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How to get floxin over the counter

IntroductionIn recent years, many studies have been published on new diagnostic possibilities and management approaches in cohorts of patients suspected to have a disorder/difference of sex development (DSD).1–13 Based on these studies, it has become clear that services how to get floxin over the counter 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 document by an how to get floxin over the counter international group of professionals and patient representatives.18 These initiatives have highlighted how cultural and financial aspects and the availability of resources differ significantly between countries and societies, a situation that hampers supranational agreement on common diagnostic protocols. As only a few national guidelines have been published in international journals, comparison of these guidelines is difficult even though such a comparison is necessary to capture the differences and initiate actions to overcome them. Nonetheless, four DSD (expert) centres located in the Netherlands and Flanders (the Dutch-speaking Northern part of Belgium) have collaborated to produce a detailed guideline on how to get floxin over the counter 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 how to get floxin over the counter 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 how to get floxin over the counter this process.20 21 Furthermore, informing patients and/or their parents about atypical sex development and why this may warrant referral to a specialised team may be challenging, especially for professionals with limited experience in DSD.22 23 Therefore, a section of the Dutch-Flemish guideline was written for these healthcare providers. 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 how to get floxin over the counter 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 how to get floxin over the counter 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 how to get floxin over the counter often troublesome to substantiate such guidelines with sufficient evidence due to the rapid changes in testing methods, for example, gene panels. All input provided by the group was synthesised by the chairperson (YvB), who also reviewed abstracts of papers on DSD published between 2010 and September 2017 for the guideline and up to October 2019 for this paper.

Abstracts had to be written in English and were identified using a broad range how to get floxin over the counter 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 how to get floxin over the counter were excluded, as were articles that were not open access or retrievable through institutional access. Based on this, a draft guideline was produced that was in line with the international principles of good diagnostic care in DSD. This draft was discussed by the writing committee how to get floxin over the counter 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 the paediatric how to get floxin over the counter and genetic associations for approval. After approval by the members of the paediatric (NVK), clinical genetic (VKGN) and genetic laboratory (VKGL) associations, the guideline was published on their respective websites.19 Although Turner syndrome and Klinefelter syndrome are considered to be part of the DSD spectrum, they are not extensively discussed in this diagnostic guideline as guidelines dedicated to these syndromes already exist.25 26 However, some individuals with Turner syndrome or Klinefelter syndrome may present with ambiguous or atypical genitalia and may therefore initially follow the DSD diagnostic process.Guideline highlightsPrenatal settingPresentationThe most frequent prenatal presentation of a DSD condition is atypical genitalia found on prenatal ultrasound as an isolated finding or in combination with other structural anomalies. This usually occurs after the 20-week routine medical ultrasound for screening of congenital anomalies, but may also occur earlier, for example, when a commercial ultrasound is performed at the request of the parents.Another way DSD can be diagnosed before birth is when invasive prenatal genetic testing carried out for a different reason, for example, due to suspicion of other structural anomalies, reveals a discrepancy how to get floxin over the counter 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 how to get floxin over the counter increasing frequency is a discrepancy between the genotypic sex revealed by non-invasive prenatal testing (NIPT), which is now available to high-risk pregnant women in the Netherlands and to all pregnant women in Belgium, and later ultrasound findings. NIPT screens for CNVs in the fetus. However, depending on legal how to get floxin over the counter restrictions and/or ethical considerations, the X and Y chromosomes are not always included in NIPT analysis and reports. If the X and Y chromosomes are included, it is important to realise that the presence of a Y-chromosome does not necessarily imply male fetal development. At the time that NIPT is performed (usually 11–13 weeks), 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 how to get floxin over the counter couple to their colleague prenatal specialists working with or in a DSD team.

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

The clinical geneticist should be experienced in prenatal counselling and well informed about the diagnostic possibilities given the limited time span in which test results need to be available to allow parents to make a well-informed decision about whether how to get floxin over the counter or not to continue the pregnancy. Termination of pregnancy can be considered, for instance, in a syndromic form of DSD with how to get floxin over the counter multiple malformations, but when the DSD occurs as an apparently isolated condition, expecting parents may also consider termination of pregnancy, which, although considered controversial by some, is legal in Belgium and the Netherlands. The psychologist of the DSD team can support parents during and after pregnancy and help them cope with feelings of uncertainty and eventual considerations of a termination of pregnancy, as well as with practical issues, for example, how to inform others. The stress of not knowing exactly what the child’s genitalia will look like and uncertainty about the diagnosis, treatment and prognosis cannot be how to get floxin over the counter 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 how to get floxin over the counter decline prenatal testing (personal experience IALG, MK, ABD, YvB, MC and HC-vdG). At birth, umbilical cord blood is a good source for (molecular) karyotyping and storage of DNA and can be obtained by the obstetrician, midwife or neonatologist. The terminology used in communication with parents should be carefully chosen,22 23 and midwives and staff of neonatal and delivery units should be clearly instructed to use gender-neutral and non-stigmatising vocabulary (eg, ‘your baby’) how to get floxin over the counter 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 are seen, the geneticist can consider specific gene defects that may how to get floxin over the counter underlie a known genetic syndrome or carry out NGS.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Credit. IStock Share Fast Facts New @HopkinsMedicine study finds African-American women with common form of hair loss at increased risk of uterine fibroids - Click to Tweet New study in @JAMADerm shows most common form of alopecia (hair loss) in African-American women associated with higher risks of uterine fibroids - Click to Tweet In a study of medical records gathered on hundreds of thousands of African-American women, Johns Hopkins researchers say they have evidence that women with a common form of hair loss have an increased chance of developing uterine leiomyomas, or fibroids.In a report on the research, published in the December 27 issue of JAMA Dermatology, the researchers call on physicians who treat women with central centrifugal cicatricial alopecia (CCCA) to make patients aware that they may be at increased risk for fibroids and should be screened for the condition, particularly if they have symptoms such as heavy bleeding and pain. CCCA predominantly affects black women and is the most common form of permanent alopecia in this population. The excess scar tissue that forms as a result of this type of hair loss may also explain the higher risk for uterine fibroids, which are characterized by fibrous growths in the lining of the womb.

Crystal Aguh, M.D., assistant professor of dermatology at the Johns Hopkins University School of Medicine, says the scarring associated with CCCA is similar to the scarring associated with excess fibrous tissue elsewhere in the body, a situation that may explain why women with this type of hair loss are at a higher risk for fibroids.People of African descent, she notes, are more prone to develop other disorders of abnormal scarring, termed fibroproliferative disorders, such as keloids (a type of raised scar after trauma), scleroderma (an autoimmune disorder marked by thickening of the skin as well as internal organs), some types of lupus and clogged arteries. During a four-year period from 2013-2017, the researchers analyzed patient data from the Johns Hopkins electronic medical record system (Epic) of 487,104 black women ages 18 and over. The prevalence of those with fibroids was compared in patients with and without CCCA. Overall, the researchers found that 13.9 percent of women with CCCA also had a history of uterine fibroids compared to only 3.3 percent of black women without the condition.

In absolute numbers, out of the 486,000 women who were reviewed, 16,212 had fibroids.Within that population, 447 had CCCA, of which 62 had fibroids. The findings translate to a fivefold increased risk of uterine fibroids in women with CCCA, compared to age, sex and race matched controls. Aguh cautions that their study does not suggest any cause and effect relationship, or prove a common cause for both conditions. €œThe cause of the link between the two conditions remains unclear,” she says.

However, the association was strong enough, she adds, to recommend that physicians and patients be made aware of it. Women with this type of scarring alopecia should be screened not only for fibroids, but also for other disorders associated with excess fibrous tissue, Aguh says. An estimated 70 percent of white women and between 80 and 90 percent of African-American women will develop fibroids by age 50, according to the NIH, and while CCCA is likely underdiagnosed, some estimates report a prevalence of rates as high as 17 percent of black women having this condition. The other authors on this paper were Ginette A.

Okoye, M.D. Of Johns Hopkins and Yemisi Dina of Meharry Medical College.Credit. The New England Journal of Medicine Share Fast Facts This study clears up how big an effect the mutational burden has on outcomes to immune checkpoint inhibitors across many different cancer types. - Click to Tweet The number of mutations in a tumor’s DNA is a good predictor of whether it will respond to a class of cancer immunotherapy drugs known as checkpoint inhibitors.

- Click to Tweet The “mutational burden,” or the number of mutations present in a tumor’s DNA, is a good predictor of whether that cancer type will respond to a class of cancer immunotherapy drugs known as checkpoint inhibitors, a new study led by Johns Hopkins Kimmel Cancer Center researchers shows. The finding, published in the Dec. 21 New England Journal of Medicine, could be used to guide future clinical trials for these drugs. Checkpoint inhibitors are a relatively new class of drug that helps the immune system recognize cancer by interfering with mechanisms cancer cells use to hide from immune cells.

