvement), may present with pleural or pericardial effusions or ascites, any of which may be chylous, as well as intestinal or pulmonary lymphangiectasia, protein losing enteropathy or chylous reflux.The International Society for the Study of Vascular Anomalies (ISSVA) updated their classification for vascular anomalies in 2018.4 The vascular malformations are subgrouped into ‘combined’, which include more than one type of vessel, ‘simple’ (only involving get microzide online one vessel type), and those ‘associated with other anomalies’.Lymphoedema due to a presumed genetic developmental fault in the structure or function of lymph conducting pathways is called primary lymphoedema.5 Some developmental faults can lead to overt structural defects of the lymph conducting pathways and are called lymphatic malformations. Such malformations if interfering with lymph drainage cause lymphoedema (truncal malformations) but some lymphatic malformations remain as isolated anomalies with no connection to main lymph drainage pathways and do not cause lymphoedema (non-truncal malformations).6 A primary lymphatic anomaly is an umbrella term referring to all lymphatic abnormalities arising from a developmental fault.For a long time, the diagnosis of primary lymphoedema was based largely on the age of presentation of the swelling, congenital, pubertal and late onset, with limited differentiation between the phenotypes. The discovery of the first causal gene, vascular endothelial growth factor receptor 3 for Milroy disease, indicated that a molecular diagnosis was possible.7 The first St George’s classification algorithm of primary lymphoedema and other primary lymphatic disorders was an attempt to guide a clearer categorisation of phenotypes and enable the discovery of further causal genes.8 Age of onset remained a key criterion, but the sites affected and associated features, for example, dysmorphology, distichiasis (aberrant eyelashes), varicose veins, vascular malformations and limb overgrowth were also considered, as was internal or systemic involvement, for example, get microzide online fetal hydrops, intestinal lymphangiectasia, pleural and pericardial effusions and chylous reflux.

A family history of lymphoedema with determination of the mode of inheritance was considered useful.More rigorous phenotyping facilitated the identification of subgroups of patients with the same broad category of primary lymphatic anomaly. These cohorts were then used for molecular studies to identify more causal get microzide online genes. Once the genotype was known then crosschecking of the clinical characteristics, natural history and inheritance patterns was possible and an accurate phenotype defined. Investigations such as lymphoscintigraphy helped to refine get microzide online the phenotype further and give insight into the mechanisms for the development of the lymphatic disorder. A first update of the classification was published in 2013.9The St George’s classification algorithm is intended to help clinicians categorise their patients and guide testing towards, where possible, a molecular diagnosis.

This algorithm is criteria matching, that is, using certain get microzide online key findings for classification through a multistep process of history taking, examination findings, mutation testing, etc. The next step using the information gathered is to advise on natural history, prognosis and risk (including genetic counselling) and to guide management. While a molecular diagnosis should provide the most get microzide online specific and accurate diagnosis, it can be seen particularly with the postzygotic mosaic disorders that one genotype can be clinically very heterogenous so there will probably always be a place for good clinical phenotyping supported by investigation to guide management.Here, we present a second update of the St George’s classification algorithm to include newly discovered genes and to bring it in-line with the 2018 ISSVA classification for vascular anomalies.4 The results of an audit, the purpose of which was to determine how well the algorithm was performing as a diagnostic aid to classify patients with primary lymphatic anomalies and guide molecular testing are also presented.MethodsSt George’s classification algorithm of primary lymphatic anomaliesThe St George’s classification algorithm was updated (figure 1) and then applied, retrospectively, to all patients presenting to the national multidisciplinary ‘Primary and Paediatric Lymphoedema’ Clinic held at St George’s Hospital over a 1-year period. Careful phenotyping was undertaken both on clinical grounds and after selective investigations, for example, lymphoscintigraphy. Where possible and appropriate, targeted genetic testing was performed get microzide online (this was prior to the introduction of a lymphoedema gene panel in our unit) for some of the genes listed in table 1.St George’s classification algorithm for primary lymphatic anomalies.

The five main groupings (colour coded) with their various clinical subtypes of disease. Primary lymphoedema is the major clinical feature in the green, get microzide online pink and purple sections. Text in red indicates the suggested genetic test and/or differential diagnosis for the subgroup, however, the indicated genes do not explain the cause of disease in all patients in each grouping. For example, only 70% of patients with Milroy disease are explained by mutations in FLT4/VEGFR3.33 get microzide online FH, family history. +ve, positive.

ˆ’ve, negative get microzide online. (Image shared by St George’s Lymphovascular Research Group under the CC BY-SA 4.0 International licence on Wikimedia Commons)." data-icon-position data-hide-link-title="0">Figure 1 St George’s classification algorithm for primary lymphatic anomalies. The five main groupings get microzide online (colour coded) with their various clinical subtypes of disease. Primary lymphoedema is the major clinical feature in the green, pink and purple sections. Text in red get microzide online indicates the suggested genetic test and/or differential diagnosis for the subgroup, however, the indicated genes do not explain the cause of disease in all patients in each grouping.

For example, only 70% of patients with Milroy disease are explained by mutations in FLT4/VEGFR3.33 FH, family history. +ve, positive get microzide online. ˆ’ve, negative. (Image shared by St George’s Lymphovascular Research Group under the CC BY-SA 4.0 International licence on Wikimedia Commons).View this table:Table 1 An overview of genetic disorders with primary lymphoedema as a frequent and dominant feature, categorised by inheritance and age of onsetWithin the St George’s classification algorithm (figure 1), there are five main categories of primary lymphatic anomalies. These are presented in the get microzide online form of colour-coded sections with the individual subtypes (including genotypes) within the categories.

For definitions of some of the terms used, see Glossary of Terms (see online supplementary section).Supplemental materialFirst, the yellow section includes the ‘vascular malformations associated with other anomalies’ and the ‘lymphatic malformations’ (as defined in the ‘Introduction’ section).Second, the patient is assessed for syndromes that have lymphoedema as a non-dominant feature (blue section), for example, the patient is dysmorphic with learning difficulties and possibly has other abnormalities.Then if not obviously syndromic, and the lymphatic problems are the dominant feature, further assessment and investigations for systemic/internal lymphatic dysfunction or central conducting anomalies (eg, chylothoraces, chylopericardial effusions, ascites or protein losing enteropathy) are undertaken (pink section). These include a careful medical history asking specifically about prenatal history (eg, get microzide online hydrothoraces, fetal hydrops), chronic diarrhoea, abdominal bloating or discomfort with fatty foods, weight loss or faltering growth (in a child) or shortness of breath on exertion. Blood investigations (including serum albumin, immunoglobulins, lymphocyte subsets, faecal levels of calprotectin or alpha-1-antitrysin), echocardiograms and chest radiographs are helpful if central lymphatic dysfunction is suspected.Where none of the above features is present, then the age of onset is used to determine the grouping. The green section deals with congenital-onset primary get microzide online lymphoedema (includes syndromes where lymphoedema is the dominant clinical problem, and which is present at birth or develops within the first year of life but is not associated with systemic/internal lymphatic dysfunction). The purple section addresses late-onset primary lymphoedema (ie, lymphoedema that is the dominant clinical problem, and which develops after the first year of life but is not associated with systemic/internal lymphatic dysfunction).

It was decided not to differentiate between pubertal onset (praecox) and later onset in life (tarda) when it was discovered that one genotype get microzide online such as FOXC2 can cause both.It is important to note that the specific diagnosis may be difficult in a neonate presenting with isolated congenital primary lymphoedema. A baby born with lymphoedema may later present with developmental delay, systemic involvement, progressive segmental overgrowth or a vascular malformation, which could suggest a diagnosis in one of the other categories. It should also be emphasised that each colour-coded section is get microzide online not exclusive. Some somatic overgrowth anomalies may possess significant internal involvement. Also, lymphoedema distichiasis syndrome is allocated to the purple late-onset lymphoedema section because the dominant feature is the late-onset lymphoedema not the associated features, which get microzide online make it a syndrome.

The blue ‘syndromic’ section refers to conditions with a collection of features where lymphoedema is not the main characteristic. The algorithm get microzide online is intended to guide a clinical diagnosis and target gene testing.Genetic methodologyFor the purposes of the audit, targeted genetic testing of FOXC2, VEGFR3, CCBE1, SOX18, RASopathy genes and PIK3CA was performed by Sanger sequencing of DNA extracted from lymphocytes or skin fibroblasts in patients in whom a specific genetic diagnosis was suspected. This was before the introduction of a lymphoedema gene panel. Some patients, who were either negative for the targeted genes or did not fit the relevant phenotypes of those genes, were included in Whole Exome Sequencing (WES) cohorts after classification, which then led to the identification of new disease genes such as EPHB4, GATA2, PIEZO1, GJC2 and FAT4.Retrospective audit of the St George’s Clinic for 2016A 12-month retrospective get microzide online audit for the year 2016 (1 January 2016–31 December 2016) was performed. The aim of the audit was to look at the proportion of patients in each category of the classification algorithm and to look at the success of making a molecular diagnosis through use of the algorithm.

The audit criteria required the patients to be seen in our specialist clinic, at any age, with a diagnosis of a primary lymphatic anomaly with data collected from medical records and laboratory results.ResultsResults of the retrospective auditOver a 12-month period in 2016, get microzide online 227 patients were seen (age range 2 weeks to 70 years), 25.6% (n=58/227) of which were new patients. Over one-third (38%) of patients seen in the clinic had a family history of primary lymphoedema.Few patients had received genetic testing prior to referral to the clinic. Targeted genetic get microzide online testing was completed in 63% (n=143) of the patients seen. At that time, a lymphoedema gene panel was not available, patients were only tested if the clinician felt there was a reasonable chance of finding a molecular cause, that is, testing was targeted.Of those tested, the underlying genetic cause was identified in 41% (n=59/143). Overall, a molecular diagnosis was made in 26% (59/227) of all the patients seen get microzide online in 2016.Vascular malformations with associated anomalies and lymphatic malformations (yellow)This group presents with malformations in the structure and organisation of blood and lymphatic vessels with a patchy, segmental distribution.

Lymphoedema may develop in combination with vascular malformations and segmental overgrowth (or occasionally, undergrowth) of tissues within the swollen limb, for example, muscle, skeletal or adipose tissues (figure 2A). The combination of lymphatic and vascular malformations in this get microzide online group reflects the mutual embryological origins of the two vascular systems.A graphic representation of the 227 audited patients seen in clinic in 2016 and their distribution across the five categories from figure 1 (pie chart). (A–G) Images show features of each category. (A) Patients with postzygotic mutations often present with asymmetrical swelling and segmental overgrowth as this patient, who is get microzide online mosaic for a mutation in KRAS. (B) Webbed neck in Noonan syndrome.

(C) In rare cases, swellings can be widespread affecting all segments of the body such as in this child with biallelic CCBE1 mutations. (D) In milder forms, get microzide online often just the dorsum of the foot is affected as in this baby with a VEGFR3 mutation. (E, F) Lower limb swelling and distichiasis (arrowheads in F) in a patient with a FOXC2 mutation. (G) Lymphoedema is a major cause of skin disease and affected patients suffer from severe get microzide online and recurrent episodes of cutaneous infection, especially HPV-associated warts as seen in patients with GATA2 mutations. GLD, generalised lymphatic dysplasia." data-icon-position data-hide-link-title="0">Figure 2 A graphic representation of the 227 audited patients seen in clinic in 2016 and their distribution across the five categories from figure 1 (pie chart).

(A–G) Images show features of get microzide online each category. (A) Patients with postzygotic mutations often present with asymmetrical swelling and segmental overgrowth as this patient, who is mosaic for a mutation in KRAS. (B) Webbed get microzide online neck in Noonan syndrome. (C) In rare cases, swellings can be widespread affecting all segments of the body such as in this child with biallelic CCBE1 mutations. (D) In milder forms, often just the dorsum of the foot is affected as in this baby with a VEGFR3 get microzide online mutation.

(E, F) Lower limb swelling and distichiasis (arrowheads in F) in a patient with a FOXC2 mutation. (G) Lymphoedema is a major cause of skin disease and affected patients suffer from severe and recurrent episodes of cutaneous infection, especially HPV-associated warts as seen in patients get microzide online with GATA2 mutations. GLD, generalised lymphatic dysplasia.These conditions are usually due to postzygotic mutations, for example, PIK3CA-related overgrowth spectrum (PROS)). Exceptions to get microzide online this are capillary malformation-arteriovenous malformation (MIM 608354) such as Parkes-Weber syndrome, which may be caused by heterozygous, germline mutations in RASA1.10Of the 227 patients seen in 2016, 17% (n=39) had lymphoedema associated with vascular malformations and/or segmental overgrowth (or undergrowth) (figure 2, pie chart) in comparison with 15% in 2010.8 It has been shown that postzygotic, gain of function mutations in PIK3CA may be responsible for many of the mosaic segmental overgrowth spectrum disorders.11 Postzygotic mutations are rarely identified in blood samples and therefore require a skin biopsy of the affected region. In the 2016 cohort, only 10 patients (26%) provided skin biopsies for genetic analysis, producing just one molecular diagnosis.

More research in this field is required to identify the genetic basis for some of the conditions get microzide online in this category. However, since the last revision, we have gained a much better understanding of the classification of some of these postzygotic mosaic conditions, therefore a brief review of the latest developments in this area is given in the online supplementary section.Syndromic lymphoedema (blue)Syndromes associated with primary lymphatic anomalies are listed in table 2 and include chromosomal abnormalities, single gene disorders and imprinting disorders. Patients attending the clinic with syndromic primary lymphoedema made up 13% (n=29) (figure 2, pie chart), similar to the 15% reported by Connell et get microzide online al.8 Nearly three-quarters (72%, n=21) of this cohort had a molecular or chromosomal diagnosis. The most frequently seen syndromes were Noonan syndrome (n=8) (figure 2B), Turner syndrome (n=4) and Phelan McDermid syndrome (n=3).View this table:Table 2 An overview of ‘Known Syndromes’ with primary lymphoedema as a non-dominant association as referred to in the St George’s classification algorithm (figure 1, blue section)Lymphoedema with prenatal or postnatal systemic involvement (pink)In some conditions, lymphoedema may be associated with internal (systemic or visceral) disturbances of the lymphatic system within thorax or abdomen, for example, fetal hydrops, intestinal lymphangiectasia (presenting as protein-losing enteropathy), pulmonary lymphangiectasia or with pericardial and/or pleural effusions (often chylous), or chylous reflux (often into the genitalia). Broadly, there are two types of lymphoedema get microzide online with systemic involvement.

(A) ‘widespread’ swelling affecting all segments of the body (figure 2C), such as that seen in generalised lymphatic dysplasia (GLD). Due to faulty development, the structural or functional abnormality of the lymphatic system is affecting the whole body get microzide online. One type is Hennekam-lymphangiectasia-lymphoedema syndrome12. (B) ‘patchy’ areas of get microzide online swelling, for example, left arm and right leg, which have been named ‘multisegmental lymphatic dysplasia’ (MLD) (figure 1).Prenatally, these conditions may present with pleural effusions (hydrothoraces), or as non-immune fetal hydrops (the accumulation of fluid in at least two compartments of a fetus such as the abdominal cavity, pleura or subcutaneous oedema). Fifteen per cent of non-immune cases of hydrops are the result of lymphatic disorders, and approximately 20% are idiopathic, some of which may be due to, as yet, unidentified lymphatic abnormalities.13In our audit, this cohort accounted for 12% (n=27) of patients (figure 2, pie chart), slightly higher than the 8% reported in 2010.8 Molecular testing was carried out in 17 patients.

Nine of those tested had GLD, and pathogenic variants were identified in get microzide online seven (78%). Five had biallelic variants in the PIEZO1 gene and one each with biallelic variants in FAT4 and SOX18. Interestingly, two of the families described by Connell et al, cases 3 and 4, have subsequently been found to be caused by biallelic variants in the PIEZO1 gene.8 14None of the eight patients, who presented with ‘patchy’ distribution of lymphoedema (MLD), had an identifiable molecular diagnosis. It is suspected that these patients could have a postzygotic mosaic mutation get microzide online or WILD syndrome.15Since the last revision of the St George’s classification algorithm was published,9 five new causal genes associated with GLD and/or non-immune fetal hydrops have been identified. ADAMTS3,16 EPHB4,17 FAT4,18 FBXL719 and PIEZO114 20 and are reviewed in the online supplementary section.Congenital onset lymphoedema (green)In this category, congenital onset is defined as lymphoedema that is present at birth or develops within the first year of life.

Bilateral lower limb swelling is the most frequent presentation (figure 2D), but the swelling may be unilateral and/or involve the arms, genitalia and/or face, get microzide online depending on the underlying cause. There are a number of different genetic disorders presenting with congenital lymphoedema (table 1). Milroy disease (ORPHA79452 get microzide online. OMIM 153100) is the most common form, occurring as a result of pathogenic variants in FLT4/VEGFR3.21 22 The mutation may occur de novo, so a family history is not essential for this diagnosis. The lymphoedema is always confined to the lower limbs but may be unilateral, and get microzide online may (rarely) involve the genitalia.

Approximately 10% of mutation carriers do not have lymphoedema. Fetuses with Milroy disease may present antenatally with pedal oedema in the third trimester, and, in a few cases, with bilateral hydrothoraces, which resolve get microzide online before birth.Pathogenic variants in VEGFC, the ligand for VEGFR3, have also been identified in association with congenital primary lymphoedema of Gordon (OMIM 615907), also affecting the lower limbs.23–26The congenital category represents 21% (n=47) of the patients seen in 2016 (figure 2, pie chart) compared with 24% in 2010.8 A pathogenic variant was identified in 19 of the 47 (40%) patients genetically tested in this category. The majority (n=18) had pathogenic variants identified in FLT4/VEGFR3 and, in one patient, a pathogenic variant in the GJC2 gene. A GJC2 mutation in a patient presenting with lymphoedema at birth is unusual but shows the variability of the phenotype.Many of the conditions listed under the other categories in the classification algorithm may initially present with congenital lymphoedema but systemic involvement, progressive overgrowth or vascular malformation may present get microzide online later and are so reclassified. Likewise, some syndromic forms may present with congenital lymphoedema before any other manifestations, making diagnosis difficult at times.

Thus, the diagnosis of ‘isolated’ congenital primary get microzide online lymphoedema may be difficult in a neonate presenting with pedal oedema. Therefore, a molecular diagnosis in the neonatal period is clinically very useful in the management of these patients.Late-onset lymphoedema (purple)‘Late-onset’ lymphoedema is defined as presenting after the first year of life. Swelling can range from being unilateral, bilateral or can get microzide online involve all four limbs and can present from early childhood up to adulthood (figures 1 and 2E). Some may present with unilateral swelling, but the contralateral limb may become involved later or show abnormalities on lymphoscintigram even when clinically uninvolved. The phenotypes also range get microzide online from mild to severe.

There are currently five genes known to be associated with late-onset lymphoedema. FOXC2 (figure 2F),27 GJC2,28 29 GATA2 get microzide online (figure 2G),30 HGF31 and CELSR132 (table 1). For many patients the molecular cause remains elusive, particularly in those patients with Meige disease and late-onset (usually pubertal) unilateral lower limb lymphoedema.Late-onset primary lymphoedema accounted for 37% (n=85) in 2016 (figure 2, pie chart) comparable to the 36% reported in 2010.8 This category has a low number of molecular diagnoses (n=12. 14%) as there are currently no causative genes for Meige disease, which made get microzide online up 36% (n=31) of patients in this category.DiscussionThis review presents an updated St George’s classification algorithm of primary lymphatic anomalies and brings it in-line with the ISSVA classification for vascular anomalies. It cites eight new causative genes since the last publication and highlights the areas where the genetic basis is still not known.

This rapidly evolving field demonstrates that primary lymphoedema and vascular malformations are highly heterogenous.The audit reports an overall get microzide online successful molecular diagnosis in 26% of patients seen in the clinic, but 41% of those patients selected for molecular testing. This is a considerable improvement on the rate of a molecular diagnosis since the algorithm was first published in 2010. Only two causal genes get microzide online were known at that time. We can conclude from the audit that the algorithm works well in targeting mutation testing. Furthermore, use of the algorithm has led to the discovery of a number of causal genes.

While it could be argued that the introduction of the lymphoedema gene panel obviates any get microzide online need for targeted gene tests, we believe that matching a phenotype to a likely gene reduces wasteful testing and helps enormously in the interpretation of variants of unknown significance, which are becoming an increasing problem in the era of next-generation sequencing.Although providing a molecular diagnosis in one-quarter of all the patients with primary lymphoedema represents a considerable improvement from when the algorithm was last reviewed, the molecular diagnosis is still not identified in the majority of patients seen in the St George’s Clinic. In the diagnostic setting, the introduction of next-generation sequencing with a targeted (virtual) ‘lymphoedema gene panel’ may improve the diagnostic rate and broaden the phenotypic spectrum of many of the known genetic disorders. Understanding of the natural history of the disorder will enable appropriate surveillance of, for example, get microzide online leukaemia in Emberger syndrome (GATA2), and allow investigations for known associated problems, for example, congenital heart disease in patients with lymphoedema distichiasis syndrome (FOXC2). Prenatal diagnosis for the more serious conditions also becomes possible. Knowledge of causal genes, get microzide online and mechanisms of pathophysiology, provide an opportunity for new, improved treatments (personalised medicine) (eg, mammalian target of rapamycin inhibitors for progressive overgrowth disorders).In conclusion, the St George’s classification algorithm for primary lymphatic anomalies has been further refined.

With this review, we have provided insight into the most recently discovered genotypes and how this algorithm can be used in the clinic to guide management of patients with primary lymphoedema.IntroductionTriphalangeal thumb (TPT) is a rare congenital hand anomaly in which the thumb has three phalanges instead of two. TPT is usually get microzide online inherited in an autosomal dominant trait and is therefore commonly seen in affected families. In 1994, Heutink et al located the pathogenic locus of TPT at chromosome 7q36.1 Subsequently, Lettice et al determined that point mutations in the zone of polarising activity regulatory sequence (ZRS) causes TPT and preaxial polydactyly.2 The ZRS is a long-range regulatory element residing in intron 5 of LMBR1 and regulates Sonic Hedgehog (SHH) expression in the embryonic limb bud. Since the identification of the ZRS region, 18 different point mutations in the ZRS have been reported in TPT families.3There is broad phenotypical variability get microzide online among different point mutations in the ZRS. For example, variants on locations 323 and 739 in the ZRS cause mild presentations of isolated TPT.2 4 Alternatively, severe anomalies such as TPT accompanied with tibial hypoplasia have been observed in families with variants on position 404 and 406 in the ZRS.2 5–9 In mildly affected phenotypes, reduced penetrance is regularly observed.

In families who are more severely affected however, no reports of reduced penetrance have been made.Identifying and reporting new variants in the ZRS is important for genotype-phenotype correlations get microzide online in TPT families. Additionally, it will also help to further elucidate the exact molecular mechanism of the role of the ZRS in the regulation of SHH expression in the embryonic limb.We therefore report two families with variants in the ZRS. These variants get microzide online were identified in Dutch families with isolated TPT. Additionally, unaffected family members shared these variants with affected family members. Although this observation suggests that the genotype is not fully penetrant, minor anomalies get microzide online within these presumed unaffected family members indicate subclinical expression of a TPT phenotype rather than reduced penetrance of the genotype.

We define subclinical phenotypes as anomalies that are not recognised by affected family members since they do not cause functional constraints in daily life, but can be recognised during clinical workup by experienced physicians.MethodsClinical evaluationFamilies 1 and 2 were identified at the outpatient clinic for Congenital Hand and Upper Limb Anomalies at the Sophia Children’s Hospital in Rotterdam, The Netherlands. The family members were clinically examined and consulted get microzide online by a clinical geneticist. In family 1, peripheral blood samples were collected from the index patient, the mother and the grandfather of the index patient (figure 1). No blood samples were obtained from the brother of this patient as he was get microzide online clinically unaffected and was below adult age.Overview of Dutch TPT family 1. (A) Pedigree of the Dutch TPT family 1.

The index get microzide online patient is patient III-2. (B) X-ray image of the hand of the index patient. An additional deltaphalanx is present get microzide online in both thumbs. (C) X-ray image of the thumbs of patient III-2. Although there is no triphalangism present, the get microzide online thumbs are remarkably broad.

TPT, triphalangeal thumb." data-icon-position data-hide-link-title="0">Figure 1 Overview of Dutch TPT family 1. (A) Pedigree of the Dutch TPT family 1. The index get microzide online patient is patient III-2. (B) X-ray image of the hand of the index patient. An additional deltaphalanx is present get microzide online in both thumbs.

(C) X-ray image of the thumbs of patient III-2. Although there is no triphalangism present, the thumbs get microzide online are remarkably broad. TPT, triphalangeal thumb.In family 2, the index patient (III-2) visited the outpatient clinic for Congenital Hand and Upper Limb Anomalies at the Sophia Children’s Hospital in Rotterdam with his parents. The other get microzide online family members were visited as part of a field study. Included family members were clinically evaluated by a clinical geneticist, photographs were obtained and peripheral blood samples were collected (Figure 2, online supplementary figure 1).

No radiographs were obtained during the get microzide online field study.Supplemental materialOverview of Dutch TPT family 2. (A) Outtake of pedigree of the Dutch TPT family 2. (B) Images of patient III-2 and his father (II-2), showing triphalangism of both thumbs with one additional ray on the left hand get microzide online. (C) Images of patients II-4 and I-1, showing no triphalangism but lack of thumb opposition and mild thenar hypoplasia. TPT, triphalangeal thumb." data-icon-position data-hide-link-title="0">Figure 2 Overview of Dutch TPT family 2 get microzide online.

(A) Outtake of pedigree of the Dutch TPT family 2. (B) Images of patient get microzide online III-2 and his father (II-2), showing triphalangism of both thumbs with one additional ray on the left hand. (C) Images of patients II-4 and I-1, showing no triphalangism but lack of thumb opposition and mild thenar hypoplasia. TPT, triphalangeal thumb.ZRS sequencingDNA samples were isolated get microzide online from peripheral blood. The fragments were amplified using standard PCR.

An 834 bp fragment covering get microzide online the ZRS (774 bp) was sequenced in family members of both families (UCSC Genome Browser, hg19, chr7:156583766–156584600). Sequencing of PCR products was executed using Big Dye Terminator 3.1. Fragments were loaded get microzide online on an ABI 3130 Sequence analyser and genetic analysis was performed with SeqScape Software (V.3.0).ResultsClinical report​Family 1Family 1 (figure 1A) consists of a nuclear family containing two affected patients with TPT. The index patient had a bilateral isolated TPT with an additional deltaphalanx (figure 1B). No other get microzide online congenital hand or other anomalies were present.

The mother of the index patient was born with a TPT accompanied with a rudimentary additional thumb on both hands, without any other hand or congenital anomaly (data not shown). The maternal grandfather of the index patient did get microzide online not have a TPT or preaxial polydactyly. However, clinical examination of the hands revealed remarkable broadness of both thumbs and mild thenar hypoplasia. Although the X-ray image of the grandfather shows no duplication of the thumb or triphalangism, the broadness of the distal phalanges is striking (figure 1C).​Family 2Family 2 comprises a large seven-generation family (Figure 2A, online supplementary figure 1). The index patient (III-2) had bilateral TPT with get microzide online preaxial polydactyly on the left hand.

