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IntroductionIn recent years, many studies have been published on new diagnostic possibilities and management approaches in cohorts of patients suspected to have a disorder/difference of sex development (DSD).1–13 Based on these studies, it has become clear that services and institutions still differ buy trazodone online no prescription in the composition of the multidisciplinary teams that provide care for patients who have a DSD.11 14 Several projects have now worked to resolve this variability in care. The European Cooperation in Science and Technology (EU COST) action BM1303 ‘A systematic elucidation of differences of sex development’ has been a platform to achieve European agreement on harmonisation of clinical management and laboratory practices.15–17 Another such initiative involved an update of the 2006 DSD consensus document by an international group of professionals and patient representatives.18 These initiatives have highlighted how cultural buy trazodone online no prescription and financial aspects and the availability of resources differ significantly between countries and societies, a situation that hampers supranational agreement on common diagnostic protocols. As only a few national guidelines have been published in international journals, comparison of these guidelines is difficult even though such a comparison is necessary to capture the differences and initiate actions to overcome them. Nonetheless, four DSD (expert) centres located in the Netherlands and Flanders (the Dutch-speaking Northern part of Belgium) have collaborated to produce a detailed guideline on diagnostics in DSD.19 This buy trazodone online no prescription shows that a supranational guideline can be a reasonable approach for countries with similarly structured healthcare systems and similar resources. Within the guideline there is agreement that optimisation of expertise and care can be achieved through centralisation, for example, by limiting analysis of next-generation sequencing (NGS)-based diagnostic panels to only a few centres and by centralising pathological review of gonadal tissues.

International networks such as the European Reference Network for rare endocrine conditions (EndoERN), in which DSD is embedded, may facilitate the expansion of this kind of collaboration across Europe.This paper highlights key discussion points in the Dutch-Flemish guideline that have been insufficiently addressed in the literature thus far because they reflect evolving technologies or buy trazodone online no prescription less visible stakeholders. For example, prenatal observation of an atypical aspect of the genitalia indicating a possible DSD is becoming increasingly common, and we discuss appropriate counselling and a diagnostic approach for these cases, including the option of using NGS-based genetic testing. So far, little attention has been paid to this process.20 21 Furthermore, informing patients and/or their parents about atypical sex development and why this may warrant referral to a specialised team may be challenging, especially for professionals with limited experience in DSD.22 23 Therefore, a section of buy trazodone online no prescription the Dutch-Flemish guideline was written for these healthcare providers. Moreover, this enables DSD specialists to refer to the guideline when advising a referral. Transition from the prenatal to the postnatal team and from the paediatric to the adult team requires optimal communication between the specialists buy trazodone online no prescription involved.

Application of NGS-based techniques may lead to a higher diagnostic yield, providing a molecular genetic diagnosis in previously unsolved cases.16 We address the timing of this testing and the problems associated with this technique such as the interpretation of variants of unknown clinical significance (VUS). Similarly, histopathological interpretation and classification of removed gonadal tissue is challenging and would benefit from international collaboration and centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary multicentre group was formed with all members responsible for updating buy trazodone online no prescription the literature for a specific part of the guideline. Literature search in PubMed was not systematic, but rather intended to be broad in order to cover all areas and follow expert opinions. This approach is more in line with the Clinical Practice Advisory Document method described by Burke et al24 for guidelines involving buy trazodone online no prescription genetic practice because it is often troublesome to substantiate such guidelines with sufficient evidence due to the rapid changes in testing methods, for example, gene panels. All input provided by the group was synthesised by the chairperson (YvB), who also reviewed abstracts of papers on DSD published between 2010 and September 2017 for the guideline and up to October 2019 for this paper.

Abstracts had to be written in English and were identified using a broad range of Medical Subject Headings terms (eg, buy trazodone online no prescription DSD, genetic, review, diagnosis, diagnostics, 46,XX DSD, 46,XY DSD, guideline, multidisciplinary care). Next, potentially relevant papers on diagnostic procedures in DSD were selected. Case reports were excluded, buy trazodone online no prescription as were articles that were not open access or retrievable through institutional access. Based on this, a draft guideline was produced that was in line with the international principles of good diagnostic care in DSD. This draft was discussed by the writing committee and, after having obtained buy trazodone online no prescription agreement on remaining points of discussion, revised into a final draft.

This version was sent to a broad group of professionals from academic centres and DSD teams whose members had volunteered to review the draft guideline. After receiving and incorporating their input, the final version was presented to the paediatric and genetic buy trazodone online no prescription associations for approval. After approval by the members of the paediatric (NVK), clinical genetic (VKGN) and genetic laboratory (VKGL) associations, the guideline was published on their respective websites.19 Although Turner syndrome and Klinefelter syndrome are considered to be part of the DSD spectrum, they are not extensively discussed in this diagnostic guideline as guidelines dedicated to these syndromes already exist.25 26 However, some individuals with Turner syndrome or Klinefelter syndrome may present with ambiguous or atypical genitalia and may therefore initially follow the DSD diagnostic process.Guideline highlightsPrenatal settingPresentationThe most frequent prenatal presentation of a DSD condition is atypical genitalia found on prenatal ultrasound as an isolated finding or in combination with other structural anomalies. This usually occurs after the 20-week routine medical ultrasound for screening of congenital anomalies, but may also occur earlier, for example, when a commercial ultrasound is performed at the request of the parents.Another way DSD can be diagnosed before birth is when invasive prenatal buy trazodone online no prescription genetic testing carried out for a different reason, for example, due to suspicion of other structural anomalies, reveals a discrepancy between the genotypic sex and the phenotypic sex seen by ultrasound. In certified laboratories, the possibility of a sample switch is extremely low but should be ruled out immediately.