As a result, the drugs cause the immune system to fight cancer in the same way that it would fight an infection. These medicines have had remarkable success in treating some types of cancers that historically have had poor prognoses, such as advanced melanoma and lung cancer. However, these therapies have had little effect on other deadly cancer types, such as pancreatic cancer and glioblastoma. The mutational burden of certain tumor types has previously been proposed as an explanation for why certain cancers respond better than others to immune checkpoint inhibitors says study leader Mark Yarchoan, M.D., chief medical oncology fellow.

Work by Dung Le, M.D., associate professor of oncology, and other researchers at the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Cancer Institute for Cancer Immunotherapy showed that colon cancers that carry a high number of mutations are more likely to respond to checkpoint inhibitors than those that have fewer mutations. However, exactly how big an effect the mutational burden has on outcomes to immune checkpoint inhibitors across many different cancer types was unclear. To investigate this question, Yarchoan and colleagues Alexander Hopkins, Ph.D., research fellow, and Elizabeth Jaffee, M.D., co-director of the Skip Viragh Center for Pancreas Cancer Clinical Research and Patient Care and associate director of the Bloomberg~Kimmel Institute, combed the medical literature for the results of clinical trials using checkpoint inhibitors on various different types of cancer. They combined these findings with data on the mutational burden of thousands of tumor samples from patients with different tumor types.

Analyzing 27 different cancer types for which both pieces of information were available, the researchers found a strong correlation. The higher a cancer type’s mutational burden tends to be, the more likely it is to respond to checkpoint inhibitors. More than half of the differences in how well cancers responded to immune checkpoint inhibitors could be explained by the mutational burden of that cancer. €œThe idea that a tumor type with more mutations might be easier to treat than one with fewer sounds a little counterintuitive.

It’s one of those things that doesn’t sound right when you hear it,” says Hopkins. €œBut with immunotherapy, the more mutations you have, the more chances the immune system has to recognize the tumor.” Although this finding held true for the vast majority of cancer types they studied, there were some outliers in their analysis, says Yarchoan. For example, Merkel cell cancer, a rare and highly aggressive skin cancer, tends to have a moderate number of mutations yet responds extremely well to checkpoint inhibitors. However, he explains, this cancer type is often caused by a virus, which seems to encourage a strong immune response despite the cancer’s lower mutational burden.

In contrast, the most common type of colorectal cancer has moderate mutational burden, yet responds poorly to checkpoint inhibitors for reasons that are still unclear. Yarchoan notes that these findings could help guide clinical trials to test checkpoint inhibitors on cancer types for which these drugs haven’t yet been tried. Future studies might also focus on finding ways to prompt cancers with low mutational burdens to behave like those with higher mutational burdens so that they will respond better to these therapies. He and his colleagues plan to extend this line of research by investigating whether mutational burden might be a good predictor of whether cancers in individual patients might respond well to this class of immunotherapy drugs.

€œThe end goal is precision medicine—moving beyond what’s true for big groups of patients to see whether we can use this information to help any given patient,” he says. Yarchoan receives funding from the Norman &. Ruth Rales Foundation and the Conquer Cancer Foundation. Through a licensing agreement with Aduro Biotech, Jaffee has the potential to receive royalties in the future..

Credit. IStock Share Fast Facts New @HopkinsMedicine study finds African-American women with common form of hair loss at increased risk of uterine fibroids - Click to Tweet New study in @JAMADerm shows most common form of alopecia (hair loss) in African-American women associated with higher risks of uterine fibroids - Click to Tweet In a study of medical records gathered on hundreds of thousands of African-American women, Johns Hopkins researchers say they have evidence that women with a common form of hair loss have an increased chance of developing uterine leiomyomas, or fibroids.In a report on the research, published in the December 27 issue of JAMA Dermatology, the researchers call on physicians who treat women with central centrifugal cicatricial alopecia (CCCA) to make patients aware that they may be at increased risk for fibroids and should be screened for the condition, particularly if they have symptoms such as heavy bleeding and pain. CCCA predominantly affects black women and is the most common form of permanent alopecia in this population. The excess scar tissue that forms as a result of this type of hair loss may also explain the higher risk for uterine fibroids, which are characterized by fibrous growths in the lining of the womb. Crystal Aguh, M.D., assistant professor of dermatology at the Johns Hopkins University School of Medicine, says the scarring associated with CCCA is similar to the scarring associated with excess fibrous tissue elsewhere in the body, a situation that may explain why women with this type of hair loss are at a higher risk for fibroids.People of African descent, she notes, are more prone to develop other disorders of abnormal scarring, termed fibroproliferative disorders, such as keloids (a type of raised scar after trauma), scleroderma (an autoimmune disorder marked by thickening of the skin as well as internal organs), some types of lupus and clogged arteries.

During a four-year period from 2013-2017, the researchers analyzed patient data from the Johns Hopkins electronic medical record system (Epic) of 487,104 black women ages 18 and over. The prevalence of those with fibroids was compared in patients with and without CCCA. Overall, the researchers found that 13.9 percent of women with CCCA also had a history of uterine fibroids compared to only 3.3 percent of black women without the condition. In absolute numbers, out of the 486,000 women who were reviewed, 16,212 had fibroids.Within that population, 447 had CCCA, of which 62 had fibroids. The findings translate to a fivefold increased risk of uterine fibroids in women with CCCA, compared to age, sex and race matched controls.

Aguh cautions that their study does not suggest any cause and effect relationship, or prove a common cause for both conditions. €œThe cause of the link between the two conditions remains unclear,” she says. However, the association was strong enough, she adds, to recommend that physicians and patients be made aware of it. Women with this type of scarring alopecia should be screened not only for fibroids, but also for other disorders associated with excess fibrous tissue, Aguh says. An estimated 70 percent of white women and between 80 and 90 percent of African-American women will develop fibroids by age 50, according to the NIH, and while CCCA is likely underdiagnosed, some estimates report a prevalence of rates as high as 17 percent of black women having this condition.

The other authors on this paper were Ginette A. Okoye, M.D. Of Johns Hopkins and Yemisi Dina of Meharry Medical College.Credit. The New England Journal of Medicine Share Fast Facts This study clears up how big an effect the mutational burden has on outcomes to immune checkpoint inhibitors across many different cancer types. - Click to Tweet The number of mutations in a tumor’s DNA is a good predictor of whether it will respond to a class of cancer immunotherapy drugs known as checkpoint inhibitors.

- Click to Tweet The “mutational burden,” or the number of mutations present in a tumor’s DNA, is a good predictor of whether that cancer type will respond to a class of cancer immunotherapy drugs known as checkpoint inhibitors, a new study led by Johns Hopkins Kimmel Cancer Center researchers shows. The finding, published in the Dec. 21 New England Journal of Medicine, could be used to guide future clinical trials for these drugs. Checkpoint inhibitors are a relatively new class of drug that helps the immune system recognize cancer by interfering with mechanisms cancer cells use to hide from immune cells. As a result, the drugs cause the immune system to fight cancer in the same way that it would fight an infection.

These medicines have had remarkable success in treating some types of cancers that historically have had poor prognoses, such as advanced melanoma and lung cancer. However, these therapies have had little effect on other deadly cancer types, such as pancreatic cancer and glioblastoma. The mutational burden of certain tumor types has previously been proposed as an explanation for why certain cancers respond better than others to immune checkpoint inhibitors says study leader Mark Yarchoan, M.D., chief medical oncology fellow. Work by Dung Le, M.D., associate professor of oncology, and other researchers at the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Cancer Institute for Cancer Immunotherapy showed that colon cancers that carry a high number of mutations are more likely to respond to checkpoint inhibitors than those that have fewer mutations. However, exactly how big an effect the mutational burden has on outcomes to immune checkpoint inhibitors across many different cancer types was unclear.

To investigate this question, Yarchoan and colleagues Alexander Hopkins, Ph.D., research fellow, and Elizabeth Jaffee, M.D., co-director of the Skip Viragh Center for Pancreas Cancer Clinical Research and Patient Care and associate director of the Bloomberg~Kimmel Institute, combed the medical literature for the results of clinical trials using checkpoint inhibitors on various different types of cancer. They combined these findings with data on the mutational burden of thousands of tumor samples from patients with different tumor types. Analyzing 27 different cancer types for which both pieces of information were available, the researchers found a strong correlation. The higher a cancer type’s mutational burden tends to be, the more likely it is to respond to checkpoint inhibitors. More than half of the differences in how well cancers responded to immune checkpoint inhibitors could be explained by the mutational burden of that cancer.