The father of the index patient (II-1) had bilateral TPT without preaxial polydactyly (figure 2B). All other family members reported get microzide online they were not affected. Although the thumbs of family members I-1 and II-2 did not show clear features of triphalangism, further examination revealed that both family members had mild thenar hypoplasia and were unable to oppose both thumbs (figure 2C). No other congenital anomalies were present in family 2.Mutation analysisSequence analysis of the 774 bp ZRS, in intron 5 of LMBR1, revealed the presence of a heterozygous A to G transition get microzide online in members of family 1 (g.156584405A>G, GRCh37/Hg19). Following the more commonly used nomenclature for loci of ZRS variants, introduced by Lettice et al,2 this variant can be defined as a 165A>G variant.2 This variant was present in the affected family members.

Patient I-1 get microzide online of family one also carried a 165A>G variant in the ZRS, despite not having TPT on either hand. This variant was not present in public databases dbSNP, Clinvar and HGMD. Additionally, this variant was not present in locally available WGS data sets (GoNL, Wellderly, Public54).10–12In family 2, we identified a 295T>variant in get microzide online the ZRS (g.156584535T>C, GRCh37/Hg19). Two family members who did not have TPT carried the 295T>C variant. This variant has previously been reported in a British family with mild cases of TPT and reduced penetrance of the genotype.13 Additionally, transgenic enhancer assays in mice showed that the 295T>C variant causes ectopic expression in the embryonic limb and therefore confirms the pathogenicity of this variant.DiscussionIn this brief report, we describe two TPT families with either a 165A>G or 295T>C variant in get microzide online the ZRS.

The aim of this paper was to show that these observations of reduced penetrance in TPT families are in retrospect caused by mild and subclinical limb phenotypes without the presence of triphalangism and therefore raise awareness for thorough clinical examination in members of TPT families who are presumed to be unaffected.Ever since the identification of ZRS by Lettice et al in 2003, 18 variants in ZRS have been published in the literature.2 4 6–9 13–20 These variants are generally fully penetrant and have been found in families with either TPT or TPT with preaxial polydactyly. Exceptions to the above are point mutations on positions 105, 404 and 406 in ZRS, which cause more severe phenotypes like tibial hypoplasia and polysyndactyly.2 5–9 21Although most variants in ZRS are considered fully penetrant, reduced get microzide online penetrance has been reported in several TPT families with variants on positions 295, 334, 463 and 739 in ZRS.13 14 16 17The first aim of this paper is to hypothesise that some of these observations might not be caused by reduced penetrance of the genotype, but by a subclinical expression of the phenotype. We base our hypothesis on two arguments. First, family members who were initially presumed unaffected do show minor anomalies or altered hand function when examined get microzide online appropriately. In family 1 of this study, the grandfather did not have TPT but had evident broadness of the thumb.

In family 2, get microzide online patients with initially normal thumbs lacked the ability of opposition, which is caused by abnormal developmental patterning of the thumb. Although this observation is based on three patients from two families, we believe that these examples clearly illustrate our postulated hypothesis.Second, reports of non-penetrance are consistently associated with mild phenotypes in TPT families and not with severe TPT phenotypes, like tibial hypoplasia and polysyndactyly. This indicates that get microzide online these observations only occur in TPT families where SHH expression is only slightly disrupted. In these families, the variability in the phenotypical spectrum is apparently broad enough that family members with variants in ZRS can present with subclinical phenotypes instead of TPT. However, it remains unclear why the disruption of SHH causes TPT in one family member and a get microzide online subclinical phenotype in another.

One example of how intrafamilial variability can be explained is based on a reported family, where different degrees of somatic mosaicism were associated with various phenotypes in affected family members.22 As the regulatory function of ZRS on SHH is extremely delicate and affected by timing, location and level of activity, it is plausible that the slightest alteration of one of these factors can cause this interindividual phenotypical variation.The second aim of this paper is to underline the importance of two aspects when clinically examining and counselling patients with an inherited type of TPT. First, it is important to get microzide online clinically investigate the presumed unaffected family members, as these patients might not encounter functional problems in their daily life and will report they are unaffected. However, a distinct broadness of the thumb, a double flexion fold in the thumb or a duplicated lunula might indicate a discrete inclination for duplication of the thumb or the presence of an additional phalanx. Additionally, functional limitations regarding thumb strength or lack of get microzide online opposition should be evaluated as well. Second, presumed unaffected family members should only be informed that their future offspring have a population-wide probability of having TPT or polydactyly after genetic evaluation.

For complete reassurance, genetic evaluation of ZRS is also indicated for unaffected family members of mildly affected patients to verify whether they share the same disease-causing variant with their affected family members..

IntroductionThe lymphatic system is a network of vessels important for whole body fluid homeostasis, lipid absorption and immune cell trafficking.1 2 microzide best price Lymphoedema is caused by lymphatic dysfunction, which leads to a build-up of interstitial fluid within the tissues. This manifests with swelling of the extremities, usually of the legs but may involve other regions or segments of the body such as the upper limbs, face, trunk or genital area. There is an increased risk of infection due to disturbances in immune cell trafficking within the segment of compromised lymph drainage.3 Lymphatic dysfunction within the thorax and abdomen, here referred to as systemic/internal involvement (but can be referred to as visceral or central involvement), may present with pleural or pericardial effusions or ascites, any of which may be chylous, as well as intestinal or pulmonary lymphangiectasia, protein losing enteropathy or chylous reflux.The International Society for the Study of Vascular Anomalies (ISSVA) updated their classification for vascular anomalies in 2018.4 The vascular microzide best price malformations are subgrouped into ‘combined’, which include more than one type of vessel, ‘simple’ (only involving one vessel type), and those ‘associated with other anomalies’.Lymphoedema due to a presumed genetic developmental fault in the structure or function of lymph conducting pathways is called primary lymphoedema.5 Some developmental faults can lead to overt structural defects of the lymph conducting pathways and are called lymphatic malformations. Such malformations if interfering with lymph drainage cause lymphoedema (truncal malformations) but some lymphatic malformations remain as isolated anomalies with no connection to main lymph drainage pathways and do not cause lymphoedema (non-truncal malformations).6 A primary lymphatic anomaly is an umbrella term referring to all lymphatic abnormalities arising from a developmental fault.For a long time, the diagnosis of primary lymphoedema was based largely on the age of presentation of the swelling, congenital, pubertal and late onset, with limited differentiation between the phenotypes. The discovery of the first causal gene, vascular endothelial microzide best price growth factor receptor 3 for Milroy disease, indicated that a molecular diagnosis was possible.7 The first St George’s classification algorithm of primary lymphoedema and other primary lymphatic disorders was an attempt to guide a clearer categorisation of phenotypes and enable the discovery of further causal genes.8 Age of onset remained a key criterion, but the sites affected and associated features, for example, dysmorphology, distichiasis (aberrant eyelashes), varicose veins, vascular malformations and limb overgrowth were also considered, as was internal or systemic involvement, for example, fetal hydrops, intestinal lymphangiectasia, pleural and pericardial effusions and chylous reflux.

A family history of lymphoedema with determination of the mode of inheritance was considered useful.More rigorous phenotyping facilitated the identification of subgroups of patients with the same broad category of primary lymphatic anomaly. These cohorts were then microzide best price used for molecular studies to identify more causal genes. Once the genotype was known then crosschecking of the clinical characteristics, natural history and inheritance patterns was possible and an accurate phenotype defined. Investigations such as lymphoscintigraphy helped microzide best price to refine the phenotype further and give insight into the mechanisms for the development of the lymphatic disorder. A first update of the classification was published in 2013.9The St George’s classification algorithm is intended to help clinicians categorise their patients and guide testing towards, where possible, a molecular diagnosis.

This algorithm is criteria matching, that is, using certain microzide best price key findings for classification through a multistep process of history taking, examination findings, mutation testing, etc. The next step using the information gathered is to advise on natural history, prognosis and risk (including genetic counselling) and to guide management. While a molecular diagnosis should provide the most specific and accurate diagnosis, it can be seen particularly with the postzygotic mosaic disorders that one genotype can be clinically very heterogenous so there will probably always be a place for good clinical phenotyping supported by investigation to microzide best price guide management.Here, we present a second update of the St George’s classification algorithm to include newly discovered genes and to bring it in-line with the 2018 ISSVA classification for vascular anomalies.4 The results of an audit, the purpose of which was to determine how well the algorithm was performing as a diagnostic aid to classify patients with primary lymphatic anomalies and guide molecular testing are also presented.MethodsSt George’s classification algorithm of primary lymphatic anomaliesThe St George’s classification algorithm was updated (figure 1) and then applied, retrospectively, to all patients presenting to the national multidisciplinary ‘Primary and Paediatric Lymphoedema’ Clinic held at St George’s Hospital over a 1-year period. Careful phenotyping was undertaken both on clinical grounds and after selective investigations, for example, lymphoscintigraphy. Where possible and appropriate, targeted genetic testing was performed (this was prior to the introduction of a lymphoedema gene panel in our unit) for some of the genes listed in table 1.St George’s microzide best price classification algorithm for primary lymphatic anomalies.

The five main groupings (colour coded) with their various clinical subtypes of disease. Primary lymphoedema is the major clinical feature microzide best price in the green, pink and purple sections. Text in red indicates the suggested genetic test and/or differential diagnosis for the subgroup, however, the indicated genes do not explain the cause of disease in all patients in each grouping. For example, microzide best price only 70% of patients with Milroy disease are explained by mutations in FLT4/VEGFR3.33 FH, family history. +ve, positive.

ˆ’ve, negative microzide best price. (Image shared by St George’s Lymphovascular Research Group under the CC BY-SA 4.0 International licence on Wikimedia Commons)." data-icon-position data-hide-link-title="0">Figure 1 St George’s classification algorithm for primary lymphatic anomalies. The five main groupings microzide best price (colour coded) with their various clinical subtypes of disease. Primary lymphoedema is the major clinical feature in the green, pink and purple sections. Text in red indicates microzide best price the suggested genetic test and/or differential diagnosis for the subgroup, however, the indicated genes do not explain the cause of disease in all patients in each grouping.

For example, only 70% of patients with Milroy disease are explained by mutations in FLT4/VEGFR3.33 FH, family history. +ve, positive microzide best price. ˆ’ve, negative. (Image shared by St George’s Lymphovascular Research Group under the CC BY-SA 4.0 International licence on Wikimedia Commons).View this table:Table 1 An overview of genetic disorders with primary lymphoedema as a frequent and dominant feature, categorised by inheritance and age of onsetWithin the St George’s classification algorithm (figure 1), there are five main categories of primary lymphatic anomalies. These are presented in the microzide best price form of colour-coded sections with the individual subtypes (including genotypes) within the categories.

For definitions of some of the terms used, see Glossary of Terms (see online supplementary section).Supplemental materialFirst, the yellow section includes the ‘vascular malformations associated with other anomalies’ and the ‘lymphatic malformations’ (as defined in the ‘Introduction’ section).Second, the patient is assessed for syndromes that have lymphoedema as a non-dominant feature (blue section), for example, the patient is dysmorphic with learning difficulties and possibly has other abnormalities.Then if not obviously syndromic, and the lymphatic problems are the dominant feature, further assessment and investigations for systemic/internal lymphatic dysfunction or central conducting anomalies (eg, chylothoraces, chylopericardial effusions, ascites or protein losing enteropathy) are undertaken (pink section). These include a careful medical history asking specifically about prenatal history (eg, microzide best price hydrothoraces, fetal hydrops), chronic diarrhoea, abdominal bloating or discomfort with fatty foods, weight loss or faltering growth (in a child) or shortness of breath on exertion. Blood investigations (including serum albumin, immunoglobulins, lymphocyte subsets, faecal levels of calprotectin or alpha-1-antitrysin), echocardiograms and chest radiographs are helpful if central lymphatic dysfunction is suspected.Where none of the above features is present, then the age of onset is used to determine the grouping. The green section deals with congenital-onset primary lymphoedema (includes syndromes where microzide best price lymphoedema is the dominant clinical problem, and which is present at birth or develops within the first year of life but is not associated with systemic/internal lymphatic dysfunction). The purple section addresses late-onset primary lymphoedema (ie, lymphoedema that is the dominant clinical problem, and which develops after the first year of life but is not associated with systemic/internal lymphatic dysfunction).

It was decided not to differentiate between pubertal onset (praecox) and later onset in life (tarda) when it was discovered that one genotype microzide best price such as FOXC2 can cause both.It is important to note that the specific diagnosis may be difficult in a neonate presenting with isolated congenital primary lymphoedema. A baby born with lymphoedema may later present with developmental delay, systemic involvement, progressive segmental overgrowth or a vascular malformation, which could suggest a diagnosis in one of the other categories. It should also be emphasised microzide best price that each colour-coded section is not exclusive. Some somatic overgrowth anomalies may possess significant internal involvement. Also, lymphoedema distichiasis syndrome is allocated to the purple late-onset lymphoedema section because the dominant feature is the late-onset lymphoedema not microzide best price the associated features, which make it a syndrome.

The blue ‘syndromic’ section refers to conditions with a collection of features where lymphoedema is not the main characteristic. The algorithm is intended to guide a clinical diagnosis and target gene testing.Genetic methodologyFor the purposes of the audit, targeted genetic testing of FOXC2, VEGFR3, CCBE1, SOX18, RASopathy genes and PIK3CA was performed by Sanger sequencing of DNA extracted microzide best price from lymphocytes or skin fibroblasts in patients in whom a specific genetic diagnosis was suspected. This was before the introduction of a lymphoedema gene panel. Some patients, who were either negative for the targeted genes or did not fit the relevant phenotypes of those genes, were included in Whole Exome Sequencing (WES) cohorts after classification, which then led to the identification of new disease genes such as EPHB4, GATA2, PIEZO1, GJC2 and FAT4.Retrospective audit of the St George’s Clinic for 2016A microzide best price 12-month retrospective audit for the year 2016 (1 January 2016–31 December 2016) was performed. The aim of the audit was to look at the proportion of patients in each category of the classification algorithm and to look at the success of making a molecular diagnosis through use of the algorithm.

The audit criteria required the patients to be seen in our specialist clinic, at any age, with a diagnosis of a primary microzide best price lymphatic anomaly with data collected from medical records and laboratory results.ResultsResults of the retrospective auditOver a 12-month period in 2016, 227 patients were seen (age range 2 weeks to 70 years), 25.6% (n=58/227) of which were new patients. Over one-third (38%) of patients seen in the clinic had a family history of primary lymphoedema.Few patients had received genetic testing prior to referral to the clinic. Targeted genetic testing was completed in 63% (n=143) of microzide best price the patients seen. At that time, a lymphoedema gene panel was not available, patients were only tested if the clinician felt there was a reasonable chance of finding a molecular cause, that is, testing was targeted.Of those tested, the underlying genetic cause was identified in 41% (n=59/143). Overall, a molecular diagnosis was made microzide best price in 26% (59/227) of all the patients seen in 2016.Vascular malformations with associated anomalies and lymphatic malformations (yellow)This group presents with malformations in the structure and organisation of blood and lymphatic vessels with a patchy, segmental distribution.

Lymphoedema may develop in combination with vascular malformations and segmental overgrowth (or occasionally, undergrowth) of tissues within the swollen limb, for example, muscle, skeletal or adipose tissues (figure 2A). The combination of lymphatic microzide best price and vascular malformations in this group reflects the mutual embryological origins of the two vascular systems.A graphic representation of the 227 audited patients seen in clinic in 2016 and their distribution across the five categories from figure 1 (pie chart). (A–G) Images show features of each category. (A) Patients microzide best price with postzygotic mutations often present with asymmetrical swelling and segmental overgrowth as this patient, who is mosaic for a mutation in KRAS. (B) Webbed neck in Noonan syndrome.

(C) In rare cases, swellings can be widespread affecting all segments of the body such as in this child with biallelic CCBE1 mutations. (D) In milder forms, often just the dorsum of the foot is affected as in microzide best price this baby with a VEGFR3 mutation. (E, F) Lower limb swelling and distichiasis (arrowheads in F) in a patient with a FOXC2 mutation. (G) Lymphoedema is a major cause of skin disease and affected patients suffer from severe and recurrent episodes of cutaneous infection, especially microzide best price HPV-associated warts as seen in patients with GATA2 mutations. GLD, generalised lymphatic dysplasia." data-icon-position data-hide-link-title="0">Figure 2 A graphic representation of the 227 audited patients seen in clinic in 2016 and their distribution across the five categories from figure 1 (pie chart).

(A–G) Images show features of each category microzide best price. (A) Patients with postzygotic mutations often present with asymmetrical swelling and segmental overgrowth as this patient, who is mosaic for a mutation in KRAS. (B) Webbed microzide best price neck in Noonan syndrome. (C) In rare cases, swellings can be widespread affecting all segments of the body such as in this child with biallelic CCBE1 mutations. (D) In microzide best price milder forms, often just the dorsum of the foot is affected as in this baby with a VEGFR3 mutation.

(E, F) Lower limb swelling and distichiasis (arrowheads in F) in a patient with a FOXC2 mutation. (G) Lymphoedema is a major cause of skin microzide best price disease and affected patients suffer from severe and recurrent episodes of cutaneous infection, especially HPV-associated warts as seen in patients with GATA2 mutations. GLD, generalised lymphatic dysplasia.These conditions are usually due to postzygotic mutations, for example, PIK3CA-related overgrowth spectrum (PROS)). Exceptions to this are capillary malformation-arteriovenous malformation (MIM 608354) such as Parkes-Weber syndrome, which may be caused by heterozygous, germline mutations in RASA1.10Of the 227 patients seen in 2016, 17% (n=39) had lymphoedema associated with vascular malformations and/or segmental overgrowth (or undergrowth) (figure 2, pie chart) in comparison with 15% in 2010.8 It has been microzide best price shown that postzygotic, gain of function mutations in PIK3CA may be responsible for many of the mosaic segmental overgrowth spectrum disorders.11 Postzygotic mutations are rarely identified in blood samples and therefore require a skin biopsy of the affected region. In the 2016 cohort, only 10 patients (26%) provided skin biopsies for genetic analysis, producing just one molecular diagnosis.

More research in this field is required microzide best price to identify the genetic basis for some of the conditions in this category. However, since the last revision, we have gained a much better understanding of the classification of some of these postzygotic mosaic conditions, therefore a brief review of the latest developments in this area is given in the online supplementary section.Syndromic lymphoedema (blue)Syndromes associated with primary lymphatic anomalies are listed in table 2 and include chromosomal abnormalities, single gene disorders and imprinting disorders. Patients attending the clinic with syndromic primary lymphoedema made up 13% (n=29) (figure 2, pie chart), similar to microzide best price the 15% reported by Connell et al.8 Nearly three-quarters (72%, n=21) of this cohort had a molecular or chromosomal diagnosis. The most frequently seen syndromes were Noonan syndrome (n=8) (figure 2B), Turner syndrome (n=4) and Phelan McDermid syndrome (n=3).View this table:Table 2 An overview of ‘Known Syndromes’ with primary lymphoedema as a non-dominant association as referred to in the St George’s classification algorithm (figure 1, blue section)Lymphoedema with prenatal or postnatal systemic involvement (pink)In some conditions, lymphoedema may be associated with internal (systemic or visceral) disturbances of the lymphatic system within thorax or abdomen, for example, fetal hydrops, intestinal lymphangiectasia (presenting as protein-losing enteropathy), pulmonary lymphangiectasia or with pericardial and/or pleural effusions (often chylous), or chylous reflux (often into the genitalia). Broadly, there microzide best price are two types of lymphoedema with systemic involvement.

(A) ‘widespread’ swelling affecting all segments of the body (figure 2C), such as that seen in generalised lymphatic dysplasia (GLD). Due to faulty development, the structural or functional abnormality of the lymphatic system is microzide best price affecting the whole body. One type is Hennekam-lymphangiectasia-lymphoedema syndrome12. (B) ‘patchy’ areas of swelling, for example, left arm and right leg, which have been named ‘multisegmental lymphatic dysplasia’ (MLD) (figure 1).Prenatally, these conditions may present with pleural effusions (hydrothoraces), microzide best price or as non-immune fetal hydrops (the accumulation of fluid in at least two compartments of a fetus such as the abdominal cavity, pleura or subcutaneous oedema). Fifteen per cent of non-immune cases of hydrops are the result of lymphatic disorders, and approximately 20% are idiopathic, some of which may be due to, as yet, unidentified lymphatic abnormalities.13In our audit, this cohort accounted for 12% (n=27) of patients (figure 2, pie chart), slightly higher than the 8% reported in 2010.8 Molecular testing was carried out in 17 patients.

Nine of those tested had GLD, and pathogenic variants were identified in microzide best price seven (78%). Five had biallelic variants in the PIEZO1 gene and one each with biallelic variants in FAT4 and SOX18. Interestingly, two of the families described by Connell et al, cases 3 and 4, have subsequently been found to be caused by biallelic variants in the PIEZO1 gene.8 14None of the eight patients, who presented with ‘patchy’ distribution of lymphoedema (MLD), had an identifiable molecular diagnosis. It is suspected that these patients could have a postzygotic mosaic mutation or WILD syndrome.15Since the last revision microzide best price of the St George’s classification algorithm was published,9 five new causal genes associated with GLD and/or non-immune fetal hydrops have been identified. ADAMTS3,16 EPHB4,17 FAT4,18 FBXL719 and PIEZO114 20 and are reviewed in the online supplementary section.Congenital onset lymphoedema (green)In this category, congenital onset is defined as lymphoedema that is present at birth or develops within the first year of life.

Bilateral lower limb swelling is the most microzide best price frequent presentation (figure 2D), but the swelling may be unilateral and/or involve the arms, genitalia and/or face, depending on the underlying cause. There are a number of different genetic disorders presenting with congenital lymphoedema (table 1). Milroy disease microzide best price (ORPHA79452. OMIM 153100) is the most common form, occurring as a result of pathogenic variants in FLT4/VEGFR3.21 22 The mutation may occur de novo, so a family history is not essential for this diagnosis. The lymphoedema is always confined to the lower limbs but may be unilateral, and may (rarely) involve the genitalia microzide best price.

Approximately 10% of mutation carriers do not have lymphoedema. Fetuses with Milroy microzide best price disease may present antenatally with pedal oedema in the third trimester, and, in a few cases, with bilateral hydrothoraces, which resolve before birth.Pathogenic variants in VEGFC, the ligand for VEGFR3, have also been identified in association with congenital primary lymphoedema of Gordon (OMIM 615907), also affecting the lower limbs.23–26The congenital category represents 21% (n=47) of the patients seen in 2016 (figure 2, pie chart) compared with 24% in 2010.8 A pathogenic variant was identified in 19 of the 47 (40%) patients genetically tested in this category. The majority (n=18) had pathogenic variants identified in FLT4/VEGFR3 and, in one patient, a pathogenic variant in the GJC2 gene. A GJC2 mutation in a patient presenting with lymphoedema at birth is unusual but shows the variability of the phenotype.Many of the conditions microzide best price listed under the other categories in the classification algorithm may initially present with congenital lymphoedema but systemic involvement, progressive overgrowth or vascular malformation may present later and are so reclassified. Likewise, some syndromic forms may present with congenital lymphoedema before any other manifestations, making diagnosis difficult at times.

Thus, the diagnosis of ‘isolated’ congenital primary lymphoedema may be difficult in a neonate presenting with pedal oedema microzide best price. Therefore, a molecular diagnosis in the neonatal period is clinically very useful in the management of these patients.Late-onset lymphoedema (purple)‘Late-onset’ lymphoedema is defined as presenting after the first year of life. Swelling can range from being unilateral, bilateral or can involve all four limbs and can present from early childhood up to adulthood (figures 1 microzide best price and 2E). Some may present with unilateral swelling, but the contralateral limb may become involved later or show abnormalities on lymphoscintigram even when clinically uninvolved. The phenotypes microzide best price also range from mild to severe.

There are currently five genes known to be associated with late-onset lymphoedema. FOXC2 (figure microzide best price 2F),27 GJC2,28 29 GATA2 (figure 2G),30 HGF31 and CELSR132 (table 1). For many patients the molecular cause remains elusive, particularly in those patients with Meige disease and late-onset (usually pubertal) unilateral lower limb lymphoedema.Late-onset primary lymphoedema accounted for 37% (n=85) in 2016 (figure 2, pie chart) comparable to the 36% reported in 2010.8 This category has a low number of molecular diagnoses (n=12. 14%) as there are currently no causative genes for Meige disease, which made up 36% (n=31) of patients microzide best price in this category.DiscussionThis review presents an updated St George’s classification algorithm of primary lymphatic anomalies and brings it in-line with the ISSVA classification for vascular anomalies. It cites eight new causative genes since the last publication and highlights the areas where the genetic basis is still not known.

This rapidly evolving field microzide best price demonstrates that primary lymphoedema and vascular malformations are highly heterogenous.The audit reports an overall successful molecular diagnosis in 26% of patients seen in the clinic, but 41% of those patients selected for molecular testing. This is a considerable improvement on the rate of a molecular diagnosis since the algorithm was first published in 2010. Only two microzide best price causal genes were known at that time. We can conclude from the audit that the algorithm works well in targeting mutation testing. Furthermore, use of the algorithm has led to the discovery of a number of causal genes.

While it could be argued that the introduction of the lymphoedema gene panel obviates any need for targeted gene tests, we believe that matching a phenotype to a likely gene reduces wasteful testing and helps enormously in the interpretation of variants of unknown microzide best price significance, which are becoming an increasing problem in the era of next-generation sequencing.Although providing a molecular diagnosis in one-quarter of all the patients with primary lymphoedema represents a considerable improvement from when the algorithm was last reviewed, the molecular diagnosis is still not identified in the majority of patients seen in the St George’s Clinic. In the diagnostic setting, the introduction of next-generation sequencing with a targeted (virtual) ‘lymphoedema gene panel’ may improve the diagnostic rate and broaden the phenotypic spectrum of many of the known genetic disorders. Understanding of the natural history of the microzide best price disorder will enable appropriate surveillance of, for example, leukaemia in Emberger syndrome (GATA2), and allow investigations for known associated problems, for example, congenital heart disease in patients with lymphoedema distichiasis syndrome (FOXC2). Prenatal diagnosis for the more serious conditions also becomes possible. Knowledge of causal genes, and mechanisms of pathophysiology, provide an opportunity for new, improved treatments (personalised medicine) (eg, mammalian target of rapamycin inhibitors for progressive overgrowth disorders).In conclusion, the St George’s classification algorithm for primary lymphatic anomalies has been microzide best price further refined.