More often, the discrepancy will be due to sex-chromosome mosaicism or buy trazodone online no prescription a true form of DSD.A situation now occurring with increasing frequency is a discrepancy between the genotypic sex revealed by non-invasive prenatal testing (NIPT), which is now available to high-risk pregnant women in the Netherlands and to all pregnant women in Belgium, and later ultrasound findings. NIPT screens for CNVs in the fetus. However, depending on legal restrictions buy trazodone online no prescription and/or ethical considerations, the X and Y chromosomes are not always included in NIPT analysis and reports. If the X and Y chromosomes are included, it is important to realise that the presence of a Y-chromosome does not necessarily imply male fetal development. At the time that NIPT is performed (usually 11–13 weeks), genital development cannot be reliably appreciated by ultrasound, so any discrepancy or atypical aspect of the genitalia will only be noticed later in pregnancy and should prompt further evaluation.Counselling and diagnosticsIf a DSD is suspected, first-line sonographers and obstetricians should refer the buy trazodone online no prescription couple to their colleague prenatal specialists working with or in a DSD team.

After confirming an atypical genital on ultrasound, the specialist team should offer the couple a referral for genetic counselling to discuss the possibility of performing invasive prenatal testing (usually an amniocentesis) to identify an underlying cause that fits the ultrasound findings.22 23 To enable the parents to make a well-informed decision, prenatal counselling should, in our opinion, include. Information on the ultrasound findings and the limitations buy trazodone online no prescription of this technique. The procedure(s) that can be followed, including the risks associated with an amniocentesis. And the buy trazodone online no prescription type of information genetic testing can and cannot provide. Knowing which information has been provided and what words have been used by the prenatal specialist is very helpful for those involved in postnatal care.It is important that parents understand that the biological sex of a baby is determined by a complex interplay of chromosomes, genes and hormones, and thus that assessment of the presence or absence of a Y-chromosome alone is insufficient to assign the sex of their unborn child or, as in any unborn child, say anything about the child’s future gender identity.Expecting parents can be counselled by the clinical geneticist and the psychologist from the DSD team, although other DSD specialists can also be involved.

The clinical geneticist buy trazodone online no prescription should be experienced in prenatal counselling and well informed about the diagnostic possibilities given the limited time span in which test results need to be available to allow parents to make a well-informed decision about whether or not to continue the pregnancy. Termination of pregnancy can be considered, for instance, in a syndromic form buy trazodone online no prescription of DSD with multiple malformations, but when the DSD occurs as an apparently isolated condition, expecting parents may also consider termination of pregnancy, which, although considered controversial by some, is legal in Belgium and the Netherlands. The psychologist of the DSD team can support parents during and after pregnancy and help them cope with feelings of uncertainty and eventual considerations of a termination of pregnancy, as well as with practical issues, for example, how to inform others. The stress of not knowing exactly what the child’s genitalia will look like and uncertainty about the buy trazodone online no prescription diagnosis, treatment and prognosis cannot be avoided completely. Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images.

In our experience, parents appreciate having already spoken to some members of the DSD team during pregnancy and having a contact person before birth.After expert prenatal counselling, a significant buy trazodone online no prescription number of pregnant couples decline prenatal testing (personal experience IALG, MK, ABD, YvB, MC and HC-vdG). At birth, umbilical cord blood is a good source for (molecular) karyotyping and storage of DNA and can be obtained by the obstetrician, midwife or neonatologist. The terminology used in communication with parents should be carefully chosen,22 23 and midwives and staff of neonatal and delivery units should be clearly instructed to use gender-neutral buy trazodone online no prescription and non-stigmatising vocabulary (eg, ‘your baby’) as long as sex assignment is pending.An algorithm for diagnostic evaluation of a suspected DSD in the prenatal situation is proposed in figure 1. When couples opt for invasive prenatal diagnosis, the genetic analysis usually involves an (SNP)-array. It was recently estimated that >30% of individuals who have a buy trazodone online no prescription DSD have additional structural anomalies, with cardiac and neurological anomalies and fetal growth restriction being particularly common.27 28 If additional anomalies are seen, the geneticist can consider specific gene defects that may underlie a known genetic syndrome or carry out NGS.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Throughout the COVID-19 pandemic, InnovaCare Health, which operates Medicare Advantage and Medicaid plans in Puerto Rico—as well as in buy cheap trazodone online Florida—has been working closely with providers and government leaders to address the virus’ spread, including doing home delivery of everything from medicines to food for its members in the territory. CEO Dr. Richard Shinto spoke with Modern Healthcare Managing Editor Matthew buy cheap trazodone online Weinstock. The following is an edited transcript.MH. What’s the state of play in Puerto Rico right now?.

Shinto. I think the government did a very good job during the first few months of the pandemic. They closed down the island. No ships were allowed to come in. Tourism was stopped.

