Menu
FRUKDE
société des amis de Pasteur
" Jeunes gens ! Ne vous laissez pas atteindre par le scepticisme dénigrant et stérile, ne vous laissez pas décourager par les tristesses de certaines heures qui passent sur une nation ! "
  • What does viagra mean

    Où rencontrer Pasteur dans Arbois

    Après les monuments dolois à l'effigie de Louis Pasteur, c'est au tour des sites arboisiens !
    Avec quelques anecdotes historiques en prime, Alain Marchal nous présente les statues, médaillons ou encore portraits qui honorent la mémoire de Louis Pasteur...

    > LIRE LA SUITE

  • [

    Where to buy generic viagra

    High burden of antibiotic-resistant Mycoplasma genitalium where to buy generic viagra in symptomatic urethritisMycoplasma genitalium is an aetiological agent of sexually transmitted urethritis. A cohort study investigated M. Genitalium prevalence, antibiotic resistance and where to buy generic viagra association with previous macrolide exposure among 1816 Chinese men who presented with symptomatic urethritis between 2011 and 2015. Infection was diagnosed by PCR, and sequencing was used to detect mutations that confer resistance to macrolides and fluoroquinolones. In 11% of where to buy generic viagra men, M.

    Genitalium was the sole pathogen identified. Nearly 90% of where to buy generic viagra infections were resistant to macrolides and fluoroquinolones. Previous macrolide exposure was associated with higher prevalence of resistance (97%). The findings where to buy generic viagra point to the need for routine screening for M. Genitalium in symptomatic men with urethritis.

    Treatment strategies to overcome where to buy generic viagra antibiotic resistance in M. Genitalium are needed.Yang L, Xiaohong S, Wenjing L, et al. Mycoplasma genitalium in symptomatic male where to buy generic viagra urethritis. Macrolide use is associated with increased resistance. Clin Infect Dis 2020;5:805–10.

    Doi:10.1093/cid/ciz294.A new entry inhibitor offers promise for treatment-experienced where to buy generic viagra patients with multidrug-resistant HIVFostemsavir, the prodrug of temsavir, is an attachment inhibitor. By targeting the gp120 protein on the HIV-1 envelope, it prevents viral interaction with the CD4 receptor. No cross-resistance has been described with other antiretroviral agents, including those that target viral where to buy generic viagra entry by other modalities. In the phase III BRIGHTE trial, 371 highly treatment-experienced patients who had exhausted ≥4 classes of antiretrovirals received fostemsavir with an optimised regimen. After 48 weeks, 54% of those with 1–2 where to buy generic viagra additional active drugs achieved viral load suppression <40 copies/mL.

    Response rates were 38% among patients lacking other active agents. Drug-related adverse events included nausea where to buy generic viagra (4%) and diarrhoea (3%). As gp120 substitutions reduced fostemsavir susceptibility in up to 70% of patients with virological failure, fostemsavir offers the most valuable salvage option in partnership with other active drugs.Kozal M, Aberg J, Pialoux G, et al. Fostemsavir in adults with multidrug-resistant HIV-1 infection where to buy generic viagra. N Engl J Med 2020;382:1232–43.

    Doi. 10.1056/NEJMoa1902493Novel tools to aid identification of hepatitis C in primary careHepatitis C can now be cured with oral antiviral treatment, and improving diagnosis is a key element of elimination strategies.1 A cluster randomised controlled trial in South West England tested performance and cost-effectiveness of an electronic algorithm that identified at-risk patients in primary care according to national recommendations,2 coupled with educational activities and interventions to increase patients’ awareness. Outcomes were testing uptake, diagnosis and referral to specialist care. Practices in the intervention arm had an increase in all outcome measures, with adjusted risk ratios of 1.59 (1.21–2.08) for uptake, 2.24 (1.47–3.42) for diagnosis and 5.78 (1.60–21.6) for referral. The intervention was highly cost-effective.

    Electronic algorithms applied to practice systems could enhance testing and diagnosis of hepatitis C in primary care, contributing to global elimination goals.Roberts K, Macleod J, Metcalfe C, et al. Cost-effectiveness of an intervention to increase uptake of hepatitis C virus testing and treatment (HepCATT). Cluster randomised controlled trial in primary care. BMJ 2020;368:m322. Doi:10.1136/bmj.m322Low completion rates for antiretroviral postexposure prophylaxis (PEP) after sexual assaultA 4-week course of triple-agent postexposure prophylaxis (PEP) is recommended following a high-risk sexual assault.3 4 A retrospective study in Barcelona identified 1695 victims attending an emergency room (ER) between 2006 and 2015.

    Overall, 883 (52%) started prophylaxis in ER, which was mostly (43%) lopinavir/ritonavir based. Follow-up appointments were arranged for those living in Catalonia (631, 71.5%), and of these, only 183 (29%) completed treatment. Loss to follow-up was more prevalent in those residing outside Barcelona. PEP non-completion was associated with a low perceived risk, previous assaults, a known aggressor and a positive cocaine test. Side effects were common, occurring in up to 65% of those taking lopinavir/ritonavir and accounting for 15% of all discontinuations.

    More tolerable PEP regimens, accessible follow-up and provision of 1-month supply may improve completion rates.Inciarte A, Leal L, Masfarre L, et al. Postexposure prophylaxis for HIV infection in sexual assault victims. HIV Med 2020;21:43–52. Doi:10.1111/hiv.12797.Effective antiretroviral therapy reduces anal high-risk HPV infection and cancer riskAmong people with HIV, effective antiretroviral therapy (ART) is expected to improve control of anal infection with high-risk human papillomavirus (HR-HPV) and reduce the progression of HPV-associated anal lesions. The magnitude of the effect is not well established.

    By meta-analysis, people on established ART (vs ART-naive) had a 35% lower prevalence of HR-HPV infection, and those with undetectable viral load (vs detectable viral load) had a 27% and 16% reduced risk of low and high-grade anal lesions, respectively. Sustained virological suppression on ART reduced by 44% the risk of anal cancer. The role of effective ART in reducing anal HR-HPV infection and cancer risks is especially salient given current limitations in anal cancer screening, high rates of anal lesion recurrence and access to vaccination.Kelly H, Chikandiwa A, Alemany Vilches L, et al. Association of antiretroviral therapy with anal high-risk human papillomavirus, anal intraepithelial neoplasia and anal cancer in people living with HIV. A systematic review and meta-analysis.

    Lancet HIV. 2020;7:e262–78. Doi:10.1016/S2352-3018(19)30434-5.The impact of sex work laws and stigma on HIV prevention among female sex workersSex work laws and stigma have been established as structural risk factors for HIV acquisition among female sex workers (FSWs). However, individual-level data assessing these relationships are limited. A study examined individual-level data collected in 2011–2018 from 7259 FSWs across 10 sub-Saharan African countries.

    An association emerged between HIV prevalence and increasingly punitive and non-protective laws. HIV prevalence among FSWs was 11.6%, 19.6% and 39.4% in contexts where sex work was partly legalised, not recognised or criminalised, respectively. Stigma measures such as fear of seeking health services, mistreatment in healthcare settings, lack of police protection, blackmail and violence were associated with higher HIV prevalence and more punitive settings. Sex work laws that protect sex workers and reduce structural risks are needed.Lyons CE, Schwartz SR, Murray SM, et al. The role of sex work laws and stigmas in increasing HIV risks among sex workers.

    Nat Commun 2020;11:773. Doi:10.1038/s41467-020-14593-6.BackgroundCumbria Sexual Health Services (CSHS) in collaboration with Cumbria Public Health and local authorities have established a COVID-19 contact tracing pathway for Cumbria. The local system was live 10 days prior to the national system on 18 May 2020. It was designed to interface and dovetail with the government’s track and trace programme.Our involvement in this initiative was due to a chance meeting between Professor Matt Phillips, Consultant in Sexual Health and HIV, and the Director of Public Health Cumbria, Colin Cox. Colin knew that Cumbria needed to act fast to prevent the transmission of COVID-19 and Matt knew that sexual health had the skills to help.ProcessDespite over 90% of the staff from CSHS being redeployed in March 2020, CSHS maintained urgent sexual healthcare for the county and a phone line for advice and guidance.

    As staff began to return to the service in May 2020 we had capacity to spare seven staff members, whose hours were the equivalent of four full-time staff. We had one system administrator, three healthcare assistants, one nurse, Health Advisor Helen Musker and myself.CSHS were paramount to the speed with which the local system began. Following approval from the Trust’s chief executive officer we had adapted our electronic patient records (EPR) system, developed a standard operating procedure and trained staff, using a stepwise competency model, within just 1 day.In collaboration with the local laboratories we developed methods for the input of positive COVID-19 results into our EPR derivative. We ensured that labs would be able to cope with the increase in testing and that testing hubs had additional capacity. Testing sites and occupational health were asked to inform patients that if they tested positive they would be contacted by our teams.This initiative involved a multiagency system including local public health (PH) teams, local authority, North Cumbria and Morecambe Bay CCGs, Public Health England (PHE) and the military.

    If CSHS recognise more than one positive result in the same area/organisation, they flag this with PH at the daily incident management meeting and environmental health officers (EHOs) provide advice and guidance for the organisation. We have had an active role in the contact tracing for clusters in local general practices, providing essential information to PH to enable them to initiate outbreak control and provide accurate advice to the practices. We are an integral part in recognising cases in large organisations and ensuring prompt action is taken to stem the spread of the disease. The team have provided out-of-hours work to ensure timely and efficient action is taken for all contacts.The local contact tracing pilot has evolved and a database was established by local authorities. Our data fed directly into this from the end of May 2020.

    This enables the multiagency team to record data in one place, improving recognition of patterns of transmission.DiscussionCumbria is covered by three National Health Service Trusts, which meant accessing data outside of our Trust was challenging and took more time to establish. There are two CCGs for Cumbria, which meant discussions regarding testing were needed with both North and South CCGs and variations in provision had to be accounted for. There are six boroughs in Cumbria with different teams of EHOs working in each. With so many people involved, not only is there need for large-scale frequent communication across a multisystem team, there is also inevitable duplication of work.Lockdown is easing and sexual health clinics are increasing capacity in a new world of virtual appointments and reduced face-to-face consultations. Staff within the contact tracing team are now balancing their commitments across both teams to maintain their skills and keep abreast of the rapid developments within our service due to COVID-19.

    We are currently applying for funding from PH in order to second staff and backfill posts in sexual health.ConclusionCSHS have been able to lend our skills effectively to the local contact tracing efforts. We have expedited the contact tracing in Cumbria and provided crucial information to help contain outbreaks. It has had a positive effect on staff morale within the service and we have gained national recognition for our work. We have developed excellent relationships with our local PH team, PHE, Cumbria Council, EHOs and both CCGs.Cumbria has the infrastructure to meet the demands of a second wave of COVID-19. The beauty of this model is that if we are faced with a second lockdown, sexual health staff will inevitably be available to help with the increased demand for contact tracing.

    Our ambition is that this model will be replicated nationally..

    What does viagra mean

    Viagra
    Levitra professional
    Fildena super active
    Tadalista super active
    Tadora
    Top avana
    Price per pill
    Online
    Possible
    Yes
    Yes
    REFILL
    Online
    Where to buy
    23h
    20h
    21h
    12h
    19h
    19h
    How often can you take
    On the market
    Indian Pharmacy
    Online Pharmacy
    Yes
    No
    Pharmacy
    Duration of action
    Yes
    Yes
    No
    No
    No
    No
    Buy with echeck
    No
    Yes
    No
    No
    No
    Yes
    Pack price
    38
    36
    31
    48
    64
    62
    Buy with Bitcoin
    Register first
    Canadian pharmacy only
    Canadian pharmacy only
    20mg
    Register first
    30mg + 50mg

    IntroductionIn recent years, many studies have been published on new diagnostic what does viagra mean possibilities and management approaches in cohorts of patients suspected to have a http://www.amisdepasteur.fr/viagra-prices-walmart/ disorder/difference of sex development (DSD).1–13 Based on these studies, it has become clear that services and institutions still differ in the composition of the multidisciplinary teams that provide care for patients who have a DSD.11 14 Several projects have now worked to resolve this variability in care. The European Cooperation in Science and Technology (EU COST) action BM1303 ‘A systematic elucidation of differences of sex development’ has been a platform to achieve European agreement on harmonisation of clinical management and laboratory practices.15–17 Another such initiative involved an update of the 2006 DSD consensus what does viagra mean document by an international group of professionals and patient representatives.18 These initiatives have highlighted how cultural and financial aspects and the availability of resources differ significantly between countries and societies, a situation that hampers supranational agreement on common diagnostic protocols. As only a few national guidelines have been published in international journals, comparison of these guidelines is difficult even though such a comparison is necessary to capture the differences and initiate actions to overcome them.

    Nonetheless, four DSD (expert) centres located in the what does viagra mean Netherlands and Flanders (the Dutch-speaking Northern part of Belgium) have collaborated to produce a detailed guideline on diagnostics in DSD.19 This shows that a supranational guideline can be a reasonable approach for countries with similarly structured healthcare systems and similar resources. Within the guideline there is agreement that optimisation of expertise and care can be achieved through centralisation, for example, by limiting analysis of next-generation sequencing (NGS)-based diagnostic panels to only a few centres and by centralising pathological review of gonadal tissues. International networks such as the European Reference Network for rare endocrine conditions what does viagra mean (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 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 what does viagra mean of the Dutch-Flemish guideline was written for these healthcare providers. Moreover, this enables DSD specialists to refer to the guideline when advising a referral.

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

    Literature search in PubMed was not systematic, but rather intended to be broad in order to cover all areas and follow expert opinions. This approach is more in line with the Clinical Practice Advisory Document method described by Burke et al24 for guidelines involving genetic practice because it is often troublesome to substantiate such guidelines with sufficient evidence due to the rapid what does viagra mean changes in testing methods, for example, gene panels. All input provided by the group was synthesised by the chairperson (YvB), who also reviewed abstracts of papers on DSD published between 2010 and September 2017 for the guideline and up to October 2019 for this paper.