With this review, we have provided insight into the most recently discovered genotypes and how this algorithm can be used in the clinic to guide management of patients with primary lymphoedema.IntroductionTriphalangeal thumb (TPT) is a rare congenital hand anomaly in which the thumb has three phalanges instead of two. TPT is usually microzide best price inherited in an autosomal dominant trait and is therefore commonly seen in affected families. In 1994, Heutink et al located the pathogenic locus of TPT at chromosome 7q36.1 Subsequently, Lettice et al determined that point mutations in the zone of polarising activity regulatory sequence (ZRS) causes TPT and preaxial polydactyly.2 The ZRS is a long-range regulatory element residing in intron 5 of LMBR1 and regulates Sonic Hedgehog (SHH) expression in the embryonic limb bud. Since the identification of the ZRS region, 18 different point mutations in the ZRS have been reported in TPT families.3There is broad phenotypical variability among different point microzide best price mutations in the ZRS. For example, variants on locations 323 and 739 in the ZRS cause mild presentations of isolated TPT.2 4 Alternatively, severe anomalies such as TPT accompanied with tibial hypoplasia have been observed in families with variants on position 404 and 406 in the ZRS.2 5–9 In mildly affected phenotypes, reduced penetrance is regularly observed.

In families who are more severely affected however, microzide best price no reports of reduced penetrance have been made.Identifying and reporting new variants in the ZRS is important for genotype-phenotype correlations in TPT families. Additionally, it will also help to further elucidate the exact molecular mechanism of the role of the ZRS in the regulation of SHH expression in the embryonic limb.We therefore report two families with variants in the ZRS. These variants were identified in Dutch families microzide best price with isolated TPT. Additionally, unaffected family members shared these variants with affected family members. Although this observation suggests that the genotype is not fully penetrant, minor anomalies within these presumed unaffected family members indicate subclinical expression of a TPT phenotype rather microzide best price than reduced penetrance of the genotype.

We define subclinical phenotypes as anomalies that are not recognised by affected family members since they do not cause functional constraints in daily life, but can be recognised during clinical workup by experienced physicians.MethodsClinical evaluationFamilies 1 and 2 were identified at the outpatient clinic for Congenital Hand and Upper Limb Anomalies at the Sophia Children’s Hospital in Rotterdam, The Netherlands. The family members were clinically examined and microzide best price consulted by a clinical geneticist. In family 1, peripheral blood samples were collected from the index patient, the mother and the grandfather of the index patient (figure 1). No blood samples were obtained from the brother of this patient as he was clinically unaffected and was microzide best price below adult age.Overview of Dutch TPT family 1. (A) Pedigree of the Dutch TPT family 1.

The index microzide best price patient is patient III-2. (B) X-ray image of the hand of the index patient. An additional microzide best price deltaphalanx is present in both thumbs. (C) X-ray image of the thumbs of patient III-2. Although there is no triphalangism present, the thumbs are remarkably broad microzide best price.

TPT, triphalangeal thumb." data-icon-position data-hide-link-title="0">Figure 1 Overview of Dutch TPT family 1. (A) Pedigree of the Dutch TPT family 1. The index patient is microzide best price patient III-2. (B) X-ray image of the hand of the index patient. An additional microzide best price deltaphalanx is present in both thumbs.

(C) X-ray image of the thumbs of patient III-2. Although there is no triphalangism present, the thumbs microzide best price are remarkably broad. TPT, triphalangeal thumb.In family 2, the index patient (III-2) visited the outpatient clinic for Congenital Hand and Upper Limb Anomalies at the Sophia Children’s Hospital in Rotterdam with his parents. The other microzide best price family members were visited as part of a field study. Included family members were clinically evaluated by a clinical geneticist, photographs were obtained and peripheral blood samples were collected (Figure 2, online supplementary figure 1).

No radiographs microzide best price were obtained during the field study.Supplemental materialOverview of Dutch TPT family 2. (A) Outtake of pedigree of the Dutch TPT family 2. (B) Images of patient microzide best price III-2 and his father (II-2), showing triphalangism of both thumbs with one additional ray on the left hand. (C) Images of patients II-4 and I-1, showing no triphalangism but lack of thumb opposition and mild thenar hypoplasia. TPT, triphalangeal thumb." data-icon-position microzide best price data-hide-link-title="0">Figure 2 Overview of Dutch TPT family 2.

(A) Outtake of pedigree of the Dutch TPT family 2. (B) Images microzide best price of patient III-2 and his father (II-2), showing triphalangism of both thumbs with one additional ray on the left hand. (C) Images of patients II-4 and I-1, showing no triphalangism but lack of thumb opposition and mild thenar hypoplasia. TPT, triphalangeal microzide best price thumb.ZRS sequencingDNA samples were isolated from peripheral blood. The fragments were amplified using standard PCR.

An 834 bp fragment covering the ZRS microzide best price (774 bp) was sequenced in family members of both families (UCSC Genome Browser, hg19, chr7:156583766–156584600). Sequencing of PCR products was executed using Big Dye Terminator 3.1. Fragments were loaded on an ABI 3130 Sequence analyser and genetic analysis was performed with SeqScape Software microzide best price (V.3.0).ResultsClinical report​Family 1Family 1 (figure 1A) consists of a nuclear family containing two affected patients with TPT. The index patient had a bilateral isolated TPT with an additional deltaphalanx (figure 1B). No other microzide best price congenital hand or other anomalies were present.

The mother of the index patient was born with a TPT accompanied with a rudimentary additional thumb on both hands, without any other hand or congenital anomaly (data not shown). The maternal grandfather microzide best price of the index patient did not have a TPT or preaxial polydactyly. However, clinical examination of the hands revealed remarkable broadness of both thumbs and mild thenar hypoplasia. Although the X-ray image of the grandfather shows no duplication of the thumb or triphalangism, the broadness of the distal phalanges is striking (figure 1C).​Family 2Family 2 comprises a large seven-generation family (Figure 2A, online supplementary figure 1). The index patient (III-2) had bilateral TPT with preaxial microzide best price polydactyly on the left hand.

The father of the index patient (II-1) had bilateral TPT without preaxial polydactyly (figure 2B). All other family microzide best price members reported they were not affected. Although the thumbs of family members I-1 and II-2 did not show clear features of triphalangism, further examination revealed that both family members had mild thenar hypoplasia and were unable to oppose both thumbs (figure 2C). No other congenital anomalies were present in family 2.Mutation analysisSequence analysis of the 774 bp ZRS, in intron 5 of LMBR1, revealed the microzide best price presence of a heterozygous A to G transition in members of family 1 (g.156584405A>G, GRCh37/Hg19). Following the more commonly used nomenclature for loci of ZRS variants, introduced by Lettice et al,2 this variant can be defined as a 165A>G variant.2 This variant was present in the affected family members.

Patient I-1 of family one also carried a 165A>G variant in the ZRS, despite not microzide best price having TPT on either hand. This variant was not present in public databases dbSNP, Clinvar and HGMD. Additionally, this variant was not present in locally available WGS data sets microzide best price (GoNL, Wellderly, Public54).10–12In family 2, we identified a 295T>variant in the ZRS (g.156584535T>C, GRCh37/Hg19). Two family members who did not have TPT carried the 295T>C variant. This variant microzide best price has previously been reported in a British family with mild cases of TPT and reduced penetrance of the genotype.13 Additionally, transgenic enhancer assays in mice showed that the 295T>C variant causes ectopic expression in the embryonic limb and therefore confirms the pathogenicity of this variant.DiscussionIn this brief report, we describe two TPT families with either a 165A>G or 295T>C variant in the ZRS.

The aim of this paper was to show that these observations of reduced penetrance in TPT families are in retrospect caused by mild and subclinical limb phenotypes without the presence of triphalangism and therefore raise awareness for thorough clinical examination in members of TPT families who are presumed to be unaffected.Ever since the identification of ZRS by Lettice et al in 2003, 18 variants in ZRS have been published in the literature.2 4 6–9 13–20 These variants are generally fully penetrant and have been found in families with either TPT or TPT with preaxial polydactyly. Exceptions to the above are point mutations on positions 105, 404 and 406 in ZRS, which cause more severe phenotypes like tibial hypoplasia and polysyndactyly.2 5–9 21Although most variants in ZRS are considered fully penetrant, reduced penetrance has been reported in several TPT families with variants on positions 295, 334, 463 and 739 in ZRS.13 14 16 17The first aim of this paper is to hypothesise that some of these observations might not be caused by reduced penetrance microzide best price of the genotype, but by a subclinical expression of the phenotype. We base our hypothesis on two arguments. First, family members who were initially presumed unaffected microzide best price do show minor anomalies or altered hand function when examined appropriately. In family 1 of this study, the grandfather did not have TPT but had evident broadness of the thumb.

In family 2, patients microzide best price with initially normal thumbs lacked the ability of opposition, which is caused by abnormal developmental patterning of the thumb. Although this observation is based on three patients from two families, we believe that these examples clearly illustrate our postulated hypothesis.Second, reports of non-penetrance are consistently associated with mild phenotypes in TPT families and not with severe TPT phenotypes, like tibial hypoplasia and polysyndactyly. This indicates that these observations only occur in TPT families where SHH expression microzide best price is only slightly disrupted. In these families, the variability in the phenotypical spectrum is apparently broad enough that family members with variants in ZRS can present with subclinical phenotypes instead of TPT. However, it remains unclear why the disruption of SHH causes TPT in one microzide best price family member and a subclinical phenotype in another.

One example of how intrafamilial variability can be explained is based on a reported family, where different degrees of somatic mosaicism were associated with various phenotypes in affected family members.22 As the regulatory function of ZRS on SHH is extremely delicate and affected by timing, location and level of activity, it is plausible that the slightest alteration of one of these factors can cause this interindividual phenotypical variation.The second aim of this paper is to underline the importance of two aspects when clinically examining and counselling patients with an inherited type of TPT. First, it is important to clinically investigate the presumed unaffected family members, as these patients might not encounter functional problems in their daily microzide best price life and will report they are unaffected. However, a distinct broadness of the thumb, a double flexion fold in the thumb or a duplicated lunula might indicate a discrete inclination for duplication of the thumb or the presence of an additional phalanx. Additionally, functional limitations regarding thumb strength or lack microzide best price of opposition should be evaluated as well. Second, presumed unaffected family members should only be informed that their future offspring have a population-wide probability of having TPT or polydactyly after genetic evaluation.

For complete reassurance, genetic evaluation of ZRS is also indicated for unaffected family members of mildly affected patients to verify whether they share the same disease-causing variant with their affected family members..

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€‚For the podcast associated with this article, buy microzide canada please visit https://academic.oup.com/eurheartj/pages/Podcasts. First scienceThe COVID-19 pandemic has changed the world and has refocused science, including cardiovascular (CV) research.1 This virus not only affects the throat and lungs, but also profoundly impacts the CV system. First of buy microzide canada all, male sex, obesity, hypertension,2 diabetes and cardiac conditions at large increased the risk of infection, possibly related to angiotensin-converting enzyme (ACE) expression,3,4 and of an unfavourable disease course. Secondly, COVID-19 affects the heart, leading to myocarditis,5,6 myocardial injury,7 scar formation and arrhythmias, and heart block,8 as well as affecting the blood vessels, leading to vascular occlusion due to local thrombus formation or embolism and eventually cardiac death.9 The mechanisms involved are the usual suspects, as outlined in the Viewpoint ‘COVID-19 is, in the end, an endothelial disease’, by Peter Libby from the Brigham and Women’s Hospital in Boston, USA and myself. It is well known that the vascular endothelium provides the crucial interface between the circulating blood and tissues, and displays remarkable properties buy microzide canada that normally maintain homeostasis.10 This tightly regulated array of functions includes control of haemostasis, fibrinolysis, inflammation, oxidative stress, vascular permeability, and eventually vasomotion and vascular structure.

While these functions participate in the moment to moment regulation of the circulation and coordinate many host defence mechanisms, they can also contribute to disease when their usually homeostatic and defensive functions overreach and turn against the host, as is the case with SARS-CoV-2, the virus causing the current pandemic (Figure 1). Figure 1Cytokine buy microzide canada storm. Proinflammatory cytokines such as IL-1 and TNF-α induce each other’s gene expression, unleashing an amplification loop that sustains the cytokine storm. The endothelial cell is a key target of cytokines, as they induce action of a central proinflammatory transcriptional hub, nuclear factor-κB. IL-1 also cause substantial increases in production by endothelial buy microzide canada and other cells of IL-6, the instigator of the hepatocyte acute phase response.

The acute phase reactants include fibrinogen, the precursor of clot, and PAI-1, the major inhibitor of our endogenous fibrinolytic system. C-reactive protein, buy microzide canada commonly elevated in COVID-19, provides a readily measured biomarker of inflammatory status. The alterations in the thrombotic/fibrinolytic balance due to the acute phase response predisposes towards thrombosis in arteries, in the microvasculature including that of organs such as the myocardium and kidney, and in veins, causing deep vein thrombosis and predisposing towards pulmonary embolism. Thus, the very same cytokines that elicit abnormal endothelial functions can unleash the acute phase response buy microzide canada which together with local endothelial dysfunction can conspire to cause the clinical complications of COVID-19. The right side of this diagram aligns therapeutic agents that attack these mechanisms of the cytokine storm and may thus limit its devastating consequences (from Libby P, Lüscher T.

COVID-19 is, in the end, an endothelial disease. See pages 3038–3044).Figure 1Cytokine storm buy microzide canada. Proinflammatory cytokines such as IL-1 and TNF-α induce each other’s gene expression, unleashing an amplification loop that sustains the cytokine storm. The endothelial cell is a key target of cytokines, as they induce action of a buy microzide canada central proinflammatory transcriptional hub, nuclear factor-κB. IL-1 also cause substantial increases in production by endothelial and other cells of IL-6, the instigator of the hepatocyte acute phase response.

The acute phase reactants include fibrinogen, the precursor of clot, and PAI-1, the major inhibitor of our buy microzide canada endogenous fibrinolytic system. C-reactive protein, commonly elevated in COVID-19, provides a readily measured biomarker of inflammatory status. The alterations in the thrombotic/fibrinolytic balance due to the acute phase response predisposes towards thrombosis in arteries, in the microvasculature including that of organs such as the myocardium and kidney, and in veins, causing deep vein thrombosis and predisposing towards pulmonary embolism. Thus, the very same cytokines that elicit abnormal endothelial functions can unleash the acute phase response which together with local endothelial dysfunction can conspire to cause buy microzide canada the clinical complications of COVID-19. The right side of this diagram aligns therapeutic agents that attack these mechanisms of the cytokine storm and may thus limit its devastating consequences (from Libby P, Lüscher T.

COVID-19 is, buy microzide canada in the end, an endothelial disease. See pages 3038–3044).It produces protean manifestations ranging from head to toe, wreaking seemingly indiscriminate havoc on multiple organ systems including the lungs, heart, brain, kidney, and the vasculature. This Viewpoint presents the hypothesis that COVID-19, buy microzide canada particularly in the later complicated stages, represents an endothelial disease. Cytokines, protein proinflammatory mediators, are key signals that shift endothelial function from the homeostatic into the defensive mode. The endgame of COVID-19 involves a cytokine storm with buy microzide canada positive feedback loops governing cytokine production that overwhelm counter-regulatory mechanisms.

This concept provides a unifying concept of this raging infection and a framework for rational treatment strategies at a time when we possess an only modest evidence base to guide our therapeutic attempts to confront this novel pandemic.11Surprisingly, emergency unit visits for acute cardiac conditions have declined markedly.12 Several reasons have been suggested. First, patients may have been wary of visiting hospitals during the pandemic.12,13 Secondly, with life on standstill, plaque ruptures and aortic dissections may have become less likely, and, thirdly, the marked reduction in pollution may also have had an influence.14 The first hypothesis is supported by the Fast Track manuscript ‘COVID-19 kills at home. The close relationship between the epidemic and the increase of out-of-hospital cardiac arrests’ by Simone Savastano and colleagues from the Fondazione IRCCS Policlinico San Matteo in Italy.15 They included all consecutive out-of-hospital cardiac arrests (OHCAs) occurring in the Provinces of Lodi, Cremona, Pavia, and Mantova in the 2 buy microzide canada months following the first documented case of COVID-19 in Lombardia compared with those that occurred in the same time window in 2019. The cumulative incidence of COVID-19 from 21 February to 20 April 2020 was 956/100 000 inhabitants and the cumulative incidence of OHCA was 21/100 000 inhabitants, with a 52% increase as compared with 2019 (Figure 2). A significant correlation was found between the difference in cumulative incidence of buy microzide canada OHCA and the cumulative incidence of COVID-19.

Thus, the OHCA excess in 2020 is closely correlated to the COVID-19 pandemic. These findings are important for furthering the understanding of the reduced emergency unit visits and for planning of future pandemics, as outlined in an Editorial by Hanno Tan from the Academic Medical Center in Amsterdam, the Netherlands.16 Figure 2(A) Over a period of 60 days from 20 February, the cumulative incidence of COVID-19 per 100 000 inhabitants in the four provinces and in the overall territory (dotted line) buy microzide canada (upper part), and the trend of the difference of OHCA between 2020 and 2019 per 100 000 inhabitants in the four provinces and in the overall territory (dotted line) (bottom part). (B) The cumulative incidence of the difference in OHCA between 2020 and 2019 per 100 000 inhabitants as a function of the cumulative incidence of COVID-19 per 100 000 inhabitants, since 20 February 2020. Dots are the observed values. The red line is the function fitted using fractional buy microzide canada polynomials.

The shaded area is the 95% CI for the estimates (from Baldi E, Maria Sechi G, Mare C, Canevari F, Brancaglione A, Primi R, Klersy C, Palo A, Contri E, Ronchi V, Beretta G, Reali F, Parogni P, Facchin F, Rizzi U, Bussi D, Ruggeri S, Visconti LO, Savastano S, on behalf of the Lombardia CARe researchers. COVID-19 kills buy microzide canada at home. The close relationship between the epidemic and the increase of out-of-hospital cardiac arrests. See pages 3045–3054).Figure 2(A) Over a period of 60 days from 20 February, the cumulative incidence of COVID-19 per 100 000 inhabitants in the four provinces and in the overall territory (dotted line) (upper part), and the trend of the difference of OHCA between 2020 and 2019 per 100 000 inhabitants in the four provinces and in the overall territory (dotted line) buy microzide canada (bottom part). (B) The cumulative incidence of the difference in OHCA between 2020 and 2019 per 100 000 inhabitants as a function of the cumulative incidence of COVID-19 per 100 000 inhabitants, since 20 February 2020.

Dots are the observed values. The red buy microzide canada line is the function fitted using fractional polynomials. The shaded area is the 95% CI for the estimates (from Baldi E, Maria Sechi G, Mare C, Canevari F, Brancaglione A, Primi R, Klersy C, Palo A, Contri E, Ronchi V, Beretta G, Reali F, Parogni P, Facchin F, Rizzi U, Bussi D, Ruggeri S, Visconti LO, Savastano S, on behalf of the Lombardia CARe researchers. COVID-19 kills at buy microzide canada home. The close relationship between the epidemic and the increase of out-of-hospital cardiac arrests.

See pages buy microzide canada 3045–3054).With a prothrombotic state of the endothelium, thrombo-embolism should increase during the COVID-19 pandemic.17 This hypothesis is pursued in a Fast Track entitled ‘Pulmonary embolism in COVID-19 patients. A French multicentre cohort study’ by Ariel Cohen from the Hopital Saint-Antoine in Paris, France.18 In a retrospective multicentric observational study, the authors included consecutive patients hospitalized for COVID-19. Among 1527 patients, 6.7% patients had pulmonary embolism confirmed by computed tomographty pulmonary angiography (CTPA). Intensive care buy microzide canada unit (ICU) transfer and mechanical ventilation were significantly higher in the pulmonary embolism group. In a univariable analysis, traditional venous thrombo-embolic risk factors and pulmonary lesion extension in chest CT were not associated with pulmonary embolism, while patients under anticoagulation prior to hospitalization or in whom it was introduced during hospitalization had a lower risk of pulmonary embolism, with an odds ratio of 0.37.

Male gender, prophylactic or therapeutic anticoagulation, C-reactive protein, and buy microzide canada time from symptom onset to hospitalization were associated with pulmonary embolism. Thus, risk factors for pulmonary embolism in COVID-19 do not include traditional thrombo-embolic risk factors, but rather independent clinical and biological findings at admission. In line with the concept outlined above, inflammation is a major driver of pulmonary embolism in COVID-19, as further discussed in a thought-provoking Editorial by Adam Torbicki from the Centre of Postgraduate Medical Education in Otwock, Poland.19Inflammation is also a trigger for atrial fibrillation as it changes the electrical properties of the atrial myocardium and eventually favours tissue fibrosis.20 Furthermore, inflammation may trigger tissue factor expression in the atrial endothelium and favour thrombus formation.21 On buy microzide canada the other hand, life on standstill may reduce sympathetic drive and hence reduce the likelihood of new-onset atrial fibrillation.22 In their article entitled ‘New-onset atrial fibrillation. Incidence, characteristics, and related events following a national COVID-19 lockdown of 5.6 million people’, Anders Holt and colleagues from the Copenhagen University Hospital, Herlev and Gentofte in Hellerup, Denmark resolved this conundrum.23 During 3 weeks of lockdown, weekly incidence rates of new-onset AF were 2.3, 1.8, and 1.5 per 1000 person-years, while during the corresponding weeks in 2019, incidence rates were 3.5, 3.4, and 3.6 per 1000 person-years. Incidence rate ratios buy microzide canada comparing the same weeks were 0.66, 0.53, and 0.41.

Patients diagnosed during lockdown were younger and had lower CHA2DS2-VASc-scores. During the first 3 weeks of lockdown, 7.8% of patients experienced an ischaemic stroke or death within 7 days of new-onset atrial fibrillation compared with 5.6% during the equivalent weeks in 2019, corresponding to an odds ratio of 1.41. Thus, following a national lockdown buy microzide canada in Denmark, new-onset atrial fibrillation declined by 47%, while ischaemic stroke or death within 7 days increased. These complex findings are put into context in an excellent Editorial by Carina Blomstrom-Lundqvist from the Department of Medical Science in Uppsala, Sweden.24Myocardial injury after non-cardiac surgery or MINS is caused by myocardial ischaemia due to a supply–demand mismatch or thrombus and is associated with an increased risk of mortality and major adverse CV events or MACE.25 In their review ‘Myocardial injury after non-cardiac surgery. Diagnosis and management’ Philip Devereaux and colleagues from McMaster University in Hamilton, Canada note that the diagnostic criteria for MINS include elevated post-operative troponin levels with no evidence of a non-ischaemic aetiology during or within 30 days after non-cardiac surgery, and without ischaemic features buy microzide canada such as chest pain or ECG changes.26 Patients with MINS should receive aspirin and a statin, unless contraindicated, and an NOAC (non-vitamin K antagonist oral anticoagulant) if not at high bleeding risk.

Cardiac catheterization is only recommended for those with recurrent ischaemia, heart failure, or high risk based on non-invasive imaging. Troponin should buy microzide canada be measured for the first few days after surgery in patients ≥65 years or with atherosclerotic disease to avoid missing MINS and the opportunity for secondary prophylactic measures and follow-up.Finally, the issue is complemented by various Discussion Forum contributions on this very timely topic. In a contribution entitled ‘Should atrial fibrillation be considered a cardiovascular risk factor for a worse prognosis in COVID-19 patients?. €™, Fabian Sanchis-Gomar from the Faculty of Medicine at the University of Valencia, Spain discuss the recent publication ‘Characteristics and outcomes of patients hospitalized for COVID-19 and cardiac disease in Northern Italy’ by Marco Metra and colleagues from Brescia, Italy.9,27 Metra et al. Respond in turn buy microzide canada.

In a comment entitled ‘ACE2 is on the X chromosome. Could this buy microzide canada explain COVID-19 gender differences?. €™ Felix Hernandez from the Universidad Autonoma de Madrid Centro de Biologia Molecular Severo Ochoa in Madrid, and his colleague Esther Culebras discuss the recent publication entitled ‘Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin–angiotensin–aldosterone inhibitors’ by Adriaan Voors and colleagues from the University Medical Center Groningen in the Netherlands.3,28 Voors et al. Respond in a separate comment.29In a contribution entitled ‘Circulating plasma buy microzide canada angiotensin-converting enzyme 2 concentrations in patients with kidney disease’, Insa Marie Schmidt and colleagues from the Boston University in Massachusetts, USA also comment on the article by Voors et al.3,30 Voors and colleagues respond in a separate message to this piece.31 Time for the last wordsThis is my last Issue@aGlance in the European Heart Journal in my role of Editor-in-Chief. It has been a pleasure and honour to serve both authors and readers of this fine journal and the European Society of Cardiology over more than a decade.

My goal has always been to make it more attractive and informative for clinicians and important and stimulating for scientists worldwide. I hope you have buy microzide canada enjoyed it. Needless to say, that was only possible thanks to an amazing team of editors, reviewers, authors, and editorial staff. I hope that you enjoy this very last issue under buy microzide canada my leadership. The time has come to hand the European Heart Journal over to the new Editor-in-Chief, Filippo Crea from Rome.

I am certain Professor Crea will do an excellent job with his new buy microzide canada team, retaining some of the experienced editorial staff from Zurich. Thank you for submitting to, reviewing for, and reading the European Heart Journal, and goodbye—I am sure we will stay in touch.With thanks to Amelia Meier-Batschelet for help with compilation of this article. References1Anker SD, Butler J, Khan MS, Abraham WT, Bauersachs J, Bocchi E, Bozkurt B, Braunwald E, Chopra VK, Cleland JG, Ezekowitz J, Filippatos G, Friede T, Hernandez AF, Lam CSP, Lindenfeld J, McMurray JJV, Mehra M, Metra M, Packer M, Pieske B, Pocock SJ, Ponikowski P, Rosano GMC, Teerlink JR, Tsutsui H, Van Veldhuisen DJ, Verma S, Voors AA, Wittes J, Zannad F, Zhang J, Seferovic P, Coats AJS. Conducting clinical trials in heart failure buy microzide canada during (and after) the COVID-19 pandemic. An Expert Consensus Position Paper from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC).

Eur Heart J 2020;41:2109–2117.2Gao C, buy microzide canada Cai Y, Zhang K, Zhou L, Zhang Y, Zhang X, Li Q, Li W, Yang S, Zhao X, Zhao Y, Wang H, Liu Y, Yin Z, Zhang R, Wang R, Yang M, Hui C, Wijns W, McEvoy JW, Soliman O, Onuma Y, Serruys PW, Tao L, Li F. Association of hypertension and antihypertensive treatment with COVID-19 mortality. A retrospective observational study buy microzide canada. Eur Heart J 2020;41:2058–2066.3Sama IE, Ravera A, Santema BT, van Goor H, Ter Maaten JM, Cleland JGF, Rienstra M, Friedrich AW, Samani NJ, Ng LL, Dickstein K, Lang CC, Filippatos G, Anker SD, Ponikowski P, Metra M, van Veldhuisen DJ, Voors AA. Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart buy microzide canada failure and effects of renin–angiotensin–aldosterone inhibitors.

Eur Heart J 2020;41:1810–1817.4Nicin L, Abplanalp WT, Mellentin H, Kattih B, Tombor L, John D, Schmitto JD, Heineke J, Emrich F, Arsalan M, Holubec T, Walther T, Zeiher AM, Dimmeler S. Cell type-specific expression of the putative SARS-CoV-2 receptor ACE2 in human hearts. Eur Heart buy microzide canada J 2020;41:1804–1806.5Kim IC, Kim JY, Kim HA, Han S. COVID-19-related myocarditis in a 21-year-old female patient. Eur Heart J 2020;41:1859.6Zhou buy microzide canada R.