The reason they did that was they don’t have a deep enough healthcare system to have ventilators and all the necessary means to protect all the residents of the island.So the governor mandated across-the-board curfews and shut everything down. They did a very good job of really suppressing the infection.Our numbers are very low. I think maybe we broke close to 400 deaths total. There’s maybe 24,000 positive cases right now. The last numbers I saw, (there were) about 400 people in the hospital.

Really, that’s more of a (recent) surge. It was even lower than that, but when everything started to open up, especially bars, all of a sudden there was another surge.Currently, the stay-at-home policy is a curfew from 10 at night until five in the morning. No alcohol (sold) after 7 p.m. On Sundays, everybody has to stay indoors unless it’s just for grocery shopping or going to the pharmacy. Again, the government is putting a lot of pressure on everybody and the difference between Puerto Rico and a lot of other places (in the U.S.), they actually do implement it and they actually do fine you.

The fines can be up to $500 if you’re not wearing a mask and you wander around the streets in Puerto Rico.MH. Can you talk about your experience working with the government in Puerto Rico versus in Florida?. Shinto. One of the things Puerto Rico has done a very good job of is creating alignment. There’s alignment between the health plans, the providers, the hospitals and the government.

So when we go to D.C. Or we speak on behalf of the island, it’s usually one voice.MH. Working with providers, you advanced payments to doctors and hospitals in the early stages of the pandemic. That’s continuing, right?. €¨Shinto.

Yes. To date we’ve paid out somewhere over $160 million of advance payments to providers, both hospitals and physicians. Many of our specialists are on fee-for-service, so we did quick calculations on what our average pay to them was. From that, we were able to advance pay them.It’s interesting about disasters and the number of them that hit the island. We learned this after Hurricane Maria—the physicians needed the income and they’re not going to be able to submit encounter data.On the pandemic, we advance paid the doctors before we shut down the offices.

We knew they needed income so they could continue to take care of the beneficiaries and members.MH. Can you talk about the work you’re doing with at-home delivery of medications and over-the-counter supplies?. Shinto. As you practice in the States, you think about mail order and you think about chain pharmacies. That doesn’t really work here.

So over the years, we got into home delivery. We do home delivery for almost everything—your pharmacy, all your over-the-counter (supplies). Even prior to the pandemic, we were already starting home delivery of food.Puerto Rico is a great testing ground. When people started to get all their medications, all their (personal protective equipment)—if they wanted masks or they needed antiseptics for their hands—they just (place an order) on the website and it gets delivered within 48 hours. Then we started delivering food and then people didn’t want it pre-cooked.

They wanted to make their own. Then we started offering groceries, so you can go onto our sites and get whatever you need.We’ve built it into our benefit design so that members can get an iPhone, because then the app is already loaded—allowing them to order all their over-the-counter (supplies) or if it’s connected into the pharmacy, they can get home delivery there as well. We believe the future of healthcare has to be in that space of delivery.MH. What challenges have you had, if any, building up a supply chain?. Shinto.

One thing we learned after (natural) disasters is you’ve got to be ahead of the supply chain. I remember all the water we had ordered after (Hurricane Maria) and the generators, but FEMA came in and took control and it bothered us that we had a great supply chain. We had pre-ordered a lot, but then the (U.S.) government comes and takes over.When COVID came, we again preplanned and we went to the supply chain. We were able to move 3,500 employees out of the offices, into their homes, in less than a week. We had a lot of supplies like computers and modems for people who needed it.

We did a great job on pre-ordering PPE and COVID testing. But again, the (U.S.) government came in and confiscated everything. Then, we had to struggle to get the masks, or we had to go to China. So that created some problems. Even today, because of the limited amount of reagent on the island, the Puerto Rican government has taken control of testing.MH.

So PPE was taken from the island and brought back to the mainland?. Shinto. It wasn’t allowed to ship to the island. Even the COVID testing, which we had pre-bought. Being a physician and thinking about looking ahead … we needed to have, masks, gowns and gloves.

We went after those and then the testing and we were able to buy a lot of testing, but then they would get stopped at the ports. The government would take over in the States and then redirect it someplace else..

Throughout the COVID-19 pandemic, InnovaCare Health, which operates Medicare Advantage and Medicaid plans in Puerto Rico—as well buy trazodone online no prescription as in Florida—has been working closely with providers and government leaders to address the virus’ spread, including doing home delivery of everything from medicines to food for its members in the territory. CEO Dr. Richard Shinto buy trazodone online no prescription spoke with Modern Healthcare Managing Editor Matthew Weinstock. The following is an edited transcript.MH. What’s the state of play in Puerto Rico right now?.

Shinto. I think the government did a very good job during the first few months of the pandemic. They closed down the island. No ships were allowed to come in. Tourism was stopped.

The reason they did that was they don’t have a deep enough healthcare system to have ventilators and all the necessary means to protect all the residents of the island.So the governor mandated across-the-board curfews and shut everything down. They did a very good job of really suppressing the infection.Our numbers are very low. I think maybe we broke close to 400 deaths total. There’s maybe 24,000 positive cases right now. The last numbers I saw, (there were) about 400 people in the hospital.

Really, that’s more of a (recent) surge. It was even lower than that, but when everything started to open up, especially bars, all of a sudden there was another surge.Currently, the stay-at-home policy is a curfew from 10 at night until five in the morning. No alcohol (sold) after 7 p.m. On Sundays, everybody has to stay indoors unless it’s just for grocery shopping or going to the pharmacy. Again, the government is putting a lot of pressure on everybody and the difference between Puerto Rico and a lot of other places (in the U.S.), they actually do implement it and they actually do fine you.