€œThe idea that a tumor type with more mutations might be easier to treat than one with fewer sounds a little counterintuitive. It’s one of those things that doesn’t sound right when you hear it,” says Hopkins. €œBut with immunotherapy, the more mutations you have, the more chances the immune system has to recognize the tumor.” Although this finding held true for the vast majority of cancer types they studied, there were some outliers in their analysis, says Yarchoan. For example, Merkel cell cancer, a rare and highly aggressive skin cancer, tends to have a moderate number of mutations yet responds extremely well to checkpoint inhibitors. However, he explains, this cancer type is often caused by a virus, which seems to encourage a strong immune response despite the cancer’s lower mutational burden.

In contrast, the most common type of colorectal cancer has moderate mutational burden, yet responds poorly to checkpoint inhibitors for reasons that are still unclear. Yarchoan notes that these findings could help guide clinical trials to test checkpoint inhibitors on cancer types for which these drugs haven’t yet been tried. Future studies might also focus on finding ways to prompt cancers with low mutational burdens to behave like those with higher mutational burdens so that they will respond better to these therapies. He and his colleagues plan to extend this line of research by investigating whether mutational burden might be a good predictor of whether cancers in individual patients might respond well to this class of immunotherapy drugs. €œThe end goal is precision medicine—moving beyond what’s true for big groups of patients to see whether we can use this information to help any given patient,” he says.

Yarchoan receives funding from the Norman &. Ruth Rales Foundation and the Conquer Cancer Foundation. Through a licensing agreement with Aduro Biotech, Jaffee has the potential to receive royalties in the future..

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Lauren Gambill, MDPediatrician, AustinMember, Texas Medical Association (TMA) Committee on Child and Adolescent HealthExecutive Board Member, how to get floxin over the counter Texas Pediatric SocietyDoctors are community leaders. This role has become even more important during the COVID-19 pandemic. As patients how to get floxin over the counter navigate our new reality, they are looking to us to determine what is safe, how to protect their families, and the future of their health care.

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

Census. The deadline has how to get floxin over the counter been cut short one month and now closes Sept. 30.COVID-19 has only increased the importance of completing the census to help our local communities and economies recover.

The novel coronavirus has inflicted unprecedented strain on patients and exacerbated inequality as more people are out of work and are many in need of help with food, health care, housing, and more. Schools also have been stretched thin, with teachers scrambling to teach students how to get floxin over the counter online. Yet, the amount of federal funding Texas has available today to help weather this emergency was driven in part by the census responses made a decade ago.

Getting an accurate count in 2020 will help Texans prepare for the decade to follow, the first few years of which most certainly will be spent rebuilding from the pandemic’s fallout. Therefore, it is vital that all Texans be counted.The federal how to get floxin over the counter dollars Texas receives generally depends on our population. A George Washington University study recently found that even a 1% undercount can lead to a $300 million loss in funding.Take Medicaid, for example.

Federal funds how to get floxin over the counter pay for 60% of the state’s program, which provides health coverage for two out of five Texas children, one in three individuals with disabilities, and 53% of all births. The complicated formula used to calculate the federal portion of this funding depends on accurate census data. If Texas’ population is undercounted, Texans may appear better off financially than they really are, resulting in Texas getting fewer federal Medicaid dollars.

If that happens, lawmakers will have to make up the difference, with cuts in services, program eligibility, or physician and provider payments, any of which are potentially detrimental.The census data also is key to funding other aspects of a community’s social safety net:Health careThe Children’s Health Insurance Program (CHIP) provides low-cost health insurance to children whose parents make too much to qualify for Medicaid, but how to get floxin over the counter not enough to afford quality coverage. Like Medicaid, how much money the federal government reimburses the state for the program depends in part on the census.Maternal and child health programs that promote public health and help ensure children are vaccinated relies on data from the census. Texas also uses this federal funding to study and respond to maternal mortality and perinatal depression.Food and how to get floxin over the counter housing As unemployment rises and families struggle financially, many live with uncertainty as to where they will find their next meal.

Already, one in seven Texans experiences food insecurity, and 20% of Texas children experience hunger. Food insecurity is rising in Texas as the pandemic continues. The Central how to get floxin over the counter Texas Food Bank saw a 206% rise in clients in March.

Funding for the Supplemental Nutrition Assistance Program and school lunch programs are both determined by the census. Funding for local housing programs also is calculated via the census. An accurate count will help ensure that people who lose their homes during this economic how to get floxin over the counter crisis have better hope of finding shelter while our communities recover.

Homelessness is closely connected with declines in overall physical and mental health.Childcare and educationAs we navigate the new reality brought on by coronavirus, more parents are taking on roles as breadwinner, parent, teacher, and caretaker. This stress how to get floxin over the counter highlights the desperate need for affordable childcare. The census determines funding for programs like Head Start that provide comprehensive early childhood education to low-income families.

The good news is you still have time to complete the census. Visit 2020census.gov how to get floxin over the counter to take it. It takes less than five minutes to complete.

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

UTHSA medical students Swetha Maddipudi, Brittany Hansen, Charles Wang, Carson Cortino, faculty advisor how to get floxin over the counter Kaparaboyna Kumar, MD, Ryan Wealther, Sidney Akabogu, Irma Ruiz, and Frank Jung pose with the TMA Be Wise Immunize banner. Photo courtesy by Ryan WealtherRyan WealtherMedical Student, UT Health San Antonio Long School of MedicineStudent Member, Texas Medical AssociationEditor’s Note. August is National Immunization Awareness Month.

This article is part of a Me&My Doctor series highlighting and promoting how to get floxin over the counter the use of vaccinations.“Can the flu shot give you the flu?. €â€œIs it dangerous for pregnant women to get a flu shot?. €â€œCan vaccines cause autism? how to get floxin over the counter.

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

Our program consisted of a vaccination drive and an interactive, educational presentation that addressed influenza, common flu shot questions, and general vaccine myths. The Alpha Home residents could ask us questions during the program.We were interested to see if our educational program could answer Alpha how to get floxin over the counter Home residents’ questions about vaccinations and allay their hesitations about getting a flu vaccination. To gauge this, we created a brief survey.(Before I discuss the results of the survey, I should define vaccine hesitancy.

Vaccine hesitancy is a concept defined by the World Health Organization. It relates to when patients do not vaccinate how to get floxin over the counter despite having access to vaccines. Vaccine hesitancy is a problem because it prevents individuals from receiving their vaccinations.

That makes them more susceptible to getting sick from vaccine-preventable diseases.)We surveyed the residents’ opinions about vaccinations before and after our educational program. While opinions about shots improved with each survey question, we saw how to get floxin over the counter the most significant attitude change reflected in answers to the questions “I am concerned that vaccinations might not be safe,” and “How likely are you to receive a flu shot today?. € We had informed the residents and improved their understanding and acceptance of immunizations.Post-survey results show more residents at the Alpha Home shifted to more positive attitudes about vaccines, after learning more about their effectiveness by trusted members of the medical community.

Graph by Ryan WealtherWhy is this how to get floxin over the counter important?. First, our findings confirm what we already knew. Education by a trusted member of the medical community can effect change.

In fact, it is widely known that physician recommendation of vaccination how to get floxin over the counter is one of the most critical factors affecting whether patients receive an influenza vaccination. Perhaps some added proof to this is that a few of the Alpha Home residents were calling me “Dr. Truth” by how to get floxin over the counter the end of the evening.Second, our findings add to our understanding of adult vaccine hesitancy.

This is significant because most of what we know about vaccine hesitancy is limited to parental attitudes toward their children’s vaccinations. Some parents question shots for their children, and many of the most deadly diseases we vaccinate against are given in childhood, including polio, tetanus, measles, and whooping cough shots. However, adults how to get floxin over the counter need some vaccinations as well, like the yearly influenza vaccine.

After taking part in the UTHSA educational program, more residents at the Alpha Home shared more willingness to receive the flu vaccine. Graph by Ryan WealtherAnother reason improving attitudes is important is that receiving a flu shot is even more timely during the COVID-19 pandemic because it decreases illnesses and conserves health care resources. Thousands of people how to get floxin over the counter each year are hospitalized from the flu, and with hospitals filling up with coronavirus patients, we could avoid adding dangerously ill flu patients to the mix.

Lastly, these findings are important because once a COVID-19 vaccination becomes available, more people might be willing to receive it if their overall attitude toward immunizations is positive. Though the COVID-19 vaccine is still in how to get floxin over the counter development, it is not immune to vaccine hesitancy. Recent polls have indicated up to one-third of Americans would not receive a COVID-19 vaccine even if it were accessible and affordable.

Work is already being done to try to raise awareness and acceptance. In addition, misinformation about the COVID vaccine how to get floxin over the counter is circulating widely. (Someone recently asked me if the COVID vaccine will implant a microchip in people, and I have seen the same myth circulating on social media.

It will not.) This myth, how to get floxin over the counter however, illustrates the need for health care professionals to answer patients’ questions and to assuage their concerns.Vaccines work best when many people in a community receive them, and vaccine hesitancy can diminish vaccination rates, leaving people who can't get certain vaccines susceptible to these vaccine-preventable diseases. For example, babies under 6 months of age should not receive a flu shot, so high community vaccination rates protect these babies from getting sick with the flu. Our educational program at Alpha Home is just one example of how health care professionals can increase awareness and acceptance of shots.