    Abstracts had to be written in English and were identified using a broad range of Medical Subject Headings terms (eg, DSD, genetic, review, diagnosis, diagnostics, 46,XX DSD, 46,XY DSD, guideline, what does viagra mean multidisciplinary care). Next, potentially relevant papers on diagnostic procedures in DSD were selected. Case reports were excluded, what does viagra mean 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 what does viagra mean 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 what does viagra mean and genetic associations for approval. After approval by the members of the paediatric (NVK), clinical genetic (VKGN) and genetic laboratory (VKGL) associations, the guideline was published on their respective websites.19 Although Turner syndrome and Klinefelter syndrome are considered to be part of the DSD spectrum, they are not extensively discussed in this diagnostic guideline as guidelines dedicated to these syndromes already exist.25 26 However, some individuals with Turner syndrome or Klinefelter syndrome may present with ambiguous or atypical genitalia and may therefore initially follow the DSD diagnostic process.Guideline highlightsPrenatal settingPresentationThe most frequent prenatal presentation of a DSD condition is atypical genitalia found on prenatal ultrasound as an isolated finding or in combination with other structural anomalies. This usually occurs after the 20-week routine medical ultrasound for screening of congenital anomalies, but may also occur earlier, for example, when a commercial ultrasound is performed at the request of the parents.Another way what does viagra mean DSD can be diagnosed before birth is when invasive prenatal genetic testing carried out for a different reason, for example, due to suspicion of other structural anomalies, reveals a discrepancy between the genotypic sex and the phenotypic sex seen by ultrasound.

    In certified laboratories, the possibility of a sample switch is extremely low but should be ruled out immediately. More often, the discrepancy will be due to sex-chromosome mosaicism or a true form of DSD.A situation now occurring with increasing frequency is a discrepancy between the genotypic sex revealed by non-invasive prenatal testing (NIPT), which is now available to high-risk pregnant women in the Netherlands and to all pregnant women in Belgium, and later ultrasound what does viagra mean findings. NIPT screens for CNVs in the fetus.

    However, depending on legal restrictions and/or ethical considerations, the X and Y chromosomes are not always what does viagra mean 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 couple to their colleague prenatal specialists working with or in a DSD team what does viagra mean.

    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 of this technique what does viagra mean. The procedure(s) that can be followed, including the risks associated with an amniocentesis.

    And the type of what does viagra mean 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 should be experienced in prenatal counselling and well informed about the diagnostic possibilities given the limited time span in which what does viagra mean test results need to be available to allow parents to make a well-informed decision about whether or not to continue the pregnancy.

    Termination of pregnancy can be considered, for instance, in a syndromic form of DSD with multiple malformations, but when the DSD occurs as an apparently isolated condition, expecting parents may what does viagra mean 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 what does viagra mean of not knowing exactly what the child’s genitalia will look like and uncertainty about the diagnosis, treatment and prognosis cannot be avoided completely.

    Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images. In our experience, parents appreciate having already spoken to some members of the DSD team during pregnancy and having a contact person before birth.After expert prenatal counselling, a significant number of pregnant couples decline prenatal testing (personal experience IALG, MK, ABD, YvB, MC what does viagra mean 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 what does viagra mean 23 and midwives and staff of neonatal and delivery units should be clearly instructed to use gender-neutral and non-stigmatising vocabulary (eg, ‘your baby’) as long as sex assignment is pending.An algorithm for diagnostic evaluation of a suspected DSD in the prenatal situation is proposed in figure 1. When couples opt for invasive prenatal diagnosis, the genetic analysis usually involves an (SNP)-array. It was recently estimated that >30% of individuals who have a DSD have additional structural anomalies, with cardiac and neurological anomalies and fetal growth restriction being particularly common.27 28 If additional anomalies what does viagra mean are seen, the geneticist can consider specific gene defects that may underlie a known genetic syndrome or carry out NGS.

    NGS-based techniques have also now made their appearance in prenatal diagnosis of congenital anomalies.29 30 Panels using these techniques can be specific for genes involved in DSD, or be larger panels covering multiple congenital anomalies, and are usually employed with trio-analysis to compare variants identified in the child with the parents’ genetics.29–31 Finding a genetic cause before delivery can help reduce parental stress in the neonatal period and speed up decisions regarding gender assignment. In such cases there is no what does viagra mean 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 do you need a prescription for viagra since 2008 related to the rapidly rising incidence.2Endometrial cancer has traditionally been classified into type I and type II based on morphology.3 The more common subtype, type I, is mostly comprised of endometrioid tumours and is oestrogen-driven, arises from a hyperplastic endometrium, presents at an early stage and has an excellent 5 year survival rate.4 By contrast, type II includes non-endometrioid tumours, specifically serous, carcinosarcoma and clear cell subtypes, which are biologically aggressive tumours with a poor prognosis that are often diagnosed at an advanced stage.5 Recent efforts have focused on a molecular classification system for more accurate categorisation of endometrial tumours into four groups with distinct prognostic profiles.6 7The majority of endometrial cancers arise through the interplay of familial, genetic and lifestyle factors.

    Two inherited cancer predisposition syndromes, Lynch syndrome and the much rarer Cowden syndrome, substantially increase the lifetime risk of endometrial cancer, but these only account for around 3–5% of cases.8–10 Having first or second degree relative(s) with endometrial or colorectal cancer increases endometrial cancer risk, although a large European twin study failed to demonstrate a strong heritable link.11 The authors failed to show that there was greater concordance in monozygotic than dizygotic twins, but the study was based on relatively small numbers of endometrial cancers. Lu and colleagues reported an association between common single nucleotide polymorphisms (SNPs) and endometrial cancer risk, revealing the potential role of SNPs in explaining part of the risk in both the familial and general populations.12 Thus far, many SNPs have been reported to modify susceptibility to endometrial cancer. However, much of this work predated genome wide association studies and is of variable quality.

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

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

    Key words including MeSH (Medical Subject Heading) terms and free-text words were searched in both titles and abstracts. The following terms were used. €œendomet*”,“uter*”, “womb”, “cancer(s)”, “neoplasm(s)”, “endometrium tumour”, “carcinoma”, “adenosarcoma”, “clear cell carcinoma”, “carcinosarcoma”, “SNP”, “single nucleotide polymorphism”, “GWAS”, and “genome-wide association study/ies”.

    No other restrictions were applied. The search was repeated with time restrictions between 2018 and June 2019 to capture any recent publications.Eligibility criteriaStudies were selected for full-text evaluation if they were primary articles investigating a relationship between endometrial cancer and SNPs. Study outcome was either the increased or decreased risk of endometrial cancer relative to controls reported as an odds ratio (OR) with corresponding 95% confidence intervals (95% CIs).Study selectionThree independent reviewers screened all articles uploaded to a screening spreadsheet developed by Helena VonVille.17 Disagreements were resolved by discussion.

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

    For the purpose of an SNP panel, articles utilising broad European or multi-ethnic cohorts were selected. Where overlapping populations were identified, the most comprehensive study was included.Data extraction and synthesisFor each study, the following data were extracted. SNP ID, nearby gene(s)/chromosome location, OR (95% CI), p value, minor or effect allele frequency (MAF/EAF), EA (effect allele) and OA (other allele), adjustment, ethnicity and ancestry, number of cases and controls, endometrial cancer type, and study type including discovery or validation study and meta-analysis.

    For risk estimates, a preference towards most adjusted results was applied. For candidate-gene studies, a standard p value of<0.05 was applied and for GWAS a p value of <5×10-8, indicating genome-wide significance, was accepted as statistically significant. However, due to the limited number of SNPs with p values reaching genome-wide significance, this threshold was then lowered to <1×10-5, allowing for marginally significant SNPs to be included.

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

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

    Additionally, SNPs in linkage disequilibrium (r2 >0.2) with each other were examined, and of those in linkage disequilibrium, the SNP with strongest association was reported. Per allele ORs were used unless stated otherwise.View this table:Table 1 List of top SNPs most likely to contribute to endometrial cancer risk identified through systematic review of recent literature21–25Study selection flow diagram. *Reasons.

    Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study. Adapted from.

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

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

    *Reasons. Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study.

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

    The PRISMA Statement. PLoS Med 6(6). E1000097.

    Doi:10.1371/journal.pmed1000097.Top SNPs associated with endometrial cancer riskFollowing careful interpretation of the data, 24 independent SNPs with the lowest p values that showed the strongest association with endometrial cancer were obtained (table 1).21–25 These SNPs are located in or around genes coding for transcription factors, cell growth and apoptosis regulators, and enzymes involved in the steroidogenesis pathway. All the SNPs presented here were reported on the basis of a GWAS or in one case, an exome-wide association study, and hence no SNPs from candidate-gene studies made it to the list. This is partly due to the nature of larger GWAS providing more comprehensive and powered results as opposed to candidate gene studies.

    Additionally, a vast majority of SNPs reported by candidate-gene studies were later refuted by large-scale GWAS such as in the case of TERT and MDM2 variants.26 27 The exception to this is the CYP19 gene, where candidate-gene studies reported an association between variants in this gene with endometrial cancer in both Asian and broad European populations, and this association was more recently confirmed by large-scale GWAS.21 28–30 Moreover, a recent article authored by O’Mara and colleagues reviewed the GWAS that identified most of the currently known SNPs associated with endometrial cancer.31Most of the studies represented in table 1 are GWAS and the majority of these involved broad European populations. Those having a multi-ethnic cohort also consisted primarily of broad European populations. Only four of the variants in table 1 are located in coding regions of a gene, or in regulatory flanking regions around the gene.

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

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

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

    These can be activated by high levels of KLF5 (transcriptional activator). Three SNPs have been identified in or around KLF5 that are associated with endometrial cancer. The G allele of rs11841589 (OR 1.15, 95% CI 1.11 to 1.21.

    P=4.83×10-11), the A allele of rs9600103 (OR 1.23, 95% CI 1.16 to 1.30. P=3.76×10-12) and C allele of rs7981863 (OR 1.16, 95% CI 1.12 to 1.20. P=2.70×10-17) have all been found to be associated with an increased likelihood of endometrial cancer in large European cohorts.21 30 34 It is worth noting that these SNPs are not independent, and hence they quite possibly tag the same causal variant.The MYC family of proto-oncogenes encode transcription factors that regulate cell proliferation, which can contribute to cancer development if dysregulated.

    The recent GWAS by O’Mara et al reported three SNPs within the MYC region that reached genome-wide significance with conditional p values reaching at least 5×10–8.35To test the utility of these SNPs as predictive markers, we devised a theoretical PRS calculation using the log ORs and EAFs per SNP from the published data. The results were very encouraging with an RR of 3.16 for the top 1% versus the mean, using all the top SNPs presented in table 1 and 2.09 when using only the SNPs that reached genome-wide significance (including AKT1).Controversy surrounding MDM2 variant SNP309MDM2 negatively regulates tumour suppressor gene TP53, and as such, has been extensively studied in relation to its potential role in predisposition to endometrial cancer. Our search identified six original studies of the association between MDM2 SNP rs2279744 (also referred to as SNP309) and endometrial cancer, all of which found a statistically significant increased risk per copy of the G allele.

    Two more original studies were identified through our full-text evaluation. However, these were not included here as they did not meet our inclusion criteria—one due to small sample size, the other due to studying rs2279744 status dependent on another SNP.36 37 Even so, the two studies were described in multiple meta-analyses that are listed in table 3. Different permutations of these eight original studies appear in at least eight published meta-analyses.

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

    We have identified the most robust SNPs in the context of endometrial cancer risk. Of those, only 19 were significant at genome-wide level and a further five were considered marginally significant. The largest GWAS conducted in this field was the discovery- and meta-GWAS by O’Mara et al, which utilised 12 096 cases and 108 979 controls.21 Despite the inclusion of all published GWAS and around 5000 newly genotyped cases, the total number did not reach anywhere near what is currently available for other common cancers such as breast cancer.

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

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

    Thus, these should be interpreted with caution. Additionally, most of the SNPs reported by candidate-gene studies were not detected by the largest GWAS to date conducted by O’Mara et al.21 However, this does not necessarily mean that the possibility of those SNPs being relevant should be completely dismissed. Moreover, meta-analyses were attempted for other variants.

    However, these showed no statistically significant association and many presented with high heterogeneity between the respective studies (data not shown). Furthermore, as many studies utilised the same set of cases and/or controls, conducting a meta-analysis was not possible for a good number of SNPs. It is therefore unequivocal that the literature is crowded with numerous small candidate-gene studies and conflicting data.

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

    Using all 24 or genome-wide significant SNPs only, women with a PRS in the top 1% of the distribution would be predicted to have a risk of endometrial cancer 3.16 and 2.09 times higher than the mean risk, respectively.However, the importance of these variants and relevance of the proximate genes in a functional or biological context is challenging to evaluate. Long distance promoter regulation by enhancers may disguise the genuine target gene. In addition, enhancers often do not loop to the nearest gene, further complicating the relevance of nearby gene(s) to a GWAS hit.

    In order to elucidate biologically relevant candidate target genes in endometrial cancer, O’Mara et al looked into promoter-associated chromatin looping using a modern HiChIP approach.47 The authors utilised normal and tumoural endometrial cell lines for this analysis which showed significant enrichment for endometrial cancer heritability, with 103 candidate target genes identified across the 13 risk loci identified by the largest ECAC GWAS. Notable genes identified here were CDKN2A and WT1, and their antisense counterparts. The former was reported to be nearby of rs1679014 and the latter of rs10835920, as shown in table 1.

    Moreover, of the 36 candidate target genes, 17 were found to be downregulated while 19 were upregulated in endometrial tumours.The authors also investigated overlap between the 13 endometrial cancer risk loci and top eQTL variants for each target gene.47 In whole blood, of the two particular lead SNPs, rs8822380 at 17q21.32 was a top eQTL for SNX11 and HOXB2, whereas rs937213 at 15q15.1 was a top eQTL for SRP14. In endometrial tumour, rs7579014 at 2p16.1 was found to be a top eQTL for BCL11A. This is particularly interesting because BCL11A was the only nearby/candidate gene that had a GWAS association reported in both endometrioid and non-endometrioid subtypes.