The fines can be up to $500 if you’re not wearing a mask and you wander around the streets in Puerto Rico.MH. Can you talk about your experience working with the government in Puerto Rico versus in Florida?. Shinto. One of the things Puerto Rico has done a very good job of is creating alignment. There’s alignment between the health plans, the providers, the hospitals and the government.

So when we go to D.C. Or we speak on behalf of the island, it’s usually one voice.MH. Working with providers, you advanced payments to doctors and hospitals in the early stages of the pandemic. That’s continuing, right?. €¨Shinto.

Yes. To date we’ve paid out somewhere over $160 million of advance payments to providers, both hospitals and physicians. Many of our specialists are on fee-for-service, so we did quick calculations on what our average pay to them was. From that, we were able to advance pay them.It’s interesting about disasters and the number of them that hit the island. We learned this after Hurricane Maria—the physicians needed the income and they’re not going to be able to submit encounter data.On the pandemic, we advance paid the doctors before we shut down the offices.

We knew they needed income so they could continue to take care of the beneficiaries and members.MH. Can you talk about the work you’re doing with at-home delivery of medications and over-the-counter supplies?. Shinto. As you practice in the States, you think about mail order and you think about chain pharmacies. That doesn’t really work here.

So over the years, we got into home delivery. We do home delivery for almost everything—your pharmacy, all your over-the-counter (supplies). Even prior to the pandemic, we were already starting home delivery of food.Puerto Rico is a great testing ground. When people started to get all their medications, all their (personal protective equipment)—if they wanted masks or they needed antiseptics for their hands—they just (place an order) on the website and it gets delivered within 48 hours. Then we started delivering food and then people didn’t want it pre-cooked.

They wanted to make their own. Then we started offering groceries, so you can go onto our sites and get whatever you need.We’ve built it into our benefit design so that members can get an iPhone, because then the app is already loaded—allowing them to order all their over-the-counter (supplies) or if it’s connected into the pharmacy, they can get home delivery there as well. We believe the future of healthcare has to be in that space of delivery.MH. What challenges have you had, if any, building up a supply chain?. Shinto.

One thing we learned after (natural) disasters is you’ve got to be ahead of the supply chain. I remember all the water we had ordered after (Hurricane Maria) and the generators, but FEMA came in and took control and it bothered us that we had a great supply chain. We had pre-ordered a lot, but then the (U.S.) government comes and takes over.When COVID came, we again preplanned and we went to the supply chain. We were able to move 3,500 employees out of the offices, into their homes, in less than a week. We had a lot of supplies like computers and modems for people who needed it.

We did a great job on pre-ordering PPE and COVID testing. But again, the (U.S.) government came in and confiscated everything. Then, we had to struggle to get the masks, or we had to go to China. So that created some problems. Even today, because of the limited amount of reagent on the island, the Puerto Rican government has taken control of testing.MH.

So PPE was taken from the island and brought back to the mainland?. Shinto. It wasn’t allowed to ship to the island. Even the COVID testing, which we had pre-bought. Being a physician and thinking about looking ahead … we needed to have, masks, gowns and gloves.

We went after those and then the testing and we were able to buy a lot of testing, but then they would get stopped at the ports. The government would take over in the States and then redirect it someplace else..

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Latest Asthma what is the generic name for trazodone News WEDNESDAY, Sept. 23, 2020 (HealthDay News) -- Perrigo inhalers have been recalled because they could clog and not provide patients with any or enough medication, the U.S. Food and Drug Administration says.The retail recall is for all unexpired albuterol sulfate inhalation aerosol made by Catalent Pharma Solutions for Perrigo Pharmaceutical what is the generic name for trazodone Company. The inhalers are used to treat asthma and other airway/lung conditions, such as chronic obstructive pulmonary disease.Patients should continue to use the Perrigo inhaler they have, as needed and as directed by a doctor, the FDA said.Some of the recalled inhalers stop working after several uses.

If their rescue albuterol inhaler malfunctions and doesn't relieve symptoms in an emergency what is the generic name for trazodone situation, patients should immediately seek emergency care if needed, the FDA advised.It recommended that patients have extra inhalers or an alternative treatment available in case of inhaler malfunction.For more information, patients should talk with their health care provider or pharmacist, the FDA said.Copyright © 2019 HealthDay. All rights reserved. SLIDESHOW What is Asthma?. Asthma Myths Debunked See Slideshow.

Latest Asthma buy trazodone online no prescription News WEDNESDAY, Sept. 23, 2020 (HealthDay News) -- Perrigo inhalers have been recalled because they could clog and not provide patients with any or enough medication, the U.S. Food and buy trazodone online no prescription Drug Administration says.The retail recall is for all unexpired albuterol sulfate inhalation aerosol made by Catalent Pharma Solutions for Perrigo Pharmaceutical Company. The inhalers are used to treat asthma and other airway/lung conditions, such as chronic obstructive pulmonary disease.Patients should continue to use the Perrigo inhaler they have, as needed and as directed by a doctor, the FDA said.Some of the recalled inhalers stop working after several uses. If their rescue albuterol inhaler malfunctions and doesn't relieve symptoms in an emergency situation, patients should immediately seek emergency care if needed, the FDA advised.It recommended that patients have extra buy trazodone online no prescription inhalers or an alternative treatment available in case of inhaler malfunction.For more information, patients should talk with their health care provider or pharmacist, the FDA said.Copyright © 2019 HealthDay.