As the COVID-19 pandemic progresses, we need to ensure children and adults receive their vaccinations as recommended by their physician how to get floxin over the counter and the Centers for Disease Control and Prevention. I encourage readers who have questions about the vaccinations they or their child may need to talk with their physician. As health care professionals, we’re more than happy to answer your questions..

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Date published buy generic floxin. October 7, 2020On this page OverviewAs the global COVID-19 pandemic emerged in December 2019, the need for coherent, pan-Canadian guidance on provincial and territorial testing was quickly recognized. Led by the National Microbiology Laboratory, initial interim guidance on laboratory testing was developed in consultation with the Canadian Public Health Lab Network and was finalized and approved by the Special Advisory Committee on April 16, 2020. This guidance was based on scientific evidence and testing resources available buy generic floxin at that time.

The recommended testing guidance focused on the molecular polymerase chain reaction (PCR) as the sole laboratory technique to accurately identify SARS-CoV-2 in a patient sample.In May 2020, based on new evidence, the National Laboratory Testing Indication Guidance for COVID-19 was updated to reflect developments in four areas. Expanded laboratory resources viral transmission from asymptomatic individuals or individuals in the pre-symptomatic phase outbreaks in congregate living and work settings new testing modalities (molecular Point of Care and serological tests)The COVID-19 landscape has further evolved and it is now necessary to update key aspects of this document to reflect recent scientific and public health data. One key consideration relates to limiting buy generic floxin asymptomatic diagnostic PCR testing where public health action could have significant benefits. Several pilot programs were conducted in Canada, confirming very low levels of COVID-19 in the general population and supporting an evidence-based approach to the relaunch of economic activity.

In addition, it enabled jurisdictions to stress-test testing capacity and prepare jurisdictions for higher testing volumes. Asymptomatic testing was buy generic floxin also found to displace diagnostic capacity for symptomatic individuals, close contacts, high-risk settings and outbreak management. The National Laboratory Testing Indication Guidancefor COVID-19 has been updated to reflect these learnings and advances in science.Recognizing that testing regimes are within provincial and territorial jurisdiction, this document reflects the collaboration among jurisdictions, leveraging learnings from one another through the different adopted approaches.Emerging testing and screening technologiesThe Pan-Canadian COVID-19 Testing and Screening Guidance is designed to reflect changing risk management approaches as the pandemic conditions change. Recognizing that one size does not fit all, the Guidance is also designed to respond to a significant increase in the need to access testing and screening technologies.

Scaling to meet increased and sustained testing buy generic floxin and screening demand will require a paradigm shift, broadening the technologies that are used in a manner that is tailored to the purpose and application of technologies in a variety of settings. Although PCR remains the gold standard in diagnostic testing, numerous technologies and testing modalities are emerging that could serve to supplement diagnostic testing. These recent testing and sampling options could create opportunities to expand the approach to testing by including broad-based approaches to screening through less sensitive and potentially more cost-effective technologies, thereby alleviating strain on the overall public health system.While they can be less sensitive, these technologies could have multiple benefits including ease and reduced cost of production, improved efficiency and reduced reliance on PCR testing supplies. They also have the potential to be less invasive depending on the buy generic floxin technology.

Antigen and extraction-free nucleic acid testing are examples of such technologies that, in addition to being more cost-effective and easier to produce, are also easily adaptable to mobile, rapid applications. However, due to their lower sensitivity than current PCR technology, these emerging technologies may be better used as a part of screening, in conjunction with repeated testing in some settings. Recognizing that these novel technologies have lower buy generic floxin sensitivity and specificity than current PCR technology, their use should be targeted to scenarios where both positive and negative are interpreted and acted upon appropriately.Complementing the deployment of these emerging technologies, techniques such as pooled testing are being used to contribute to the preservation of testing resources. Governments are also tapping non-traditional data sources to complement case data.

For example, data for wastewater testing could complement COVID-19 surveillance systems by providing readily accessible pooled community samples and data for communities where testing is not available or underutilized.As of September 29, Health Canada has authorized 36 COVID-19 testing devices (PCR and serological). Health Canada is fast-tracking the review of submissions related to antigen and nucleic acid buy generic floxin tests. Submissions that are reviewed include various sample types, including saliva. Consult the list of authorized medical devices for uses related to COVID-19.In anticipation of regulatory approval for antigen tests, an Interim Guidance on Antigen Testing has been developed to outline potential scenarios such as routine outbreak monitoring, monitoring in different situations including high-risk settings (for example, long-term care facilities) and possible adaptation into mobile, rapid testing in rural and remote communities.Pan-Canadian COVID-19 Testing and Screening GuidanceLike the Laboratory Testing Guidance, the Pan-Canadian COVID-19 Testing and Screening Guidance (“Guidance”) is based on new public health evidence and emerging technologies, while adopting a broadened approach that leverages and tailors technologies to appropriate uses.

The Guidance is designed to protect and expand buy generic floxin the resilience of federal, provincial and territorial testing and screening capacity.The Guidance is based on a portfolio approach that uses different types of testing technologies for various purposes (diagnostic, screening, surveillance). The intent of the Guidance is to better use testing resources to target the most relevant test in particular situations or use cases to address specific problems or purposes. Figure 1. Technology streams of Pan-Canadian COVID-19 Testing buy generic floxin and Screening Guidance Figure 1.

Technology streams of Pan-Canadian COVID-19 Testing and Screening Guidance - Text equivalent Testing. Definitive diagnosis of COVID-19 with high sensitivity PCR-based tests, with potential refinements to specimen collecting modalities (for example, saliva) Less amenable to high frequency conduct due to greater resource utilization Screening. Indicative of COVID-19 status, with lower sensitivity Typically newer, rapid technology approaches Amenable to higher frequency repetition and more easily scalable Surveillance buy generic floxin. Use of traditional and non-traditional data sources to complement case data Wastewater surveillance complements conventional COVID-19 surveillance systems by providing.

efficient pooled community sample data for communities where timely clinical testing is underutilized or unavailable data at the local level Five key foundational, interrelated pillars support the advancement of the Guidance. Scientific integrity regulatory excellence proactive procurement robust data and capacity strategic communication and partnershipsUpdates to laboratory testing and buy generic floxin antigen testing guidance founded on rigorous scientific integrity enable and inform decision-making on testing allocations within Canada, and support jurisdictions in the timely use of emerging technologies once regulatory approval is received. Regulatory excellence is equally important as a foundational pillar to implementing the Guidance in a manner that allows for rapid approvals while still preserving the scientific integrity of the process.In addition, undertaking a proactive procurement approach ensures steady access to equipment and supplies for testing and screening. Governments continue to take a proactive procurement approach, purchasing whenever possible, contingent on regulatory approvals.Timely and comprehensive data is critical, underpinning decision-making by governments.

Governments have established a new data set for buy generic floxin COVID-19 cases that provides more targeted information, improving the ability to understand whether infections are acquired via domestic or international travel, or if they are linked to a known outbreak. Race and ethnicity indicators have been added as well as greater information on health care workers, allowing a better understanding of the COVID-19 experience among different population groups. In addition to the case data, key data on turnaround times for testing and contact tracing, for example, can also help identify issues related to capacity and timeliness of interventions.Finally, in addition to strong federal, provincial and territorial partnerships, relationships are being further enhanced with key partners in industry and the scientific community. While ensuring rapid and effective progress buy generic floxin is critical, it is also important to communicate what we know, what we are doing and what we are going to do.

This collaboration and transparency supports critical decisions, including what additional capacity may be required as part of the Guidance, for instance, federal surge capacity to supplement provincial and territorial leadership. Strategic communications and partnerships are critical to maintaining and strengthening the confidence of Canadians in Governments' actions to address COVID-19. Implementation plan of the Pan-Canadian COVID-19 buy generic floxin Testing and Screening Guidance. Updated Guidance Scientific integrity Regulatory excellence Proactive procurement Robust data and capacity Strategic communications and partnerships Regularly updated public health advice as science evolves Updated national lab testing indication guidance Interim antigen testing guidance Guidance on sample types Prioritized, timely review of emerging and promising technologies Responsive to testing, screening and surveillance developments Founded in and driven by scientific excellence Linking regulatory pipeline with production capacity Prioritizing made in Canada solutions Advance purchasing of promising technologies Surge capacity through full value chain and timely, comprehensive data Improving national performance data (turnaround times) Surge capacity for sample collection, lab testing contact tracing Working closely with key partners FPT.