    The study looked at protein–protein interactions between endometrial cancer drivers and candidate target gene products. Significant interactions were observed with TP53 (most significant), AKT, PTEN, ESR1 and KRAS, among others. Finally, when 103 target candidate genes and 387 proteins were combined together, 462 pathways were found to be significantly enriched.

    Many of these are related to gene regulation, cancer, obesity, insulinaemia and oestrogen exposure. This study clearly showed a potential biological relevance for some of the SNPs reported by ECAC GWAS in 2018.Most of the larger included studies used cohorts primarily composed of women of broad European descent. Hence, there are negligible data available for other ethnicities, particularly African women.

    This is compounded by the lack of reference genotype data available for comparative analysis, making it harder for research to be conducted in ethnicities other than Europeans. This poses a problem for developing risk prediction models that are equally valuable and predictive across populations. Thus, our results also are of limited applicability to non-European populations.Furthermore, considering that non-endometrioid cases comprise a small proportion (~20%) of all endometrial cancer cases, much larger cohort sizes are needed to detect any genuine signals for non-endometrioid tumours.

    Most of the evaluated studies looked at either overall/mixed endometrial cancer subtypes or endometrioid histology, and those that looked at variant associations with non-endometrioid histology were unlikely to have enough power to detect any signal with statistical significance. This is particularly concerning because non-endometrioid subtypes are biologically aggressive tumours with a much poorer prognosis that contribute disproportionately to mortality from endometrial cancer. It is particularly important that attempts to improve early detection and prevention of endometrial cancer focus primarily on improving outcomes from these subtypes.

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

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

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

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

    International networks such as the European Reference Network for rare endocrine conditions (EndoERN), in which DSD is embedded, may facilitate the expansion of this kind of collaboration across Europe.This paper highlights key discussion points in the Dutch-Flemish guideline that have been insufficiently addressed in the literature thus far because they reflect evolving technologies or less visible stakeholders where to buy generic viagra. 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 where to buy generic viagra team may be challenging, especially for professionals with limited experience in DSD.22 23 Therefore, a section of the Dutch-Flemish guideline was written for these healthcare providers. Moreover, this enables DSD specialists to refer to the guideline when advising a referral. Transition from the prenatal to the postnatal team and from the paediatric to the adult where to buy generic viagra team requires optimal communication between the specialists involved.

    Application of NGS-based techniques may lead to a higher diagnostic yield, providing a molecular genetic diagnosis in previously unsolved cases.16 We address the timing of this testing and the problems associated with this technique such as the interpretation of variants of unknown clinical significance (VUS). Similarly, histopathological interpretation and classification of removed gonadal tissue is challenging where to buy generic viagra 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 the literature for a specific part of the guideline. Literature search in PubMed was not systematic, but rather intended to be broad in order to cover all areas and follow expert opinions. This approach is more in line with the Clinical Practice Advisory Document method described by Burke et al24 for guidelines involving genetic practice because it is often troublesome to substantiate such guidelines with sufficient evidence due to the rapid changes in testing where to buy generic viagra 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 where to buy generic viagra were identified using a broad range of Medical Subject Headings terms (eg, DSD, genetic, review, diagnosis, diagnostics, 46,XX DSD, 46,XY DSD, guideline, multidisciplinary care). Next, potentially relevant papers on diagnostic procedures in DSD were selected. Case reports were excluded, as were articles that were not open access or retrievable through institutional access where to buy generic viagra. 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 where to buy generic viagra the writing committee and, after having obtained agreement on remaining points of discussion, revised into a final draft.

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

    More often, the discrepancy will be due to sex-chromosome mosaicism or a true form of DSD.A situation now occurring with increasing frequency is a discrepancy between the genotypic sex revealed by non-invasive prenatal testing (NIPT), which is now available to high-risk pregnant women in the Netherlands and to where to buy generic viagra all pregnant women in Belgium, and later ultrasound findings. NIPT screens for CNVs in the fetus. However, depending on legal restrictions and/or ethical considerations, the X and Y chromosomes are where to buy generic viagra 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 couple to their colleague where to buy generic viagra 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 of this where to buy generic viagra technique. The procedure(s) that can be followed, including the risks associated with an amniocentesis. And the type of where to buy generic viagra 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 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 where to buy generic viagra well-informed decision about whether or not to continue the pregnancy. Termination of pregnancy can be considered, for instance, in a syndromic form of DSD with multiple malformations, but when where to buy generic viagra 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 diagnosis, treatment and where to buy generic viagra 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 where to buy generic viagra before birth.After expert prenatal counselling, a significant number of pregnant couples decline prenatal testing (personal experience IALG, MK, ABD, YvB, MC and HC-vdG). At birth, umbilical cord blood is a good source for (molecular) karyotyping and storage of DNA and can be obtained by the obstetrician, midwife or neonatologist. The terminology used in communication with parents should where to buy generic viagra be carefully chosen,22 23 and midwives and staff of neonatal and delivery units should be clearly instructed to use gender-neutral and non-stigmatising vocabulary (eg, ‘your baby’) as long as sex assignment is pending.An algorithm for diagnostic evaluation of a suspected DSD in the prenatal situation is proposed in figure 1. When couples opt for invasive prenatal diagnosis, the genetic analysis usually involves an (SNP)-array. It was recently estimated that >30% of individuals who have a DSD have where to buy generic viagra 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 cases there is no tight time limit, where to buy generic viagra 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..

    How should I take Viagra?

    Take Viagra by mouth with a glass of water. The dose is usually taken 1 hour before sexual activity. You should not take the dose more than once per day. Do not take your medicine more often than directed. Overdosage: If you think you have taken too much of Viagra contact a poison control center or emergency room at once. NOTE: Viagra is only for you. Do not share Viagra with others.

    Viagra alternatives over the counter

    The data extract viagra alternatives over the counter is a series of compressed UTF-8 text visit the site files of the database. The uncompressed size of the files is approximately 65 MB. In order to utilize the data, the file must be loaded into an existing database or information system viagra alternatives over the counter. The typical user is most likely a third party claims adjudicator, provincial formulary, insurance company, etc. For a casual user to use this file, they must be familiar with database structure and capable of setting up their own queries.

    The "Read me" file contains the data structure required to download the zipped files.The DPD extract files contain complete product information for all approved (filename_ap.zip), marketed (filename.zip), cancelled (filename_ia.zip) and dormant (filename_dr.zip) products, for human, viagra alternatives over the counter veterinary, disinfectant and radiopharmaceutical use.For more information on the Data Extract structure consult the Read me file.Notice. Change effective June 1, 2018As of June 2018, the URLs for each of the DPD Data Extract zipped files have been updated from hc-sc.gc.ca to Canada.ca. The hc-sc.gc.ca URLs will be removed and will no longer be available.Mailing ListIf you would like to receive communications regarding future changes to the DPD data extracts, please send an email to the following address to sign up for the mailing list. SIPD-Systems@hc-sc.gc.ca. CopyrightFor information on copyright and who to contact, please visit the Drug Product Database Terms and Conditions.Notice – Release of ICH M9.

    Biopharmaceutics Classification System (BCS) Based Biowaivers August 26, 2020Our file number. 20-109235-116 Health Canada is pleased to announce the implementation of International Council for Harmonisation of Technical Requirements of Pharmaceuticals for Human Use (ICH) Guidance M9. Biopharmaceutics Classification System (BCS) Based Biowaivers. This guidance has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. The ICH Assembly has endorsed the final draft and recommended its implementation by membership of ICH.

    In implementing the ICH M9 guideline, it replaces the Health Canada guidance document. Biopharmaceutics Classification System Based Biowaiver. It is recommended that the Health Canada BCS Based Biowaiver Evaluation Template be completed for drug submissions that include a biowaiver request. As per its commitment to ICH as a standing member, Health Canada is implementing this guidance with no modifications. In implementing this ICH guidance, Health Canada endorses the principles and practices described therein.

    This document should be read in conjunction with this accompanying notice and with the relevant sections of other applicable Health Canada guidances. This and other Guidance documents are available on the ICH Website. Please note that the ICH website is only available in English. If you would like to request a copy of the French version of the document, please contact the HPFB ICH inbox. Should you have any questions or comments regarding the content of the guidance, please contact.

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

    It also provides guidance on how to meet these criteria in an application under the IO pathway. Diagnostic testing is a key element in both. identifying cases of infection preventing the spread of the coronavirus A test swab may be used to collect a sample for either Polymerase Chain Reaction (PCR) laboratory testing or point-of-care testing. Point-of-care testing can be done directly in a hospital or doctor’s office. Once the sample has been taken, the swab is either placed in a preserving liquid and sent to a laboratory for testing, or placed directly in a testing device (point-of-care).Swabs may be packaged in a variety of virus transport media (VTM).

    Specifications for individual VTMs are beyond the scope of this document. Swabs play a role in the accuracy of COVID-19 diagnostic testing. For example, false negatives can occur in PCR tests if. the swab material inhibits the test reaction or the swab design doesn’t provide enough surface area to obtain a sufficient sample Test swabs that are not safe and effective may cause or lead to harm. For example.

    A swab that breaks during sample collection can cause physical injury a non-sterile swab that produces an incorrect test result can lead to harmHealth Canada has published a guidance document to support the preparation of applications submitted under the IO. It should be read in conjunction with this document. We are processing applications as quickly as possible. To avoid delays, please ensure you have completed your application properly.Medical Devices Regulations (MDR) classification In the Canadian regulatory framework, Class I devices present the lowest potential risk and Class IV the highest. Swabs are classified according to their labelling and intended use.

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

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

    These data should be based on test samples representative of finished swabs that have undergone sterilization prior to bench testing.Dimensions Swabs should have minimum length specifications and minimum and maximum head diameter specifications in order to be safe and effective. Minimum length specification for example, adult NP swabs require ≥14 cm to reach the posterior nasopharynx minimum and maximum head diameter specification for example, adult NP swabs require 1–4 mm to pass into the mid-inferior portion of the inferior turbinate and maneuver well FlexibilitySwab flexibility is assessed through. Durability for example, tolerate 20 rough repeated insertions into a 4 mm inner diameter clear plastic tube curved back on itself with a curve radius of 3 cm bendability for example, bend tip and neck 90º without breaking ability to maintain initial form for example, restore to initial form following 45º bending Manufacturers may describe the test performed, the number of samples, and a summary of the results.Strength/Breakpoint (failure) To limit the potential for patient harm, the minimum breakpoint distance should be approximately 8 to 9 cm from the nasopharynx. However, no breaks or fractures should occur following reasonable manipulation. Applicants should submit a rationale for the design of the breakpoint distance from the swab tip.

    It should demonstrate that the breakpoint length can be accommodated by commercially available swab/media tubes.Surface propertiesThe swab surface should be free of. processing aids (such as disinfectants) foreign materials degreasers mold release agents For injection molded swabs, no burrs, flashing, or sharp edges should be present. Design validationProvide swab validation (performance) data in a summary report that demonstrates that the swab. can acquire samples comparable to a commercially available swab control, and will not inhibit the PCR reactionThese data should be based on test samples representative of finished swabs that have undergone sterilization prior to testing.Comparable sample acquisition to a control, and PCR compatibilityThe manufacturer should demonstrate test swab cycle threshold (Ct) recovery values (RT-PCR) that are statistically comparable to those obtained from a commercially available swab control using SARS-CoV-2 (or a scientifically justified surrogate).Pass/Fail criteria. Values ≥ 2Cts indicate significantly less efficient ribonucleic acid collection and/or elution.Clinical feasibility/suitability simulationManufacturers should submit either.

    A clinical test report or previous clinical data Clinical test reportThe clinical test report should describe the use of the proposed finished swab (sterilized) in a sufficient number of individuals by trained healthcare professionals in a minimum of 30 patients that have tested positive for SARS-CoV-2, or a scientifically justified surrogate virus. Include comparisons of the proposed swab against a flocked swab commercially available in Canada with respect to. flexibility fit ability to navigate to the nasopharynx (or other areas specified in the indications) ability to collect a specimen/respiratory epithelial cells for example, using the RNase P housekeeping gene test results agreement for example, ≥ 90% positive % agreement using a composite control (positive % agreement calculation that includes all positive findings from control and test swabs) Clinical testing considerations A scientifically justified surrogate virus may be used if COVID-positive patients are not available. Positive % agreement should not be determined using high Ct samples. One-half (1/2) to two-thirds (2/3) of COVID-positive samples should have a high viral loads (Cts <.

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

    Use of different VTM/universal transport media (V/UTM) across COVID-positive samples may contribute to Ct variability. Ensure consistency by using the same media/tubes for each specimen within a clinical evaluation. Validate the chosen V/UTM media/tubes to show they will not interfere with the PCR test results. For example, allowing 7 days of swab positive specimen incubation with the chosen media/vial is considered a worst-case transportation scenario to evaluate maximal leaching/interaction potential). Use a single PCR test platform throughout each clinical evaluation.

    The platform should have been previously authorized by HC or another jurisdiction. Location (for example, left vs right nostril) and order of sampling (for example, control vs. Test swab) can affect specimen quality and results variability. Location and swab sampling order should be randomized.For additional information on collecting, handling, and testing COVID-19 specimens, please refer to the Centers for Disease Control and Prevention (CDC) Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens for COVID-19.Previous clinical dataPreviously obtained clinical data may be submitted in lieu of clinical testing. Those data should demonstrate the safe and effective use of a swab of identical design and materials in human subjects.