All rights reserved. SLIDESHOW What buy trazodone online no prescription is Asthma?. Asthma Myths Debunked See Slideshow.

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Lauren Gambill, MDPediatrician, AustinMember, Texas Medical Association (TMA) Committee on Child and Adolescent trazodone dosage for insomnia HealthExecutive Board Member, Texas Pediatric SocietyDoctors are community leaders. This role has become even more important during the COVID-19 pandemic. As patients navigate our new reality, they are looking to us to determine what is safe, how to protect their families, and the future of their health trazodone dosage for insomnia care. As more Texans lose their jobs, their health insurance, or even their homes, it is crucial that Texas receives the resources it needs to uphold our social safety net.

The U.S. Census helps determine funding for those resources, and that is why it trazodone dosage for insomnia is of the upmost importance that each and every Texan, no matter address, immigration status, or age, respond to the 2020 U.S. Census. The deadline has been cut short one month and now closes Sept trazodone dosage for insomnia.

30.COVID-19 has only increased the importance of completing the census to help our local communities and economies recover. The novel coronavirus has inflicted unprecedented strain on patients and exacerbated inequality as more people are out of work and are many in need of help with food, health care, housing, and more. Schools also have been stretched thin, with trazodone dosage for insomnia teachers scrambling to teach students online. Yet, the amount of federal funding Texas has available today to help weather this emergency was driven in part by the census responses made a decade ago.

Getting an accurate count in 2020 will help Texans prepare for the decade to follow, the first few years of which most certainly will be spent rebuilding from the pandemic’s fallout. Therefore, it is vital that all Texans be counted.The federal dollars Texas receives generally depends trazodone dosage for insomnia on our population. A George Washington University study recently found that even a 1% undercount can lead to a $300 million loss in funding.Take Medicaid, for example. Federal funds pay for 60% of the state’s program, which provides health coverage for two out of five Texas children, one in three individuals with disabilities, and trazodone dosage for insomnia 53% of all births.

The complicated formula used to calculate the federal portion of this funding depends on accurate census data. If Texas’ population is undercounted, Texans may appear better off financially than they really are, resulting in Texas getting fewer federal Medicaid dollars. If that happens, lawmakers will have to make up the difference, with cuts in services, program eligibility, or physician and provider payments, any of which are potentially detrimental.The census data also is key to funding other aspects of a community’s social safety net:Health careThe Children’s Health Insurance Program (CHIP) provides low-cost health trazodone dosage for insomnia insurance to children whose parents make too much to qualify for Medicaid, but not enough to afford quality coverage. Like Medicaid, how much money the federal government reimburses the state for the program depends in part on the census.Maternal and child health programs that promote public health and help ensure children are vaccinated relies on data from the census.

Texas also uses this federal funding to study and respond to maternal mortality trazodone dosage for insomnia and perinatal depression.Food and housing As unemployment rises and families struggle financially, many live with uncertainty as to where they will find their next meal. Already, one in seven Texans experiences food insecurity, and 20% of Texas children experience hunger. Food insecurity is rising in Texas as the pandemic continues. The Central Texas Food trazodone dosage for insomnia Bank saw a 206% rise in clients in March.

Funding for the Supplemental Nutrition Assistance Program and school lunch programs are both determined by the census. Funding for local housing programs also is calculated via the census. An accurate count will help ensure that people trazodone dosage for insomnia who lose their homes during this economic crisis have better hope of finding shelter while our communities recover. Homelessness is closely connected with declines in overall physical and mental health.Childcare and educationAs we navigate the new reality brought on by coronavirus, more parents are taking on roles as breadwinner, parent, teacher, and caretaker.

This stress trazodone dosage for insomnia highlights the desperate need for affordable childcare. The census determines funding for programs like Head Start that provide comprehensive early childhood education to low-income families. The good news is you still have time to complete the census. Visit 2020census.gov to trazodone dosage for insomnia take it.

It takes less than five minutes to complete. Then talk trazodone dosage for insomnia to your family, neighbors, and colleagues about doing the same. If you are wondering who counts, the answer is everyone, whether it’s a newborn baby, child in foster care, undocumented immigrant, or an individual experiencing homelessness.Completing the census is one of the best things that you can do for the health of your community, especially during the pandemic. Thank you for helping Texas heal and for supporting these essential safety net programs.(L to R).

UTHSA medical students Swetha Maddipudi, Brittany Hansen, Charles Wang, Carson Cortino, faculty advisor Kaparaboyna Kumar, MD, Ryan Wealther, Sidney trazodone dosage for insomnia Akabogu, Irma Ruiz, and Frank Jung pose with the TMA Be Wise Immunize banner. Photo courtesy by Ryan WealtherRyan WealtherMedical Student, UT Health San Antonio Long School of MedicineStudent Member, Texas Medical AssociationEditor’s Note. August is National Immunization Awareness Month. This article is part of a Me&My Doctor series highlighting and trazodone dosage for insomnia promoting the use of vaccinations.“Can the flu shot give you the flu?.