Does SARS-CoV-2 cause viral myocarditis in COVID-19 patients?. Eur Heart J 2020;41:2123.7Shi S, Qin M, buy microzide canada Cai Y, Liu T, Shen B, Yang F, Cao S, Liu X, Xiang Y, Zhao Q, Huang H, Yang B, Huang C. Characteristics and clinical significance of myocardial injury in patients with severe coronavirus disease 2019. Eur Heart J 2020;41:2070–2079.8Azarkish M, Laleh Far V, Eslami M, Mollazadeh R. Transient complete buy microzide canada heart block in a patient with critical COVID-19.

Eur Heart J 2020;41:2131.9Inciardi RM, Adamo M, Lupi L, Cani DS, Di Pasquale M, Tomasoni D, Italia L, Zaccone G, Tedino C, Fabbricatore D, Curnis A, Faggiano P, Gorga E, Lombardi CM, Milesi G, Vizzardi E, Volpini M, Nodari S, Specchia C, Maroldi R, Bezzi M, Metra M. Characteristics and outcomes of patients hospitalized for COVID-19 and cardiac disease buy microzide canada in Northern Italy. Eur Heart J 2020;41:1821–1829.10Libby P, Lüscher T. COVID-19 is, in the end, an endothelial disease buy microzide canada. Eur Heart J 2020;41:3038–3044.11Pericàs JM, Hernandez-Meneses M, Sheahan TP, Quintana E, Ambrosioni J, Sandoval E, Falces C, Marcos MA, Tuset M, Vilella A, Moreno A, Miro JM.

COVID-19. From epidemiology to treatment buy microzide canada. Eur Heart J 2020;41:2092–2112.12De Rosa S, Spaccarotella C, Basso C, Calabrò MP, Curcio A, Filardi PP, Mancone M, Mercuro G, Muscoli S, Nodari S, Pedrinelli R, Sinagra G, Indolfi C. Reduction of hospitalizations for myocardial infarction buy microzide canada in Italy in the COVID-19 era. Eur Heart J 2020;41:2083–2088.13Mafham MM, Spata E, Goldacre R, Gair D, Curnow P, Bray M, Hollings S, Roebuck C, Gale CP, Mamas MA, Deanfield JE, de Belder MA, Luescher TF, Denwood T, Landray MJ, Emberson JR, Collins R, Morris EJA, Casadei B, Baigent C.

COVID-19 pandemic buy microzide canada and admission rates for and management of acute coronary syndromes in England. Lancet 2020;396:381–389.14Lelieveld J, Münzel T. Air pollution, buy microzide canada the underestimated cardiovascular risk factor. Eur Heart J 2020;41:904–905.15Baldi E, Sechi GM, Mare C, Canevari F, Brancaglione A, Primi R, Klersy C, Palo A, Contri E, Ronchi V, Beretta G, Reali F, Parogni P, Facchin F, Rizzi U, Bussi D, Ruggeri S, Oltrona Visconti L, Savastano S. COVID-19 kills at home.

The close relationship between the epidemic buy microzide canada and the increase of out-of-hospital cardiac arrests. Eur Heart J 2020;41:3045–3054.16Tan HL. How does buy microzide canada COVID-19 kill at home. And what should we do about it?. Eur Heart J 2020;41:3055–3057.17Gue buy microzide canada YX, Gorog DA.

Reduction in ACE2 may mediate the prothrombotic phenotype in COVID-19. Eur Heart J 2020;doi:10.1093/eurheartj/ehaa534.18Fauvel C, Weizman O, Trimaille A, Mika D, Pommier T, Pace N, Douair A, Barbin E, Fraix A, Bouchot O, Benmansour O, Godeau G, Mecheri Y, Lebourdon R, Yvorel C, Massin M, Leblon T, Chabbi C, Cugney E, Benabou L, Aubry M, Chan C, Boufoula I, Barnaud C, Bothorel L, Duceau B, Sutter W, Waldmann V, Bonnet G, Cohen A, Pezel T. Pulmonary embolism in buy microzide canada COVID-19 patients. A French multicentre cohort study. Eur Heart buy microzide canada J 2020;41:3058–3068.19Torbicki A.

COVID-19 and pulmonary embolism. An unwanted buy microzide canada alliance. Eur Heart J 2020;41:3069–3071.20Lazzerini PE, Laghi-Pasini F, Acampa M, Srivastava U, Bertolozzi I, Giabbani B, Finizola F, Vanni F, Dokollari A, Natale M, Cevenini G, Selvi E, Migliacci N, Maccherini M, Boutjdir M, Capecchi PL. Systemic inflammation rapidly induces reversible atrial electrical remodeling. The role buy microzide canada of interleukin-6-mediated changes in connexin expression.

J Am Heart Assoc 2019;8:e011006.21Steffel J, Lüscher TF, Tanner FC. Tissue factor in buy microzide canada cardiovascular diseases. Molecular mechanisms and clinical implications. Circulation 2006;113:722–731.22Chen PS, buy microzide canada Chen LS, Fishbein MC, Lin SF, Nattel S. Role of the autonomic nervous system in atrial fibrillation.

Pathophysiology and therapy. Circ Res 2014;114:1500–1515.23Holt A, Gislason GH, Schou M, Zareini B, Biering-Sørensen T, Phelps M, Kragholm K, Andersson C, Fosbøl EL, Hansen ML, Gerds buy microzide canada TA, Køber L, Torp-Pedersen C, Lamberts M. New-onset atrial fibrillation. Incidence, characteristics, and related events following a buy microzide canada national COVID-19 lockdown of 5.6 million people. Eur Heart J 2020;41:3072–3079.24Blomström-Lundqvist C.

Effects of buy microzide canada COVID-19 lockdown strategies on management of atrial fibrillation. Eur Heart J 2020;41:3080–3082.25Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galiè N, Gibbs JSR, Huisman MV, Humbert M, Kucher N, Lang I, Lankeit M, Lekakis J, Maack C, Mayer E, Meneveau N, Perrier A, Pruszczyk P, Rasmussen LH, Schindler TH, Svitil P, Vonk Noordegraaf A, Zamorano JL, Zompatori M, Zamorano JL, Achenbach S, Baumgartner H, Bax JJ, Bueno H, Dean V, Deaton C, Erol Ç, Fagard R, Ferrari R, Hasdai D, Hoes A, Kirchhof P, Knuuti J, Kolh P, Lancellotti P, Linhart A, Nihoyannopoulos P, Piepoli MF, Ponikowski P, Sirnes PA, Tamargo JL, Tendera M, Torbicki A, Wijns W, Windecker S, Erol Ç, Jimenez D, Ageno W, Agewall S, Asteggiano R, Bauersachs R, Becattini C, Bounameaux H, Büller HR, Davos CH, Deaton C, Geersing G-J, Sanchez MAG, Hendriks J, Hoes A, Kilickap M, Mareev V, Monreal M, Morais J, Nihoyannopoulos P, Popescu BA, Sanchez O, Spyropoulos AC. 2014 ESC buy microzide canada Guidelines on the diagnosis and management of acute pulmonary embolism. The Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Endorsed by the European Respiratory Society (ERS).

Eur Heart J 2014;35:3033–3080.26Devereaux PJ, buy microzide canada Szczeklik W. Myocardial injury after non-cardiac surgery. Diagnosis and management buy microzide canada. Eur Heart J 2020;41:3083–3091.27Sanchis-Gomar F, Perez-Quilis C, Lavie CJ. Should atrial fibrillation be considered a cardiovascular risk factor for a worse prognosis in buy microzide canada COVID-19 patients?.

Eur Heart J 2020;41:3092–3093.28Culebras E, Hernández F. ACE2 is on the X chromosome. Could this buy microzide canada explain COVID-19 gender differences?. Eur Heart J 2020;41:3095.29Sama IE, Voors AA. Men more buy microzide canada vulnerable to COVID-19.

Explained by ACE2 on the X chromosome?. Eur Heart J 2020;41:3096.30Schmidt IM, Verma A, Waikar SS buy microzide canada. Circulating plasma angiotensin-converting enzyme 2 concentrations in patients with kidney disease. Eur Heart J 2020;41:3097–3098.31Sama IE, Voors AA. Circulating plasma buy microzide canada angiotensin-converting enzyme 2 concentration is elevated in patients with kidney disease and diabetes.

Eur Heart J 2020;41:3099. Published on behalf of the European Society buy microzide canada of Cardiology. All rights reserved. © The Author(s) 2020 buy microzide canada. For permissions, please email.

€‚For the podcast associated with this article, please visit microzide best price https://academic.oup.com/eurheartj/pages/Podcasts. First scienceThe COVID-19 pandemic has changed the world and has refocused science, including cardiovascular (CV) research.1 This virus not only affects the throat and lungs, but also profoundly impacts the CV system. First of microzide best price all, male sex, obesity, hypertension,2 diabetes and cardiac conditions at large increased the risk of infection, possibly related to angiotensin-converting enzyme (ACE) expression,3,4 and of an unfavourable disease course.

Secondly, COVID-19 affects the heart, leading to myocarditis,5,6 myocardial injury,7 scar formation and arrhythmias, and heart block,8 as well as affecting the blood vessels, leading to vascular occlusion due to local thrombus formation or embolism and eventually cardiac death.9 The mechanisms involved are the usual suspects, as outlined in the Viewpoint ‘COVID-19 is, in the end, an endothelial disease’, by Peter Libby from the Brigham and Women’s Hospital in Boston, USA and myself. It is well known that the vascular endothelium provides the crucial interface between the circulating blood and tissues, and displays remarkable properties that normally maintain homeostasis.10 This tightly regulated array of functions includes control of haemostasis, fibrinolysis, inflammation, oxidative stress, vascular permeability, microzide best price and eventually vasomotion and vascular structure. While these functions participate in the moment to moment regulation of the circulation and coordinate many host defence mechanisms, they can also contribute to disease when their usually homeostatic and defensive functions overreach and turn against the host, as is the case with SARS-CoV-2, the virus causing the current pandemic (Figure 1).

Figure microzide best price 1Cytokine storm. Proinflammatory cytokines such as IL-1 and TNF-α induce each other’s gene expression, unleashing an amplification loop that sustains the cytokine storm. The endothelial cell is a key target of cytokines, as they induce action of a central proinflammatory transcriptional hub, nuclear factor-κB.

IL-1 also cause substantial increases in production by endothelial and other cells of IL-6, the instigator of the hepatocyte acute phase microzide best price response. The acute phase reactants include fibrinogen, the precursor of clot, and PAI-1, the major inhibitor of our endogenous fibrinolytic system. C-reactive protein, microzide best price commonly elevated in COVID-19, provides a readily measured biomarker of inflammatory status.

The alterations in the thrombotic/fibrinolytic balance due to the acute phase response predisposes towards thrombosis in arteries, in the microvasculature including that of organs such as the myocardium and kidney, and in veins, causing deep vein thrombosis and predisposing towards pulmonary embolism. Thus, the very same cytokines that microzide best price elicit abnormal endothelial functions can unleash the acute phase response which together with local endothelial dysfunction can conspire to cause the clinical complications of COVID-19. The right side of this diagram aligns therapeutic agents that attack these mechanisms of the cytokine storm and may thus limit its devastating consequences (from Libby P, Lüscher T.

COVID-19 is, in the end, an endothelial disease. See pages 3038–3044).Figure 1Cytokine storm microzide best price. Proinflammatory cytokines such as IL-1 and TNF-α induce each other’s gene expression, unleashing an amplification loop that sustains the cytokine storm.

The endothelial cell is a key target of cytokines, as microzide best price they induce action of a central proinflammatory transcriptional hub, nuclear factor-κB. IL-1 also cause substantial increases in production by endothelial and other cells of IL-6, the instigator of the hepatocyte acute phase response. The acute phase reactants include fibrinogen, the precursor of clot, microzide best price and PAI-1, the major inhibitor of our endogenous fibrinolytic system.

C-reactive protein, commonly elevated in COVID-19, provides a readily measured biomarker of inflammatory status. The alterations in the thrombotic/fibrinolytic balance due to the acute phase response predisposes towards thrombosis in arteries, in the microvasculature including that of organs such as the myocardium and kidney, and in veins, causing deep vein thrombosis and predisposing towards pulmonary embolism. Thus, the very same cytokines that elicit abnormal endothelial functions can unleash the acute microzide best price phase response which together with local endothelial dysfunction can conspire to cause the clinical complications of COVID-19.

The right side of this diagram aligns therapeutic agents that attack these mechanisms of the cytokine storm and may thus limit its devastating consequences (from Libby P, Lüscher T. COVID-19 is, in microzide best price the end, an endothelial disease. See pages 3038–3044).It produces protean manifestations ranging from head to toe, wreaking seemingly indiscriminate havoc on multiple organ systems including the lungs, heart, brain, kidney, and the vasculature.

This Viewpoint presents the hypothesis that COVID-19, particularly microzide best price in the later complicated stages, represents an endothelial disease. Cytokines, protein proinflammatory mediators, are key signals that shift endothelial function from the homeostatic into the defensive mode. The endgame of COVID-19 involves a cytokine microzide best price storm with positive feedback loops governing cytokine production that overwhelm counter-regulatory mechanisms.

This concept provides a unifying concept of this raging infection and a framework for rational treatment strategies at a time when we possess an only modest evidence base to guide our therapeutic attempts to confront this novel pandemic.11Surprisingly, emergency unit visits for acute cardiac conditions have declined markedly.12 Several reasons have been suggested. First, patients may have been wary of visiting hospitals during the pandemic.12,13 Secondly, with life on standstill, plaque ruptures and aortic dissections may have become less likely, and, thirdly, the marked reduction in pollution may also have had an influence.14 The first hypothesis is supported by the Fast Track manuscript ‘COVID-19 kills at home. The close relationship between the epidemic and the increase of out-of-hospital cardiac arrests’ by Simone Savastano and colleagues from the Fondazione IRCCS Policlinico San Matteo in Italy.15 They included all consecutive out-of-hospital cardiac arrests (OHCAs) occurring in the Provinces of Lodi, Cremona, Pavia, and Mantova in the 2 months following the first documented microzide best price case of COVID-19 in Lombardia compared with those that occurred in the same time window in 2019.

The cumulative incidence of COVID-19 from 21 February to 20 April 2020 was 956/100 000 inhabitants and the cumulative incidence of OHCA was 21/100 000 inhabitants, with a 52% increase as compared with 2019 (Figure 2). A significant correlation was found between the difference in cumulative incidence of microzide best price OHCA and the cumulative incidence of COVID-19. Thus, the OHCA excess in 2020 is closely correlated to the COVID-19 pandemic.

These findings are important for furthering the understanding of the reduced emergency unit visits and for planning of future pandemics, as outlined in an Editorial by Hanno Tan from the Academic Medical Center in Amsterdam, the Netherlands.16 Figure 2(A) Over a period of 60 days from 20 February, the cumulative incidence of COVID-19 per 100 000 inhabitants in the four provinces and in the overall territory (dotted line) (upper part), and the trend of the difference of OHCA between 2020 and 2019 per 100 microzide best price 000 inhabitants in the four provinces and in the overall territory (dotted line) (bottom part). (B) The cumulative incidence of the difference in OHCA between 2020 and 2019 per 100 000 inhabitants as a function of the cumulative incidence of COVID-19 per 100 000 inhabitants, since 20 February 2020. Dots are the observed values.

The red line is the function fitted microzide best price using fractional polynomials. The shaded area is the 95% CI for the estimates (from Baldi E, Maria Sechi G, Mare C, Canevari F, Brancaglione A, Primi R, Klersy C, Palo A, Contri E, Ronchi V, Beretta G, Reali F, Parogni P, Facchin F, Rizzi U, Bussi D, Ruggeri S, Visconti LO, Savastano S, on behalf of the Lombardia CARe researchers. COVID-19 kills microzide best price at home.

The close relationship between the epidemic and the increase of out-of-hospital cardiac arrests. See pages 3045–3054).Figure 2(A) Over a period of 60 days from 20 February, the cumulative incidence of COVID-19 per 100 000 inhabitants in the microzide best price four provinces and in the overall territory (dotted line) (upper part), and the trend of the difference of OHCA between 2020 and 2019 per 100 000 inhabitants in the four provinces and in the overall territory (dotted line) (bottom part). (B) The cumulative incidence of the difference in OHCA between 2020 and 2019 per 100 000 inhabitants as a function of the cumulative incidence of COVID-19 per 100 000 inhabitants, since 20 February 2020.

Dots are the observed values. The red line is the function fitted microzide best price using fractional polynomials. The shaded area is the 95% CI for the estimates (from Baldi E, Maria Sechi G, Mare C, Canevari F, Brancaglione A, Primi R, Klersy C, Palo A, Contri E, Ronchi V, Beretta G, Reali F, Parogni P, Facchin F, Rizzi U, Bussi D, Ruggeri S, Visconti LO, Savastano S, on behalf of the Lombardia CARe researchers.

COVID-19 kills at home microzide best price. The close relationship between the epidemic and the increase of out-of-hospital cardiac arrests. See pages 3045–3054).With a microzide best price prothrombotic state of the endothelium, thrombo-embolism should increase during the COVID-19 pandemic.17 This hypothesis is pursued in a Fast Track entitled ‘Pulmonary embolism in COVID-19 patients.

A French multicentre cohort study’ by Ariel Cohen from the Hopital Saint-Antoine in Paris, France.18 In a retrospective multicentric observational study, the authors included consecutive patients hospitalized for COVID-19. Among 1527 patients, 6.7% patients had pulmonary embolism confirmed by computed tomographty pulmonary angiography (CTPA). Intensive care unit (ICU) transfer and mechanical ventilation were microzide best price significantly higher in the pulmonary embolism group.

In a univariable analysis, traditional venous thrombo-embolic risk factors and pulmonary lesion extension in chest CT were not associated with pulmonary embolism, while patients under anticoagulation prior to hospitalization or in whom it was introduced during hospitalization had a lower risk of pulmonary embolism, with an odds ratio of 0.37. Male gender, prophylactic or therapeutic microzide best price anticoagulation, C-reactive protein, and time from symptom onset to hospitalization were associated with pulmonary embolism. Thus, risk factors for pulmonary embolism in COVID-19 do not include traditional thrombo-embolic risk factors, but rather independent clinical and biological findings at admission.

In line with the concept outlined above, inflammation is a major driver of pulmonary embolism in COVID-19, as further discussed in a thought-provoking Editorial by Adam Torbicki from the Centre of Postgraduate Medical Education in Otwock, Poland.19Inflammation is also a trigger for atrial fibrillation as it changes the electrical properties of the atrial myocardium and eventually favours tissue fibrosis.20 Furthermore, inflammation may trigger tissue factor expression in the atrial endothelium and favour thrombus formation.21 On the other hand, life on standstill may reduce sympathetic drive and hence reduce the likelihood of new-onset atrial fibrillation.22 In their article entitled ‘New-onset microzide best price atrial fibrillation. Incidence, characteristics, and related events following a national COVID-19 lockdown of 5.6 million people’, Anders Holt and colleagues from the Copenhagen University Hospital, Herlev and Gentofte in Hellerup, Denmark resolved this conundrum.23 During 3 weeks of lockdown, weekly incidence rates of new-onset AF were 2.3, 1.8, and 1.5 per 1000 person-years, while during the corresponding weeks in 2019, incidence rates were 3.5, 3.4, and 3.6 per 1000 person-years. Incidence rate ratios comparing the microzide best price same weeks were 0.66, 0.53, and 0.41.

Patients diagnosed during lockdown were younger and had lower CHA2DS2-VASc-scores. During the first 3 weeks of lockdown, 7.8% of patients experienced an ischaemic stroke or death within 7 days of new-onset atrial fibrillation compared with 5.6% during the equivalent weeks in 2019, corresponding to an odds ratio of 1.41. Thus, following a national microzide best price lockdown in Denmark, new-onset atrial fibrillation declined by 47%, while ischaemic stroke or death within 7 days increased.

These complex findings are put into context in an excellent Editorial by Carina Blomstrom-Lundqvist from the Department of Medical Science in Uppsala, Sweden.24Myocardial injury after non-cardiac surgery or MINS is caused by myocardial ischaemia due to a supply–demand mismatch or thrombus and is associated with an increased risk of mortality and major adverse CV events or MACE.25 In their review ‘Myocardial injury after non-cardiac surgery. Diagnosis and management’ Philip Devereaux and colleagues from McMaster University in Hamilton, Canada note that the diagnostic criteria for MINS include elevated post-operative troponin levels with no evidence of a non-ischaemic aetiology during or within 30 days after non-cardiac microzide best price surgery, and without ischaemic features such as chest pain or ECG changes.26 Patients with MINS should receive aspirin and a statin, unless contraindicated, and an NOAC (non-vitamin K antagonist oral anticoagulant) if not at high bleeding risk. Cardiac catheterization is only recommended for those with recurrent ischaemia, heart failure, or high risk based on non-invasive imaging.

Troponin should be measured for microzide best price the first few days after surgery in patients ≥65 years or with atherosclerotic disease to avoid missing MINS and the opportunity for secondary prophylactic measures and follow-up.Finally, the issue is complemented by various Discussion Forum contributions on this very timely topic. In a contribution entitled ‘Should atrial fibrillation be considered a cardiovascular risk factor for a worse prognosis in COVID-19 patients?. €™, Fabian Sanchis-Gomar from the Faculty of Medicine at the University of Valencia, Spain discuss the recent publication ‘Characteristics and outcomes of patients hospitalized for COVID-19 and cardiac disease in Northern Italy’ by Marco Metra and colleagues from Brescia, Italy.9,27 Metra et al.

Respond in microzide best price turn. In a comment entitled ‘ACE2 is on the X chromosome. Could this microzide best price explain COVID-19 gender differences?.

€™ Felix Hernandez from the Universidad Autonoma de Madrid Centro de Biologia Molecular Severo Ochoa in Madrid, and his colleague Esther Culebras discuss the recent publication entitled ‘Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin–angiotensin–aldosterone inhibitors’ by Adriaan Voors and colleagues from the University Medical Center Groningen in the Netherlands.3,28 Voors et al. Respond in a separate comment.29In a contribution entitled ‘Circulating plasma angiotensin-converting enzyme 2 concentrations in patients with kidney disease’, Insa Marie Schmidt and colleagues from the Boston University in Massachusetts, USA also comment on the article by Voors et al.3,30 Voors and colleagues respond in a separate message to this piece.31 Time microzide best price for the last wordsThis is my last Issue@aGlance in the European Heart Journal in my role of Editor-in-Chief. It has been a pleasure and honour to serve both authors and readers of this fine journal and the European Society of Cardiology over more than a decade.

My goal has always been to make it more attractive and informative for clinicians and important and stimulating for scientists worldwide. I hope you microzide best price have enjoyed it. Needless to say, that was only possible thanks to an amazing team of editors, reviewers, authors, and editorial staff.

I hope that you enjoy this very microzide best price last issue under my leadership. The time has come to hand the European Heart Journal over to the new Editor-in-Chief, Filippo Crea from Rome. I am certain Professor Crea will do an microzide best price excellent job with his new team, retaining some of the experienced editorial staff from Zurich.

Thank you for submitting to, reviewing for, and reading the European Heart Journal, and goodbye—I am sure we will stay in touch.With thanks to Amelia Meier-Batschelet for help with compilation of this article. References1Anker SD, Butler J, Khan MS, Abraham WT, Bauersachs J, Bocchi E, Bozkurt B, Braunwald E, Chopra VK, Cleland JG, Ezekowitz J, Filippatos G, Friede T, Hernandez AF, Lam CSP, Lindenfeld J, McMurray JJV, Mehra M, Metra M, Packer M, Pieske B, Pocock SJ, Ponikowski P, Rosano GMC, Teerlink JR, Tsutsui H, Van Veldhuisen DJ, Verma S, Voors AA, Wittes J, Zannad F, Zhang J, Seferovic P, Coats AJS. Conducting clinical trials in heart microzide best price failure during (and after) the COVID-19 pandemic.

An Expert Consensus Position Paper from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur Heart J microzide best price 2020;41:2109–2117.2Gao C, Cai Y, Zhang K, Zhou L, Zhang Y, Zhang X, Li Q, Li W, Yang S, Zhao X, Zhao Y, Wang H, Liu Y, Yin Z, Zhang R, Wang R, Yang M, Hui C, Wijns W, McEvoy JW, Soliman O, Onuma Y, Serruys PW, Tao L, Li F. Association of hypertension and antihypertensive treatment with COVID-19 mortality.

A retrospective observational study microzide best price. Eur Heart J 2020;41:2058–2066.3Sama IE, Ravera A, Santema BT, van Goor H, Ter Maaten JM, Cleland JGF, Rienstra M, Friedrich AW, Samani NJ, Ng LL, Dickstein K, Lang CC, Filippatos G, Anker SD, Ponikowski P, Metra M, van Veldhuisen DJ, Voors AA. Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and microzide best price effects of renin–angiotensin–aldosterone inhibitors.

Eur Heart J 2020;41:1810–1817.4Nicin L, Abplanalp WT, Mellentin H, Kattih B, Tombor L, John D, Schmitto JD, Heineke J, Emrich F, Arsalan M, Holubec T, Walther T, Zeiher AM, Dimmeler S. Cell type-specific expression of the putative SARS-CoV-2 receptor ACE2 in human hearts. Eur Heart J 2020;41:1804–1806.5Kim IC, Kim microzide best price JY, Kim HA, Han S.

COVID-19-related myocarditis in a 21-year-old female patient. Eur Heart microzide best price J 2020;41:1859.6Zhou R. Does SARS-CoV-2 cause viral myocarditis in COVID-19 patients?.

Eur Heart J microzide best price 2020;41:2123.7Shi S, Qin M, Cai Y, Liu T, Shen B, Yang F, Cao S, Liu X, Xiang Y, Zhao Q, Huang H, Yang B, Huang C. Characteristics and clinical significance of myocardial injury in patients with severe coronavirus disease 2019. Eur Heart J 2020;41:2070–2079.8Azarkish M, Laleh Far V, Eslami M, Mollazadeh R.

Transient complete heart block in a patient with critical COVID-19 microzide best price. Eur Heart J 2020;41:2131.9Inciardi RM, Adamo M, Lupi L, Cani DS, Di Pasquale M, Tomasoni D, Italia L, Zaccone G, Tedino C, Fabbricatore D, Curnis A, Faggiano P, Gorga E, Lombardi CM, Milesi G, Vizzardi E, Volpini M, Nodari S, Specchia C, Maroldi R, Bezzi M, Metra M. Characteristics and outcomes of patients hospitalized for COVID-19 and cardiac microzide best price disease in Northern Italy.

Eur Heart J 2020;41:1821–1829.10Libby P, Lüscher T. COVID-19 is, in the end, an endothelial microzide best price disease. Eur Heart J 2020;41:3038–3044.11Pericàs JM, Hernandez-Meneses M, Sheahan TP, Quintana E, Ambrosioni J, Sandoval E, Falces C, Marcos MA, Tuset M, Vilella A, Moreno A, Miro JM.