Enables agile responses to emerging issues Industry. Linking public health and workforce requirements Tapping emerging tech Public education/understanding Looking forwardThe Guidance is expected to evolve as the state of knowledge and risk management strategies continue to develop. Guidance on sample types is expected to be finalized during the fall and the balance of testing and screening technologies will be adjusted to respond to the needs of various populations. Researchers and companies continue to innovate and develop new technologies and solutions.

Guidance will need to keep pace with, and take advantage of, these innovations. The continuous updating of this Guidance will rely on strong federal, provincial and territorial partnerships and collaboration leveraging key governance bodies, including the Special Advisory Committee. The Guidance will also capitalize on opportunities to leverage input and the capacity to mobilize knowledge in Canada and from around the world.Related links.

Date published how to get floxin over the counter. October 7, 2020On this page OverviewAs the global COVID-19 pandemic emerged in December 2019, the need for coherent, pan-Canadian guidance on provincial and territorial testing was quickly recognized. Led by the National Microbiology Laboratory, initial interim guidance on laboratory testing was developed in consultation with the Canadian Public Health Lab Network and was finalized and approved by the Special Advisory Committee on April 16, 2020.

This guidance was based on scientific evidence and testing resources available at that how to get floxin over the counter time. The recommended testing guidance focused on the molecular polymerase chain reaction (PCR) as the sole laboratory technique to accurately identify SARS-CoV-2 in a patient sample.In May 2020, based on new evidence, the National Laboratory Testing Indication Guidance for COVID-19 was updated to reflect developments in four areas. Expanded laboratory resources viral transmission from asymptomatic individuals or individuals in the pre-symptomatic phase outbreaks in congregate living and work settings new testing modalities (molecular Point of Care and serological tests)The COVID-19 landscape has further evolved and it is now necessary to update key aspects of this document to reflect recent scientific and public health data.

One key consideration relates to limiting how to get floxin over the counter asymptomatic diagnostic PCR testing where public health action could have significant benefits. Several pilot programs were conducted in Canada, confirming very low levels of COVID-19 in the general population and supporting an evidence-based approach to the relaunch of economic activity. In addition, it enabled jurisdictions to stress-test testing capacity and prepare jurisdictions for higher testing volumes.

Asymptomatic testing was also found to displace diagnostic capacity how to get floxin over the counter for symptomatic individuals, close contacts, high-risk settings and outbreak management. The National Laboratory Testing Indication Guidancefor COVID-19 has been updated to reflect these learnings and advances in science.Recognizing that testing regimes are within provincial and territorial jurisdiction, this document reflects the collaboration among jurisdictions, leveraging learnings from one another through the different adopted approaches.Emerging testing and screening technologiesThe Pan-Canadian COVID-19 Testing and Screening Guidance is designed to reflect changing risk management approaches as the pandemic conditions change. Recognizing that one size does not fit all, the Guidance is also designed to respond to a significant increase in the need to access testing and screening technologies.

Scaling to meet increased and sustained testing and screening demand will require a paradigm shift, how to get floxin over the counter broadening the technologies that are used in a manner that is tailored to the purpose and application of technologies in a variety of settings. Although PCR remains the gold standard in diagnostic testing, numerous technologies and testing modalities are emerging that could serve to supplement diagnostic testing. These recent testing and sampling options could create opportunities to expand the approach to testing by including broad-based approaches to screening through less sensitive and potentially more cost-effective technologies, thereby alleviating strain on the overall public health system.While they can be less sensitive, these technologies could have multiple benefits including ease and reduced cost of production, improved efficiency and reduced reliance on PCR testing supplies.

They also have the potential to be less invasive depending how to get floxin over the counter on the technology. Antigen and extraction-free nucleic acid testing are examples of such technologies that, in addition to being more cost-effective and easier to produce, are also easily adaptable to mobile, rapid applications. However, due to their lower sensitivity than current PCR technology, these emerging technologies may be better used as a part of screening, in conjunction with repeated testing in some settings.

Recognizing that these novel technologies have lower sensitivity and specificity than current PCR technology, their use should be targeted to scenarios where both positive and negative are interpreted and acted upon appropriately.Complementing the deployment of these emerging technologies, techniques such as pooled testing are being used to how to get floxin over the counter contribute to the preservation of testing resources. Governments are also tapping non-traditional data sources to complement case data. For example, data for wastewater testing could complement COVID-19 surveillance systems by providing readily accessible pooled community samples and data for communities where testing is not available or underutilized.As of September 29, Health Canada has authorized 36 COVID-19 testing devices (PCR and serological).

Health Canada is fast-tracking how to get floxin over the counter the review of submissions related to antigen and nucleic acid tests. Submissions that are reviewed include various sample types, including saliva. Consult the list of authorized medical devices for uses related to COVID-19.In anticipation of regulatory approval for antigen tests, an Interim Guidance on Antigen Testing has been developed to outline potential scenarios such as routine outbreak monitoring, monitoring in different situations including high-risk settings (for example, long-term care facilities) and possible adaptation into mobile, rapid testing in rural and remote communities.Pan-Canadian COVID-19 Testing and Screening GuidanceLike the Laboratory Testing Guidance, the Pan-Canadian COVID-19 Testing and Screening Guidance (“Guidance”) is based on new public health evidence and emerging technologies, while adopting a broadened approach that leverages and tailors technologies to appropriate uses.

The Guidance is designed to protect and expand the resilience of federal, provincial and territorial testing and screening capacity.The Guidance is based on a portfolio approach that uses different types of testing technologies for various purposes (diagnostic, how to get floxin over the counter screening, surveillance). The intent of the Guidance is to better use testing resources to target the most relevant test in particular situations or use cases to address specific problems or purposes. Figure 1.

Technology streams how to get floxin over the counter of Pan-Canadian COVID-19 Testing and Screening Guidance Figure 1. Technology streams of Pan-Canadian COVID-19 Testing and Screening Guidance - Text equivalent Testing. Definitive diagnosis of COVID-19 with high sensitivity PCR-based tests, with potential refinements to specimen collecting modalities (for example, saliva) Less amenable to high frequency conduct due to greater resource utilization Screening.

Indicative of COVID-19 status, with lower sensitivity Typically newer, rapid technology approaches Amenable to higher frequency repetition and how to get floxin over the counter more easily scalable Surveillance. Use of traditional and non-traditional data sources to complement case data Wastewater surveillance complements conventional COVID-19 surveillance systems by providing. efficient pooled community sample data for communities where timely clinical testing is underutilized or unavailable data at the local level Five key foundational, interrelated pillars support the advancement of the Guidance.

Scientific integrity regulatory excellence proactive procurement robust data and capacity strategic communication and partnershipsUpdates to laboratory how to get floxin over the counter testing and antigen testing guidance founded on rigorous scientific integrity enable and inform decision-making on testing allocations within Canada, and support jurisdictions in the timely use of emerging technologies once regulatory approval is received. Regulatory excellence is equally important as a foundational pillar to implementing the Guidance in a manner that allows for rapid approvals while still preserving the scientific integrity of the process.In addition, undertaking a proactive procurement approach ensures steady access to equipment and supplies for testing and screening. Governments continue to take a proactive procurement approach, purchasing whenever possible, contingent on regulatory approvals.Timely and comprehensive data is critical, underpinning decision-making by governments.

Governments have established a new data set for COVID-19 cases that provides more targeted information, improving the ability to understand whether infections are acquired how to get floxin over the counter via domestic or international travel, or if they are linked to a known outbreak. Race and ethnicity indicators have been added as well as greater information on health care workers, allowing a better understanding of the COVID-19 experience among different population groups. In addition to the case data, key data on turnaround times for testing and contact tracing, for example, can also help identify issues related to capacity and timeliness of interventions.Finally, in addition to strong federal, provincial and territorial partnerships, relationships are being further enhanced with key partners in industry and the scientific community.

While ensuring rapid and effective progress is critical, it is also important to communicate what we know, what we are doing and what we how to get floxin over the counter are going to do. This collaboration and transparency supports critical decisions, including what additional capacity may be required as part of the Guidance, for instance, federal surge capacity to supplement provincial and territorial leadership. Strategic communications and partnerships are critical to maintaining and strengthening the confidence of Canadians in Governments' actions to address COVID-19.

Implementation plan of the Pan-Canadian COVID-19 Testing and Screening Guidance how to get floxin over the counter. Updated Guidance Scientific integrity Regulatory excellence Proactive procurement Robust data and capacity Strategic communications and partnerships Regularly updated public health advice as science evolves Updated national lab testing indication guidance Interim antigen testing guidance Guidance on sample types Prioritized, timely review of emerging and promising technologies Responsive to testing, screening and surveillance developments Founded in and driven by scientific excellence Linking regulatory pipeline with production capacity Prioritizing made in Canada solutions Advance purchasing of promising technologies Surge capacity through full value chain and timely, comprehensive data Improving national performance data (turnaround times) Surge capacity for sample collection, lab testing contact tracing Working closely with key partners FPT. Enables agile responses to emerging issues Industry.