€â€œIs it dangerous for pregnant women to get a flu shot?. €â€œCan vaccines cause trazodone dosage for insomnia autism?. €These were questions women at Alpha Home, a residential substance abuse rehabilitation center in San Antonio, asked my fellow medical students and me during a flu vaccine discussion. It is easy to see why these questions were asked, as vaccine misinformation is common today.UTHSA medical student Frank Jing (left) gets a vaccine fromKaparaboyna Kumar, MD, (right).Photo courtesy of Ryan Wealther“No” is the answer to all the questions.

These were exactly the types of myths we set out to dispel at our vaccination drive.UT Health San Antonio Long School of Medicine medical students (under the supervision of Kaparaboyna Ashok Kumar, MD, faculty advisor for the Texas Medical Association Medical Student Section at UT Health San Antonio) hosted the vaccine drive at Alpha trazodone dosage for insomnia Home with the support of TMA’s Be Wise – Immunize℠ program, a public health initiative that aims to increase vaccinations and vaccine awareness through shot clinics and education. Our program consisted of a vaccination drive and an interactive, educational presentation that addressed influenza, common flu shot questions, and general vaccine myths. The Alpha Home residents could ask us questions during the program.We were interested to see if our educational program could answer Alpha Home residents’ questions about trazodone dosage for insomnia vaccinations and allay their hesitations about getting a flu vaccination. To gauge this, we created a brief survey.(Before I discuss the results of the survey, I should define vaccine hesitancy.

Vaccine hesitancy is a concept defined by the World Health Organization. It relates trazodone dosage for insomnia to when patients do not vaccinate despite having access to vaccines. Vaccine hesitancy is a problem because it prevents individuals from receiving their vaccinations. That makes them more susceptible to getting sick from vaccine-preventable diseases.)We surveyed the residents’ opinions about vaccinations before and after our educational program.

While opinions about shots improved with each survey question, we saw the most significant attitude change reflected in answers to the questions “I am concerned that vaccinations might not be safe,” trazodone dosage for insomnia and “How likely are you to receive a flu shot today?. € We had informed the residents and improved their understanding and acceptance of immunizations.Post-survey results show more residents at the Alpha Home shifted to more positive attitudes about vaccines, after learning more about their effectiveness by trusted members of the medical community. Graph by trazodone dosage for insomnia Ryan WealtherWhy is this important?. First, our findings confirm what we already knew.

Education by a trusted member of the medical community can effect change. In fact, it is widely known trazodone dosage for insomnia that physician recommendation of vaccination is one of the most critical factors affecting whether patients receive an influenza vaccination. Perhaps some added proof to this is that a few of the Alpha Home residents were calling me “Dr. Truth” by the end of the evening.Second, our findings add to our trazodone dosage for insomnia understanding of adult vaccine hesitancy.

This is significant because most of what we know about vaccine hesitancy is limited to parental attitudes toward their children’s vaccinations. Some parents question shots for their children, and many of the most deadly diseases we vaccinate against are given in childhood, including polio, tetanus, measles, and whooping cough shots. However, adults trazodone dosage for insomnia need some vaccinations as well, like the yearly influenza vaccine. After taking part in the UTHSA educational program, more residents at the Alpha Home shared more willingness to receive the flu vaccine.

Graph by Ryan WealtherAnother reason improving attitudes is important is that receiving a flu shot is even more timely during the COVID-19 pandemic because it decreases illnesses and conserves health care resources. Thousands of people each year are trazodone dosage for insomnia hospitalized from the flu, and with hospitals filling up with coronavirus patients, we could avoid adding dangerously ill flu patients to the mix. Lastly, these findings are important because once a COVID-19 vaccination becomes available, more people might be willing to receive it if their overall attitude toward immunizations is positive. Though the COVID-19 vaccine is still in trazodone dosage for insomnia development, it is not immune to vaccine hesitancy.

Recent polls have indicated up to one-third of Americans would not receive a COVID-19 vaccine even if it were accessible and affordable. Work is already being done to try to raise awareness and acceptance. In addition, misinformation about the COVID vaccine trazodone dosage for insomnia is circulating widely. (Someone recently asked me if the COVID vaccine will implant a microchip in people, and I have seen the same myth circulating on social media.

It will not.) This myth, however, illustrates the need for health care professionals to answer patients’ questions and to assuage their concerns.Vaccines work best when many people in a community receive them, and vaccine hesitancy can diminish vaccination rates, leaving people trazodone dosage for insomnia who can't get certain vaccines susceptible to these vaccine-preventable diseases. For example, babies under 6 months of age should not receive a flu shot, so high community vaccination rates protect these babies from getting sick with the flu. Our educational program at Alpha Home is just one example of how health care professionals can increase awareness and acceptance of shots. As the COVID-19 pandemic progresses, we need to ensure children and adults receive their vaccinations as recommended by their physician and the Centers for trazodone dosage for insomnia Disease Control and Prevention.

I encourage readers who have questions about the vaccinations they or their child may need to talk with their physician. As health care professionals, we’re more than happy to answer your questions..

Lauren Gambill, MDPediatrician, AustinMember, Texas Medical Association (TMA) Committee on buy trazodone online no prescription Child and Adolescent HealthExecutive Board Member, Texas Pediatric SocietyDoctors are community leaders. This role has become even more important during the COVID-19 pandemic. As patients navigate our new reality, they are looking to us to determine what is safe, how to protect their families, and the future of their health buy trazodone online no prescription care.