COVID-19. From epidemiology to microzide best price treatment. Eur Heart J 2020;41:2092–2112.12De Rosa S, Spaccarotella C, Basso C, Calabrò MP, Curcio A, Filardi PP, Mancone M, Mercuro G, Muscoli S, Nodari S, Pedrinelli R, Sinagra G, Indolfi C.

Reduction of hospitalizations for myocardial infarction microzide best price in Italy in the COVID-19 era. Eur Heart J 2020;41:2083–2088.13Mafham MM, Spata E, Goldacre R, Gair D, Curnow P, Bray M, Hollings S, Roebuck C, Gale CP, Mamas MA, Deanfield JE, de Belder MA, Luescher TF, Denwood T, Landray MJ, Emberson JR, Collins R, Morris EJA, Casadei B, Baigent C. COVID-19 pandemic and admission rates for and microzide best price management of acute coronary syndromes in England.

Lancet 2020;396:381–389.14Lelieveld J, Münzel T. Air pollution, the underestimated cardiovascular microzide best price risk factor. Eur Heart J 2020;41:904–905.15Baldi E, Sechi GM, Mare C, Canevari F, Brancaglione A, Primi R, Klersy C, Palo A, Contri E, Ronchi V, Beretta G, Reali F, Parogni P, Facchin F, Rizzi U, Bussi D, Ruggeri S, Oltrona Visconti L, Savastano S.

COVID-19 kills at home. The close relationship between the epidemic and the increase of out-of-hospital cardiac microzide best price arrests. Eur Heart J 2020;41:3045–3054.16Tan HL.

How does microzide best price COVID-19 kill at home. And what should we do about it?. Eur Heart J 2020;41:3055–3057.17Gue microzide best price YX, Gorog DA.

Reduction in ACE2 may mediate the prothrombotic phenotype in COVID-19. Eur Heart J 2020;doi:10.1093/eurheartj/ehaa534.18Fauvel C, Weizman O, Trimaille A, Mika D, Pommier T, Pace N, Douair A, Barbin E, Fraix A, Bouchot O, Benmansour O, Godeau G, Mecheri Y, Lebourdon R, Yvorel C, Massin M, Leblon T, Chabbi C, Cugney E, Benabou L, Aubry M, Chan C, Boufoula I, Barnaud C, Bothorel L, Duceau B, Sutter W, Waldmann V, Bonnet G, Cohen A, Pezel T. Pulmonary embolism in COVID-19 patients microzide best price.

A French multicentre cohort study. Eur Heart J 2020;41:3058–3068.19Torbicki microzide best price A. COVID-19 and pulmonary embolism.

An unwanted alliance microzide best price. Eur Heart J 2020;41:3069–3071.20Lazzerini PE, Laghi-Pasini F, Acampa M, Srivastava U, Bertolozzi I, Giabbani B, Finizola F, Vanni F, Dokollari A, Natale M, Cevenini G, Selvi E, Migliacci N, Maccherini M, Boutjdir M, Capecchi PL. Systemic inflammation rapidly induces reversible atrial electrical remodeling.

The role of interleukin-6-mediated changes in connexin expression microzide best price. J Am Heart Assoc 2019;8:e011006.21Steffel J, Lüscher TF, Tanner FC. Tissue factor microzide best price in cardiovascular diseases.

Molecular mechanisms and clinical implications. Circulation 2006;113:722–731.22Chen PS, Chen LS, Fishbein MC, Lin SF, Nattel S microzide best price. Role of the autonomic nervous system in atrial fibrillation.

Pathophysiology and therapy. Circ Res 2014;114:1500–1515.23Holt A, Gislason GH, Schou M, Zareini B, Biering-Sørensen T, Phelps M, microzide best price Kragholm K, Andersson C, Fosbøl EL, Hansen ML, Gerds TA, Køber L, Torp-Pedersen C, Lamberts M. New-onset atrial fibrillation.

Incidence, characteristics, and microzide best price related events following a national COVID-19 lockdown of 5.6 million people. Eur Heart J 2020;41:3072–3079.24Blomström-Lundqvist C. Effects of COVID-19 microzide best price lockdown strategies on management of atrial fibrillation.

Eur Heart J 2020;41:3080–3082.25Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galiè N, Gibbs JSR, Huisman MV, Humbert M, Kucher N, Lang I, Lankeit M, Lekakis J, Maack C, Mayer E, Meneveau N, Perrier A, Pruszczyk P, Rasmussen LH, Schindler TH, Svitil P, Vonk Noordegraaf A, Zamorano JL, Zompatori M, Zamorano JL, Achenbach S, Baumgartner H, Bax JJ, Bueno H, Dean V, Deaton C, Erol Ç, Fagard R, Ferrari R, Hasdai D, Hoes A, Kirchhof P, Knuuti J, Kolh P, Lancellotti P, Linhart A, Nihoyannopoulos P, Piepoli MF, Ponikowski P, Sirnes PA, Tamargo JL, Tendera M, Torbicki A, Wijns W, Windecker S, Erol Ç, Jimenez D, Ageno W, Agewall S, Asteggiano R, Bauersachs R, Becattini C, Bounameaux H, Büller HR, Davos CH, Deaton C, Geersing G-J, Sanchez MAG, Hendriks J, Hoes A, Kilickap M, Mareev V, Monreal M, Morais J, Nihoyannopoulos P, Popescu BA, Sanchez O, Spyropoulos AC. 2014 ESC Guidelines on the diagnosis and management microzide best price of acute pulmonary embolism. The Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC).

Endorsed by the European Respiratory Society (ERS). Eur Heart J 2014;35:3033–3080.26Devereaux PJ, Szczeklik W microzide best price. Myocardial injury after non-cardiac surgery.

Diagnosis and microzide best price management. Eur Heart J 2020;41:3083–3091.27Sanchis-Gomar F, Perez-Quilis C, Lavie CJ. Should atrial fibrillation microzide best price be considered a cardiovascular risk factor for a worse prognosis in COVID-19 patients?.

Eur Heart J 2020;41:3092–3093.28Culebras E, Hernández F. ACE2 is on the X chromosome. Could this microzide best price explain COVID-19 gender differences?.

Eur Heart J 2020;41:3095.29Sama IE, Voors AA. Men more microzide best price vulnerable to COVID-19. Explained by ACE2 on the X chromosome?.

Eur Heart microzide best price J 2020;41:3096.30Schmidt IM, Verma A, Waikar SS. Circulating plasma angiotensin-converting enzyme 2 concentrations in patients with kidney disease. Eur Heart J 2020;41:3097–3098.31Sama IE, Voors AA.

Circulating plasma microzide best price angiotensin-converting enzyme 2 concentration is elevated in patients with kidney disease and diabetes. Eur Heart J 2020;41:3099. Published on behalf of the European Society microzide best price of Cardiology.

All rights reserved. © The Author(s) microzide best price 2020. For permissions, please email.

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Start Preamble Centers for Medicare & where can i buy microzide. Medicaid Services (CMS), HHS. Extension of timeline for publication of final rule where can i buy microzide. This notice announces an extension of the timeline for publication of a Medicare final rule in accordance with the Social Security Act, which allows us to extend the timeline for publication of the final rule.

As of August 26, 2020, the timeline for publication of the final rule to finalize the provisions of the October 17, 2019 proposed rule (84 where can i buy microzide FR 55766) is extended until August 31, 2021. Start Further Info Lisa O. Wilson, (410) 786-8852. End Further Info End Preamble Start Supplemental Information In the October 17, 2019 Federal Register (84 FR 55766), we published a proposed rule that where can i buy microzide addressed undue regulatory impact and burden of the physician self-referral law.

The proposed rule was issued in conjunction with the Centers for Medicare &. Medicaid Services' (CMS) Patients over Paperwork initiative and the Department of Health where can i buy microzide and Human Services' (the Department or HHS) Regulatory Sprint to Coordinated Care. In the proposed rule, we proposed exceptions to the physician self-referral law for certain value-based compensation arrangements between or among physicians, providers, and suppliers. A new exception for certain arrangements under which a physician receives limited remuneration for items or services actually provided by the physician.

A new where can i buy microzide exception for donations of cybersecurity technology and related services. And amendments to the existing exception for electronic health records (EHR) items and services. The proposed rule also provides critically necessary guidance for physicians and health care providers and suppliers whose financial relationships are governed by where can i buy microzide the physician self-referral statute and regulations. This notice announces an extension of the timeline for publication of the final rule and the continuation of effectiveness of the proposed rule.

Section 1871(a)(3)(A) of the Social Security Act (the Act) requires us to establish and publish a regular timeline for the publication of final regulations based on the previous publication of a proposed regulation. In accordance with section 1871(a)(3)(B) of the Act, the timeline may vary among different regulations based on differences in the complexity of where can i buy microzide the regulation, the number and scope of comments received, and other relevant factors, but may not be longer than 3 years except under exceptional circumstances. In addition, in accordance with section 1871(a)(3)(B) of the Act, the Secretary may extend the initial targeted publication date of the final regulation if the Secretary, no later than the regulation's previously established proposed publication date, publishes a notice with the new target date, and such notice includes a brief explanation of the justification for the variation. We announced in the Spring 2020 Unified Agenda (June 30, where can i buy microzide 2020, www.reginfo.gov) that we would issue the final rule in August 2020.

However, we are still working through the Start Printed Page 52941complexity of the issues raised by comments received on the proposed rule and therefore we are not able to meet the announced publication target date. This notice extends the timeline for publication of the final where can i buy microzide rule until August 31, 2021. Start Signature Dated. August 24, 2020.

Wilma M where can i buy microzide. Robinson, Deputy Executive Secretary to the Department, Department of Health and Human Services. End Signature End where can i buy microzide Supplemental Information [FR Doc. 2020-18867 Filed 8-26-20.

8:45 am]BILLING CODE 4120-01-PStart Preamble Notice of amendment. The Secretary issues this where can i buy microzide amendment pursuant to section 319F-3 of the Public Health Service Act to add additional categories of Qualified Persons and amend the category of disease, health condition, or threat for which he recommends the administration or use of the Covered Countermeasures. This amendment to the Declaration published on March 17, 2020 (85 FR 15198) is effective as of August 24, 2020. Start Further Info Robert P where can i buy microzide.

Kadlec, MD, MTM&H, MS, Assistant Secretary for Preparedness and Response, Office of the Secretary, Department of Health and Human Services, 200 Independence Avenue SW, Washington, DC 20201. Telephone. 202-205-2882. End Further Info End Preamble Start Supplemental Information The Public Readiness and Emergency Preparedness Act (PREP Act) authorizes the Secretary of Health and Human Services (the Secretary) to issue a Declaration to provide liability immunity to certain individuals and entities (Covered Persons) against any claim of loss caused by, arising out of, relating to, or resulting from the manufacture, distribution, administration, or use of medical countermeasures (Covered Countermeasures), except for claims involving “willful misconduct” as defined in the PREP Act.

Under the PREP Act, a Declaration may be amended as circumstances warrant. The PREP Act was enacted on December 30, 2005, as Public Law 109-148, Division C, § 2. It amended the Public Health Service (PHS) Act, adding section 319F-3, which addresses liability immunity, and section 319F-4, which creates a compensation program. These sections are codified at 42 U.S.C.

247d-6d and 42 U.S.C. 247d-6e, respectively. Section 319F-3 of the PHS Act has been amended by the Pandemic and All-Hazards Preparedness Reauthorization Act (PAHPRA), Public Law 113-5, enacted on March 13, 2013 and the Coronavirus Aid, Relief, and Economic Security (CARES) Act, Public Law 116-136, enacted on March 27, Start Printed Page 521372020, to expand Covered Countermeasures under the PREP Act. On January 31, 2020, the Secretary declared a public health emergency pursuant to section 319 of the PHS Act, 42 U.S.C.

247d, effective January 27, 2020, for the entire United States to aid in the response of the nation's health care community to the COVID-19 outbreak. Pursuant to section 319 of the PHS Act, the Secretary renewed that declaration on April 26, 2020, and July 25, 2020. On March 10, 2020, the Secretary issued a Declaration under the PREP Act for medical countermeasures against COVID-19 (85 FR 15198, Mar. 17, 2020) (the Declaration).

On April 10, the Secretary amended the Declaration under the PREP Act to extend liability immunity to covered countermeasures authorized under the CARES Act (85 FR 21012, Apr. 15, 2020). On June 4, the Secretary amended the Declaration to clarify that covered countermeasures under the Declaration include qualified countermeasures that limit the harm COVID-19 might otherwise cause. The Secretary now amends section V of the Declaration to identify as qualified persons covered under the PREP Act, and thus authorizes, certain State-licensed pharmacists to order and administer, and pharmacy interns (who are licensed or registered by their State board of pharmacy and acting under the supervision of a State-licensed pharmacist) to administer, any vaccine that the Advisory Committee on Immunization Practices (ACIP) recommends to persons ages three through 18 according to ACIP's standard immunization schedule (ACIP-recommended vaccines).[] The Secretary also amends section VIII of the Declaration to clarify that the category of disease, health condition, or threat for which he recommends the administration or use of the Covered Countermeasures includes not only COVID-19 caused by SARS-CoV-2 or a virus mutating therefrom, but also other diseases, health conditions, or threats that may have been caused by COVID-19, SARS-CoV-2, or a virus mutating therefrom, including the decrease in the rate of childhood immunizations, which will lead to an increase in the rate of infectious diseases.

Description of This Amendment by Section Section V. Covered Persons Under the PREP Act and the Declaration, a “qualified person” is a “covered person.” Subject to certain limitations, a covered person is immune from suit and liability under Federal and State law with respect to all claims for loss caused by, arising out of, relating to, or resulting from the administration or use of a covered countermeasure if a declaration under subsection (b) has been issued with respect to such countermeasure. €œQualified person” includes (A) a licensed health professional or other individual who is authorized to prescribe, administer, or dispense such countermeasures under the law of the State in which the countermeasure was prescribed, administered, or dispensed. Or (B) “a person within a category of persons so identified in a declaration by the Secretary” under subsection (b) of the PREP Act.

42 U.S.C. 247d-6d(i)(8).[] By this amendment to the Declaration, the Secretary identifies an additional category of persons who are qualified persons under section 247d-6d(i)(8)(B).[] On May 8, 2020, CDC reported, “The identified declines in routine pediatric vaccine ordering and doses administered might indicate that U.S. Children and their communities face increased risks for outbreaks of vaccine-preventable diseases,” and suggested that a decrease in rates of routine childhood vaccinations were due to changes in healthcare access, social distancing, and other COVID-19 mitigation strategies.[] The report also stated that “[p]arental concerns about potentially exposing their children to COVID-19 during well child visits might contribute to the declines observed.” [] On July 10, 2020, CDC reported its findings of a May survey it conducted to assess the capacity of pediatric health care practices to provide immunization services to children during the COVID-19 pandemic. The survey, which was limited to practices participating in the Vaccines for Children program, found that, as of mid-May, 15 percent of Northeast pediatric practices were closed, 12.5 percent of Midwest practices were closed, 6.2 percent of practices in the South were closed, and 10 percent of practices in the West were closed.

Most practices had reduced office hours for in-person visits. When asked whether their practices would likely be able to accommodate new patients for immunization services through August, 418 practices (21.3 percent) either responded that this was not likely or the practice was permanently closed or not resuming immunization services for all patients, and 380 (19.6 percent) responded that they were unsure. Urban practices and those in the Northeast were less likely to be able to accommodate new patients compared with rural practices and those in the South, Midwest, or West.[] In response to these troubling developments, CDC and the American Academy of Pediatrics have stressed, “Well-child visits and vaccinations are essential services and help make sure children are protected.” [] The Secretary re-emphasizes that important recommendation to parents and legal guardians here. If your child is due for a well-child visit, contact your pediatrician's or other primary-care provider's office and ask about ways that the office safely offers well-child visits and vaccinations.

Many medical offices are taking extra steps to make sure that well-child visits can occur safely during the COVID-19 pandemic, including. Scheduling sick visits and well-child visits during different times of the Start Printed Page 52138day or days of the week, or at different locations. Asking patients to remain outside until it is time for their appointments to reduce the number of people in waiting rooms. Adhering to recommended social (physical) distancing and other infection-control practices, such as the use of masks.

The decrease in childhood-vaccination rates is a public health threat and a collateral harm caused by COVID-19. Together, the United States must turn to available medical professionals to limit the harm and public health threats that may result from decreased immunization rates. We must quickly do so to avoid preventable infections in children, additional strains on our healthcare system, and any further increase in avoidable adverse health consequences—particularly if such complications coincide with additional resurgence of COVID-19. Together with pediatricians and other healthcare professionals, pharmacists are positioned to expand access to childhood vaccinations.

Many States already allow pharmacists to administer vaccines to children of any age.[] Other States permit pharmacists to administer vaccines to children depending on the age—for example, 2, 3, 5, 6, 7, 9, 10, 11, or 12 years of age and older.[] Few States restrict pharmacist-administered vaccinations to only adults.[] Many States also allow properly trained individuals under the supervision of a trained pharmacist to administer those vaccines.[] Pharmacists are well positioned to increase access to vaccinations, particularly in certain areas or for certain populations that have too few pediatricians and other primary-care providers, or that are otherwise medically underserved.[] As of 2018, nearly 90 percent of Americans lived within five miles of a community pharmacy.[] Pharmacies often offer extended hours and added convenience. What is more, pharmacists are trusted healthcare professionals with established relationships with their patients. Pharmacists also have strong relationships with local medical providers and hospitals to refer patients as appropriate. For example, pharmacists already play a significant role in annual influenza vaccination.

In the early 2018-19 season, they administered the influenza vaccine to nearly a third of all adults who received the vaccine.[] Given the potential danger of serious influenza and continuing COVID-19 outbreaks this autumn and the impact that such concurrent outbreaks may have on our population, our healthcare system, and our whole-of-nation response to the COVID-19 pandemic, we must quickly expand access to influenza vaccinations. Allowing more qualified pharmacists to administer the influenza vaccine to children will make vaccinations more accessible. Therefore, the Secretary amends the Declaration to identify State-licensed pharmacists (and pharmacy interns acting under their supervision if the pharmacy intern is licensed or registered by his or her State board of pharmacy) as qualified persons under section 247d-6d(i)(8)(B) when the pharmacist orders and either the pharmacist or the supervised pharmacy intern administers vaccines to individuals ages three through 18 pursuant to the following requirements. The vaccine must be FDA-authorized or FDA-approved.

The vaccination must be ordered and administered according to ACIP's standard immunization schedule.[] The licensed pharmacist must complete a practical training program of at least 20 hours that is approved by the Accreditation Council for Pharmacy Education (ACPE). This training Start Printed Page 52139program must include hands-on injection technique, clinical evaluation of indications and contraindications of vaccines, and the recognition and treatment of emergency reactions to vaccines.[] The licensed or registered pharmacy intern must complete a practical training program that is approved by the ACPE. This training program must include hands-on injection technique, clinical evaluation of indications and contraindications of vaccines, and the recognition and treatment of emergency reactions to vaccines.[] The licensed pharmacist and licensed or registered pharmacy intern must have a current certificate in basic cardiopulmonary resuscitation.[] The licensed pharmacist must complete a minimum of two hours of ACPE-approved, immunization-related continuing pharmacy education during each State licensing period.[] The licensed pharmacist must comply with recordkeeping and reporting requirements of the jurisdiction in which he or she administers vaccines, including informing the patient's primary-care provider when available, submitting the required immunization information to the State or local immunization information system (vaccine registry), complying with requirements with respect to reporting adverse events, and complying with requirements whereby the person administering a vaccine must review the vaccine registry or other vaccination records prior to administering a vaccine.[] The licensed pharmacist must inform his or her childhood-vaccination patients and the adult caregivers accompanying the children of the importance of a well-child visit with a pediatrician or other licensed primary-care provider and refer patients as appropriate.[] These requirements are consistent with those in many States that permit licensed pharmacists to order and administer vaccines to children and permit licensed or registered pharmacy interns acting under their supervision to administer vaccines to children.[] Administering vaccinations to children age three and older is less complicated and requires less training and resources than administering vaccinations to younger children. That is because ACIP generally recommends administering intramuscular injections in the deltoid muscle for individuals age three and older.[] For individuals less than three years of age, ACIP generally recommends administering intramuscular injections in the anterolateral aspect of the thigh muscle.[] Administering injections in the thigh muscle often presents additional complexities and requires additional training and resources including additional personnel to safely position the child while another healthcare professional injects the vaccine.[] Moreover, as of 2018, 40% of three-year-olds were enrolled in preprimary programs (i.e.

Preschool or kindergarten programs).[] Preprimary programs are beginning in the coming weeks or months, so the Secretary has concluded that it is particularly important for individuals ages three through 18 to receive ACIP-recommended vaccines according to ACIP's standard immunization schedule. All States require children to be vaccinated against certain communicable diseases as a condition of school attendance. These laws often apply to both public and private schools with identical immunization and exemption provisions.[] As nurseries, preschools, kindergartens, and schools reopen, increased access to childhood vaccinations is essential to ensuring children can return. Notwithstanding any State or local scope-of-practice legal requirements, (1) qualified licensed pharmacists are identified as qualified persons to order and administer ACIP-recommended vaccines and (2) qualified State-licensed or registered pharmacy interns are identified as qualified persons to administer the ACIP-recommended vaccines ordered by their supervising qualified licensed pharmacist.[] Both the PREP Act and the June 4, 2020 Second Amendment to the Declaration define “covered countermeasures” to include qualified pandemic and epidemic products that “limit the harm such pandemic or epidemic might otherwise cause.” [] The troubling decrease in ACIP-recommended childhood vaccinations and the resulting increased risk of associated diseases, adverse health conditions, and other threats are categories of harms otherwise caused by Start Printed Page 52140COVID-19 as set forth in Sections VI and VIII of this Declaration.[] Hence, such vaccinations are “covered countermeasures” under the PREP Act and the June 4, 2020 Second Amendment to the Declaration.

Nothing in this Declaration shall be construed to affect the National Vaccine Injury Compensation Program, including an injured party's ability to obtain compensation under that program. Covered countermeasures that are subject to the National Vaccine Injury Compensation Program authorized under 42 U.S.C. 300aa-10 et seq. Are covered under this Declaration for the purposes of liability immunity and injury compensation only to the extent that injury compensation is not provided under that Program.

All other terms and conditions of the Declaration apply to such covered countermeasures. Section VIII. Category of Disease, Health Condition, or Threat As discussed, the troubling decrease in ACIP-recommended childhood vaccinations and the resulting increased risk of associated diseases, adverse health conditions, and other threats are categories of harms otherwise caused by COVID-19. The Secretary therefore amends section VIII, which describes the category of disease, health condition, or threat for which he recommends the administration or use of the Covered Countermeasures, to clarify that the category of disease, health condition, or threat for which he recommends the administration or use of the Covered Countermeasures is not only COVID-19 caused by SARS-CoV-2 or a virus mutating therefrom, but also other diseases, health conditions, or threats that may have been caused by COVID-19, SARS-CoV-2, or a virus mutating therefrom, including the decrease in the rate of childhood immunizations, which will lead to an increase in the rate of infectious diseases.

Amendments to Declaration Amended Declaration for Public Readiness and Emergency Preparedness Act Coverage for medical countermeasures against COVID-19. Sections V and VIII of the March 10, 2020 Declaration under the PREP Act for medical countermeasures against COVID-19, as amended April 10, 2020 and June 4, 2020, are further amended pursuant to section 319F-3(b)(4) of the PHS Act as described below. All other sections of the Declaration remain in effect as published at 85 FR 15198 (Mar. 17, 2020) and amended at 85 FR 21012 (Apr.

15, 2020) and 85 FR 35100 (June 8, 2020). 1. Covered Persons, section V, delete in full and replace with. V.

Covered Persons 42 U.S.C. 247d-6d(i)(2), (3), (4), (6), (8)(A) and (B) Covered Persons who are afforded liability immunity under this Declaration are “manufacturers,” “distributors,” “program planners,” “qualified persons,” and their officials, agents, and employees, as those terms are defined in the PREP Act, and the United States. In addition, I have determined that the following additional persons are qualified persons. (a) Any person authorized in accordance with the public health and medical emergency response of the Authority Having Jurisdiction, as described in Section VII below, to prescribe, administer, deliver, distribute or dispense the Covered Countermeasures, and their officials, agents, employees, contractors and volunteers, following a Declaration of an emergency.

(b) any person authorized to prescribe, administer, or dispense the Covered Countermeasures or who is otherwise authorized to perform an activity under an Emergency Use Authorization in accordance with Section 564 of the FD&C Act. (c) any person authorized to prescribe, administer, or dispense Covered Countermeasures in accordance with Section 564A of the FD&C Act. And (d) a State-licensed pharmacist who orders and administers, and pharmacy interns who administer (if the pharmacy intern acts under the supervision of such pharmacist and the pharmacy intern is licensed or registered by his or her State board of pharmacy), vaccines that the Advisory Committee on Immunization Practices (ACIP) recommends to persons ages three through 18 according to ACIP's standard immunization schedule. Such State-licensed pharmacists and the State-licensed or registered interns under their supervision are qualified persons only if the following requirements are met.

The vaccine must be FDA-authorized or FDA-approved. The vaccination must be ordered and administered according to ACIP's standard immunization schedule. The licensed pharmacist must complete a practical training program of at least 20 hours that is approved by the Accreditation Council for Pharmacy Education (ACPE). This training program must include hands-on injection technique, clinical evaluation of indications and contraindications of vaccines, and the recognition and treatment of emergency reactions to vaccines.

The licensed or registered pharmacy intern must complete a practical training program that is approved by the ACPE. This training program must include hands-on injection technique, clinical evaluation of indications and contraindications of vaccines, and the recognition and treatment of emergency reactions to vaccines. The licensed pharmacist and licensed or registered pharmacy intern must have a current certificate in basic cardiopulmonary resuscitation. The licensed pharmacist must complete a minimum of two hours of ACPE-approved, immunization-related continuing pharmacy education during each State licensing period.

The licensed pharmacist must comply with recordkeeping and reporting requirements of the jurisdiction in which he or she administers vaccines, including informing the patient's primary-care provider when available, submitting the required immunization information to the State or local immunization information system (vaccine registry), complying with requirements with respect to reporting adverse events, and complying with requirements whereby the person administering a vaccine must review the vaccine registry or other vaccination records prior to administering a vaccine. The licensed pharmacist must inform his or her childhood-vaccination patients and the adult caregiver accompanying the child of the importance of a well-child visit with a pediatrician or other licensed primary-care provider and refer patients as appropriate. Nothing in this Declaration shall be construed to affect the National Vaccine Injury Compensation Program, including an injured party's ability to obtain compensation under that program. Covered countermeasures that are subject to the National Vaccine Injury Compensation Program authorized under 42 U.S.C.

300aa-10 et seq. Are covered under this Declaration for the purposes of liability immunity and injury compensation only to the extent that injury compensation is not provided under that Program. All other Start Printed Page 52141terms and conditions of the Declaration apply to such covered countermeasures. 2.