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

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

    25 kGy (World Health Organization, The International Pharmacopoeia, 9th Ed., 2019) Sterilization Process Spore (Indicator Organism) Steam Geobacillus stearothermophilus(formerly Bacillus stearothermophilus) Dry Heat Bacillus atrophaeus (formerly Bacillus subtilis var. Niger) Ethlylene Oxide Bacillus atrophaeus (formerly Bacillus subtilis var. Niger) Hydrogen Peroxide Geobacillus stearothermophilus(formerly Bacillus stearothermophilus) Source. US Food and Drug Administration, "Biological Indicator (BI) Premarket Notification [510(k)] Submissions," October 2007. [Online].Packaging validation Provide packaging validation data in a summary report.

    It should demonstrate that the swab packaging system will maintain a sterile environment across the labelled shelf life (for example, ASTM F1980). without leakage (for example, ASTM D3078-02) with adequate seal strength (for example, ASTM F88/EN 868-5)Test packaging samples should be representative of finished swab packages that have undergone sterilization prior to testing.Biocompatibility Provide biocompatibility data in a summary report. It should demonstrate compliance with biocompatibility tests recommended for devices in limited contact (≤24 hrs) with mucosal membranes, as per ISO 10993-1. These include. cytotoxicity sensitization irritation/intracutaneous reactivityThese data should be based on test samples representative of finished swabs that have undergone sterilization prior to testing.LabellingSwabs should be individually packaged and labelled.

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

    Medical devices are classified into 4 groups (Class I, II, III and IV) based on their risk to health and safety. Class I devices, such as gauze bandages, pose the lowest potential risk, while Class IV devices, such as pacemakers, pose the greatest potential risk. In Canada, face shields are Class I medical devices. A face shield has a transparent window or visor that shields the face and associated mucous membranes (eyes, nose and mouth). It protects the wearer against exposure from splashes and sprays of body fluids.

    Face shields are made of shatterproof plastic, fit over the face and are held in place by head straps or caps. They may be made of polycarbonate, propionate, acetate, polyvinyl chloride, or polyethylene terephthalate. They are usually worn with other PPE, such as a medical mask, respirator or eyewear. Health Canada strongly advises against the use of plastic bags as an alternative to face shields. Standards and requirements for face shields Organizations that are manufacturing face shields are advised to consult some or all of the following standards throughout the design and testing stages.

    ANSI/ISEA Z.87.1 (2015), American National Standard for Occupational and Educational Personal Eye and Face Protection Devices CSA Z94.3 (2020), Eye and Face Protectors CSA Z94.3.1 (2016), Guideline for Selection, Use, and Care of Eye and Face Protectors BS EN 166 (2002), Personal Eye Protection. Specifications. Minimum specifications must be incorporated into the design and verification stages to ensure safe and effective face shields. Provide adequate coverage (CSA Z94.3 Sections 0.2.1/10.2.2/10.3/10.4). The size of the face shield is important because it must protect the face and front part of the head.

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

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

    Provide user-contacting materials that have adequate material biocompatibility (skin sensitivity and cytotoxic testing) (ISO 10993-5, 10). Other items to take note of include. Face shields used for protection in hospital settings do not have to be impact- or flame- resistant. If the device is specifically designed to withstand impact from sharp or fast projectiles, it must comply with set-out standards (ANSI Z87.1, sections 9.2 and 9.3, CSA Z94.3, section 10.1). For reuse, manufacturers must provide validated cleaning instructions.

    Sterilization procedures must not compromise the shield in any way, such as deformation or cracking. Regulatory authorization Most PPE, including face shields, are Class I medical devices if they are manufactured, sold or represented for use for reducing the risk of or preventing the user from infection. This includes COVID-19. Face shields may be authorized for sale or import into Canada through the following regulatory pathways. Pathway 1.

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

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

    If you intend to manufacture 3D print face shields in response to the COVID-19 crisis, see. 3D printing and other manufacturing of personal protective equipment in response to COVID-19 Feedback If you have any questions or comments about this notice, contact the Medical Devices Directorate at hc.meddevices-instrumentsmed.sc@canada.ca R. J. Roberge, "Face shields for infection control. A review," Journal of Occupational and Environmental Hygiene, pp.

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

    235-242, 2016.Return to footnote 1 referrer.

    The data extract is where to buy generic viagra a series of compressed UTF-8 text files of the database. The uncompressed size of the files is approximately 65 MB. In order to utilize the data, the file must be loaded into an where to buy generic viagra existing database or information system.

    The typical user is most likely a third party claims adjudicator, provincial formulary, insurance company, etc. For a casual user to use this file, they must be familiar with database structure and capable of setting up their own queries. The "Read me" file contains the data structure required to download the zipped files.The DPD extract files contain complete product information for all approved (filename_ap.zip), marketed (filename.zip), cancelled (filename_ia.zip) and dormant (filename_dr.zip) products, for human, veterinary, disinfectant and radiopharmaceutical use.For more information on the where to buy generic viagra Data Extract structure consult the Read me file.Notice.

    Change effective June 1, 2018As of June 2018, the URLs for each of the DPD Data Extract zipped files have been updated from hc-sc.gc.ca to Canada.ca. The hc-sc.gc.ca URLs will be removed and will no longer be available.Mailing ListIf you would like to receive communications regarding future changes to the DPD data extracts, please send an email to the following address to sign up for the mailing list. SIPD-Systems@hc-sc.gc.ca.

    CopyrightFor information on copyright and who to contact, please visit the Drug Product Database Terms and Conditions.Notice – Release of ICH M9. Biopharmaceutics Classification System (BCS) Based Biowaivers August 26, 2020Our file number. 20-109235-116 Health Canada is pleased to announce the implementation of International Council for Harmonisation of Technical Requirements of Pharmaceuticals for Human Use (ICH) Guidance M9.

    Biopharmaceutics Classification System (BCS) Based Biowaivers. This guidance has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. The ICH Assembly has endorsed the final draft and recommended its implementation by membership of ICH.

    In implementing the ICH M9 guideline, it replaces the Health Canada guidance document. Biopharmaceutics Classification System Based Biowaiver. It is recommended that the Health Canada BCS Based Biowaiver Evaluation Template be completed for drug submissions that include a biowaiver request.

    As per its commitment to ICH as a standing member, Health Canada is implementing this guidance with no modifications. In implementing this ICH guidance, Health Canada endorses the principles and practices described therein. This document should be read in conjunction with this accompanying notice and with the relevant sections of other applicable Health Canada guidances.

    This and other Guidance documents are available on the ICH Website. Please note that the ICH website is only available in English. If you would like to request a copy of the French version of the document, please contact the HPFB ICH inbox.

    Should you have any questions or comments regarding the content of the guidance, please contact. Health Canada - ICH CoordinatorE-mail. HPFB_ICH_DGPSA@hc-sc.gc.caDate published.

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

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

    Point-of-care testing can be done directly in a hospital or doctor’s office. Once the sample has been taken, the swab is either placed in a preserving liquid and sent to a laboratory for testing, or placed directly in a testing device (point-of-care).Swabs may be packaged in a variety of virus transport media (VTM). Specifications for individual VTMs are beyond the scope of this document.

    Swabs play a role in the accuracy of COVID-19 diagnostic testing. For example, false negatives can occur in PCR tests if. the swab material inhibits the test reaction or the swab design doesn’t provide enough surface area to obtain a sufficient sample Test swabs that are not safe and effective may cause or lead to harm.

    For example. A swab that breaks during sample collection can cause physical injury a non-sterile swab that produces an incorrect test result can lead to harmHealth Canada has published a guidance document to support the preparation of applications submitted under the IO. It should be read in conjunction with this document.

    We are processing applications as quickly as possible. To avoid delays, please ensure you have completed your application properly.Medical Devices Regulations (MDR) classification In the Canadian regulatory framework, Class I devices present the lowest potential risk and Class IV the highest. Swabs are classified according to their labelling and intended use.

    For example, if a swab is labelled for nasopharyngeal (NP) or oropharyngeal (OP) use only, it will be classified as a Class I medical device according to Classification Rule 2(2) of the MDR. If a swab is not exclusively for use in oral or nasal cavities, or its use is not explicitly stated, it will be classified as a Class II device by Rule 2(1). These swabs belong to a higher risk class because their use in other body orifices for the collection of tissue samples (for example, to test for chlamydia or ureaplasma) is associated with greater risk.

    Rule 2 Subject to subrules (2) to (4), all invasive devices that penetrate the body through a body orifice or that come into contact with the surface of the eye are classified as Class II. A device described in subrule (1) that is intended to be placed in the oral or nasal cavities as far as the pharynx or in the ear canal up to the ear drum is classified as Class I.Regulatory pathways for COVID-19 devicesManufacturers of Class I swabs may seek authorization to import and sell their products under either. A Medical Device Establishment Licence (MDEL) MDEL is an establishment oversight framework that is not product-specific and not designed to assess safety and effectiveness an IO authorization information on safety and effectiveness are required as part of the application Health Canada is encouraging a sub-group of swab manufacturers to use the IO authorization pathway for Class I swabs, especially if they are.

    New to the manufacturing of swabs and manufacturing in Canada (such as a company that has re-tooled to manufacture), or using a new manufacturing process or design for swabs (such as 3D printing or honeycomb design)IO applications for swabs should include the following information.Device description The device description should include. A picture and/or engineering drawing identification of all materials used in the production of the swab the intended use(s) (for example, NP swabs)Quality manufacturingManufacturers must either. demonstrate compliance with Quality Manufacturing Systems (for example, ISO 13485 certificate) applicable to the swab, or provide a clear description of the planned quality manufacturing systems that are consistent with similar existing manufacturing systemsDesign verificationProvide swab design verification (bench testing) data in a summary report.

    It should show that the essential minimum design characteristics are met. These data should be based on test samples representative of finished swabs that have undergone sterilization prior to bench testing.Dimensions Swabs should have minimum length specifications and minimum and maximum head diameter specifications in order to be safe and effective. Minimum length specification for example, adult NP swabs require ≥14 cm to reach the posterior nasopharynx minimum and maximum head diameter specification for example, adult NP swabs require 1–4 mm to pass into the mid-inferior portion of the inferior turbinate and maneuver well FlexibilitySwab flexibility is assessed through.

    Durability for example, tolerate 20 rough repeated insertions into a 4 mm inner diameter clear plastic tube curved back on itself with a curve radius of 3 cm bendability for example, bend tip and neck 90º without breaking ability to maintain initial form for example, restore to initial form following 45º bending Manufacturers may describe the test performed, the number of samples, and a summary of the results.Strength/Breakpoint (failure) To limit the potential for patient harm, the minimum breakpoint distance should be approximately 8 to 9 cm from the nasopharynx. However, no breaks or fractures should occur following reasonable manipulation. Applicants should submit a rationale for the design of the breakpoint distance from the swab tip.

    It should demonstrate that the breakpoint length can be accommodated by commercially available swab/media tubes.Surface propertiesThe swab surface should be free of. processing aids (such as disinfectants) foreign materials degreasers mold release agents For injection molded swabs, no burrs, flashing, or sharp edges should be present. Design validationProvide swab validation (performance) data in a summary report that demonstrates that the swab.

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

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

    One-half (1/2) to two-thirds (2/3) of COVID-positive samples should have a high viral loads (Cts <. 30). Report agreement between control and test swabs in terms of quantitative (Ct) and qualitative (+/- test) values with appropriate descriptive statistics.

    Include patient symptomatology for samples. For example, days from symptom onset, known vs. Suspected COVID status.

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

    For example, allowing 7 days of swab positive specimen incubation with the chosen media/vial is considered a worst-case transportation scenario to evaluate maximal leaching/interaction potential). Use a single PCR test platform throughout each clinical evaluation. The platform should have been previously authorized by HC or another jurisdiction.

    Location (for example, left vs right nostril) and order of sampling (for example, control vs. Test swab) can affect specimen quality and results variability. Location and swab sampling order should be randomized.For additional information on collecting, handling, and testing COVID-19 specimens, please refer to the Centers for Disease Control and Prevention (CDC) Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens for COVID-19.Previous clinical dataPreviously obtained clinical data may be submitted in lieu of clinical testing.

    Those data should demonstrate the safe and effective use of a swab of identical design and materials in human subjects. The proposed swab should be compared against a flocked swab commercially available in Canada with respect to. flexibility fit ability to navigate to the nasopharynx (or other areas specified in the indications) ability to collect a specimen/respiratory epithelial cells for example, using the RNase P housekeeping gene test results agreement for example, ≥ 90% positive % agreement) using a composite control (positive % agreement calculation that includes all positive findings from control and test swabs) Sterility Provide sterilization validation data in a summary report.

    It should demonstrate that the chosen sterilization method will achieve a minimum Sterility Assurance Level (SAL) of 10-6 for the proposed swab, using an appropriate biological indicator (BI) organism (see below). If the swab will be sterilized using an ethylene oxide (EtO) method, you should demonstrate that EtO and ethylene chlorohydrin (ECH) residuals meet the tolerable contact limits (TCL) specified in ISO 10993-7. Commonly used swab materials, compatible sterilization methods, and appropriate biological indicators are described below.

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

    Return to footnote * referrer Appropriate BIIf ionizing radiation will be used to sterilize the swab. Bacillus pumilus spores are recommended for doses of 25 kGy Bacillus cereus or Bacillus sphaericus spores are recommended for doses of >. 25 kGy (World Health Organization, The International Pharmacopoeia, 9th Ed., 2019) Sterilization Process Spore (Indicator Organism) Steam Geobacillus stearothermophilus(formerly Bacillus stearothermophilus) Dry Heat Bacillus atrophaeus (formerly Bacillus subtilis var.

    Niger) Ethlylene Oxide Bacillus atrophaeus (formerly Bacillus subtilis var. Niger) Hydrogen Peroxide Geobacillus stearothermophilus(formerly Bacillus stearothermophilus) Source. US Food and Drug Administration, "Biological Indicator (BI) Premarket Notification [510(k)] Submissions," October 2007.