Linking public health and workforce requirements Tapping emerging tech Public education/understanding Looking how to get floxin over the counter forwardThe Guidance is expected to evolve as the state of knowledge and risk management strategies continue to develop. Guidance on sample types is expected to be finalized during the fall and the balance of testing and screening technologies will be adjusted to respond to the needs of various populations. Researchers and companies continue to innovate and develop new technologies and solutions.

Guidance will how to get floxin over the counter need to keep pace with, and take advantage of, these innovations. The continuous updating of this Guidance will rely on strong federal, provincial and territorial partnerships and collaboration leveraging key governance bodies, including the Special Advisory Committee. The Guidance will also capitalize on opportunities to leverage input and the capacity to mobilize knowledge in Canada and from around the world.Related links.

Can you buy over the counter floxin

GREAT FALLS, can you buy over the counter floxin Mont. €” For months, the jail in central Montana’s Cascade County was free of the coronavirus, which seemed as distant a threat as it did in much of the nation’s rural Mountain West.Then a few people who had the virus were arrested. By the time Paul Krogue, the jail’s medical director, can you buy over the counter floxin realized there was a problem, nearly 50 inmates were infected in the jail, where some had been sleeping on mats on an overcrowded floor.

After several weeks, Mr. Krogue got a call that infections were spreading to a side of the jail that had been virus-free.He hung up the phone and put his head in his hands.“I just can you buy over the counter floxin kind of lost it, like, ‘My God, I don’t know how much longer I can do this,’” Mr. Krogue, a nurse practitioner, recalled.

€œI was just scared that I’m not going to be able to see it through, that I’m going to get sick — you just feel so exhausted and it’s just a lot.”The Mountain West, which for months avoided the worst of the pandemic, has rapidly devolved into one of the most alarming hot spots in a country that recorded its eight millionth confirmed case on Thursday, a day when more than 65,000 cases were announced nationwide, the most in a single day since July.Seventeen states, including many in the Mountain West, have added more cases in the past week than any other week of the pandemic. And the spread through sparsely populated areas of rural America has created problems in small towns that lack critical resources — including doctors — even in ordinary times.Wyoming, which did not have 1,000 total cases until June, recently added more than 1,000 in a can you buy over the counter floxin single week. Reports of new infections have recently reached record levels in Alaska, Colorado and Idaho.

And Montana, where more than half of the state’s cases have been announced since August, is averaging more than 500 cases per day.In Cascade County, more than 300 inmates and staff members have been infected in a facility meant to hold 365 people, the county’s first major outbreak in a region where the virus is suddenly surging.The county can you buy over the counter floxin seat, Great Falls, is seeing its worst case numbers yet. The local hospital and its 27-bed Covid-19 unit is at capacity. The county health department is racing to hire new contact tracers.

And Mr can you buy over the counter floxin. Krogue, who also teaches nursing at Montana State University’s Great Falls campus, has seen attendance in his classes dwindle as students fall ill or quarantine.“I was just scared that I’m not going to be able to see it through, that I’m going to get sick,” said Paul Krogue, the jail’s medical director.Credit...Tailyr Irvine for The New York TimesOne place where the infections have spread has been local jails, which are confined, often crowded spaces. Jails are staples of local communities and tend to have people coming can you buy over the counter floxin and going more quickly than prisons.

Jails can hold everyone from people awaiting criminal trials for months to those picked up for a suspended driver’s license for a few hours. With so many people filtering in and out, jails pose can you buy over the counter floxin extra risks for the virus’s spread — not only inside facilities but in potentially feeding outbreaks in the rest of the community.Nationally, jails and prisons have seen disproportionate rates of infection and death, with a mortality rate twice as high as in the general population and an infection rate more than four times as high, according to recent data.A New York Times database has tracked clusters of at least 50 coronavirus cases in a dozen rural jails in Montana, Idaho, Utah and New Mexico during the pandemic. Among them.

The Purgatory Correctional Center in Hurricane, Utah, with 166 infections. The jail in can you buy over the counter floxin Twin Falls, Idaho, with 279. And, in New Mexico, the Cibola County Correctional Center, which has reported 357 cases.In Cascade County, infections at the jail make up about a quarter of all known virus cases in the county.

Health authorities say that the jail’s outbreak, which began in mid-August, was not believed to be the main cause can you buy over the counter floxin of the community’s recent surge, but that it had led to some cases. In the past two months, Mr. Krogue said, the jail released 29 people who were considered actively infected.Infections at the jail make up about a quarter of Cascade County’s known virus cases.Credit...Tailyr Irvine for The New York TimesGreat Falls, home to about 58,000 residents, is in the less mountainous part of Montana, with the Missouri River flowing through and a large oil refinery on its banks.

The Cascade County Detention Center sits along a highway at the edge of can you buy over the counter floxin town. Drive five miles in any direction and you are surrounded by wide-open plains.Montana requires that masks be worn inside businesses and indoor public spaces, and many people in Great Falls wear them when walking around downtown’s Central Avenue, where shops and cafes are still recovering from shutting down in the spring. Others go without masks, citing the open space and lack of can you buy over the counter floxin crowds.Bob Kelly, the mayor, said people had not been overly worried about how the jail outbreak might affect the rest of town when it started.“I think that by the very definition of a jail, hopefully, the disease will be incarcerated, as well as the patients,” he said.

€œIs there concern?. Sure, can you buy over the counter floxin there’s concern. But is there overreaction?.

No.”The mayor of Great Falls said that residents had considered the jail’s outbreak a distant concern at first.Credit...Tailyr Irvine for The New York TimesSome residents’ nonchalance about the risks of the virus, said Mr. Krogue, the jail’s medical director, can be traced can you buy over the counter floxin to a spring and early summer when almost no one in Cascade County knew anyone who had been sickened.“We benefited from that early on,” he said. €œBut in some ways, I think it did us a disservice, too, because it also created a certain level of complacency.”That has quickly shifted now, he said, as cases have spiked.The number of active cases known to county officials on any given day has risen sharply to about 600, according to Trisha Gardner, Cascade County’s health officer.

The county has seen 1,261 cases and six can you buy over the counter floxin deaths during the pandemic, a Times database shows. Some of the cases have been tied to the jail outbreak, she said, and others have been connected to bars and restaurants. Even figuring out what has led to some cases has been complex, she said, as residents have been reluctant to cooperate with contact tracers.“Our hospitals are at capacity, our public health system is at capacity,” she said.

€œIt’s not sustainable at this rate.”When the outbreak at the jail began, social distancing was impossible, the authorities can you buy over the counter floxin said. Three inmates shared cells designed for two. At night, men slept on thin blue can you buy over the counter floxin pads in every available space.

On the floor in the day room, in shower stalls, in stairwells, in hallways outside of cells.Inmates did not receive masks until August, and jail officials said many have refused to wear them.In interviews with more than a dozen inmates and their family members, inmates described the jail during the outbreak as chaotic and unsanitary. They said their pleas for help often went unanswered by nurses and guards.Newly arriving inmates were not always quarantined from one another before their test results were known because of a lack of space, inmates and jail officials said.Owen Hawley, 30, said every inmate in his living area of 38 men had tested positive for the virus. He said he had been unable to eat for three days, had intensive body aches and suffered from a headache so powerful it felt as if it was “behind my eyes.”“After the fourth day of like, not eating and stuff, I just can you buy over the counter floxin shut off, you know?.

€ he said.A jail area set aside for quarantining new inmates.Credit...Tailyr Irvine for The New York TimesAt one point, Mr. Hawley said, he and other prisoners protested the way the virus was being handled by refusing to leave their living areas and by blocking new inmates can you buy over the counter floxin from entering. Everyone was ultimately tested, Mr.

Hawley said, and each prisoner was given a disposable mask.Sierra Jasmine Wells, 25, another inmate, said women in her dormitory had grown ill, one after the next.“Everyone around me was getting sick and it was tough on can you buy over the counter floxin me,” she said. €œBy then, I had already accepted the fact that I was going to get sick.”When she became infected, she said, she was given cough syrup and Tylenol.“I kind of was just left alone to deal with it,” she said.Jesse Slaughter, the county sheriff who oversees the jail, said that the jail’s medical staff was doing everything it could, and that he had been seeking health care assistance from other counties. Officials defended their handling of the outbreak, noting that all inmates received standard medications including Tylenol twice a day and were taken to area hospitals when they needed added care.

Seven inmates, as well as can you buy over the counter floxin some staff members, were hospitalized. No one from the jail has died from the virus, officials said.Sheriff Jesse Slaughter, who oversees the jail, said he had been seeking health care assistance from other counties.Credit...Tailyr Irvine for The New York TimesMr. Krogue said that since the start of the outbreak he had been working up to 16 hours each day and sleeping in his can you buy over the counter floxin basement, away from his wife and children.