As more Texans lose their jobs, their health insurance, or even their homes, it is crucial that Texas receives the resources it needs to uphold our social safety net. The U.S. Census helps determine funding for those resources, and that is why it is of buy trazodone online no prescription the upmost importance that each and every Texan, no matter address, immigration status, or age, respond to the 2020 U.S.

Census. The deadline buy trazodone online no prescription has been cut short one month and now closes Sept. 30.COVID-19 has only increased the importance of completing the census to help our local communities and economies recover.

The novel coronavirus has inflicted unprecedented strain on patients and exacerbated inequality as more people are out of work and are many in need of help with food, health care, housing, and more. Schools also have been stretched thin, buy trazodone online no prescription with teachers scrambling to teach students online. Yet, the amount of federal funding Texas has available today to help weather this emergency was driven in part by the census responses made a decade ago.

Getting an accurate count in 2020 will help Texans prepare for the decade to follow, the first few years of which most certainly will be spent rebuilding from the pandemic’s fallout. Therefore, it is vital that all Texans be counted.The federal dollars buy trazodone online no prescription Texas receives generally depends on our population. A George Washington University study recently found that even a 1% undercount can lead to a $300 million loss in funding.Take Medicaid, for example.

Federal funds pay for 60% of the state’s program, which provides health coverage for two out of five Texas children, one in three individuals with disabilities, and 53% buy trazodone online no prescription of all births. The complicated formula used to calculate the federal portion of this funding depends on accurate census data. If Texas’ population is undercounted, Texans may appear better off financially than they really are, resulting in Texas getting fewer federal Medicaid dollars.

If that happens, lawmakers will have to make up the difference, with cuts in services, program eligibility, or physician and provider payments, any of which buy trazodone online no prescription are potentially detrimental.The census data also is key to funding other aspects of a community’s social safety net:Health careThe Children’s Health Insurance Program (CHIP) provides low-cost health insurance to children whose parents make too much to qualify for Medicaid, but not enough to afford quality coverage. Like Medicaid, how much money the federal government reimburses the state for the program depends in part on the census.Maternal and child health programs that promote public health and help ensure children are vaccinated relies on data from the census. Texas also buy trazodone online no prescription uses this federal funding to study and respond to maternal mortality and perinatal depression.Food and housing As unemployment rises and families struggle financially, many live with uncertainty as to where they will find their next meal.

Already, one in seven Texans experiences food insecurity, and 20% of Texas children experience hunger. Food insecurity is rising in Texas as the pandemic continues. The Central Texas Food Bank saw a 206% rise buy trazodone online no prescription in clients in March.

Funding for the Supplemental Nutrition Assistance Program and school lunch programs are both determined by the census. Funding for local housing programs also is calculated via the census. An accurate count will help ensure that people who lose their homes during this economic crisis buy trazodone online no prescription have better hope of finding shelter while our communities recover.

Homelessness is closely connected with declines in overall physical and mental health.Childcare and educationAs we navigate the new reality brought on by coronavirus, more parents are taking on roles as breadwinner, parent, teacher, and caretaker. This stress buy trazodone online no prescription highlights the desperate need for affordable childcare. The census determines funding for programs like Head Start that provide comprehensive early childhood education to low-income families.

The good news is you still have time to complete the census. Visit 2020census.gov to take it buy trazodone online no prescription. It takes less than five minutes to complete.

Then talk to your buy trazodone online no prescription family, neighbors, and colleagues about doing the same. If you are wondering who counts, the answer is everyone, whether it’s a newborn baby, child in foster care, undocumented immigrant, or an individual experiencing homelessness.Completing the census is one of the best things that you can do for the health of your community, especially during the pandemic. Thank you for helping Texas heal and for supporting these essential safety net programs.(L to R).

UTHSA medical students Swetha Maddipudi, Brittany Hansen, Charles Wang, Carson Cortino, faculty buy trazodone online no prescription advisor Kaparaboyna Kumar, MD, Ryan Wealther, Sidney Akabogu, Irma Ruiz, and Frank Jung pose with the TMA Be Wise Immunize banner. Photo courtesy by Ryan WealtherRyan WealtherMedical Student, UT Health San Antonio Long School of MedicineStudent Member, Texas Medical AssociationEditor’s Note. August is National Immunization Awareness Month.

This article is part of a Me&My Doctor series buy trazodone online no prescription highlighting and promoting the use of vaccinations.“Can the flu shot give you the flu?. €â€œIs it dangerous for pregnant women to get a flu shot?. €â€œCan vaccines buy trazodone online no prescription cause autism?.

€These were questions women at Alpha Home, a residential substance abuse rehabilitation center in San Antonio, asked my fellow medical students and me during a flu vaccine discussion. It is easy to see why these questions were asked, as vaccine misinformation is common today.UTHSA medical student Frank Jing (left) gets a vaccine fromKaparaboyna Kumar, MD, (right).Photo courtesy of Ryan Wealther“No” is the answer to all the questions. These were exactly the types of myths we set out to dispel at our vaccination drive.UT Health San Antonio Long School of Medicine medical students (under the supervision of Kaparaboyna Ashok Kumar, MD, faculty advisor for the Texas Medical Association Medical Student Section at UT Health San Antonio) hosted the vaccine drive at Alpha Home with the support of TMA’s Be Wise – buy trazodone online no prescription Immunize℠ program, a public health initiative that aims to increase vaccinations and vaccine awareness through shot clinics and education.