    [Online].Packaging validation Provide packaging validation data in a summary report. It should demonstrate that the swab packaging system will maintain a sterile environment across the labelled shelf life (for example, ASTM F1980). without leakage (for example, ASTM D3078-02) with adequate seal strength (for example, ASTM F88/EN 868-5)Test packaging samples should be representative of finished swab packages that have undergone sterilization prior to testing.Biocompatibility Provide biocompatibility data in a summary report.

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

    The application must include the swab label, which must include. The name and model number of the device the term ‘sterile’, along with the sterilization method (EtO = ethylene oxide. R = gamma irradiation), if the swab is intended to be sold in a sterile condition the name and address of the manufacturer manufacturing and expiry datesIf swabs are not sterile but must be sterilized at the user facility, then the sterilization parameters and method should be clearly described in accompanying instructions for use documentation.Post-market requirementsAs stated in Section 12 of the IO, within 10 days of becoming aware of an incident in Canada, all IO authorization holders must.

    report the incident specify the nature of the incident specify the circumstances surrounding the incidentOn this page About face shields Personal protective equipment (PPE) can help prevent potential exposure to infectious disease. They are considered medical devices in Canada and therefore must follow the requirements outlined in the Medical Devices Regulations. Medical devices are classified into 4 groups (Class I, II, III and IV) based on their risk to health and safety.

    Class I devices, such as gauze bandages, pose the lowest potential risk, while Class IV devices, such as pacemakers, pose the greatest potential risk. In Canada, face shields are Class I medical devices. A face shield has a transparent window or visor that shields the face and associated mucous membranes (eyes, nose and mouth).

    It protects the wearer against exposure from splashes and sprays of body fluids. Face shields are made of shatterproof plastic, fit over the face and are held in place by head straps or caps. They may be made of polycarbonate, propionate, acetate, polyvinyl chloride, or polyethylene terephthalate.

    They are usually worn with other PPE, such as a medical mask, respirator or eyewear. Health Canada strongly advises against the use of plastic bags as an alternative to face shields. Standards and requirements for face shields Organizations that are manufacturing face shields are advised to consult some or all of the following standards throughout the design and testing stages.

    ANSI/ISEA Z.87.1 (2015), American National Standard for Occupational and Educational Personal Eye and Face Protection Devices CSA Z94.3 (2020), Eye and Face Protectors CSA Z94.3.1 (2016), Guideline for Selection, Use, and Care of Eye and Face Protectors BS EN 166 (2002), Personal Eye Protection. Specifications. Minimum specifications must be incorporated into the design and verification stages to ensure safe and effective face shields.

    Provide adequate coverage (CSA Z94.3 Sections 0.2.1/10.2.2/10.3/10.4). The size of the face shield is important because it must protect the face and front part of the head. This includes the eyes, forehead, cheeks, nose, mouth, and chin.

    Protection may also need to extend to the front of the neck in situations with flying particles and sprays of hazardous liquids. Fit snugly to afford a good seal to the forehead area and to prevent slippage of the device Footnote 1. Be made of optically clear, distortion-free, lightweight materials (CSA Z94.3.1-16 and Footnote 1).

    Be free of visible defects or flaws that would impede vision (ANSI Z87.1 Section 9.4). Be comfortable and easy to assemble, use and remove by health care professionals. Provide adequate space between the wearer’s face and the inner surface of the visor to allow for the use of ancillary equipment (for example, medical mask, respirator, eyewear) Footnote 1.

    The characteristics and performance requirements of face shields must not be altered when attaching shields to other protective equipment, such as hats or caps. Display anti-fog characteristics on inside and outside of shield (CSA Z94.3.1-16). For face shields that are not fog resistant, anti-fog spray must be provided.

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

    If the device is specifically designed to withstand impact from sharp or fast projectiles, it must comply with set-out standards (ANSI Z87.1, sections 9.2 and 9.3, CSA Z94.3, section 10.1). For reuse, manufacturers must provide validated cleaning instructions. Sterilization procedures must not compromise the shield in any way, such as deformation or cracking.

    Regulatory authorization Most PPE, including face shields, are Class I medical devices if they are manufactured, sold or represented for use for reducing the risk of or preventing the user from infection. This includes COVID-19. Face shields may be authorized for sale or import into Canada through the following regulatory pathways.

    Pathway 1. Interim order authorization to import and sell medical devices related to COVID-19. Pathway 2.

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

    Exceptional importation and sale of certain non-compliant medical devices related to COVID-19. Note that a sale generally requires the transfer of ownership of a device from one party to another and does not necessitate any transfer of money. Applicants should carefully review the pathways and select the most appropriate authorization route for their product.

    For more information, see Personal protective equipment (COVID-19). How to get authorization. If you intend to manufacture 3D print face shields in response to the COVID-19 crisis, see.

    3D printing and other manufacturing of personal protective equipment in response to COVID-19 Feedback If you have any questions or comments about this notice, contact the Medical Devices Directorate at hc.meddevices-instrumentsmed.sc@canada.ca R. J. Roberge, "Face shields for infection control.

    A review," Journal of Occupational and Environmental Hygiene, pp. 235-242, 2016. Related links FootnotesFootnote 1 R.

    J. Roberge, "Face shields for infection control. A review," Journal of Occupational and Environmental Hygiene, pp.

    235-242, 2016.Return to footnote 1 referrer.

    Viagra after prostate removal

    NYS announced the 2020 Income and Resource levels in GIS 19 MA/12 – 2020 viagra after prostate removal Medicaid Levels and Other Updates ) and levels based on the Federal Poverty Level are in GIS 20 MA/02 – 2020 Federal Poverty Levels Here is the 2020 HRA Income and Resources Level Chart Non-MAGI - 2020 Disabled, 65+ or Blind ("DAB" or SSI-Related) and have Medicare MAGI (2020) (<. 65, Does not have Medicare)(OR has Medicare and has dependent child <. 18 or <.

    19 in school) viagra after prostate removal 138% FPL*** Children <. 5 and pregnant women have HIGHER LIMITS than shown ESSENTIAL PLAN For MAGI-eligible people over MAGI income limit up to 200% FPL No long term care. See info here 1 2 1 2 3 1 2 Income $875 (up from $859 in 201) $1284 (up from $1,267 in 2019) $1,468 $1,983 $2,498 $2,127 $2,873 Resources $15,750 (up from $15,450 in 2019) $23,100 (up from $22,800 in 2019) NO LIMIT** NO LIMIT SOURCE for 2019 figures is GIS 18 MA/015 - 2019 Medicaid Levels and Other Updates (PDF).

    All of the attachments with the viagra after prostate removal various levels are posted here. NEED TO KNOW PAST MEDICAID INCOME AND RESOURCE LEVELS?. Which household size applies?.

    The rules are viagra after prostate removal complicated. See rules here. On the HRA Medicaid Levels chart - Boxes 1 and 2 are NON-MAGI Income and Resource levels -- Age 65+, Blind or Disabled and other adults who need to use "spend-down" because they are over the MAGI income levels.

    Box 10 on page 3 are the MAGI income levels -- The Affordable Care Act changed viagra after prostate removal the rules for Medicaid income eligibility for many BUT NOT ALL New Yorkers. People in the "MAGI" category - those NOT on Medicare -- have expanded eligibility up to 138% of the Federal Poverty Line, so may now qualify for Medicaid even if they were not eligible before, or may now be eligible for Medicaid without a "spend-down." They have NO resource limit. Box 3 on page 1 is Spousal Impoverishment levels for Managed Long Term Care &.

    Nursing Homes and Box 8 has the Transfer Penalty rates for nursing home eligibility Box 4 has Medicaid Buy-In for Working People viagra after prostate removal with Disabilities Under Age 65 (still 2017 levels til April 2018) Box 6 are Medicare Savings Program levels (will be updated in April 2018) MAGI INCOME LEVEL of 138% FPL applies to most adults who are not disabled and who do not have Medicare, AND can also apply to adults with Medicare if they have a dependent child/relative under age 18 or under 19 if in school. 42 C.F.R. § 435.4.

    Certain populations have an even higher income limit - 224% FPL for pregnant women viagra after prostate removal and babies <. Age 1, 154% FPL for children age 1 - 19. CAUTION.

    What is counted viagra after prostate removal as income may not be what you think. For the NON-MAGI Disabled/Aged 65+/Blind, income will still be determined by the same rules as before, explained in this outline and these charts on income disregards. However, for the MAGI population - which is virtually everyone under age 65 who is not on Medicare - their income will now be determined under new rules, based on federal income tax concepts - called "Modifed Adjusted Gross Income" (MAGI).

    There are good viagra after prostate removal changes and bad changes. GOOD. Veteran's benefits, Workers compensation, and gifts from family or others no longer count as income.

    BAD viagra after prostate removal. There is no more "spousal" or parental refusal for this population (but there still is for the Disabled/Aged/Blind.) and some other rules. For all of the rules see.

    ALSO SEE 2018 Manual on Lump Sums and Impact on Public Benefits - with resource rules The income limits increase with the "household size." viagra after prostate removal In other words, the income limit for a family of 5 may be higher than the income limit for a single person. HOWEVER, Medicaid rules about how to calculate the household size are not intuitive or even logical. There are different rules depending on the "category" of the person seeking Medicaid.

    Here are the 2 basic categories viagra after prostate removal and the rules for calculating their household size. People who are Disabled, Aged 65+ or Blind - "DAB" or "SSI-Related" Category -- NON-MAGI - See this chart for their household size. These same rules apply to the Medicare Savings Program, with some exceptions explained in this article.

    Everyone else -- MAGI - All children and viagra after prostate removal adults under age 65, including people with disabilities who are not yet on Medicare -- this is the new "MAGI" population. Their household size will be determined using federal income tax rules, which are very complicated. New rule is explained in State's directive 13 ADM-03 - Medicaid Eligibility Changes under the Affordable Care Act (ACA) of 2010 (PDF) pp.

    8-10 of the PDF, This PowerPoint by NYLAG on MAGI Budgeting attempts to explain the new MAGI budgeting, including how to determine viagra after prostate removal the Household Size. See slides 28-49. Also seeLegal Aid Society and Empire Justice Center materials OLD RULE used until end of 2013 -- Count the person(s) applying for Medicaid who live together, plus any of their legally responsible relatives who do not receive SNA, ADC, or SSI and reside with an applicant/recipient.

    Spouses viagra after prostate removal or legally responsible for one another, and parents are legally responsible for their children under age 21 (though if the child is disabled, use the rule in the 1st "DAB" category. Under this rule, a child may be excluded from the household if that child's income causes other family members to lose Medicaid eligibility. See 18 NYCRR 360-4.2, MRG p.

    573, NYS GIS 2000 viagra after prostate removal MA-007 CAUTION. Different people in the same household may be in different "categories" and hence have different household sizes AND Medicaid income and resource limits. If a man is age 67 and has Medicare and his wife is age 62 and not disabled or blind, the husband's household size for Medicaid is determined under Category 1/ Non-MAGI above and his wife's is under Category 2/MAGI.

    The following programs were available prior to 2014, but viagra after prostate removal are now discontinued because they are folded into MAGI Medicaid. Prenatal Care Assistance Program (PCAP) was Medicaid for pregnant women and children under age 19, with higher income limits for pregnant woman and infants under one year (200% FPL for pregnant women receiving perinatal coverage only not full Medicaid) than for children ages 1-18 (133% FPL). Medicaid for adults between ages 21-65 who are not disabled and without children under 21 in the household.

    It was viagra after prostate removal sometimes known as "S/CC" category for Singles and Childless Couples. This category had lower income limits than DAB/ADC-related, but had no asset limits. It did not allow "spend down" of excess income.

    This category has now been subsumed under the new MAGI adult group whose limit is viagra after prostate removal now raised to 138% FPL. Family Health Plus - this was an expansion of Medicaid to families with income up to 150% FPL and for childless adults up to 100% FPL. This has now been folded into the new MAGI adult group whose limit is 138% FPL.

    For applicants between 138%-150% FPL, they will be eligible for a new program where Medicaid will subsidize their purchase of Qualified Health Plans on the viagra after prostate removal Exchange. PAST INCOME &. RESOURCE LEVELS -- Past Medicaid income and resource levels in NYS are shown on these oldNYC HRA charts for 2001 through 2019, in chronological order.

    These include Medicaid levels viagra after prostate removal for MAGI and non-MAGI populations, Child Health Plus, MBI-WPD, Medicare Savings Programs and other public health programs in NYS. This article was authored by the Evelyn Frank Legal Resources Program of New York Legal Assistance Group.A huge barrier to people returning to the community from nursing homes is the high cost of housing. One way New York State is trying to address that barrier is with the Special Housing Disregard that allows certain members of Managed Long Term Care or FIDA plans to keep more of their income to pay for rent or other shelter costs, rather than having to "spend down" their "excess income" or spend-down on the cost of Medicaid home care.

    The special income standard for housing expenses helps pay for housing expenses to viagra after prostate removal help certain nursing home or adult home residents to safely transition back to the community with MLTC. Originally it was just for former nursing home residents but in 2014 it was expanded to include people who lived in adult homes. GIS 14/MA-017 Since you are allowed to keep more of your income, you may no longer need to use a pooled trust.

    KNOW YOUR RIGHTS - FACT SHEET on THREE viagra after prostate removal ways to Reduce Spend-down, including this Special Income Standard. September 2018 NEWS -- Those already enrolled in MLTC plans before they are admitted to a nursing home or adult home may obtain this budgeting upon discharge, if they meet the other criteria below. "How nursing home administrators, adult home operators and MLTC plans should identify individuals who are eligible for the special income standard" and explains their duties to identify eligible individuals, and the MLTC plan must notify the local DSS that the individual may qualify.

    "Nursing home administrators, nursing home discharge planning staff, adult home operators and MLTC health plans are encouraged to identify individuals who may qualify for the special income standard, if they can be safely discharged back to the community from a nursing home and enroll in, or remain enrolled in, an MLTC viagra after prostate removal plan. Once an individual has been accepted into an MLTC plan, the MLTC plan must notify the individual's local district of social services that the transition has occurred and that the individual may qualify for the special income standard. The special income standard will be effective upon enrollment into the MLTC plan, or, for nursing home residents already enrolled in an MLTC plan, the month of discharge to the community.