He remains healthy but says he fears bringing the virus home. The virus has slowed some in the jail, and officials have moved some inmates to other facilities, but other prisons and jails in the state are now seeing outbreaks.“You can start to see what some of these other places experienced much earlier on, and we just didn’t have that experience, but it’s certainly happening now,” Mr. Krogue said can you buy over the counter floxin.

€œIt’s just real in a way that it wasn’t.”Lucy Tompkins reported from Great Falls, Maura Turcotte from Chicago and Libby Seline from Lincoln, Neb. Reporting was contributed by Izzy Colón from Columbia, Mo., Brendon Derr from Phoenix, Rebecca Griesbach from Tuscaloosa, Ala., Danya Issawi and Timothy Williams can you buy over the counter floxin from New York, Ann Hinga Klein from Des Moines, K.B. Mensah from Silver Spring, Md., and Mitch Smith from Chicago.Start Preamble Federal Transit Administration (FTA), DOT.

Notice of funding opportunity can you buy over the counter floxin. The Coronavirus Disease 2019 (COVID-19) public health emergency Start Printed Page 63654has had a significant impact on transit operations. During a series of FTA listening sessions held over the last three months, transit agencies asked FTA to support research to identify solutions to address the operational challenges that they are facing as a result of COVID-19.

In response, FTA makes available through this Notice of Funding Opportunity (NOFO) funding to support research can you buy over the counter floxin demonstration grants to public transit agencies to develop, deploy, and demonstrate innovative solutions that improve the operational efficiency of transit agencies, as well as enhance the mobility of transit users affected by the COVID-19 public health emergency. Demonstration grants under this NOFO are authorized under FTA's Public Transportation Innovation Program (49 U.S.C. 5312).

Eligible projects will demonstrate innovative solutions to improve the operational efficiencies of transit systems and enhance mobility for their communities in four major areas. (1) Vehicle, facility, equipment and infrastructure cleaning and disinfection. (2) exposure mitigation measures.

(3) innovative mobility such as contactless payments. And (4) measures that strengthen public confidence in transit services. The total funding available for awards under this NOFO is $10,000,000.

FTA may supplement this amount if additional funding becomes available. Applicants must submit completed proposals for funding opportunity FTA-2020-015-TRI through the GRANTS.GOV “APPLY” function by 11:59 p.m. Eastern Time on November 2, 2020.

Prospective applicants should register as soon as possible on the GRANTS.GOV website to ensure they can complete the application process before the submission deadline. Application instructions are available on FTA's website at http://transit.dot.gov/​howtoapply and in the “FIND” module of GRANTS.GOV. FTA will not accept mail and fax submissions.

Start Further Info Please send any questions on this notice to Jamel El-Hamri email. Jamel.El-Hamri@dot.gov phone. 2020-366-8985.

A Telecommunication Device for the Deaf (TDD) is available for individuals who are deaf or hard of hearing at 1-800-877-8339. End Further Info End Preamble Start Supplemental Information Table of Contents A. Program Description B.

Federal Award Information C. Eligibility Information D. Application and Submission Information E.

Application Review Information F. Federal Award Administration Information G. Federal Awarding Agency Contact Information A.

Program Description The Public Transportation COVID-19 Research Demonstration Grant Program is funded through the Public Transportation Innovation Program (49 U.S.C. 5312), with the goal to develop, deploy, and demonstrate innovative solutions that improve the operational efficiency of transit agencies, as well as enhance the mobility of transit users affected by the COVID-19 public health emergency. Eligible projects will propose to develop and deploy innovative solutions in four major areas.

(1) Vehicle, facility, equipment and infrastructure cleaning and disinfection. (2) exposure mitigation measures. (3) innovative mobility such as contactless payments.

And (4) measures that strengthen public confidence in transit. As required by 49 U.S.C. 5312(e)(4), projects funded under this NOFO must participate in an evaluation by an independent outside entity that will conduct a comprehensive evaluation of the success or failure of the projects funded under this subsection and any plan for broad-based implementation of the innovation promoted by successful projects.

B. Federal Award Information FTA makes available $10,000,000 in fiscal year (FY) 2020 funds under the Public Transportation Innovation Program (49 U.S.C. 5312) to finance the Public Transportation COVID-19 Research Demonstration Grant Program.

FTA may supplement the total funds available if additional funding becomes available at the time project selections are made. FTA will grant pre-award authority starting on the date of the project award announcement for selected projects and should be completed within 24 months from the date of award. Funds are available only for eligible expenses incurred after the announcement of project selections.

C. Eligibility Information (1) Eligible Applicants Eligible applicants include State and local governmental authorities, direct recipients of Urbanized Area (49 U.S.C. 5307) and Rural Area (49 U.S.C.

5311) formula funds, and Indian tribes. Eligible applicants are limited to FTA grantees or subrecipients who would be the primary beneficiaries of the innovative products and services that are developed—typically public transit agencies. Except for projects proposed by Indian tribes, proposals for projects in rural (non-urbanized) areas must be submitted as part of a consolidated State proposal.

States and other eligible applicants also may submit consolidated proposals for projects in urbanized areas. The submission of the Statewide application will not preclude the submission and consideration of any application from other eligible recipients in an urbanized area in a State. Proposals may contain projects to be implemented by the recipient or its subrecipients.

Eligible subrecipients include public agencies, private nonprofit organizations, and private providers engaged in public transportation. Eligible applicants may submit consolidated proposals for projects. (2) Cost Sharing or Matching The maximum Federal share of project costs is 100 percent.

FTA may give additional consideration to applicants that propose a local share and may view these applicants as more competitive. The applicant must document the source(s) of the local match, if any, in the grant application. For any applicants proposing match, eligible local match sources include the following.

Cash from non-Government sources other than revenues from providing public transportation services. Revenues derived from the sale of advertising and concessions. Revenues generated from value capture financing mechanisms.

Funds from an undistributed cash surplus. Replacement or depreciation cash fund or reserve. New capital.

Or in-kind contributions. (3) Eligible Projects Eligible projects will propose innovative solutions to improve operational efficiencies of transit agencies and enhance the mobility of transit users, through projects that demonstrate innovative solutions for. Vehicle, facility, equipment and infrastructure cleaning and disinfection.

Exposure mitigation measures such a real-time notification of rail and bus passenger loads. New multi-modal payment innovative mobility systems such as contactless payments. And measures that strengthen public confidence in transit.

Each applicant may only submit one proposal.Start Printed Page 63655 D. Application and Submission Information (1) Address and Form of Application Submission Applications must be submitted through GRANTS.GOV. Applicants can find general information for submitting applications through GRANTS.GOV at www.fta.dot.gov/​howtoapply, along with specific instructions for the forms and attachments required for submission.

Mail and fax submissions will not be accepted. (2) Content and Form of Application Submission a. Proposal Submission A complete proposal submission consists of at least two forms.

1. The SF-424 Mandatory Form (downloadable from GRANTS.GOV) and 2. The supplemental form for the FY 2020 COVID-19 Demonstration Program (downloadable from GRANTS.GOV), which is available on FTA's website at (placeholder for FTA COVID-19 Demonstration Program).

The application must include responses to all sections of the SF-424 mandatory form and the supplemental form unless a section is indicated as optional. FTA will use the information on the supplemental form to determine applicant and project eligibility for the program and to evaluate the proposal against the selection criteria described in part E of this notice. FTA will accept only one supplemental form per SF-424 submission.

FTA encourages applicants to consider submitting a single supplemental form that includes multiple activities to be evaluated as a consolidated proposal. Applicants may attach additional supporting information to the SF-424 submission, including but not limited to letters of support, project budgets, or excerpts from relevant planning documents. Supporting documentation must be described and referenced by file name in the appropriate response section of the supplemental form, or it may not be reviewed.

Information such as applicant name, Federal amount requested, local match amount, description of areas served, etc., may be requested in varying degrees of detail on both the SF-424 form and supplemental form. Applicants must fill in all fields unless stated otherwise on the forms. If applicants copy information into the supplemental form from another source, they should verify that the supplemental form has fully captured pasted text and that it has not truncated the text due to character limits built into the form.

Applicants should use both the “Check Package for Errors” and the “Validate Form” validation buttons on both forms to check all required fields. Applicants should also ensure that the Federal and local amounts specified are consistent. Addressing the deteriorating conditions and disproportionately high fatality rates on our rural transportation infrastructure is of critical interest to the Department, as rural transportation networks face unique challenges in safety, infrastructure condition, and passenger and freight usage.

Consistent with the R.O.U.T.E.S. Initiative, the Department encourages applicants to consider how the project will address the challenges faced by rural areas. B.

Application Content The SF-424 Mandatory Form and the supplemental form will prompt applicants for the required information, including. I. Applicant Name ii.

Dun and Bradstreet (D&B) Data Universal Numbering System (DUNS) number iii. Key contact information (contact name, address, email address, and phone number) iv. Congressional district(s) where project will take place v.