Category of Disease, Health Condition, or Threat, section VIII, delete in full and replace with. VIII. Category of Disease, Health Condition, or Threat 42 U.S.C. 247d-6d(b)(2)(A) The category of disease, health condition, or threat for which I recommend the administration or use of the Covered Countermeasures is not only COVID-19 caused by SARS-CoV-2 or a virus mutating therefrom, but also other diseases, health conditions, or threats that may have been caused by COVID-19, SARS-CoV-2, or a virus mutating therefrom, including the decrease in the rate of childhood immunizations, which will lead to an increase in the rate of infectious diseases.

Start Authority 42 U.S.C. 247d-6d. End Authority Start Signature Dated. August 19, 2020.

Alex M. Azar II, Secretary of Health and Human Services. End Signature End Supplemental Information [FR Doc. 2020-18542 Filed 8-20-20.

Start Preamble Centers for Medicare & microzide best price. Medicaid Services (CMS), HHS. Extension of timeline for publication of final rule microzide best price. This notice announces an extension of the timeline for publication of a Medicare final rule in accordance with the Social Security Act, which allows us to extend the timeline for publication of the final rule.

As of August 26, 2020, the timeline for publication of the final rule to finalize the provisions microzide best price of the October 17, 2019 proposed rule (84 FR 55766) is extended until August 31, 2021. Start Further Info Lisa O. Wilson, (410) 786-8852. End Further Info End Preamble Start Supplemental Information In the October microzide best price 17, 2019 Federal Register (84 FR 55766), we published a proposed rule that addressed undue regulatory impact and burden of the physician self-referral law.

The proposed rule was issued in conjunction with the Centers for Medicare &. Medicaid Services' (CMS) Patients over Paperwork initiative microzide best price and the Department of Health and Human Services' (the Department or HHS) Regulatory Sprint to Coordinated Care. In the proposed rule, we proposed exceptions to the physician self-referral law for certain value-based compensation arrangements between or among physicians, providers, and suppliers. A new exception for certain arrangements under which a physician receives limited remuneration for items or services actually provided by the physician.

A new exception for donations microzide best price of cybersecurity technology and related services. And amendments to the existing exception for electronic health records (EHR) items and services. The proposed rule also provides critically necessary guidance for microzide best price physicians and health care providers and suppliers whose financial relationships are governed by the physician self-referral statute and regulations. This notice announces an extension of the timeline for publication of the final rule and the continuation of effectiveness of the proposed rule.

Section 1871(a)(3)(A) of the Social Security Act (the Act) requires us to establish and publish a regular timeline for the publication of final regulations based on the previous publication of a proposed regulation. In accordance with section 1871(a)(3)(B) of the Act, the timeline may vary among different regulations based on differences in the complexity of the regulation, the number and scope of comments received, and other relevant factors, but may not be longer than 3 years microzide best price except under exceptional circumstances. In addition, in accordance with section 1871(a)(3)(B) of the Act, the Secretary may extend the initial targeted publication date of the final regulation if the Secretary, no later than the regulation's previously established proposed publication date, publishes a notice with the new target date, and such notice includes a brief explanation of the justification for the variation. We announced in the Spring 2020 Unified Agenda (June microzide best price 30, 2020, www.reginfo.gov) that we would issue the final rule in August 2020.

However, we are still working through the Start Printed Page 52941complexity of the issues raised by comments received on the proposed rule and therefore we are not able to meet the announced publication target date. This notice extends the timeline for publication of the final rule microzide best price until August 31, 2021. Start Signature Dated. August 24, 2020.

Wilma M microzide best price. Robinson, Deputy Executive Secretary to the Department, Department of Health and Human Services. End Signature End Supplemental microzide best price Information [FR Doc. 2020-18867 Filed 8-26-20.

8:45 am]BILLING CODE 4120-01-PStart Preamble Notice of amendment. The Secretary issues this amendment pursuant to section 319F-3 of the Public Health microzide best price Service Act to add additional categories of Qualified Persons and amend the category of disease, health condition, or threat for which he recommends the administration or use of the Covered Countermeasures. This amendment to the Declaration published on March 17, 2020 (85 FR 15198) is effective as of August 24, 2020. Start Further Info Robert microzide best price P.

Kadlec, MD, MTM&H, MS, Assistant Secretary for Preparedness and Response, Office of the Secretary, Department of Health and Human Services, 200 Independence Avenue SW, Washington, DC 20201. Telephone. 202-205-2882. End Further Info End Preamble Start Supplemental Information The Public Readiness and Emergency Preparedness Act (PREP Act) authorizes the Secretary of Health and Human Services (the Secretary) to issue a Declaration to provide liability immunity to certain individuals and entities (Covered Persons) against any claim of loss caused by, arising out of, relating to, or resulting from the manufacture, distribution, administration, or use of medical countermeasures (Covered Countermeasures), except for claims involving “willful misconduct” as defined in the PREP Act.

Under the PREP Act, a Declaration may be amended as circumstances warrant. The PREP Act was enacted on December 30, 2005, as Public Law 109-148, Division C, § 2. It amended the Public Health Service (PHS) Act, adding section 319F-3, which addresses liability immunity, and section 319F-4, which creates a compensation program. These sections are codified at 42 U.S.C.

247d-6d and 42 U.S.C. 247d-6e, respectively. Section 319F-3 of the PHS Act has been amended by the Pandemic and All-Hazards Preparedness Reauthorization Act (PAHPRA), Public Law 113-5, enacted on March 13, 2013 and the Coronavirus Aid, Relief, and Economic Security (CARES) Act, Public Law 116-136, enacted on March 27, Start Printed Page 521372020, to expand Covered Countermeasures under the PREP Act. On January 31, 2020, the Secretary declared a public health emergency pursuant to section 319 of the PHS Act, 42 U.S.C.

247d, effective January 27, 2020, for the entire United States to aid in the response of the nation's health care community to the COVID-19 outbreak. Pursuant to section 319 of the PHS Act, the Secretary renewed that declaration on April 26, 2020, and July 25, 2020. On March 10, 2020, the Secretary issued a Declaration under the PREP Act for medical countermeasures against COVID-19 (85 FR 15198, Mar. 17, 2020) (the Declaration).

On April 10, the Secretary amended the Declaration under the PREP Act to extend liability immunity to covered countermeasures authorized under the CARES Act (85 FR 21012, Apr. 15, 2020). On June 4, the Secretary amended the Declaration to clarify that covered countermeasures under the Declaration include qualified countermeasures that limit the harm COVID-19 might otherwise cause. The Secretary now amends section V of the Declaration to identify as qualified persons covered under the PREP Act, and thus authorizes, certain State-licensed pharmacists to order and administer, and pharmacy interns (who are licensed or registered by their State board of pharmacy and acting under the supervision of a State-licensed pharmacist) to administer, any vaccine that the Advisory Committee on Immunization Practices (ACIP) recommends to persons ages three through 18 according to ACIP's standard immunization schedule (ACIP-recommended vaccines).[] The Secretary also amends section VIII of the Declaration to clarify that the category of disease, health condition, or threat for which he recommends the administration or use of the Covered Countermeasures includes not only COVID-19 caused by SARS-CoV-2 or a virus mutating therefrom, but also other diseases, health conditions, or threats that may have been caused by COVID-19, SARS-CoV-2, or a virus mutating therefrom, including the decrease in the rate of childhood immunizations, which will lead to an increase in the rate of infectious diseases.

Description of This Amendment by Section Section V. Covered Persons Under the PREP Act and the Declaration, a “qualified person” is a “covered person.” Subject to certain limitations, a covered person is immune from suit and liability under Federal and State law with respect to all claims for loss caused by, arising out of, relating to, or resulting from the administration or use of a covered countermeasure if a declaration under subsection (b) has been issued with respect to such countermeasure. €œQualified person” includes (A) a licensed health professional or other individual who is authorized to prescribe, administer, or dispense such countermeasures under the law of the State in which the countermeasure was prescribed, administered, or dispensed. Or (B) “a person within a category of persons so identified in a declaration by the Secretary” under subsection (b) of the PREP Act.

42 U.S.C. 247d-6d(i)(8).[] By this amendment to the Declaration, the Secretary identifies an additional category of persons who are qualified persons under section 247d-6d(i)(8)(B).[] On May 8, 2020, CDC reported, “The identified declines in routine pediatric vaccine ordering and doses administered might indicate that U.S. Children and their communities face increased risks for outbreaks of vaccine-preventable diseases,” and suggested that a decrease in rates of routine childhood vaccinations were due to changes in healthcare access, social distancing, and other COVID-19 mitigation strategies.[] The report also stated that “[p]arental concerns about potentially exposing their children to COVID-19 during well child visits might contribute to the declines observed.” [] On July 10, 2020, CDC reported its findings of a May survey it conducted to assess the capacity of pediatric health care practices to provide immunization services to children during the COVID-19 pandemic. The survey, which was limited to practices participating in the Vaccines for Children program, found that, as of mid-May, 15 percent of Northeast pediatric practices were closed, 12.5 percent of Midwest practices were closed, 6.2 percent of practices in the South were closed, and 10 percent of practices in the West were closed.

Most practices had reduced office hours for in-person visits. When asked whether their practices would likely be able to accommodate new patients for immunization services through August, 418 practices (21.3 percent) either responded that this was not likely or the practice was permanently closed or not resuming immunization services for all patients, and 380 (19.6 percent) responded that they were unsure. Urban practices and those in the Northeast were less likely to be able to accommodate new patients compared with rural practices and those in the South, Midwest, or West.[] In response to these troubling developments, CDC and the American Academy of Pediatrics have stressed, “Well-child visits and vaccinations are essential services and help make sure children are protected.” [] The Secretary re-emphasizes that important recommendation to parents and legal guardians here. If your child is due for a well-child visit, contact your pediatrician's or other primary-care provider's office and ask about ways that the office safely offers well-child visits and vaccinations.

Many medical offices are taking extra steps to make sure that well-child visits can occur safely during the COVID-19 pandemic, including. Scheduling sick visits and well-child visits during different times of the Start Printed Page 52138day or days of the week, or at different locations. Asking patients to remain outside until it is time for their appointments to reduce the number of people in waiting rooms. Adhering to recommended social (physical) distancing and other infection-control practices, such as the use of masks.

The decrease in childhood-vaccination rates is a public health threat and a collateral harm caused by COVID-19. Together, the United States must turn to available medical professionals to limit the harm and public health threats that may result from decreased immunization rates. We must quickly do so to avoid preventable infections in children, additional strains on our healthcare system, and any further increase in avoidable adverse health consequences—particularly if such complications coincide with additional resurgence of COVID-19. Together with pediatricians and other healthcare professionals, pharmacists are positioned to expand access to childhood vaccinations.

Many States already allow pharmacists to administer vaccines to children of any age.[] Other States permit pharmacists to administer vaccines to children depending on the age—for example, 2, 3, 5, 6, 7, 9, 10, 11, or 12 years of age and older.[] Few States restrict pharmacist-administered vaccinations to only adults.[] Many States also allow properly trained individuals under the supervision of a trained pharmacist to administer those vaccines.[] Pharmacists are well positioned to increase access to vaccinations, particularly in certain areas or for certain populations that have too few pediatricians and other primary-care providers, or that are otherwise medically underserved.[] As of 2018, nearly 90 percent of Americans lived within five miles of a community pharmacy.[] Pharmacies often offer extended hours and added convenience. What is more, pharmacists are trusted healthcare professionals with established relationships with their patients. Pharmacists also have strong relationships with local medical providers and hospitals to refer patients as appropriate. For example, pharmacists already play a significant role in annual influenza vaccination.

In the early 2018-19 season, they administered the influenza vaccine to nearly a third of all adults who received the vaccine.[] Given the potential danger of serious influenza and continuing COVID-19 outbreaks this autumn and the impact that such concurrent outbreaks may have on our population, our healthcare system, and our whole-of-nation response to the COVID-19 pandemic, we must quickly expand access to influenza vaccinations. Allowing more qualified pharmacists to administer the influenza vaccine to children will make vaccinations more accessible. Therefore, the Secretary amends the Declaration to identify State-licensed pharmacists (and pharmacy interns acting under their supervision if the pharmacy intern is licensed or registered by his or her State board of pharmacy) as qualified persons under section 247d-6d(i)(8)(B) when the pharmacist orders and either the pharmacist or the supervised pharmacy intern administers vaccines to individuals ages three through 18 pursuant to the following requirements. The vaccine must be FDA-authorized or FDA-approved.

The vaccination must be ordered and administered according to ACIP's standard immunization schedule.[] The licensed pharmacist must complete a practical training program of at least 20 hours that is approved by the Accreditation Council for Pharmacy Education (ACPE). This training Start Printed Page 52139program must include hands-on injection technique, clinical evaluation of indications and contraindications of vaccines, and the recognition and treatment of emergency reactions to vaccines.[] The licensed or registered pharmacy intern must complete a practical training program that is approved by the ACPE. This training program must include hands-on injection technique, clinical evaluation of indications and contraindications of vaccines, and the recognition and treatment of emergency reactions to vaccines.[] The licensed pharmacist and licensed or registered pharmacy intern must have a current certificate in basic cardiopulmonary resuscitation.[] The licensed pharmacist must complete a minimum of two hours of ACPE-approved, immunization-related continuing pharmacy education during each State licensing period.[] The licensed pharmacist must comply with recordkeeping and reporting requirements of the jurisdiction in which he or she administers vaccines, including informing the patient's primary-care provider when available, submitting the required immunization information to the State or local immunization information system (vaccine registry), complying with requirements with respect to reporting adverse events, and complying with requirements whereby the person administering a vaccine must review the vaccine registry or other vaccination records prior to administering a vaccine.[] The licensed pharmacist must inform his or her childhood-vaccination patients and the adult caregivers accompanying the children of the importance of a well-child visit with a pediatrician or other licensed primary-care provider and refer patients as appropriate.[] These requirements are consistent with those in many States that permit licensed pharmacists to order and administer vaccines to children and permit licensed or registered pharmacy interns acting under their supervision to administer vaccines to children.[] Administering vaccinations to children age three and older is less complicated and requires less training and resources than administering vaccinations to younger children. That is because ACIP generally recommends administering intramuscular injections in the deltoid muscle for individuals age three and older.[] For individuals less than three years of age, ACIP generally recommends administering intramuscular injections in the anterolateral aspect of the thigh muscle.[] Administering injections in the thigh muscle often presents additional complexities and requires additional training and resources including additional personnel to safely position the child while another healthcare professional injects the vaccine.[] Moreover, as of 2018, 40% of three-year-olds were enrolled in preprimary programs (i.e.

Preschool or kindergarten programs).[] Preprimary programs are beginning in the coming weeks or months, so the Secretary has concluded that it is particularly important for individuals ages three through 18 to receive ACIP-recommended vaccines according to ACIP's standard immunization schedule. All States require children to be vaccinated against certain communicable diseases as a condition of school attendance. These laws often apply to both public and private schools with identical immunization and exemption provisions.[] As nurseries, preschools, kindergartens, and schools reopen, increased access to childhood vaccinations is essential to ensuring children can return. Notwithstanding any State or local scope-of-practice legal requirements, (1) qualified licensed pharmacists are identified as qualified persons to order and administer ACIP-recommended vaccines and (2) qualified State-licensed or registered pharmacy interns are identified as qualified persons to administer the ACIP-recommended vaccines ordered by their supervising qualified licensed pharmacist.[] Both the PREP Act and the June 4, 2020 Second Amendment to the Declaration define “covered countermeasures” to include qualified pandemic and epidemic products that “limit the harm such pandemic or epidemic might otherwise cause.” [] The troubling decrease in ACIP-recommended childhood vaccinations and the resulting increased risk of associated diseases, adverse health conditions, and other threats are categories of harms otherwise caused by Start Printed Page 52140COVID-19 as set forth in Sections VI and VIII of this Declaration.[] Hence, such vaccinations are “covered countermeasures” under the PREP Act and the June 4, 2020 Second Amendment to the Declaration.

Nothing in this Declaration shall be construed to affect the National Vaccine Injury Compensation Program, including an injured party's ability to obtain compensation under that program. Covered countermeasures that are subject to the National Vaccine Injury Compensation Program authorized under 42 U.S.C. 300aa-10 et seq. Are covered under this Declaration for the purposes of liability immunity and injury compensation only to the extent that injury compensation is not provided under that Program.

All other terms and conditions of the Declaration apply to such covered countermeasures. Section VIII. Category of Disease, Health Condition, or Threat As discussed, the troubling decrease in ACIP-recommended childhood vaccinations and the resulting increased risk of associated diseases, adverse health conditions, and other threats are categories of harms otherwise caused by COVID-19. The Secretary therefore amends section VIII, which describes the category of disease, health condition, or threat for which he recommends the administration or use of the Covered Countermeasures, to clarify that the category of disease, health condition, or threat for which he recommends the administration or use of the Covered Countermeasures is not only COVID-19 caused by SARS-CoV-2 or a virus mutating therefrom, but also other diseases, health conditions, or threats that may have been caused by COVID-19, SARS-CoV-2, or a virus mutating therefrom, including the decrease in the rate of childhood immunizations, which will lead to an increase in the rate of infectious diseases.

Amendments to Declaration Amended Declaration for Public Readiness and Emergency Preparedness Act Coverage for medical countermeasures against COVID-19. Sections V and VIII of the March 10, 2020 Declaration under the PREP Act for medical countermeasures against COVID-19, as amended April 10, 2020 and June 4, 2020, are further amended pursuant to section 319F-3(b)(4) of the PHS Act as described below. All other sections of the Declaration remain in effect as published at 85 FR 15198 (Mar. 17, 2020) and amended at 85 FR 21012 (Apr.

15, 2020) and 85 FR 35100 (June 8, 2020). 1. Covered Persons, section V, delete in full and replace with. V.

Covered Persons 42 U.S.C. 247d-6d(i)(2), (3), (4), (6), (8)(A) and (B) Covered Persons who are afforded liability immunity under this Declaration are “manufacturers,” “distributors,” “program planners,” “qualified persons,” and their officials, agents, and employees, as those terms are defined in the PREP Act, and the United States. In addition, I have determined that the following additional persons are qualified persons. (a) Any person authorized in accordance with the public health and medical emergency response of the Authority Having Jurisdiction, as described in Section VII below, to prescribe, administer, deliver, distribute or dispense the Covered Countermeasures, and their officials, agents, employees, contractors and volunteers, following a Declaration of an emergency.

(b) any person authorized to prescribe, administer, or dispense the Covered Countermeasures or who is otherwise authorized to perform an activity under an Emergency Use Authorization in accordance with Section 564 of the FD&C Act. (c) any person authorized to prescribe, administer, or dispense Covered Countermeasures in accordance with Section 564A of the FD&C Act. And (d) a State-licensed pharmacist who orders and administers, and pharmacy interns who administer (if the pharmacy intern acts under the supervision of such pharmacist and the pharmacy intern is licensed or registered by his or her State board of pharmacy), vaccines that the Advisory Committee on Immunization Practices (ACIP) recommends to persons ages three through 18 according to ACIP's standard immunization schedule. Such State-licensed pharmacists and the State-licensed or registered interns under their supervision are qualified persons only if the following requirements are met.

The vaccine must be FDA-authorized or FDA-approved. The vaccination must be ordered and administered according to ACIP's standard immunization schedule. The licensed pharmacist must complete a practical training program of at least 20 hours that is approved by the Accreditation Council for Pharmacy Education (ACPE). This training program must include hands-on injection technique, clinical evaluation of indications and contraindications of vaccines, and the recognition and treatment of emergency reactions to vaccines.

The licensed or registered pharmacy intern must complete a practical training program that is approved by the ACPE. This training program must include hands-on injection technique, clinical evaluation of indications and contraindications of vaccines, and the recognition and treatment of emergency reactions to vaccines. The licensed pharmacist and licensed or registered pharmacy intern must have a current certificate in basic cardiopulmonary resuscitation. The licensed pharmacist must complete a minimum of two hours of ACPE-approved, immunization-related continuing pharmacy education during each State licensing period.

The licensed pharmacist must comply with recordkeeping and reporting requirements of the jurisdiction in which he or she administers vaccines, including informing the patient's primary-care provider when available, submitting the required immunization information to the State or local immunization information system (vaccine registry), complying with requirements with respect to reporting adverse events, and complying with requirements whereby the person administering a vaccine must review the vaccine registry or other vaccination records prior to administering a vaccine. The licensed pharmacist must inform his or her childhood-vaccination patients and the adult caregiver accompanying the child of the importance of a well-child visit with a pediatrician or other licensed primary-care provider and refer patients as appropriate. Nothing in this Declaration shall be construed to affect the National Vaccine Injury Compensation Program, including an injured party's ability to obtain compensation under that program. Covered countermeasures that are subject to the National Vaccine Injury Compensation Program authorized under 42 U.S.C.

300aa-10 et seq. Are covered under this Declaration for the purposes of liability immunity and injury compensation only to the extent that injury compensation is not provided under that Program. All other Start Printed Page 52141terms and conditions of the Declaration apply to such covered countermeasures. 2.

Category of Disease, Health Condition, or Threat, section VIII, delete in full and replace with. VIII. Category of Disease, Health Condition, or Threat 42 U.S.C. 247d-6d(b)(2)(A) The category of disease, health condition, or threat for which I recommend the administration or use of the Covered Countermeasures is not only COVID-19 caused by SARS-CoV-2 or a virus mutating therefrom, but also other diseases, health conditions, or threats that may have been caused by COVID-19, SARS-CoV-2, or a virus mutating therefrom, including the decrease in the rate of childhood immunizations, which will lead to an increase in the rate of infectious diseases.

Start Authority 42 U.S.C. 247d-6d. End Authority Start Signature Dated. August 19, 2020.

Alex M. Azar II, Secretary of Health and Human Services. End Signature End Supplemental Information [FR Doc. 2020-18542 Filed 8-20-20.

Generic microzide online for sale

The coronavirus pandemic, social distancing, and generic microzide online for sale resulting economic downturn have had considerable implications for the U.S. Health system, including health insurers. The pandemic caused a sizable decrease in the use of health care services during the first half of 2020, job losses appear to have led to coverage loss in the employer market and increases in Medicaid enrollment, and insurers projecting costs for next year must assess the relative effects of pent-up demand for delayed care, the continuing pandemic, and a potential vaccine.In this brief, we analyze data from 2013 to 2020 to examine generic microzide online for sale how insurance markets performed through the first half of this year as the pandemic developed and worsened in the U.S. We use financial data reported by insurance companies to the National Association of Insurance Commissioners and compiled by Mark Farrah Associates to look at average medical loss ratios and gross margins in the individual (also known as non-group), fully-insured group (employer), and Medicare Advantage health insurance markets. A more detailed description of each market is included in the Appendix.We find that, as of the end of June 2020, average margins have increased and loss ratios have dropped across the fully-insured group and Medicare Advantage generic microzide online for sale markets, relative to the same time period in 2019.

If administrative costs were roughly the same in 2020 as in 2019, these findings suggest higher profits for many insurers during the pandemic. Individual market loss ratios were already generic microzide online for sale quite low and remained flat into 2020, suggesting continued profitability. The results for the individual and group markets indicate that commercial insurers are on track to owe substantial rebates to consumers again next year under the Affordable Care Act (ACA) Medical Loss Ratio provision.Gross MarginsOne way to assess insurer financial performance is to examine average gross margins per member per month, or the average amount by which premium income exceeds claims costs per enrollee in a given month. Gross margins are an indicator of performance, but positive generic microzide online for sale margins do not necessarily translate into profitability since they do not account for administrative expenses. However, a sharp increase in margins from one year to the next, without a commensurate increase in administrative costs, would indicate that these health insurance markets have become more profitable during the pandemic.Despite many insurers covering the full cost of coronavirus testing and treatment for their enrollees, insurers across most markets have seen their claims costs fall, and margins increase since the start of the pandemic, and relative to 2019.

This is consistent with the sharp drop in utilization documented in other analyses.Gross margins among group market plans increased 22% (or generic microzide online for sale $20 pmpm) through the second quarter of 2020 relative to the same period in 2019. Gross margins among Medicare Advantage plans also increased, rising 41% (or $64 pmpm) through the first six months of 2020 compared to gross margins at the same point last year. (Gross margins per member per month tend to be higher for Medicare Advantage than for the other health insurance markets mainly because Medicare covers an older, sicker population with higher average costs) generic microzide online for sale. Prior to the pandemic, margins in the group and Medicare Advantage markets had grown gradually over recent years.Figure 1. Average Gross Margins Per generic microzide online for sale Member Per Month Through June, 2013 – 2020​Individual market margins have been more volatile than the other private markets since the early years of the Affordable Care Act (ACA), as described in more depth in our earlier analyses of individual market financial performance.

Individual market margins remained relatively stable through the first six months of 2020, decreasing just $4 per member per month, and remaining much higher than in the earlier years of the ACA. These data suggest generic microzide online for sale that insurers in the individual market remain financially healthy after a year and a half with no individual mandate penalty, even while the coronavirus outbreak worsened.Medical Loss RatiosAnother way to assess insurer financial performance is to look at medical loss ratios, which are the percent of premium income that insurers pay out in the form of medical claims. Generally, lower medical loss ratios mean that insurers have more income remaining, after paying medical costs, to use for administrative costs or keep as profits. Each health insurance market has different administrative needs and costs, generic microzide online for sale so low loss ratios in one market do not necessarily mean that market is more profitable than another market. However, in a given market, if administrative costs hold mostly constant from one year to the next, a drop in loss ratios would imply that plans are becoming more profitable.Medical loss ratios are used in state and federal insurance regulation in a variety of ways.

In the commercial insurance (individual and group) markets, insurers must issue rebates to individuals and businesses if their loss ratios fail to reach minimum standards set by the generic microzide online for sale ACA. Medicare Advantage insurers are required to report loss ratios at the contract level. They are also required to issue rebates to the federal generic microzide online for sale government if they fall short of 85%, and are subject to additional penalties if they fail to meet loss ratio requirements for multiple consecutive years in a row.The loss ratios shown in this issue brief differ from the definition of MLR in the ACA, which makes some adjustments for quality improvement and taxes, and do not account for reinsurance, risk corridors, or risk adjustment payments. The chart below shows simple medical loss ratios, or the share of premium income that insurers pay out in claims, without any modifications (Figure 2). Loss ratios in the Medicare Advantage market decreased 5 percentage points through the first six months of 2020 relative to the same generic microzide online for sale period in 2019, and group market loss ratios decreased by an average of 3 percentage points relative to last year.Figure 2.

Average Medical Loss Ratios Through June, 2013 – 2020​The individual market was the only market in which average loss ratios held steady from last year. Even so, loss ratios in the individual market were already quite low and insurers in that market are issuing record-large generic microzide online for sale rebates to consumers based in part on their 2019 experience.DiscussionAlthough we cannot measure profits directly, all signs suggest that health insurers in most markets have become more profitable so far during the pandemic. Medicare Advantage and group health plans saw rising margins and falling loss ratios through June 2020, relative to the same time last year. In contrast, margins and loss ratios among individual market insurers have generally remained flat through the second quarter compared to the same time last year, though insurers in this market already had high margins and low loss ratios last year.That insurers appear to be becoming generic microzide online for sale more profitable during a pandemic may be counter-intuitive. Insurers were generally required to cover COVID-19 testing costs, and many also voluntarily covered the full cost of COVID-19 treatment for a period of time (see for example, announcements from UnitedHealthcare, CVSHealth (Aetna), and Cigna).