    Questions regarding the viagra after prostate removal special income standard may be directed to DOH at 518-474-8887. Who is eligible for this special income standard?. must be age 18+, must have been in a nursing home or an adult home for 30 days or more, must have had Medicaid pay toward the nursing home care, and must enroll in or REMAIN ENROLLED IN a Managed Long Term Care (MLTC) plan or FIDA plan upon leaving the nursing home or adult home must have a housing expense if married, spouse may not receive a "spousal impoverishment" allowance once the individual is enrolled in MLTC.

    How viagra after prostate removal much is the allowance?. The rates vary by region and change yearly. Region Counties Deduction (2020) Central Broome, Cayuga, Chenango, Cortland, Herkimer, Jefferson, Lewis, Madison, Oneida, Onondaga, Oswego, St.

    Lawrence, Tioga, Tompkins $436 Long Island Nassau, Suffolk $1,361 NYC Bronx, Kings, Manhattan, Queens, Richmond $1,451 (up from 1,300 in 2019) Northeastern Albany, Clinton, Columbia, Delaware, Essex, Franklin, Fulton, Greene, Hamilton, Montgomery, Otsego, Rensselaer, Saratoga, Schenectady, Schoharie, Warren, Washington $483 North Metropolitan Dutchess, Orange, Putnam, Rockland, Sullivan, Ulster, Westchester $930 Rochester Chemung, Livingston, Monroe, Ontario, Schuyler, Seneca, Steuben, Wayne, Yates $444 Western Allegany, Cattaraugus, Chautauqua, Erie, Genesee, Niagara, Orleans, Wyoming $386 Past rates published as follows, available on DOH website 2020 rates published in Attachment I to GIS 19 MA/12 – 2020 Medicaid Levels and Other Updates 2019 rates published in Attachment 1 to GIS 18/MA015 - 2019 Medicaid Levels and Other Updates 2018 rates published in GIS 17 MA/020 - 2018 Medicaid Levels and Other Updates. The guidance on how the standardized amount of the disregard is calculated is found in NYS DOH 12- ADM-05. 2017 rate -- GIS 16 MA/018 - 2016 Medicaid Only Income and Resource Levels and Spousal Impoverishment Standards Attachment 12016 rate -- GIS 15-MA/0212015 rate -- Were not posted by DOH but were updated in WMS.

    2015 Central $382 Long Island $1,147 NYC $1,001 Northeastern $440 N. Metropolitan $791 Rochester $388 Western $336 2014 rate -- GIS-14-MA/017 HOW DOES IT WORK?. Here is a sample budget for a single person in NYC with Social Security income of $2,386/month paying a Medigap premium of $261/mo.

    Gross monthly income $2,575.50 DEDUCT Health insurance premiums (Medicare Part B) - 135.50 (Medigap) - 261.00 DEDUCT Unearned income disregard - 20 DEDUCT Shelter deduction (NYC—2019) - 1,300 DEDUCT Income limit for single (2019) - 859 Excess income or Spend-down $0 WITH NO SPEND-DOWN, May NOT NEED POOLED TRUST!. HOW TO OBTAIN THE HOUSING DISREGARD. When you are ready to leave the nursing home or adult home, or soon after you leave, you or your MLTC plan must request that your local Medicaid program change your Medicaid budget to give you the Housing Disregard.

    See September 2018 NYS DOH Medicaid Update that requires MLTC plan to help you ask for it. The procedures in NYC are explained in this Troubleshooting guide. NYC Medicaid program prefers that your MLTC plan file the request, using Form MAP-3057E - Special income housing Expenses NH-MLTC.pdf and Form MAP-3047B - MLTC/NHED Cover Sheet Form MAP-259f (revised 7-31-18)(page 7 of PDF)(DIscharge Notice) - NH must file with HRA upon discharge, certifying resident was informed of availability of this disregard.

    GOVERNMENT DIRECTIVES (beginning with oldest). NYS DOH 12- ADM-05 - Special Income Standard for Housing Expenses for Individuals Discharged from a Nursing Facility who Enroll into the Managed Long Term Care (MLTC) Program Attachment II - OHIP-0057 - Notice of Intent to Change Medicaid Coverage, (Recipient Discharged from a Skilled Nursing Facility and Enrolled in a Managed Long Term Care Plan) Attachment III - Attachment III – OHIP-0058 - Notice of Intent to Change Medicaid Coverage, (Recipient Disenrolled from a Managed Long Term Care Plan, No Special Income Standard) MLTC Policy 13.02. MLTC Housing Disregard NYC HRA Medicaid Alert Special Income Standard for housing expenses NH-MLTC 2-9-2013.pdf 2018-07-28 HRA MICSA ALERT Special Income Standard for Housing Expenses for Individuals Discharged from a Nursing Facility and who Enroll into the MLTC Program - update on previous policy.

    References Form MAP-259f (revised 7-31-18)(page 7 of PDF)(Discharge Notice) - NH must file with HRA upon discharge, certifying resident was informed of availability of this disregard.

    NYS announced the 2020 Income and Resource levels in GIS 19 MA/12 – 2020 Medicaid Levels and where to buy generic viagra Other Updates ) and levels who can buy viagra online based on the Federal Poverty Level are in GIS 20 MA/02 – 2020 Federal Poverty Levels Here is the 2020 HRA Income and Resources Level Chart Non-MAGI - 2020 Disabled, 65+ or Blind ("DAB" or SSI-Related) and have Medicare MAGI (2020) (<. 65, Does not have Medicare)(OR has Medicare and has dependent child <. 18 or <. 19 in where to buy generic viagra school) 138% FPL*** Children <. 5 and pregnant women have HIGHER LIMITS than shown ESSENTIAL PLAN For MAGI-eligible people over MAGI income limit up to 200% FPL No long term care.

    See info here 1 2 1 2 3 1 2 Income $875 (up from $859 in 201) $1284 (up from $1,267 in 2019) $1,468 $1,983 $2,498 $2,127 $2,873 Resources $15,750 (up from $15,450 in 2019) $23,100 (up from $22,800 in 2019) NO LIMIT** NO LIMIT SOURCE for 2019 figures is GIS 18 MA/015 - 2019 Medicaid Levels and Other Updates (PDF). All of where to buy generic viagra the attachments with the various levels are posted here. NEED TO KNOW PAST MEDICAID INCOME AND RESOURCE LEVELS?. Which household size applies?. The rules are where to buy generic viagra complicated.

    See rules here. On the HRA Medicaid Levels chart - Boxes 1 and 2 are NON-MAGI Income and Resource levels -- Age 65+, Blind or Disabled and other adults who need to use "spend-down" because they are over the MAGI income levels. Box 10 on page 3 are the MAGI income levels -- The Affordable Care Act changed the rules where to buy generic viagra for Medicaid income eligibility for many BUT NOT ALL New Yorkers. People in the "MAGI" category - those NOT on Medicare -- have expanded eligibility up to 138% of the Federal Poverty Line, so may now qualify for Medicaid even if they were not eligible before, or may now be eligible for Medicaid without a "spend-down." They have NO resource limit. Box 3 on page 1 is Spousal Impoverishment levels for Managed Long Term Care &.

    Nursing Homes and Box 8 has the Transfer Penalty rates for nursing home eligibility Box 4 has Medicaid Buy-In for Working People with Disabilities Under Age 65 (still 2017 levels til April 2018) Box 6 are Medicare Savings Program levels (will be updated in April 2018) MAGI INCOME LEVEL where to buy generic viagra of 138% FPL applies to most adults who are not disabled and who do not have Medicare, AND can also apply to adults with Medicare if they have a dependent child/relative under age 18 or under 19 if in school. 42 C.F.R. § 435.4. Certain populations have an even higher income limit - 224% FPL for where to buy generic viagra pregnant women and babies <. Age 1, 154% FPL for children age 1 - 19.

    CAUTION. What is counted as income may not be where to buy generic viagra what you think. For the NON-MAGI Disabled/Aged 65+/Blind, income will still be determined by the same rules as before, explained in this outline and these charts on income disregards. However, for the MAGI population - which is virtually everyone under age 65 who is not on Medicare - their income will now be determined under new rules, based on federal income tax concepts - called "Modifed Adjusted Gross Income" (MAGI). There are good changes where to buy generic viagra and bad changes.

    GOOD. Veteran's benefits, Workers compensation, and gifts from family or others no longer count as income. BAD where to buy generic viagra. There is no more "spousal" or parental refusal for this population (but there still is for the Disabled/Aged/Blind.) and some other rules. For all of the rules see.

    ALSO SEE 2018 Manual on Lump Sums and Impact on Public Benefits - with resource rules The income limits increase with the "household size." In other words, the income limit for a where to buy generic viagra family of 5 may be higher than the income limit for a single person. HOWEVER, Medicaid rules about how to calculate the household size are not intuitive or even logical. There are different rules depending on the "category" of the person seeking Medicaid. Here are the 2 basic categories and the rules for calculating where to buy generic viagra their household size. People who are Disabled, Aged 65+ or Blind - "DAB" or "SSI-Related" Category -- NON-MAGI - See this chart for their household size.

    These same rules apply to the Medicare Savings Program, with some exceptions explained in this article. Everyone else -- MAGI - All children and adults under age 65, including people with disabilities who are not yet on Medicare -- this is where to buy generic viagra the new "MAGI" population. Their household size will be determined using federal income tax rules, which are very complicated. New rule is explained in State's directive 13 ADM-03 - Medicaid Eligibility Changes under the Affordable Care Act (ACA) of 2010 (PDF) pp. 8-10 of the PDF, This where to buy generic viagra PowerPoint by NYLAG on MAGI Budgeting attempts to explain the new MAGI budgeting, including how to determine the Household Size.

    See slides 28-49. Also seeLegal Aid Society and Empire Justice Center materials OLD RULE used until end of 2013 -- Count the person(s) applying for Medicaid who live together, plus any of their legally responsible relatives who do not receive SNA, ADC, or SSI and reside with an applicant/recipient. Spouses or legally responsible for one another, and parents are legally responsible for their children under age where to buy generic viagra 21 (though if the child is disabled, use the rule in the 1st "DAB" category. Under this rule, a child may be excluded from the household if that child's income causes other family members to lose Medicaid eligibility. See 18 NYCRR 360-4.2, MRG p.

    573, NYS GIS 2000 MA-007 CAUTION where to buy generic viagra. Different people in the same household may be in different "categories" and hence have different household sizes AND Medicaid income and resource limits. If a man is age 67 and has Medicare and his wife is age 62 and not disabled or blind, the husband's household size for Medicaid is determined under Category 1/ Non-MAGI above and his wife's is under Category 2/MAGI. The following programs were available prior to where to buy generic viagra 2014, but are now discontinued because they are folded into MAGI Medicaid. Prenatal Care Assistance Program (PCAP) was Medicaid for pregnant women and children under age 19, with higher income limits for pregnant woman and infants under one year (200% FPL for pregnant women receiving perinatal coverage only not full Medicaid) than for children ages 1-18 (133% FPL).

    Medicaid for adults between ages 21-65 who are not disabled and without children under 21 in the household. It was sometimes known as "S/CC" category for where to buy generic viagra Singles and Childless Couples. This category had lower income limits than DAB/ADC-related, but had no asset limits. It did not allow "spend down" of excess income. This category has now been subsumed where to buy generic viagra under the new MAGI adult group whose limit is now raised to 138% FPL.

    Family Health Plus - this was an expansion of Medicaid to families with income up to 150% FPL and for childless adults up to 100% FPL. This has now been folded into the new MAGI adult group whose limit is 138% FPL. For applicants between 138%-150% where to buy generic viagra FPL, they will be eligible for a new program where Medicaid will subsidize their purchase of Qualified Health Plans on the Exchange. PAST INCOME &. RESOURCE LEVELS -- Past Medicaid income and resource levels in NYS are shown on these oldNYC HRA charts for 2001 through 2019, in chronological order.

    These include Medicaid levels for MAGI and non-MAGI populations, Child Health Plus, MBI-WPD, Medicare Savings Programs and other public health programs in NYS where to buy generic viagra. This article was authored by the Evelyn Frank Legal Resources Program of New York Legal Assistance Group.A huge barrier to people returning to the community from nursing homes is the high cost of housing. One way New York State is trying to address that barrier is with the Special Housing Disregard that allows certain members of Managed Long Term Care or FIDA plans to keep more of their income to pay for rent or other shelter costs, rather than having to "spend down" their "excess income" or spend-down on the cost of Medicaid home care. The special income standard for housing expenses helps pay for housing where to buy generic viagra expenses to help certain nursing home or adult home residents to safely transition back to the community with MLTC. Originally it was just for former nursing home residents but in 2014 it was expanded to include people who lived in adult homes.

    GIS 14/MA-017 Since you are allowed to keep more of your income, you may no longer need to use a pooled trust. KNOW YOUR RIGHTS - FACT where to buy generic viagra SHEET on THREE ways to Reduce Spend-down, including this Special Income Standard. September 2018 NEWS -- Those already enrolled in MLTC plans before they are admitted to a nursing home or adult home may obtain this budgeting upon discharge, if they meet the other criteria below. "How nursing home administrators, adult home operators and MLTC plans should identify individuals who are eligible for the special income standard" and explains their duties to identify eligible individuals, and the MLTC plan must notify the local DSS that the individual may qualify. "Nursing home administrators, nursing home discharge planning staff, adult home operators and MLTC health plans are encouraged to identify individuals who may qualify for the where to buy generic viagra special income standard, if they can be safely discharged back to the community from a nursing home and enroll in, or remain enrolled in, an MLTC plan.