Our program consisted of a vaccination drive and an interactive, educational presentation that addressed influenza, common flu shot questions, and general vaccine myths. The Alpha buy trazodone online no prescription Home residents could ask us questions during the program.We were interested to see if our educational program could answer Alpha Home residents’ questions about vaccinations and allay their hesitations about getting a flu vaccination. To gauge this, we created a brief survey.(Before I discuss the results of the survey, I should define vaccine hesitancy.

Vaccine hesitancy is a concept defined by the World Health Organization. It relates to when patients do not vaccinate despite buy trazodone online no prescription having access to vaccines. Vaccine hesitancy is a problem because it prevents individuals from receiving their vaccinations.

That makes them more susceptible to getting sick from vaccine-preventable diseases.)We surveyed the residents’ opinions about vaccinations before and after our educational program. While opinions about shots improved with each survey question, we saw the most significant attitude change reflected in answers to the questions “I am concerned that vaccinations might not be buy trazodone online no prescription safe,” and “How likely are you to receive a flu shot today?. € We had informed the residents and improved their understanding and acceptance of immunizations.Post-survey results show more residents at the Alpha Home shifted to more positive attitudes about vaccines, after learning more about their effectiveness by trusted members of the medical community.

Graph by Ryan WealtherWhy is this important? buy trazodone online no prescription. First, our findings confirm what we already knew. Education by a trusted member of the medical community can effect change.

In fact, it is widely known that physician recommendation of vaccination is buy trazodone online no prescription one of the most critical factors affecting whether patients receive an influenza vaccination. Perhaps some added proof to this is that a few of the Alpha Home residents were calling me “Dr. Truth” by buy trazodone online no prescription the end of the evening.Second, our findings add to our understanding of adult vaccine hesitancy.

This is significant because most of what we know about vaccine hesitancy is limited to parental attitudes toward their children’s vaccinations. Some parents question shots for their children, and many of the most deadly diseases we vaccinate against are given in childhood, including polio, tetanus, measles, and whooping cough shots. However, adults need buy trazodone online no prescription some vaccinations as well, like the yearly influenza vaccine.

After taking part in the UTHSA educational program, more residents at the Alpha Home shared more willingness to receive the flu vaccine. Graph by Ryan WealtherAnother reason improving attitudes is important is that receiving a flu shot is even more timely during the COVID-19 pandemic because it decreases illnesses and conserves health care resources. Thousands of people each year are hospitalized from the flu, and with hospitals filling up with coronavirus patients, we could avoid adding dangerously ill flu patients to the buy trazodone online no prescription mix.

Lastly, these findings are important because once a COVID-19 vaccination becomes available, more people might be willing to receive it if their overall attitude toward immunizations is positive. Though the COVID-19 vaccine buy trazodone online no prescription is still in development, it is not immune to vaccine hesitancy. Recent polls have indicated up to one-third of Americans would not receive a COVID-19 vaccine even if it were accessible and affordable.

Work is already being done to try to raise awareness and acceptance. In addition, misinformation about the COVID vaccine buy trazodone online no prescription is circulating widely. (Someone recently asked me if the COVID vaccine will implant a microchip in people, and I have seen the same myth circulating on social media.

It will not.) This myth, however, illustrates the buy trazodone online no prescription need for health care professionals to answer patients’ questions and to assuage their concerns.Vaccines work best when many people in a community receive them, and vaccine hesitancy can diminish vaccination rates, leaving people who can't get certain vaccines susceptible to these vaccine-preventable diseases. For example, babies under 6 months of age should not receive a flu shot, so high community vaccination rates protect these babies from getting sick with the flu. Our educational program at Alpha Home is just one example of how health care professionals can increase awareness and acceptance of shots.

As the COVID-19 pandemic progresses, we need to ensure children and adults receive buy trazodone online no prescription their vaccinations as recommended by their physician and the Centers for Disease Control and Prevention. I encourage readers who have questions about the vaccinations they or their child may need to talk with their physician. As health care professionals, we’re more than happy to answer your questions..

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The sixth annual National Apprenticeship Week (NAW) is buy trazodone online no prescription Nov. 8-14. It’s a great time to learn more about the benefits of apprenticeship, or to buy trazodone online no prescription get the word out about your program!.

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11 September 2020 We are pleased to announce enhanced flexibility of training for senior healthcare scientists The Institute of are trazodone opiate based Biomedical Science (IBMS), Royal College 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 Scientists to apply is are trazodone opiate based 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 are trazodone opiate based 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 for Biomedical are trazodone opiate based 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 Scientist Education are pleased to announce a are trazodone opiate based 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 process to determine suitability and are trazodone opiate based 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 rounds are trazodone opiate based. 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 are trazodone opiate based programme 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 are trazodone opiate based. 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 buy trazodone online no prescription Science (IBMS), Royal College 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 Scientists to apply is hugely welcomed and the buy trazodone online no prescription 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 buy trazodone online no prescription 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 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 buy trazodone online no prescription tremendous news 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 buy trazodone online no prescription 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 process to determine suitability buy trazodone online no prescription 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 buy trazodone online no prescription 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 are identical for Clinical Scientists and Biomedical Scientists on HSST.This buy trazodone online no prescription 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 buy trazodone online no prescription 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.

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