Even with these increased pandemic-related generic microzide online for sale expenses, though, many insurers saw claims costs fall as enrollees delayed or went without other types of health care due to social distancing restrictions, cancelation of elective procedures, or out of fear of contracting the virus. Job losses and economic instability may also affect health care utilization.The drop in utilization that has contributed to higher gross margins and lower medical loss ratios presents uncertainty and challenges for insurers, particularly given the unknown trajectory of the pandemic. For Medicare Advantage insurers, these trends may result in plans offering more benefits than they currently do, which are popular and attract enrollees generic microzide online for sale. But if insurers fall short in meeting required loss ratio requirements for multiple years, they face additional penalties, including the possibility of being terminated. In the individual and group markets, insurers are reporting pandemic-related uncertainty as they set generic microzide online for sale premiums for next year, and insurers are making different assumptions about the extent to which utilization will rebound or health costs will change due to factors like the potential for widespread vaccination.Unless these patterns change substantially in late 2020, ACA medical loss ratio rebates in 2021 likely will be exceptionally large across commercial markets.

Rebates to consumers are calculated using a three-year average of medical loss ratios, meaning that 2021 rebates will be based on insurer performance in 2018, 2019, and 2020. In the individual market generic microzide online for sale in particular, insurers were quite profitable in 2018 and 2019, so even if 2020 turns out to be a more average year, these insurers will likely owe large rebates to consumers. Group market insurers may also owe larger rebates to employers and employees than plans have in typical years, as loss ratios have dropped substantially. This may, in part, explain why many generic microzide online for sale commercial insurers have volunteered to cover COVID-19 treatment costs, waived telemedicine cost-sharing, or expanded mental health services during the pandemic. By increasing their claims costs, insurers can proactively increase loss ratios and owe smaller rebates next year.What’s happened?.

We have received reports of fraudulent telephone calls from an individual or organisation claiming to be a representative of the Australian Digital Health Agency generic microzide online for sale. It has been reported that the caller says they are calling from the “digital health agency” to enrol people to get a “health record”.What do I need to do?. If you receive a call from generic microzide online for sale someone offering to enrol you for a “health record”, do not provide any personal information, hang up the call and report it to scamwatch.gov.au.The Australian Digital Health Agency will not telephone you with an offer to enrol you for a My Health Record. For more information on how to register for a My Health Record, visit myhealthrecord.gov.au.If you have shared your Medicare number with an unknown caller, report this to Services Australia who will place your details on a watch list to monitor for any compromise or misuse of your Medicare record. Email [email protected] or phone 1800 941 126 generic microzide online for sale.

How could this affect me?. The caller is requesting personal information which could be used to steal your identity generic microzide online for sale or commit financial fraud. Reports indicate that the caller is requesting the following personal information:• Medicare number• Date of birth• Email address• Mobile telephone number• Credit card detailsIdentity theft (also known as identity fraud) occurs when one person uses another individual’s personal information without their consent, usually for personal gain or to conduct further crimes.Where can I get more information?. If you have shared personal information and believe you may be at risk, you can contact generic microzide online for sale IDCARE, a not for profit organisation that provides assistance and support to victims of identity theft and other cybercrime. Visit idcare.org or telephone 1800 595 160.The Office of the Australian Information Commissioner provides information about identity fraud including what to do if your identity has been stolen.For additional information about scams, visit scamwatch.gov.au – you can also subscribe to a free alert service to receive updates about the latest scams.The Australian Cyber Security Centre also provides advice for individuals, a free alert service to help you understand the latest online threats and the ability to report online crimes via the ReportCyber page..

The coronavirus pandemic, social microzide best price distancing, and resulting economic downturn have had considerable implications for the U.S. Health system, including health insurers. The pandemic caused a sizable decrease in the use of health care services during the first half of 2020, job losses appear to have led to coverage loss in the employer market and increases microzide best price in Medicaid enrollment, and insurers projecting costs for next year must assess the relative effects of pent-up demand for delayed care, the continuing pandemic, and a potential vaccine.In this brief, we analyze data from 2013 to 2020 to examine how insurance markets performed through the first half of this year as the pandemic developed and worsened in the U.S.

We use financial data reported by insurance companies to the National Association of Insurance Commissioners and compiled by Mark Farrah Associates to look at average medical loss ratios and gross margins in the individual (also known as non-group), fully-insured group (employer), and Medicare Advantage health insurance markets. A more detailed description of each market is included in the Appendix.We find that, as of the end of June 2020, average margins have increased and loss ratios have dropped across the fully-insured group and Medicare Advantage markets, relative to the microzide best price same time period in 2019. If administrative costs were roughly the same in 2020 as in 2019, these findings suggest higher profits for many insurers during the pandemic.

Individual market loss ratios were already quite low and remained flat into 2020, suggesting continued profitability microzide best price. The results for the individual and group markets indicate that commercial insurers are on track to owe substantial rebates to consumers again next year under the Affordable Care Act (ACA) Medical Loss Ratio provision.Gross MarginsOne way to assess insurer financial performance is to examine average gross margins per member per month, or the average amount by which premium income exceeds claims costs per enrollee in a given month. Gross margins microzide best price are an indicator of performance, but positive margins do not necessarily translate into profitability since they do not account for administrative expenses.

However, a sharp increase in margins from one year to the next, without a commensurate increase in administrative costs, would indicate that these health insurance markets have become more profitable during the pandemic.Despite many insurers covering the full cost of coronavirus testing and treatment for their enrollees, insurers across most markets have seen their claims costs fall, and margins increase since the start of the pandemic, and relative to 2019. This is consistent with the sharp drop in microzide best price utilization documented in other analyses.Gross margins among group market plans increased 22% (or $20 pmpm) through the second quarter of 2020 relative to the same period in 2019. Gross margins among Medicare Advantage plans also increased, rising 41% (or $64 pmpm) through the first six months of 2020 compared to gross margins at the same point last year.

(Gross margins per member per month tend to be higher microzide best price for Medicare Advantage than for the other health insurance markets mainly because Medicare covers an older, sicker population with higher average costs). Prior to the pandemic, margins in the group and Medicare Advantage markets had grown gradually over recent years.Figure 1. Average Gross Margins Per Member Per Month Through June, microzide best price 2013 – 2020​Individual market margins have been more volatile than the other private markets since the early years of the Affordable Care Act (ACA), as described in more depth in our earlier analyses of individual market financial performance.

Individual market margins remained relatively stable through the first six months of 2020, decreasing just $4 per member per month, and remaining much higher than in the earlier years of the ACA. These data suggest that insurers in the individual market remain financially healthy microzide best price after a year and a half with no individual mandate penalty, even while the coronavirus outbreak worsened.Medical Loss RatiosAnother way to assess insurer financial performance is to look at medical loss ratios, which are the percent of premium income that insurers pay out in the form of medical claims. Generally, lower medical loss ratios mean that insurers have more income remaining, after paying medical costs, to use for administrative costs or keep as profits.

Each health microzide best price insurance market has different administrative needs and costs, so low loss ratios in one market do not necessarily mean that market is more profitable than another market. However, in a given market, if administrative costs hold mostly constant from one year to the next, a drop in loss ratios would imply that plans are becoming more profitable.Medical loss ratios are used in state and federal insurance regulation in a variety of ways. In the commercial insurance (individual and group) markets, insurers must issue rebates to individuals and businesses if their loss microzide best price ratios fail to reach minimum standards set by the ACA.

Medicare Advantage insurers are required to report loss ratios at the contract level. They are also required to issue rebates to the federal government if they fall short of 85%, and microzide best price are subject to additional penalties if they fail to meet loss ratio requirements for multiple consecutive years in a row.The loss ratios shown in this issue brief differ from the definition of MLR in the ACA, which makes some adjustments for quality improvement and taxes, and do not account for reinsurance, risk corridors, or risk adjustment payments. The chart below shows simple medical loss ratios, or the share of premium income that insurers pay out in claims, without any modifications (Figure 2).

Loss ratios in the Medicare Advantage market decreased 5 percentage points through the microzide best price first six months of 2020 relative to the same period in 2019, and group market loss ratios decreased by an average of 3 percentage points relative to last year.Figure 2. Average Medical Loss Ratios Through June, 2013 – 2020​The individual market was the only market in which average loss ratios held steady from last year. Even so, loss ratios in the individual market were already quite low and insurers in that market are issuing record-large rebates to microzide best price consumers based in part on their 2019 experience.DiscussionAlthough we cannot measure profits directly, all signs suggest that health insurers in most markets have become more profitable so far during the pandemic.

Medicare Advantage and group health plans saw rising margins and falling loss ratios through June 2020, relative to the same time last year. In contrast, margins and loss ratios among individual market insurers have generally remained flat through the second quarter compared to the same time last year, though insurers in this market already had high margins and low loss ratios last year.That insurers appear to be becoming more microzide best price profitable during a pandemic may be counter-intuitive. Insurers were generally required to cover COVID-19 testing costs, and many also voluntarily covered the full cost of COVID-19 treatment for a period of time (see for example, announcements from UnitedHealthcare, CVSHealth (Aetna), and Cigna).

Even with these increased pandemic-related expenses, though, many insurers saw claims costs fall as enrollees delayed or went without other types of health microzide best price care due to social distancing restrictions, cancelation of elective procedures, or out of fear of contracting the virus. Job losses and economic instability may also affect health care utilization.The drop in utilization that has contributed to higher gross margins and lower medical loss ratios presents uncertainty and challenges for insurers, particularly given the unknown trajectory of the pandemic. For Medicare microzide best price Advantage insurers, these trends may result in plans offering more benefits than they currently do, which are popular and attract enrollees.

But if insurers fall short in meeting required loss ratio requirements for multiple years, they face additional penalties, including the possibility of being terminated. In the individual and group markets, insurers are reporting pandemic-related uncertainty as they set premiums for next year, and insurers are making different assumptions about the extent to which utilization will rebound or microzide best price health costs will change due to factors like the potential for widespread vaccination.Unless these patterns change substantially in late 2020, ACA medical loss ratio rebates in 2021 likely will be exceptionally large across commercial markets. Rebates to consumers are calculated using a three-year average of medical loss ratios, meaning that 2021 rebates will be based on insurer performance in 2018, 2019, and 2020.

In the individual market in particular, insurers were quite profitable in 2018 and 2019, so even if 2020 turns out to be a more average year, these insurers will likely owe microzide best price large rebates to consumers. Group market insurers may also owe larger rebates to employers and employees than plans have in typical years, as loss ratios have dropped substantially. This may, in part, explain why many commercial insurers have volunteered to cover COVID-19 treatment costs, waived telemedicine cost-sharing, or expanded mental health microzide best price services during the pandemic.

By increasing their claims costs, insurers can proactively increase loss ratios and owe smaller rebates next year.What’s happened?. We have received reports of fraudulent telephone calls from an individual or microzide best price organisation claiming to be a representative of the Australian Digital Health Agency. It has been reported that the caller says they are calling from the “digital health agency” to enrol people to get a “health record”.What do I need to do?.

If you receive a call from someone offering to enrol you for a microzide best price “health record”, do not provide any personal information, hang up the call and report it to scamwatch.gov.au.The Australian Digital Health Agency will not telephone you with an offer to enrol you for a My Health Record. For more information on how to register for a My Health Record, visit myhealthrecord.gov.au.If you have shared your Medicare number with an unknown caller, report this to Services Australia who will place your details on a watch list to monitor for any compromise or misuse of your Medicare record. Email [email protected] or phone 1800 941 126 microzide best price.

How could this affect me?. The caller is requesting personal information which could be used to steal your identity microzide best price or commit financial fraud. Reports indicate that the caller is requesting the following personal information:• Medicare number• Date of birth• Email address• Mobile telephone number• Credit card detailsIdentity theft (also known as identity fraud) occurs when one person uses another individual’s personal information without their consent, usually for personal gain or to conduct further crimes.Where can I get more information?.

If you have shared personal information and believe you may be at risk, you can contact IDCARE, a not for profit organisation that provides assistance and support microzide best price to victims of identity theft and other cybercrime. Visit idcare.org or telephone 1800 595 160.The Office of the Australian Information Commissioner provides information about identity fraud including what to do if your identity has been stolen.For additional information about scams, visit scamwatch.gov.au – you can also subscribe to a free alert service to receive updates about the latest scams.The Australian Cyber Security Centre also provides advice for individuals, a free alert service to help you understand the latest online threats and the ability to report online crimes via the ReportCyber page..

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11 September 2020 We are pleased to announce enhanced flexibility of training for senior healthcare scientists The Institute of Biomedical Science (IBMS), Royal College can i buy microzide over the counter of Pathologists (RCPath), National School of Healthcare Science in Health Education England (NSHCS in HEE), Academy for Healthcare Science (ACHS) and Manchester Academy of Healthcare Science Education (MAHSE) have come together to broaden the eligibility criteria for the Higher Specialist Scientific Training (HSST) Programme. The changes will have a direct and positive impact on newly eligible IBMS members who wish to undertake the program.Professor Berne Ferry, Head of the National School of Healthcare Science, who contributed towards the changes commented:Opening up the entry criteria for HSST to allow all eligible scientists to enter the programme is a positive step forward in Healthcare Scientist Education and Training. Allowing eligible Biomedical can i buy microzide over the counter Scientists to apply is hugely welcomed and the NSHCS in HEE is delighted to jointly announce this initiative with the IBMS, RCPath, the ACHS and the MAHSE. Having Biomedical Scientists undertaking HSST alongside Clinical Scientist colleagues can only strengthen, diversify and unify the NHS scientific workforce and help to deliver the necessary scientific leadership which will be crucial for patients in the future.IBMS Council member Dr Jane Needham, the IBMS lead on this project, commented:This is really wonderful news. It provides a career pathway and an exciting opportunity for our Biomedical Scientists to apply and develop their clinical and scientific knowledge and expertise through the consultant level HSST training programme, with the key benefit of improving and enhancing the clinical care and services we provide to our patients.On reviewing the changes, IBMS President Allan Wilson commented:The inclusion of Biomedical Scientists as an eligible professional group for the HSST programme will provide a route to consultant level posts for Biomedical Scientists and recognises the breadth and depth of can i buy microzide over the counter experience and clinical skills that exist within the profession.

This new training route will improve patient pathways by the addition of experienced clinical experts to the currently stretched consultant capacity. This is tremendous news for Biomedical Scientists and healthcare in the UK.If you have any questions after reading the statement can i buy microzide over the counter please contact us via. Website@ibms.orgRead the statement and new eligibility criteria in full (or download) below:Joint Statement on HSST EligibilitySignificant scientific workforce shortages at senior levels have been identified in several Life Science specialties, which have been further highlighted during the COVID-19 pandemic. The Higher Specialist Scientific Training (HSST) Programme trains Healthcare can i buy microzide over the counter Scientists to consultant level, however HSST is currently not open to all individual scientists with the potential to develop and take on the role of a consultant scientist.The National School of Healthcare Science in Health Education England, Academy for Healthcare Science, Institute of Biomedical Science (IBMS), Royal College of Pathologists (RCPath) and Manchester Academy of Healthcare Scientist Education are pleased to announce a widening of the of the eligibility criteria for HSST. The new criteria will allow appropriately qualified senior Biomedical Scientists, who can demonstrate ability to work at Level 7 via academic and professional qualifications, to apply to join the programme.

Both Biomedical Scientists and Clinical Scientists will be subject to the same HSST interview can i buy microzide over the counter process to determine suitability and readiness. The qualifications to confer eligibility will include:1) HCPC Registration as a Biomedical Scientist, IBMS Specialist Diploma and relevant MSc2) HCPC Registration as a Biomedical Scientist, IBMS Specialist Diploma and IBMS Higher Specialist Diploma or IBMS 2-part Fellowship Special Exam3) HCPC Registration as a Biomedical Scientist, IBMS Specialist Diploma and IBMS Diploma of Expert PracticeEligible individuals will also need to meet the requirements of the Universities to commence a doctoral level programme, including a First or 2:1 Bachelor’s degree and a Master’s degree in a relevant subject area or evidence of having written at that standard, and a minimum of four years working in a professional role. In addition, training departments will need to achieve HSST training accreditation can i buy microzide over the counter through the NSHCS to be successful in the commissioning rounds. This includes demonstration of suitable workplace and research supervision at doctoral level, access to training to meet the specialism curriculum and HSS Standards of Proficiency, and senior level trust support.All Life Science HSSTs must obtain Fellowship of the Royal College of Pathologists during the programme in order to complete HSST, in addition to the academic qualification and evidence of their workplace training. These requirements of the programme can i buy microzide over the counter are identical for Clinical Scientists and Biomedical Scientists on HSST.This revised admission criteria to HSST is endorsed by NHS Education for Scotland - Healthcare Science.

We look forward to working with all agencies concerned with the development of the next generation of consultant-level healthcare scientists.All scientists who successfully complete the HSST programme or equivalence are eligible to join the Academy for Healthcare Science HSS Register and become a Fellow.This change to the HSST eligibility criteria will apply from 2021 entry to the HSST programme.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 CPD event, The Biomedical Scientist Live, will feature a packed line up of knowledge sharing sessions including. Workshops, seminars, discussions and demonstrations can i buy microzide over the counter. 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..

11 September 2020 We are pleased to announce enhanced flexibility of training for senior healthcare scientists The Institute of Biomedical Science (IBMS), Royal College of Pathologists (RCPath), microzide best price National School of Healthcare Science in Health Education England (NSHCS in HEE), Academy for Healthcare Science (ACHS) and Manchester Academy of Healthcare Science Education (MAHSE) have come together to broaden the eligibility criteria for the Higher Specialist Scientific Training (HSST) Programme. The changes will have a direct and positive impact on newly eligible IBMS members who wish to undertake the program.Professor Berne Ferry, Head of the National School of Healthcare Science, who contributed towards the changes commented:Opening up the entry criteria for HSST to allow all eligible scientists to enter the programme is a positive step forward in Healthcare Scientist Education and Training. Allowing eligible Biomedical Scientists to apply is hugely welcomed and the NSHCS in HEE is delighted to jointly announce microzide best price this initiative with the IBMS, RCPath, the ACHS and the MAHSE. Having Biomedical Scientists undertaking HSST alongside Clinical Scientist colleagues can only strengthen, diversify and unify the NHS scientific workforce and help to deliver the necessary scientific leadership which will be crucial for patients in the future.IBMS Council member Dr Jane Needham, the IBMS lead on this project, commented:This is really wonderful news. It provides a career pathway and an exciting opportunity for our Biomedical Scientists to apply and develop their clinical and scientific knowledge and expertise through the consultant level HSST training programme, with the key benefit of improving and enhancing the clinical care and services we provide to our patients.On reviewing the changes, IBMS President microzide best price Allan Wilson commented:The inclusion of Biomedical Scientists as an eligible professional group for the HSST programme will provide a route to consultant level posts for Biomedical Scientists and recognises the breadth and depth of experience and clinical skills that exist within the profession.

This new training route will improve patient pathways by the addition of experienced clinical experts to the currently stretched consultant capacity. This is tremendous news microzide best price for Biomedical Scientists and healthcare in the UK.If you have any questions after reading the statement please contact us via. Website@ibms.orgRead the statement and new eligibility criteria in full (or download) below:Joint Statement on HSST EligibilitySignificant scientific workforce shortages at senior levels have been identified in several Life Science specialties, which have been further highlighted during the COVID-19 pandemic. The Higher Specialist Scientific Training (HSST) Programme trains Healthcare Scientists to consultant level, however HSST is currently not open to all individual scientists with the potential to develop and take on the role of a consultant scientist.The National School of Healthcare Science in Health Education England, Academy for Healthcare Science, Institute of Biomedical Science (IBMS), Royal College of Pathologists (RCPath) and Manchester Academy of Healthcare microzide best price Scientist Education are pleased to announce a widening of the of the eligibility criteria for HSST. The new criteria will allow appropriately qualified senior Biomedical Scientists, who can demonstrate ability to work at Level 7 via academic and professional qualifications, to apply to join the programme.

Both Biomedical Scientists and Clinical Scientists will be subject to the same microzide best price HSST interview process to determine suitability and readiness. The qualifications to confer eligibility will include:1) HCPC Registration as a Biomedical Scientist, IBMS Specialist Diploma and relevant MSc2) HCPC Registration as a Biomedical Scientist, IBMS Specialist Diploma and IBMS Higher Specialist Diploma or IBMS 2-part Fellowship Special Exam3) HCPC Registration as a Biomedical Scientist, IBMS Specialist Diploma and IBMS Diploma of Expert PracticeEligible individuals will also need to meet the requirements of the Universities to commence a doctoral level programme, including a First or 2:1 Bachelor’s degree and a Master’s degree in a relevant subject area or evidence of having written at that standard, and a minimum of four years working in a professional role. In addition, training departments will need to achieve HSST training accreditation through the NSHCS to be successful in the commissioning microzide best price rounds. This includes demonstration of suitable workplace and research supervision at doctoral level, access to training to meet the specialism curriculum and HSS Standards of Proficiency, and senior level trust support.All Life Science HSSTs must obtain Fellowship of the Royal College of Pathologists during the programme in order to complete HSST, in addition to the academic qualification and evidence of their workplace training. These requirements of the programme are identical for Clinical Scientists and Biomedical Scientists on HSST.This revised admission criteria to HSST is endorsed microzide best price by NHS Education for Scotland - Healthcare Science.

We look forward to working with all agencies concerned with the development of the next generation of consultant-level healthcare scientists.All scientists who successfully complete the HSST programme or equivalence are eligible to join the Academy for Healthcare Science HSS Register and become a Fellow.This change to the HSST eligibility criteria will apply from 2021 entry to the HSST programme.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 CPD event, The Biomedical Scientist Live, will feature a packed line up of knowledge sharing sessions including. Workshops, seminars, microzide best price 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..

Microzide uses

The wildfire season is off to microzide uses a roaring start. The hot summer is worsening drought and drying out vegetation—an unfortunately ideal environment for wildfires to rage. But that’s just one consequence microzide uses of global warming. It’s also leading to flooding, torrential rainstorms and heat-related deaths.

In fact, the climate crisis has led to a widespread public health crisis. And as an microzide uses ear, nose and throat physician, I see the effects more and more often. I vividly remember a patient who came in late for her appointment during a July heat wave. When I walked in, she said, “I’m so sorry I’m late, I was up all night walking my grandbaby around the train station.” Without air conditioning at home, the child was sweating through her clothes in the heat of the night, putting her at risk for dehydration.

July 2019 was the microzide uses hottest July on record. September 2019 was the hottest on record. January 2020 was the hottest on record. May 2020 was the hottest on record microzide uses.

This is not a coincidence. It is a pattern. Carbon dioxide, an important greenhouse gas contributing to global warming, microzide uses has increased by 9 percent since 2005 and by 31 percent since 1950. A U.N.

Intergovernmental Panel on Climate Change special report pointed out that the world has already warmed about one microzide uses degree Celsius from pre-industrial levels. It stressed the urgency to act to limit warming to 1.5 degrees, and that a two-degree increase will lead to unprecedented extreme heat, water scarcity and food shortages around the globe. Heat affects every part of our body. It can lead microzide uses to heat exhaustion, heat stroke, anxiety, impaired cognitive function and even premature death from heart and lung disease.

Across the country, the health concerns of the climate crisis are increasingly being recognized, pushing thousands of medical providers—doctors, nurses, pharmacists, therapists, medical students—to become advocates for change. In my own practice, I explain to patients how the climate crisis affects their health. For example, apart from contributing to global warming, rising carbon dioxide levels increase the amount of pollen microzide uses that plants produce as a consequence of higher rates of photosynthesis. This rise in pollen levels can lead to worsening allergy symptoms.

Another example is fine particulate matter (known as PM2.5) associated with air pollution, much of it linked to the burning of fossil fuels that help drive the warming. When we breathe in these particles, they travel microzide uses down the airway and settle in the tiny air sacs called alveoli of the lungs, causing inflammation and potentially worsening asthma symptoms. The explanations are simple, but the health risks are widespread and complex. Ground-level ozone pollution, which is worse in hotter weather, can also harm people with asthma and other respiratory diseases.

And that harm falls disproportionately on microzide uses the poor. Wealthier people living in North America have a per capita carbon footprint that is 25 percent higher than those of lower-income residents, with some affluent suburbs producing emissions 15 times higher than nearby neighborhoods. These carbon emissions contribute to global warming, and the subsequent health consequences are microzide uses felt far beyond the neighborhood that produces them. Older adults, children, low-income communities and communities of color are less resilient on average to the health impacts of climate change.

The climate crisis is thus leading to a disproportionate public health crisis—and worse, it is a threat multiplier. At a time when many microzide uses Americans are economically challenged, continued heat waves and the higher energy bills they trigger threaten access to water and energy security. The economic benefits of a low-carbon economy are clear. Estimates suggest that without climate investments, the United States will face economic damage from climate change equivalent to 1–3 percent of GDP per year by 2100.

The majority of Americans think global warming microzide uses is happening. The climate crisis has unfairly been labeled as political, when in fact, people recognize that something needs to be done about it. Even for those who are seemingly unaffected, there is increasing global recognition that the safeguards of living in a protected community and affording expert medical care will eventually fail if global warming continues unchecked. Unfortunately, there will be no vaccine in microzide uses six months or a year for the climate crisis.

The only treatment is collective climate action in the present. Climate action is required of our elected leaders, and we must mandate it of ourselves. It can be as simple as educating family and friends, while making sustainable shopping and traveling microzide uses choices. It includes eating less meat, unplugging electronics and raising a voice against the fossil fuel industry.

With a rise in demand for absentee ballots for the election this November, it is crucial to request mail-in microzide uses ballots right away to make sure our voices are heard. The United States is the second largest emitter of greenhouse gases, and we must vote for green policy. Legislative action and policy change work, as evidenced by the Clean Air Act and its subsequent amendments, which are projected to save 230,000 lives in 2020. The climate microzide uses crisis is a public health issue, and we must start healing the planet in order to heal each other.

Fighting against the climate crisis is one of the most patriotic things we can do right now. It will protect our health and the health of our neighbors across the country and the globe, and will allow all of us to live on this planet, the only home we have.The items below are highlights from the free newsletter, “Smart, useful, science stuff about COVID-19.” To receive newsletter issues daily in your inbox, sign up here. Please consider a microzide uses monthly contribution to support this newsletter. Women’s immune response to SARS-CoV-2 is stronger than men’s immune response to the virus, according to a study published 8/26/20 in Nature and covered the same day by Apoorva Mandavilli at The New York Times.

The finding could explain why men “are twice as likely to become severely sick and to die [from COVID-19] as women of the same age,” Mandavilli writes. The study also suggests that older men might need multiple shots of a coronavirus vaccine compared perhaps with young microzide uses women, who might need just one shot, according to an immunologist quoted in the story. He's at the Heinrich Pette Institute and the University Medical Center Hamburg-Eppendorf in Germany. The study leader, a Yale University immunologist, is quoted in the story as saying, “Women who are older — even very old, like 90 years — the women are still making pretty good, decent immune response” to SARS-CoV-2.