    Once an individual has been accepted into an MLTC plan, the MLTC plan must notify the individual's local district of social services that the transition has occurred and that the individual may qualify for the special income standard. The special income standard will be effective upon enrollment into the MLTC plan, or, for nursing home residents already enrolled in an MLTC plan, the month of discharge to the community. Questions regarding the special income standard may be where to buy generic viagra directed to DOH at 518-474-8887. Who is eligible for this special income standard?. must be age 18+, must have been in a nursing home or an adult home for 30 days or more, must have had Medicaid pay toward the nursing home care, and must enroll in or REMAIN ENROLLED IN a Managed Long Term Care (MLTC) plan or FIDA plan upon leaving the nursing home or adult home must have a housing expense if married, spouse may not receive a "spousal impoverishment" allowance once the individual is enrolled in MLTC.

    How much is the allowance? where to buy generic viagra. The rates vary by region and change yearly. Region Counties Deduction (2020) Central Broome, Cayuga, Chenango, Cortland, Herkimer, Jefferson, Lewis, Madison, Oneida, Onondaga, Oswego, St. Lawrence, Tioga, Tompkins $436 Long Island Nassau, Suffolk $1,361 NYC Bronx, Kings, Manhattan, Queens, Richmond $1,451 (up from 1,300 in 2019) Northeastern Albany, Clinton, Columbia, Delaware, Essex, Franklin, Fulton, Greene, Hamilton, Montgomery, Otsego, Rensselaer, Saratoga, Schenectady, Schoharie, Warren, Washington $483 North Metropolitan Dutchess, Orange, Putnam, Rockland, Sullivan, Ulster, Westchester $930 Rochester Chemung, Livingston, Monroe, Ontario, Schuyler, Seneca, Steuben, Wayne, Yates $444 Western Allegany, Cattaraugus, Chautauqua, Erie, Genesee, Niagara, Orleans, Wyoming $386 Past rates published as follows, available on DOH website 2020 rates published in Attachment I to GIS 19 MA/12 – 2020 Medicaid Levels and Other Updates 2019 rates published in Attachment 1 to GIS 18/MA015 - 2019 Medicaid Levels and Other Updates 2018 rates published in GIS 17 MA/020 - 2018 Medicaid Levels and Other Updates. The guidance on how the standardized amount of the disregard is calculated is found in NYS DOH 12- ADM-05.

    2017 rate -- GIS 16 MA/018 - 2016 Medicaid Only Income and Resource Levels and Spousal Impoverishment Standards Attachment 12016 rate -- GIS 15-MA/0212015 rate -- Were not posted by DOH but were updated in WMS. 2015 Central $382 Long Island $1,147 NYC $1,001 Northeastern $440 N. Metropolitan $791 Rochester $388 Western $336 2014 rate -- GIS-14-MA/017 HOW DOES IT WORK?. Here is a sample budget for a single person in NYC with Social Security income of $2,386/month paying a Medigap premium of $261/mo. Gross monthly income $2,575.50 DEDUCT Health insurance premiums (Medicare Part B) - 135.50 (Medigap) - 261.00 DEDUCT Unearned income disregard - 20 DEDUCT Shelter deduction (NYC—2019) - 1,300 DEDUCT Income limit for single (2019) - 859 Excess income or Spend-down $0 WITH NO SPEND-DOWN, May NOT NEED POOLED TRUST!.

    HOW TO OBTAIN THE HOUSING DISREGARD. When you are ready to leave the nursing home or adult home, or soon after you leave, you or your MLTC plan must request that your local Medicaid program change your Medicaid budget to give you the Housing Disregard. See September 2018 NYS DOH Medicaid Update that requires MLTC plan to help you ask for it. The procedures in NYC are explained in this Troubleshooting guide. NYC Medicaid program prefers that your MLTC plan file the request, using Form MAP-3057E - Special income housing Expenses NH-MLTC.pdf and Form MAP-3047B - MLTC/NHED Cover Sheet Form MAP-259f (revised 7-31-18)(page 7 of PDF)(DIscharge Notice) - NH must file with HRA upon discharge, certifying resident was informed of availability of this disregard.

    GOVERNMENT DIRECTIVES (beginning with oldest). NYS DOH 12- ADM-05 - Special Income Standard for Housing Expenses for Individuals Discharged from a Nursing Facility who Enroll into the Managed Long Term Care (MLTC) Program Attachment II - OHIP-0057 - Notice of Intent to Change Medicaid Coverage, (Recipient Discharged from a Skilled Nursing Facility and Enrolled in a Managed Long Term Care Plan) Attachment III - Attachment III – OHIP-0058 - Notice of Intent to Change Medicaid Coverage, (Recipient Disenrolled from a Managed Long Term Care Plan, No Special Income Standard) MLTC Policy 13.02. MLTC Housing Disregard NYC HRA Medicaid Alert Special Income Standard for housing expenses NH-MLTC 2-9-2013.pdf 2018-07-28 HRA MICSA ALERT Special Income Standard for Housing Expenses for Individuals Discharged from a Nursing Facility and who Enroll into the MLTC Program - update on previous policy. References Form MAP-259f (revised 7-31-18)(page 7 of PDF)(Discharge Notice) - NH must file with HRA upon discharge, certifying resident was informed of availability of this disregard.

    Viagra online canadian pharmacy

    High burden do you need a prescription for viagra of antibiotic-resistant Mycoplasma genitalium in symptomatic urethritisMycoplasma genitalium is an aetiological agent of sexually viagra online canadian pharmacy transmitted urethritis. A cohort study investigated M. Genitalium prevalence, antibiotic resistance and association with previous macrolide exposure among 1816 Chinese men who presented with symptomatic urethritis between 2011 and 2015 viagra online canadian pharmacy. Infection was diagnosed by PCR, and sequencing was used to detect mutations that confer resistance to macrolides and fluoroquinolones.

    In 11% of men, viagra online canadian pharmacy M. Genitalium was the sole pathogen identified. Nearly 90% of viagra online canadian pharmacy infections were resistant to macrolides and fluoroquinolones. Previous macrolide exposure was associated with higher prevalence of resistance (97%).

    The findings point to the need for routine screening for viagra online canadian pharmacy M. Genitalium in symptomatic men with urethritis. Treatment strategies to overcome antibiotic resistance viagra online canadian pharmacy in M. Genitalium are needed.Yang L, Xiaohong S, Wenjing L, et al.

    Mycoplasma genitalium in symptomatic viagra online canadian pharmacy male urethritis. Macrolide use is associated with increased resistance. Clin Infect Dis 2020;5:805–10. Doi:10.1093/cid/ciz294.A new entry inhibitor offers promise for treatment-experienced patients with multidrug-resistant HIVFostemsavir, viagra online canadian pharmacy the prodrug of temsavir, is an attachment inhibitor.

    By targeting the gp120 protein on the HIV-1 envelope, it prevents viral interaction with the CD4 receptor. No cross-resistance has been described with other antiretroviral agents, viagra online canadian pharmacy including those that target viral entry by other modalities. In the phase III BRIGHTE trial, 371 highly treatment-experienced patients who had exhausted ≥4 classes of antiretrovirals received fostemsavir with an optimised regimen. After 48 weeks, 54% of those with 1–2 additional active drugs achieved viral viagra online canadian pharmacy load suppression <40 copies/mL.

    Response rates were 38% among patients lacking other active agents. Drug-related adverse viagra online canadian pharmacy events included nausea (4%) and diarrhoea (3%). As gp120 substitutions reduced fostemsavir susceptibility in up to 70% of patients with virological failure, fostemsavir offers the most valuable salvage option in partnership with other active drugs.Kozal M, Aberg J, Pialoux G, et al. Fostemsavir in adults with viagra online canadian pharmacy multidrug-resistant HIV-1 infection.

    N Engl J Med 2020;382:1232–43. Doi. 10.1056/NEJMoa1902493Novel tools to aid identification of hepatitis C in primary careHepatitis C can now be cured with oral antiviral treatment, and improving diagnosis is a key element of elimination strategies.1 A cluster randomised controlled trial in South West England tested performance and cost-effectiveness of an electronic algorithm that identified at-risk patients in primary care according to national recommendations,2 coupled with educational activities and interventions to increase patients’ awareness. Outcomes were testing uptake, diagnosis and referral to specialist care.

    Practices in the intervention arm had an increase in all outcome measures, with adjusted risk ratios of 1.59 (1.21–2.08) for uptake, 2.24 (1.47–3.42) for diagnosis and 5.78 (1.60–21.6) for referral. The intervention was highly cost-effective. Electronic algorithms applied to practice systems could enhance testing and diagnosis of hepatitis C in primary care, contributing to global elimination goals.Roberts K, Macleod J, Metcalfe C, et al. Cost-effectiveness of an intervention to increase uptake of hepatitis C virus testing and treatment (HepCATT).

    Cluster randomised controlled trial in primary care. BMJ 2020;368:m322. Doi:10.1136/bmj.m322Low completion rates for antiretroviral postexposure prophylaxis (PEP) after sexual assaultA 4-week course of triple-agent postexposure prophylaxis (PEP) is recommended following a high-risk sexual assault.3 4 A retrospective study in Barcelona identified 1695 victims attending an emergency room (ER) between 2006 and 2015. Overall, 883 (52%) started prophylaxis in ER, which was mostly (43%) lopinavir/ritonavir based.

    Follow-up appointments were arranged for those living in Catalonia (631, 71.5%), and of these, only 183 (29%) completed treatment. Loss to follow-up was more prevalent in those residing outside Barcelona. PEP non-completion was associated with a low perceived risk, previous assaults, a known aggressor and a positive cocaine test. Side effects were common, occurring in up to 65% of those taking lopinavir/ritonavir and accounting for 15% of all discontinuations.

    More tolerable PEP regimens, accessible follow-up and provision of 1-month supply may improve completion rates.Inciarte A, Leal L, Masfarre L, et al. Postexposure prophylaxis for HIV infection in sexual assault victims. HIV Med 2020;21:43–52. Doi:10.1111/hiv.12797.Effective antiretroviral therapy reduces anal high-risk HPV infection and cancer riskAmong people with HIV, effective antiretroviral therapy (ART) is expected to improve control of anal http://www.amisdepasteur.fr/can-you-buy-viagra-over-the-counter/ infection with high-risk human papillomavirus (HR-HPV) and reduce the progression of HPV-associated anal lesions.

    The magnitude of the effect is not well established. By meta-analysis, people on established ART (vs ART-naive) had a 35% lower prevalence of HR-HPV infection, and those with undetectable viral load (vs detectable viral load) had a 27% and 16% reduced risk of low and high-grade anal lesions, respectively. Sustained virological suppression on ART reduced by 44% the risk of anal cancer. The role of effective ART in reducing anal HR-HPV infection and cancer risks is especially salient given current limitations in anal cancer screening, high rates of anal lesion recurrence and access to vaccination.Kelly H, Chikandiwa A, Alemany Vilches L, et al.

    Association of antiretroviral therapy with anal high-risk human papillomavirus, anal intraepithelial neoplasia and anal cancer in people living with HIV. A systematic review and meta-analysis. Lancet HIV. 2020;7:e262–78.

    Doi:10.1016/S2352-3018(19)30434-5.The impact of sex work laws and stigma on HIV prevention among female sex workersSex work laws and stigma have been established as structural risk factors for HIV acquisition among female sex workers (FSWs). However, individual-level data assessing these relationships are limited. A study examined individual-level data collected in 2011–2018 from 7259 FSWs across 10 sub-Saharan African countries. An association emerged between HIV prevalence and increasingly punitive and non-protective laws.

    HIV prevalence among FSWs was 11.6%, 19.6% and 39.4% in contexts where sex work was partly legalised, not recognised or criminalised, respectively. Stigma measures such as fear of seeking health services, mistreatment in healthcare settings, lack of police protection, blackmail and violence were associated with higher HIV prevalence and more punitive settings. Sex work laws that protect sex workers and reduce structural risks are needed.Lyons CE, Schwartz SR, Murray SM, et al. The role of sex work laws and stigmas in increasing HIV risks among sex workers.

    Nat Commun 2020;11:773. Doi:10.1038/s41467-020-14593-6.BackgroundCumbria Sexual Health Services (CSHS) in collaboration with Cumbria Public Health and local authorities have established a COVID-19 contact tracing pathway for Cumbria. The local system was live 10 days prior to the national system on 18 May 2020. It was designed to interface and dovetail with the government’s track and trace programme.Our involvement in this initiative was due to a chance meeting between Professor Matt Phillips, Consultant in Sexual Health and HIV, and the Director of Public Health Cumbria, Colin Cox.

    Colin knew that Cumbria needed to act fast to prevent the transmission of COVID-19 and Matt knew that sexual health had the skills to help.ProcessDespite over 90% of the staff from CSHS being redeployed in March 2020, CSHS maintained urgent sexual healthcare for the county and a phone line for advice and guidance. As staff began to return to the service in May 2020 we had capacity to spare seven staff members, whose hours were the equivalent of four full-time staff. We had one system administrator, three healthcare assistants, one nurse, Health Advisor Helen Musker and myself.CSHS were paramount to the speed with which the local system began. Following approval from the Trust’s chief executive officer we had adapted our electronic patient records (EPR) system, developed a standard operating procedure and trained staff, using a stepwise competency model, within just 1 day.In collaboration with the local laboratories we developed methods for the input of positive COVID-19 results into our EPR derivative.

    We ensured that labs would be able to cope with the increase in testing and that testing hubs had additional capacity. Testing sites and occupational health were asked to inform patients that if they tested positive they would be contacted by our teams.This initiative involved a multiagency system including local public health (PH) teams, local authority, North Cumbria and Morecambe Bay CCGs, Public Health England (PHE) and the military. If CSHS recognise more than one positive result in the same area/organisation, they flag this with PH at the daily incident management meeting and environmental health officers (EHOs) provide advice and guidance for the organisation. We have had an active role in the contact tracing for clusters in local general practices, providing essential information to PH to enable them to initiate outbreak control and provide accurate advice to the practices.

    We are an integral part in recognising cases in large organisations and ensuring prompt action is taken to stem the spread of the disease. The team have provided out-of-hours work to ensure timely and efficient action is taken for all contacts.The local contact tracing pilot has evolved and a database was established by local authorities. Our data fed directly into this from the end of May 2020. This enables the multiagency team to record data in one place, improving recognition of patterns of transmission.DiscussionCumbria is covered by three National Health Service Trusts, which meant accessing data outside of our Trust was challenging and took more time to establish.

    There are two CCGs for Cumbria, which meant discussions regarding testing were needed with both North and South CCGs and variations in provision had to be accounted for. There are six boroughs in Cumbria with different teams of EHOs working in each. With so many people involved, not only is there need for large-scale frequent communication across a multisystem team, there is also inevitable duplication of work.Lockdown is easing and sexual health clinics are increasing capacity in a new world of virtual appointments and reduced face-to-face consultations. Staff within the contact tracing team are now balancing their commitments across both teams to maintain their skills and keep abreast of the rapid developments within our service due to COVID-19.

    We are currently applying for funding from PH in order to second staff and backfill posts in sexual health.ConclusionCSHS have been able to lend our skills effectively to the local contact tracing efforts. We have expedited the contact tracing in Cumbria and provided crucial information to help contain outbreaks. It has had a positive effect on staff morale within the service and we have gained national recognition for our work. We have developed excellent relationships with our local PH team, PHE, Cumbria Council, EHOs and both CCGs.Cumbria has the infrastructure to meet the demands of a second wave of COVID-19.

    The beauty of this model is that if we are faced with a second lockdown, sexual health staff will inevitably be available to help with the increased demand for contact tracing. Our ambition is that this model will be replicated nationally..

    High burden of antibiotic-resistant Mycoplasma genitalium in symptomatic urethritisMycoplasma genitalium is an aetiological agent where to buy generic viagra of sexually transmitted urethritis is viagra a blood thinner. A cohort study investigated M. Genitalium prevalence, antibiotic resistance and association with previous macrolide exposure among 1816 Chinese men who presented with where to buy generic viagra symptomatic urethritis between 2011 and 2015. Infection was diagnosed by PCR, and sequencing was used to detect mutations that confer resistance to macrolides and fluoroquinolones.

    In 11% of men, where to buy generic viagra M. Genitalium was the sole pathogen identified. Nearly 90% of infections were resistant to where to buy generic viagra macrolides and fluoroquinolones. Previous macrolide exposure was associated with higher prevalence of resistance (97%).

    The findings point to the where to buy generic viagra need for routine screening for M. Genitalium in symptomatic men with urethritis. Treatment strategies to overcome antibiotic resistance where to buy generic viagra in M. Genitalium are needed.Yang L, Xiaohong S, Wenjing L, et al.

    Mycoplasma genitalium in symptomatic male urethritis where to buy generic viagra. Macrolide use is associated with increased resistance. Clin Infect Dis 2020;5:805–10. Doi:10.1093/cid/ciz294.A new entry inhibitor offers promise for treatment-experienced patients with multidrug-resistant HIVFostemsavir, the prodrug of temsavir, is an where to buy generic viagra attachment inhibitor.

    By targeting the gp120 protein on the HIV-1 envelope, it prevents viral interaction with the CD4 receptor. No cross-resistance has where to buy generic viagra been described with other antiretroviral agents, including those that target viral entry by other modalities. In the phase III BRIGHTE trial, 371 highly treatment-experienced patients who had exhausted ≥4 classes of antiretrovirals received fostemsavir with an optimised regimen. After 48 weeks, 54% of those with 1–2 additional active where to buy generic viagra drugs achieved viral load suppression <40 copies/mL.

    Response rates were 38% among patients lacking other active agents. Drug-related adverse events included nausea where to buy generic viagra (4%) and diarrhoea (3%). As gp120 substitutions reduced fostemsavir susceptibility in up to 70% of patients with virological failure, fostemsavir offers the most valuable salvage option in partnership with other active drugs.Kozal M, Aberg J, Pialoux G, et al. Fostemsavir in where to buy generic viagra adults with multidrug-resistant HIV-1 infection.

    N Engl J Med 2020;382:1232–43. Doi. 10.1056/NEJMoa1902493Novel tools to aid identification of hepatitis C in primary careHepatitis C can now be cured with oral antiviral treatment, and improving diagnosis is a key element of elimination strategies.1 A cluster randomised controlled trial in South West England tested performance and cost-effectiveness of an electronic algorithm that identified at-risk patients in primary care according to national recommendations,2 coupled with educational activities and interventions to increase patients’ awareness. Outcomes were testing uptake, diagnosis and referral to specialist care.

    Practices in the intervention arm had an increase in all outcome measures, with adjusted risk ratios of 1.59 (1.21–2.08) for uptake, 2.24 (1.47–3.42) for diagnosis and 5.78 (1.60–21.6) for referral. The intervention was highly cost-effective. Electronic algorithms applied to practice systems could enhance testing and diagnosis of hepatitis C in primary care, contributing to global elimination goals.Roberts K, Macleod J, Metcalfe C, et al. Cost-effectiveness of an intervention to increase uptake of hepatitis C virus testing and treatment (HepCATT).

    Cluster randomised controlled trial in primary care. BMJ 2020;368:m322. Doi:10.1136/bmj.m322Low completion rates for antiretroviral postexposure prophylaxis (PEP) after sexual assaultA 4-week course of triple-agent postexposure prophylaxis (PEP) is recommended following a high-risk sexual assault.3 4 A retrospective study in Barcelona identified 1695 victims attending an emergency room (ER) between 2006 and 2015. Overall, 883 (52%) started prophylaxis in ER, which was mostly (43%) lopinavir/ritonavir based.

    Follow-up appointments were arranged for those living in Catalonia (631, 71.5%), and of these, only 183 (29%) completed treatment. Loss to follow-up was more prevalent in those residing outside Barcelona. PEP non-completion was associated with a low perceived risk, previous assaults, a known aggressor and a positive cocaine test. Side effects were common, occurring in up to 65% of those taking lopinavir/ritonavir and accounting for 15% of all discontinuations.

    More tolerable PEP regimens, accessible follow-up and provision of 1-month supply may improve completion rates.Inciarte A, Leal L, Masfarre L, et al. Postexposure prophylaxis for HIV infection in sexual assault victims. HIV Med 2020;21:43–52. Doi:10.1111/hiv.12797.Effective antiretroviral therapy over the counter viagra usa reduces anal high-risk HPV infection and cancer riskAmong people with HIV, effective antiretroviral therapy (ART) is expected to improve control of anal infection with high-risk human papillomavirus (HR-HPV) and reduce the progression of HPV-associated anal lesions.

    The magnitude of the effect is not well established. By meta-analysis, people on established ART (vs ART-naive) had a 35% lower prevalence of HR-HPV infection, and those with undetectable viral load (vs detectable viral load) had a 27% and 16% reduced risk of low and high-grade anal lesions, respectively. Sustained virological suppression on ART reduced by 44% the risk of anal cancer. The role of effective ART in reducing anal HR-HPV infection and cancer risks is especially salient given current limitations in anal cancer screening, high rates of anal lesion recurrence and access to vaccination.Kelly H, Chikandiwa A, Alemany Vilches L, et al.

    Association of antiretroviral therapy with anal high-risk human papillomavirus, anal intraepithelial neoplasia and anal cancer in people living with HIV. A systematic review and meta-analysis. Lancet HIV. 2020;7:e262–78.

    Doi:10.1016/S2352-3018(19)30434-5.The impact of sex work laws and stigma on HIV prevention among female sex workersSex work laws and stigma have been established as structural risk factors for HIV acquisition among female sex workers (FSWs). However, individual-level data assessing these relationships are limited. A study examined individual-level data collected in 2011–2018 from 7259 FSWs across 10 sub-Saharan African countries. An association emerged between HIV prevalence and increasingly punitive and non-protective laws.

    HIV prevalence among FSWs was 11.6%, 19.6% and 39.4% in contexts where sex work was partly legalised, not recognised or criminalised, respectively. Stigma measures such as fear of seeking health services, mistreatment in healthcare settings, lack of police protection, blackmail and violence were associated with higher HIV prevalence and more punitive settings. Sex work laws that protect sex workers and reduce structural risks are needed.Lyons CE, Schwartz SR, Murray SM, et al. The role of sex work laws and stigmas in increasing HIV risks among sex workers.

    Nat Commun 2020;11:773. Doi:10.1038/s41467-020-14593-6.BackgroundCumbria Sexual Health Services (CSHS) in collaboration with Cumbria Public Health and local authorities have established a COVID-19 contact tracing pathway for Cumbria. The local system was live 10 days prior to the national system on 18 May 2020. It was designed to interface and dovetail with the government’s track and trace programme.Our involvement in this initiative was due to a chance meeting between Professor Matt Phillips, Consultant in Sexual Health and HIV, and the Director of Public Health Cumbria, Colin Cox.

    Colin knew that Cumbria needed to act fast to prevent the transmission of COVID-19 and Matt knew that sexual health had the skills to help.ProcessDespite over 90% of the staff from CSHS being redeployed in March 2020, CSHS maintained urgent sexual healthcare for the county and a phone line for advice and guidance. As staff began to return to the service in May 2020 we had capacity to spare seven staff members, whose hours were the equivalent of four full-time staff. We had one system administrator, three healthcare assistants, one nurse, Health Advisor Helen Musker and myself.CSHS were paramount to the speed with which the local system began. Following approval from the Trust’s chief executive officer we had adapted our electronic patient records (EPR) system, developed a standard operating procedure and trained staff, using a stepwise competency model, within just 1 day.In collaboration with the local laboratories we developed methods for the input of positive COVID-19 results into our EPR derivative.

    We ensured that labs would be able to cope with the increase in testing and that testing hubs had additional capacity. Testing sites and occupational health were asked to inform patients that if they tested positive they would be contacted by our teams.This initiative involved a multiagency system including local public health (PH) teams, local authority, North Cumbria and Morecambe Bay CCGs, Public Health England (PHE) and the military. If CSHS recognise more than one positive result in the same area/organisation, they flag this with PH at the daily incident management meeting and environmental health officers (EHOs) provide advice and guidance for the organisation. We have had an active role in the contact tracing for clusters in local general practices, providing essential information to PH to enable them to initiate outbreak control and provide accurate advice to the practices.

    We are an integral part in recognising cases in large organisations and ensuring prompt action is taken to stem the spread of the disease. The team have provided out-of-hours work to ensure timely and efficient action is taken for all contacts.The local contact tracing pilot has evolved and a database was established by local authorities. Our data fed directly into this from the end of May 2020. This enables the multiagency team to record data in one place, improving recognition of patterns of transmission.DiscussionCumbria is covered by three National Health Service Trusts, which meant accessing data outside of our Trust was challenging and took more time to establish.

    There are two CCGs for Cumbria, which meant discussions regarding testing were needed with both North and South CCGs and variations in provision had to be accounted for. There are six boroughs in Cumbria with different teams of EHOs working in each. With so many people involved, not only is there need for large-scale frequent communication across a multisystem team, there is also inevitable duplication of work.Lockdown is easing and sexual health clinics are increasing capacity in a new world of virtual appointments and reduced face-to-face consultations. Staff within the contact tracing team are now balancing their commitments across both teams to maintain their skills and keep abreast of the rapid developments within our service due to COVID-19.

    We are currently applying for funding from PH in order to second staff and backfill posts in sexual health.ConclusionCSHS have been able to lend our skills effectively to the local contact tracing efforts. We have expedited the contact tracing in Cumbria and provided crucial information to help contain outbreaks. It has had a positive effect on staff morale within the service and we have gained national recognition for our work. We have developed excellent relationships with our local PH team, PHE, Cumbria Council, EHOs and both CCGs.Cumbria has the infrastructure to meet the demands of a second wave of COVID-19.

    The beauty of this model is that if we are faced with a second lockdown, sexual health staff will inevitably be available to help with the increased demand for contact tracing. Our ambition is that this model will be replicated nationally..

  • What does viagra mean

    Où rencontrer Pasteur dans Dole

    A la façon du Circuit du Chat Perché qui permet de découvrir les sites les plus attractifs de Dole, Alain Marchal nous propose de déambuler dans certains lieux publics dolois...pour admirer statues, fresques trompe-l’œil, mosaïques ou bustes à l'effigie...

    > LIRE LA SUITE

  • What does viagra mean

    Où rencontrer Pasteur dans Dole

    A la façon du Circuit du Chat Perché qui permet de découvrir les sites les plus attractifs de Dole, Alain Marchal nous propose de déambuler dans certains lieux publics dolois...pour admirer statues, fresques trompe-l’œil, mosaïques ou bustes à l'effigie...

    > LIRE LA SUITE

  • What does viagra mean

    Visite passion

    Pendant les vacances , venez faire la connaissance de Louis PASTEUR, visitez sa maison natale à Dole et la salle scientifique exposant les découvertes de notre grand savant Jurassien.
    Les bénévoles des Amis de PASTEUR vous proposent une "visite passion...

    > LIRE LA SUITE

  • What does viagra mean

    Visite passion

    Pendant les vacances , venez faire la connaissance de Louis PASTEUR, visitez sa maison natale à Dole et la salle scientifique exposant les découvertes de notre grand savant Jurassien.
    Les bénévoles des Amis de PASTEUR vous proposent une "visite passion...

    > LIRE LA SUITE

  • What does viagra mean

    Louis Pasteur et le ver à soie :


    Une exposition présentera à la Maison natale des aspects actuels de l'utilisation de la soie, dans les domaines industriels et techniques, dans la création artistique, avec un clin d'oeil aux travaux de Pasteur sur les maladies des vers à soie en...

    > LIRE LA SUITE

  • What does viagra mean

    Visite passion

    Pendant les vacances , venez faire la connaissance de Louis PASTEUR, visitez sa maison natale à Dole et la salle scientifique exposant les découvertes de notre grand savant Jurassien.
    Les bénévoles des Amis de PASTEUR vous proposent une "visite passion...

    > LIRE LA SUITE