The U.S microzide uses. Food and Drug Administration (FDA) on 8/26/20 gave emergency-use authorization to Abbott Laboratories' $5, portable nasal-swab SARS-CoV-2 test that returns results in 15 minutes, reports Sheila Kaplan at The New York Times (8/26/20). The test detects viral fragments called antigens. Such tests miss more infections than widely used, slower tests that rely on a microzide uses technology called polymerase chain reaction (PCR).

But the speed of antigen tests, three others of which previously received FDA emergency-use approval, could prove useful in relieving test backlogs. Abbott says its new antigen test will become available in September, microzide uses the story states. Autopsies of 11 people who died of COVID-19 revealed that their spleens and lymph nodes lacked sites called germinal centers where B cells (immune cells) gather to “mature and refine their antibody response to the virus,” writes Jon Cohen at Science (8/25/20). The researchers compared tissue from the people who died of COVID-19 with tissue from 6 people who died of other causes, the story states.

The finding, which confirms an earlier study’s findings in a smaller group, could provide insights into the progression of severe cases microzide uses of COVID-19, the story states. The studies “establish a profound lack of [antibody] responses in the deceased population of COVID-19 patients,” says a Huazhong University of Science and Technology (HUST) researcher who co-authored the smaller study and is quoted in the story. The missing germinal centers in severe COVID-19 patients could be linked to the biochemical “cytokine storms” that often occur in the dangerous, second phase of the disease, the HUST researcher is quoted as saying. Meanwhile, a MGH, MIT and Harvard immunologist who is a co-author of the newer study, published earlier this month in the journal Cell, says it won’t be difficult to stop SARS-CoV-2 with a microzide uses vaccine.

He is quoted as saying, “This is a piece of cake.” The United States, UK, Japan, and the European Union nations all have pre-ordered in bulk doses of vaccines under development to protect against SARS-CoV-2, reports Ewen Callaway at Nature (8/24/20). Some of these candidate vaccines could be approved in late 2020 or early 2021 at the earliest, the story states. But only "1 billion doses will be available by the fourth quarter of 2021,” according microzide uses to a life-sciences market analytics firm, the story states. A different organization estimates 2 billion to 4 billion doses will be available by the end of 2021, the story states.

A chart near the top of the piece illustrates pre-order details by vaccine manufacturer, nation and number of doses. Meanwhile, an international effort to secure vaccine doses for people living in a total of 92 low- and middle-income, as well as some wealthier countries, is “far short of raising the roughly $18 billion microzide uses that it estimates” will be needed to meet its target number of doses, Callaway reports. Lower in the piece, a chart illustrates pre-orders made by several countries and regions worldwide. Callaway writes that “patents and intellectual property are not what’s standing in the way of fair distribution of COVID-19 vaccines…rather, equitable access and affordable prices require collaboration between governments and vaccine makers,” according to the head of microzide uses the International AIDS Vaccine Initiative in New York City, which reportedly is co-developing a COVID-19 vaccine.

In an 8/22/20 essay for The Washington Post, Elizabeth Svoboda writes that many people in the U.S. Have become desensitized to the risks of SARS-CoV-2, which has led to some behavioral backsliding, especially in crowded places. €œThis habituation stems from a principle microzide uses well-known in psychological therapy,” Svoboda writes. €œThe more we’re exposed to a given threat, the less intimidating it seems.” Some researchers recommend a return to stricter distancing, outdoor masking and stay-at-home orders, the essay suggests.

But we also need authorities to “supply in-your-face reminders of those mandates, especially visual cues, so people won’t draw their own erroneous conclusions about what’s safe,” she writes. In any case, we should cultivate an awareness of the diminishing microzide uses effectiveness of our “snap judgments about COVID-19’s dangers,” and make more careful decisions, a la Nobel laureate Daniel Kahneman's “slow thinking,” she advises. Ventilation discussions in public-health circles predate the current pandemic. Infection control theories born of the U.S.

Experience with the Spanish flu pandemic of 1918-1919 inspired engineers of the microzide uses early 20th century to design steam-heating systems for buildings that could be effective in cold weather even with apartment windows open, reports Patrick Sisson for Bloomberg CityLab. That’s right. Steam-heat radiators were designed to be used with the open windows, allowing fresh air to gush in, which “health officials thought (correctly)…would ward off airborne diseases,” Sisson writes. The piece draws from microzide uses a 1992 book “The Lost Art of Steam Heating,” by heating-systems researcher Dan Holohan.

Radiators were designed, according to Holohan the story states, in response to a New York City Board of Health order that windows should remain open for ventilation in the winter. €œAnybody who’s thrown their windows open in January, microzide uses when their apartment is stifling, is in an odd way, replicating what engineers hoped would happen a century ago,” Sisson writes (8/5/20). You might enjoy. €œJerry Seinfeld.

So You Think New York Is ‘Dead’ (It’s not.)” (8/24/20).In four days of speeches lasting more than microzide uses eight hours at the Republican National Convention, climate change was never mentioned as a threat to the country. That silence stands apart from the climate alarm bells that have been sounding since Donald Trump accepted his first nomination for president four years ago. Thousands of Americans have been killed in natural disasters such as hurricanes and wildfires during Trump’s first term in office. Each of microzide uses those four years has been among the world’s hottest on record.

Leaders of other nations have taken action as the United States ignores the issue. Even Wall Street has begun to take notice of how climate change could affect economic growth. None of microzide uses that was apparent during the convention. Instead, Republican speakers insisted that the real concern was the climate ideas presented by Democrats.

Many experts say that if climate change is left unanswered, it could cost trillions of dollars to the U.S. Economy. Republicans said the real costs would come from Democratic plans to restrain the use of fossil fuels. €œBiden has promised to abolish the production of American oil, coal, shale and natural gas—laying waste to the economies of Pennsylvania, Ohio, Texas, North Dakota, Oklahoma, Colorado and New Mexico,” Trump said.

€œMillions of jobs will be lost, and energy prices will soar.” (Biden’s plan does not call for a fracking ban). Those sentiments play well with Trump’s core supporters, but they’re askew from what most voters believe, including younger Republicans, according to polls. They don’t reflect the events that many Americans are either experiencing or seeing online. Uncontrolled wildfires in California and the strongest hurricane to hit Louisiana in 160 years.

Even as an unrelinquishing pandemic has killed more than 180,000 people in the United States and kept millions of children across the country from returning to school, climate change remains on the minds of voters, polls show. Here are five climate themes that have advanced since Trump accepted his first nomination in 2016. Natural disasters More than 3,000 Americans have died in natural catastrophes during the past four years. Most of them were victims of Hurricane Maria in 2017.

The massive Category 5 storm killed an estimated 2,975 people in Puerto Rico and forced thousands to flee the U.S. Territory. The devastation continues to have ripple effects three years later. Tens of thousands of people still live under leaky blue tarps.

The island’s power supply, never reliable to begin with, has become far worse, and some parts of Puerto Rico were without power for a year. That was the same year that Hurricane Harvey dumped 60 inches of rain on parts of Houston, becoming the wettest cyclone on record. Tens of thousands of homes were damaged, and about 70 people were killed. Harvey caused more than $100 billion in damage, making it one of the costliest disasters to strike the United States.

Record wildfires have also burned across the West. The 2018 Camp Fire in California was the deadliest. It killed 85 people and destroyed more than 10,000 homes. It was fueled by drought, an outcome of climate change.

This week, California continued to battle the second- and third-largest wildfires in state history. Officials have connected the fires to climate change. €œAll but three of the Top 20 Largest #Wildfires have occurred since 2000, with 10 of these large and damaging wildfires occurring in the last decade,” the California Department of Forestry and Fire Protection tweeted yesterday. €œAs fire weather continues to become more extreme, California is adjusting to fight these larger and more destructive wildfires.” Heat The Trump years have been some of the hottest since record-keeping began after the Civil War, according to NASA.

After a record-warm July, this year may break the all-time annual heat record set in 2016. That’s a likely outcome, said Gavin Schmidt, director of the NASA Goddard Institute for Space Studies. That’s notable because four years ago, the record warmth was fueled by El Niño, a band of warm water covering the tropical Pacific Ocean. That influence is absent this year, Schmidt said, and long-term trends point to rising heat.

€œWe know that the trend is moving up. On average, every decade is warmer than the last,” he said. €œThe changes we’re seeing now are so far outside what would be possible in an un-globally-warmed world.” Public opinion Polling shows that voter concern about climate change has been growing for years and that it has not diminished as a result of the coronavirus pandemic. Concern among some voters has spiked during Trump’s tenure.

Before the virus, polling showed climate change was the second-most important issue for Democratic primary voters, behind only health care. Now, responding to the virus and restoring the economy top the list. But the public still wants the federal government to address climate change, recent polling shows. More Americans than ever—about 25%—view climate change as “extremely personally important,” according to a poll released last week by Stanford University, Resources for the Future and ReconMR.

That number is twice as large as it was in 2006, said the poll, which surveyed 1,000 adults between May and August. It also found that 82% of respondents want the federal government to act on climate change. And three-quarters of those surveyed said they had personally experienced the effects of global warming. €œThe COVID-19 pandemic has offered a unique opportunity to learn how people feel about climate change when faced with a global crisis,” said Ray Kopp, vice president of research and policy engagement at Resources for the Future.

€œThe claim that we can’t do anything about climate change without crashing the economy, or that we need to focus only on the pandemic and not do anything on climate right now, simply doesn’t resonate with Americans,” he said. The U.S. (and everyone else) Since Trump pledged to withdraw from the Paris climate agreement in 2017, world leaders have pressed him to rejoin and to take the issue seriously. Among them are German Chancellor Angela Merkel and French President Emmanuel Macron.

Last year, Trump said Prince Charles spent 90 minutes talking to him about climate change, trying to convince him to take stronger action and to once again make the United States a world leader. In response, Trump said he wanted “good climate,” but his administration has continued to roll back environmental safeguards meant to reduce emissions. In December, Macron said other governments, including China, Russia and the European Union, would lead the world in reducing emissions. The yearslong process of withdrawing from the Paris Agreement won’t be done until November.

Yesterday, Biden tweeted that if he wins the election, he would rejoin the pact on the first day of his presidency. Climate hits Wall Street This week, it was announced that Exxon Mobil Corp. Would be dropped from the Dow Jones Industrial Average stock index. It’s a significant departure, as Exxon was the longest-tenured company on the Dow, having been listed for almost a century.

It’s also a reflection of how oil companies have taken a financial hit amid growing concerns about climate change and as a result of declining consumption due to the pandemic. At the same time, some solar and wind companies have grown bigger than their fossil fuel competitors. The same factors that have weakened fossil fuel companies, including more aggressive climate targets, helped drive clean energy technologies. On Wall Street, business interests are increasingly warning the Federal Reserve and other regulators that climate change could pose a significant risk to the economy.

Earlier this year, 40 investment firms and organizations that handle more than $1 trillion in assets urged Fed Chairman Jerome Powell to take action. They warned him that climate “threats have the potential to compound in ways we don’t yet understand, with disastrous impacts the likes of which we haven’t seen before.” Reprinted from Climatewire with permission from E&E News. E&E provides daily coverage of essential energy and environmental news at www.eenews.net..

The wildfire season is off to a microzide best price roaring start. The hot summer is worsening drought and drying out vegetation—an unfortunately ideal environment for wildfires to rage. But that’s microzide best price just one consequence of global warming. It’s also leading to flooding, torrential rainstorms and heat-related deaths. In fact, the climate crisis has led to a widespread public health crisis.

And as an ear, nose and throat physician, I see the microzide best price effects more and more often. I vividly remember a patient who came in late for her appointment during a July heat wave. When I walked in, she said, “I’m so sorry I’m late, I was up all night walking my grandbaby around the train station.” Without air conditioning at home, the child was sweating through her clothes in the heat of the night, putting her at risk for dehydration. July 2019 microzide best price was the hottest July on record. September 2019 was the hottest on record.

January 2020 was the hottest on record. May 2020 microzide best price was the hottest on record. This is not a coincidence. It is a pattern. Carbon dioxide, an important greenhouse gas contributing to global warming, has increased by 9 microzide best price percent since 2005 and by 31 percent since 1950.

A U.N. Intergovernmental Panel microzide best price on Climate Change special report pointed out that the world has already warmed about one degree Celsius from pre-industrial levels. It stressed the urgency to act to limit warming to 1.5 degrees, and that a two-degree increase will lead to unprecedented extreme heat, water scarcity and food shortages around the globe. Heat affects every part of our body. It can lead to heat exhaustion, heat stroke, anxiety, impaired cognitive function and even premature death microzide best price from heart and lung disease.

Across the country, the health concerns of the climate crisis are increasingly being recognized, pushing thousands of medical providers—doctors, nurses, pharmacists, therapists, medical students—to become advocates for change. In my own practice, I explain to patients how the climate crisis affects their health. For example, apart from contributing to global warming, rising carbon dioxide levels microzide best price increase the amount of pollen that plants produce as a consequence of higher rates of photosynthesis. This rise in pollen levels can lead to worsening allergy symptoms. Another example is fine particulate matter (known as PM2.5) associated with air pollution, much of it linked to the burning of fossil fuels that help drive the warming.

When we breathe in these microzide best price particles, they travel down the airway and settle in the tiny air sacs called alveoli of the lungs, causing inflammation and potentially worsening asthma symptoms. The explanations are simple, but the health risks are widespread and complex. Ground-level ozone pollution, which is worse in hotter weather, can also harm people with asthma and other respiratory diseases. And that harm falls disproportionately microzide best price on the poor. Wealthier people living in North America have a per capita carbon footprint that is 25 percent higher than those of lower-income residents, with some affluent suburbs producing emissions 15 times higher than nearby neighborhoods.

These carbon emissions contribute to global warming, and the subsequent health consequences are felt far beyond the neighborhood that produces them microzide best price. Older adults, children, low-income communities and communities of color are less resilient on average to the health impacts of climate change. The climate crisis is thus leading to a disproportionate public health crisis—and worse, it is a threat multiplier. At a time when many Americans are economically challenged, continued heat waves and the higher energy bills they trigger microzide best price threaten access to water and energy security. The economic benefits of a low-carbon economy are clear.

Estimates suggest that without climate investments, the United States will face economic damage from climate change equivalent to 1–3 percent of GDP per year by 2100. The majority of Americans think global microzide best price warming is happening. The climate crisis has unfairly been labeled as political, when in fact, people recognize that something needs to be done about it. Even for those who are seemingly unaffected, there is increasing global recognition that the safeguards of living in a protected community and affording expert medical care will eventually fail if global warming continues unchecked. Unfortunately, there will be no microzide best price vaccine in six months or a year for the climate crisis.

The only treatment is collective climate action in the present. Climate action is required of our elected leaders, and we must mandate it of ourselves. It can be as simple as educating family and friends, while making microzide best price sustainable shopping and traveling choices. It includes eating less meat, unplugging electronics and raising a voice against the fossil fuel industry. With a rise in demand for absentee ballots for the election this November, it is crucial to request mail-in ballots right away to make sure our microzide best price voices are heard.

The United States is the second largest emitter of greenhouse gases, and we must vote for green policy. Legislative action and policy change work, as evidenced by the Clean Air Act and its subsequent amendments, which are projected to save 230,000 lives in 2020. The climate crisis is a public health issue, and we must start healing the planet in order to heal each other microzide best price. Fighting against the climate crisis is one of the most patriotic things we can do right now. It will protect our health and the health of our neighbors across the country and the globe, and will allow all of us to live on this planet, the only home we have.The items below are highlights from the free newsletter, “Smart, useful, science stuff about COVID-19.” To receive newsletter issues daily in your inbox, sign up here.

Please consider microzide best price a monthly contribution to support this newsletter. Women’s immune response to SARS-CoV-2 is stronger than men’s immune response to the virus, according to a study published 8/26/20 in Nature and covered the same day by Apoorva Mandavilli at The New York Times. The finding could explain why men “are twice as likely to become severely sick and to die [from COVID-19] as women of the same age,” Mandavilli writes. The study also suggests that older men might need multiple shots of microzide best price a coronavirus vaccine compared perhaps with young women, who might need just one shot, according to an immunologist quoted in the story. He's at the Heinrich Pette Institute and the University Medical Center Hamburg-Eppendorf in Germany.

The study leader, a Yale University immunologist, is quoted in the story as saying, “Women who are older — even very old, like 90 years — the women are still making pretty good, decent immune response” to SARS-CoV-2. The U.S microzide best price. Food and Drug Administration (FDA) on 8/26/20 gave emergency-use authorization to Abbott Laboratories' $5, portable nasal-swab SARS-CoV-2 test that returns results in 15 minutes, reports Sheila Kaplan at The New York Times (8/26/20). The test detects viral fragments called antigens. Such tests miss microzide best price more infections than widely used, slower tests that rely on a technology called polymerase chain reaction (PCR).

But the speed of antigen tests, three others of which previously received FDA emergency-use approval, could prove useful in relieving test backlogs. Abbott says its new antigen test will become available in September, the story states microzide best price. Autopsies of 11 people who died of COVID-19 revealed that their spleens and lymph nodes lacked sites called germinal centers where B cells (immune cells) gather to “mature and refine their antibody response to the virus,” writes Jon Cohen at Science (8/25/20). The researchers compared tissue from the people who died of COVID-19 with tissue from 6 people who died of other causes, the story states. The finding, which confirms an earlier study’s microzide best price findings in a smaller group, could provide insights into the progression of severe cases of COVID-19, the story states.

The studies “establish a profound lack of [antibody] responses in the deceased population of COVID-19 patients,” says a Huazhong University of Science and Technology (HUST) researcher who co-authored the smaller study and is quoted in the story. The missing germinal centers in severe COVID-19 patients could be linked to the biochemical “cytokine storms” that often occur in the dangerous, second phase of the disease, the HUST researcher is quoted as saying. Meanwhile, a MGH, MIT and Harvard immunologist who is a co-author of the newer study, published earlier this month in the journal Cell, says it won’t be difficult to stop SARS-CoV-2 with microzide best price a vaccine. He is quoted as saying, “This is a piece of cake.” The United States, UK, Japan, and the European Union nations all have pre-ordered in bulk doses of vaccines under development to protect against SARS-CoV-2, reports Ewen Callaway at Nature (8/24/20). Some of these candidate vaccines could be approved in late 2020 or early 2021 at the earliest, the story states.

But only "1 billion doses will be available by the fourth quarter of 2021,” according to a life-sciences market analytics firm, the story states microzide best price. A different organization estimates 2 billion to 4 billion doses will be available by the end of 2021, the story states. A chart near the top of the piece illustrates pre-order details by vaccine manufacturer, nation and number of doses. Meanwhile, an international effort to secure vaccine doses for people living in a total of 92 low- and middle-income, as well as some wealthier countries, is “far short of raising the roughly $18 billion that it estimates” will be needed to meet microzide best price its target number of doses, Callaway reports. Lower in the piece, a chart illustrates pre-orders made by several countries and regions worldwide.

Callaway writes that “patents and intellectual property are not what’s standing in the way of fair distribution of COVID-19 vaccines…rather, equitable microzide best price access and affordable prices require collaboration between governments and vaccine makers,” according to the head of the International AIDS Vaccine Initiative in New York City, which reportedly is co-developing a COVID-19 vaccine. In an 8/22/20 essay for The Washington Post, Elizabeth Svoboda writes that many people in the U.S. Have become desensitized to the risks of SARS-CoV-2, which has led to some behavioral backsliding, especially in crowded places. €œThis habituation microzide best price stems from a principle well-known in psychological therapy,” Svoboda writes. €œThe more we’re exposed to a given threat, the less intimidating it seems.” Some researchers recommend a return to stricter distancing, outdoor masking and stay-at-home orders, the essay suggests.

But we also need authorities to “supply in-your-face reminders of those mandates, especially visual cues, so people won’t draw their own erroneous conclusions about what’s safe,” she writes. In any case, we should cultivate an awareness of the diminishing effectiveness of our “snap judgments about COVID-19’s dangers,” and make more careful decisions, a la Nobel laureate Daniel Kahneman's “slow microzide best price thinking,” she advises. Ventilation discussions in public-health circles predate the current pandemic. Infection control theories born of the U.S. Experience with the Spanish flu microzide best price pandemic of 1918-1919 inspired engineers of the early 20th century to design steam-heating systems for buildings that could be effective in cold weather even with apartment windows open, reports Patrick Sisson for Bloomberg CityLab.

That’s right. Steam-heat radiators were designed to be used with the open windows, allowing fresh air to gush in, which “health officials thought (correctly)…would ward off airborne diseases,” Sisson writes. The piece draws microzide best price from a 1992 book “The Lost Art of Steam Heating,” by heating-systems researcher Dan Holohan. Radiators were designed, according to Holohan the story states, in response to a New York City Board of Health order that windows should remain open for ventilation in the winter. €œAnybody who’s thrown their microzide best price windows open in January, when their apartment is stifling, is in an odd way, replicating what engineers hoped would happen a century ago,” Sisson writes (8/5/20).

You might enjoy. €œJerry Seinfeld. So You Think New York Is ‘Dead’ (It’s not.)” (8/24/20).In four days of speeches lasting more than eight microzide best price hours at the Republican National Convention, climate change was never mentioned as a threat to the country. That silence stands apart from the climate alarm bells that have been sounding since Donald Trump accepted his first nomination for president four years ago. Thousands of Americans have been killed in natural disasters such as hurricanes and wildfires during Trump’s first term in office.

Each of those four years microzide best price has been among the world’s hottest on record. Leaders of other nations have taken action as the United States ignores the issue. Even Wall Street has begun to take notice of how climate change could affect economic growth. None of that was apparent during the microzide best price convention. Instead, Republican speakers insisted that the real concern was the climate ideas presented by Democrats.

Many experts say that if climate change is left unanswered, it could cost trillions of dollars to the U.S. Economy. Republicans said the real costs would come from Democratic plans to restrain the use of fossil fuels. €œBiden has promised to abolish the production of American oil, coal, shale and natural gas—laying waste to the economies of Pennsylvania, Ohio, Texas, North Dakota, Oklahoma, Colorado and New Mexico,” Trump said. €œMillions of jobs will be lost, and energy prices will soar.” (Biden’s plan does not call for a fracking ban).

Those sentiments play well with Trump’s core supporters, but they’re askew from what most voters believe, including younger Republicans, according to polls. They don’t reflect the events that many Americans are either experiencing or seeing online. Uncontrolled wildfires in California and the strongest hurricane to hit Louisiana in 160 years. Even as an unrelinquishing pandemic has killed more than 180,000 people in the United States and kept millions of children across the country from returning to school, climate change remains on the minds of voters, polls show. Here are five climate themes that have advanced since Trump accepted his first nomination in 2016.

Natural disasters More than 3,000 Americans have died in natural catastrophes during the past four years. Most of them were victims of Hurricane Maria in 2017. The massive Category 5 storm killed an estimated 2,975 people in Puerto Rico and forced thousands to flee the U.S. Territory. The devastation continues to have ripple effects three years later.

Tens of thousands of people still live under leaky blue tarps. The island’s power supply, never reliable to begin with, has become far worse, and some parts of Puerto Rico were without power for a year. That was the same year that Hurricane Harvey dumped 60 inches of rain on parts of Houston, becoming the wettest cyclone on record. Tens of thousands of homes were damaged, and about 70 people were killed. Harvey caused more than $100 billion in damage, making it one of the costliest disasters to strike the United States.

Record wildfires have also burned across the West. The 2018 Camp Fire in California was the deadliest. It killed 85 people and destroyed more than 10,000 homes. It was fueled by drought, an outcome of climate change. This week, California continued to battle the second- and third-largest wildfires in state history.

Officials have connected the fires to climate change. €œAll but three of the Top 20 Largest #Wildfires have occurred since 2000, with 10 of these large and damaging wildfires occurring in the last decade,” the California Department of Forestry and Fire Protection tweeted yesterday. €œAs fire weather continues to become more extreme, California is adjusting to fight these larger and more destructive wildfires.” Heat The Trump years have been some of the hottest since record-keeping began after the Civil War, according to NASA. After a record-warm July, this year may break the all-time annual heat record set in 2016. That’s a likely outcome, said Gavin Schmidt, director of the NASA Goddard Institute for Space Studies.

That’s notable because four years ago, the record warmth was fueled by El Niño, a band of warm water covering the tropical Pacific Ocean. That influence is absent this year, Schmidt said, and long-term trends point to rising heat. €œWe know that the trend is moving up. On average, every decade is warmer than the last,” he said. €œThe changes we’re seeing now are so far outside what would be possible in an un-globally-warmed world.” Public opinion Polling shows that voter concern about climate change has been growing for years and that it has not diminished as a result of the coronavirus pandemic.

Concern among some voters has spiked during Trump’s tenure. Before the virus, polling showed climate change was the second-most important issue for Democratic primary voters, behind only health care. Now, responding to the virus and restoring the economy top the list. But the public still wants the federal government to address climate change, recent polling shows. More Americans than ever—about 25%—view climate change as “extremely personally important,” according to a poll released last week by Stanford University, Resources for the Future and ReconMR.

That number is twice as large as it was in 2006, said the poll, which surveyed 1,000 adults between May and August. It also found that 82% of respondents want the federal government to act on climate change. And three-quarters of those surveyed said they had personally experienced the effects of global warming. €œThe COVID-19 pandemic has offered a unique opportunity to learn how people feel about climate change when faced with a global crisis,” said Ray Kopp, vice president of research and policy engagement at Resources for the Future. €œThe claim that we can’t do anything about climate change without crashing the economy, or that we need to focus only on the pandemic and not do anything on climate right now, simply doesn’t resonate with Americans,” he said.

The U.S. (and everyone else) Since Trump pledged to withdraw from the Paris climate agreement in 2017, world leaders have pressed him to rejoin and to take the issue seriously. Among them are German Chancellor Angela Merkel and French President Emmanuel Macron. Last year, Trump said Prince Charles spent 90 minutes talking to him about climate change, trying to convince him to take stronger action and to once again make the United States a world leader. In response, Trump said he wanted “good climate,” but his administration has continued to roll back environmental safeguards meant to reduce emissions.

In December, Macron said other governments, including China, Russia and the European Union, would lead the world in reducing emissions. The yearslong process of withdrawing from the Paris Agreement won’t be done until November. Yesterday, Biden tweeted that if he wins the election, he would rejoin the pact on the first day of his presidency. Climate hits Wall Street This week, it was announced that Exxon Mobil Corp. Would be dropped from the Dow Jones Industrial Average stock index.

It’s a significant departure, as Exxon was the longest-tenured company on the Dow, having been listed for almost a century. It’s also a reflection of how oil companies have taken a financial hit amid growing concerns about climate change and as a result of declining consumption due to the pandemic. At the same time, some solar and wind companies have grown bigger than their fossil fuel competitors. The same factors that have weakened fossil fuel companies, including more aggressive climate targets, helped drive clean energy technologies. On Wall Street, business interests are increasingly warning the Federal Reserve and other regulators that climate change could pose a significant risk to the economy.

Earlier this year, 40 investment firms and organizations that handle more than $1 trillion in assets urged Fed Chairman Jerome Powell to take action. They warned him that climate “threats have the potential to compound in ways we don’t yet understand, with disastrous impacts the likes of which we haven’t seen before.” Reprinted from Climatewire with permission from E&E News. E&E provides daily coverage of essential energy and environmental news at www.eenews.net..

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