Project Information (title, executive summary, and type) vi. A detailed description of the need for the project vii. A detailed description of how the project will support the Program objectives viii.

Evidence that the applicant can provide the local cost shares ix. A description of the technical, legal, and financial capacity of the applicant x. A detailed project budget xi.

Details on the local matching funds xii. A detailed project timeline xiii. Whether the project impacts an Opportunity Zone (3) Unique Entity Identifier and System for Award Management (SAM) Each applicant is required to.

(1) Be registered in SAM before submitting an application. (2) provide a valid unique entity identifier in its application. And (3) continue to maintain an active SAM registration with current information at all times during which the applicant has an active Federal award or an application or plan under consideration by FTA.

These requirements do not apply if the applicant. (1) Is excepted from the requirements under 2 CFR 25.110(b) or (c). Or (2) has an exception approved by FTA under 2 CFR 25.110(d).

FTA may not make an award until the applicant has complied with all applicable unique entity identifier and SAM requirements. If an applicant has not fully complied with the requirements by the time FTA is ready to make an award, FTA may determine that the applicant is not qualified to receive an award and use that determination as a basis for making a Federal award to another applicant. All applicants must provide a unique entity identifier provided by SAM.

Registration in SAM may take as little as 3-5 business days, but there can be unexpected steps or delays. For example, the applicant may need to obtain an Employer Identification Number. FTA recommends allowing ample time, up to several weeks, to complete all steps.

For additional information on obtaining a unique entity identifier, please visit www.sam.gov. (4) Submission Dates and Times Project proposals must be submitted electronically through GRANTS.GOV by 11:59 p.m. Eastern on November 2, 2020.

Mail and fax submissions will not be accepted. FTA urges applicants to submit applications at least 72 hours prior to the due date to allow time to correct any problems that may have caused either GRANTS.GOV or FTA systems to reject the submission. Proposals submitted after the deadline will only be considered under extraordinary circumstances not within the applicant's control.

Deadlines will not be extended due to scheduled website maintenance. GRANTS.GOV scheduled maintenance and outage times are announced on the GRANTS.GOV website. Within 48 hours after submitting an electronic application, the applicant should receive two email messages from GRANTS.GOV.

(1) Confirmation of successful transmission to GRANTS.GOV. And (2) confirmation of successful validation by GRANTS.GOV. If the applicant does not receive confirmation of successful validation or receives a notice of failed validation or incomplete materials, the applicant must address the reason for the failed validation, as described in the email notice, and resubmit before the submission deadline.

If making a resubmission for any reason, applicants must include all original attachments regardless of which attachments were updated and check the box on the supplemental form indicating this is a resubmission. Applicants are encouraged to begin the process of registration on the GRANTS.GOV site well in advance of the submission deadline. Registration is Start Printed Page 63656a multi-step process, which may take several weeks to complete before an application can be submitted.

Registered applicants may still be required to update their registration before submitting an application. Registration in SAM is renewed annually and persons making submissions on behalf of the Authorized Organization Representative (AOR) must be authorized in GRANTS.GOV by the AOR to make submissions. (5) Funding Restrictions Funds may be used for post-award expenditures only.

Funds under this NOFO cannot be used to reimburse projects for otherwise eligible expenses incurred prior to the date of project award announcements. (6) Other Submission Requirements FTA encourages applicants to identify scaled funding options in case insufficient funding is available to fund a project at the full requested amount. If an applicant indicates that a project is scalable, the applicant must provide an appropriate minimum funding amount that will fund an eligible project that achieves the objectives of the program and meets all relevant program requirements.

The applicant must provide a clear explanation of how a reduced award would affect the project budget and scope. FTA may award a lesser amount whether or not the applicant provides a scalable option. E.

Application Review Information (1) Project Evaluation Criteria Addressing the deteriorating conditions and disproportionately high fatality rates on our rural transportation infrastructure is of critical interest to the Department, as rural transportation networks face unique challenges in safety, infrastructure condition, and passenger and freight usage. Consistent with the R.O.U.T.E.S. Initiative, the Department will consider how the project will address the challenges faced by rural areas.

In addition, the Department will review and consider applications for funding pursuant to this Notice in accordance with the President's September 2, 2020 memorandum, entitled Memorandum on Reviewing Funding to State and Local Government Recipients of Federal Funds that Are Permitting Anarchy, Violence, and Destruction in American Cities, consistent with guidance from the Office of Management and Budget and the Attorney General and with all applicable laws. FTA will evaluate proposals submitted according to the following criteria. (a) Project Innovation and Impact.

(b) Project Approach. (c) National Applicability. (d) Commercialization and/or Knowledge Transfer.

And (e) Technical, Legal and Financial Capacity. FTA encourages each applicant to demonstrate how a project supports all criteria with the most relevant information the applicant can provide, regardless of whether such information has been specifically requested or identified in this notice. A.

Project Innovation and Impact i. Effectiveness of the project in achieving and demonstrating the specific objectives of this program. Ii.

Demonstration of benefits in addressing the needs of the transit agency and industry and impacts to infrastructure, equipment, transit workforce, and riders. Iii. Degree of improvement over current and existing technologies, designs, and/or practices applicable to the transit industry.

B. Project Approach i. Quality of the project approach such as existing partnerships, collaboration strategies and level of commitment of the project partners.

Ii. Proposal is realistic in its approach to fulfill the milestones/deliverables, schedule and goals. C.

National Applicability i. Degree to which the project could be replicated by other transit agencies regionally or nationally. Ii.

Ability to evaluate technologies, designs and/or practices in a wide variety of conditions and locales. Iii. Degree to which the technology, designs and/or practices can be replicated by other transportation modes.

D. Commercialization and/or Knowledge Transfer i. Demonstrates a realistic plan for moving the results of the project into the transit marketplace (patents, conferences, articles in trade magazines, webinar, site visits, etc.).

Ii. How the project team plans to work with the industry on improving best practices, guidance and/or standards, if applicable. Iii.

Demonstrate a clear understanding and robust approach to data collection, access and management. E. Technical, Legal and Financial Capacity Capacity of the applicant and any partners to successfully execute the project effort.

There should be no outstanding legal, technical, or financial issues with the applicant that would make this a high-risk project. (2) Review and Selection Process An FTA technical evaluation committee will evaluate proposals based on the published project evaluation criteria. Members of the technical evaluation committee will rate the applications and may seek clarification about any statement in an application.

The FTA Administrator will determine the final selection and amount of funding for each project after consideration of the findings of the technical evaluation committee. Geographic diversity, diversity of the project type, the amount of local match to be provided, and the applicant's receipt and management of other Federal transit funds may be considered in FTA's award decisions. Prior fare payment innovation efforts may receive priority consideration.

The FTA Administrator will consider the following key DOT objectives. A. Utilizing alternative funding sources and innovative financing models to attract non-Federal sources of investment.

B. Whether the project is located in or supports public transportation service in a qualified opportunity zone designated pursuant to 26.U.S.C. 1400Z-1.

And c. The extent to which the project addresses challenges specific to the provision of rural public transportation. (3) FAPIIS Review Prior to making a grant award, FTA is required to review and consider any information about the applicant that is in the Federal Awardee Performance and Integrity Information System (FAPIIS) accessible through SAM.

An applicant may review and comment on information about itself that a Federal awarding agency previously entered. FTA will consider any comments by the applicant, in addition to the other information in FAPIIS, in making a judgment about the applicant's integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 2 CFR 200.205 Federal Awarding Agency Review of Risk Posed by Applicants. F.

Federal Award Administration Information (1) Federal Award Notices FTA will announce the final project selections on the FTA website. Project recipients should contact their FTA Regional Office for additional information regarding allocations for Start Printed Page 63657projects. At the time project selections are announced, FTA will extend pre-award authority for the selected projects.

There is no blanket pre-award authority for these projects before announcement. There is no minimum or maximum grant award amount, but FTA intends to fund as many meritorious projects as possible. FTA only will consider proposals from eligible recipients for eligible activities.

Due to funding limitations, projects selected for funding may receive less than the amount originally requested. In those cases, applicants must be able to demonstrate that the proposed projects are still viable and can be completed with the amount awarded. (2) Administrative and National Policy Requirements a.

Pre-Award Authority FTA will issue specific guidance to recipients regarding pre-award authority at the time of selection. FTA does not provide pre-award authority for competitive funds until projects are selected, and there are Federal requirements that must be met before costs are incurred. For more information about FTA's policy on pre-award authority, see the FY 2020 Apportionments Notice published on June 3, 2020, at https://www.govinfo.gov/​content/​pkg/​FR-2020-06-03/​pdf/​2020-11946.pdf.

b. Grant Requirements Selected applicants will submit a grant application through FTA's electronic grant management system and adhere to the customary FTA grant requirements for research project (insert Circular name). All competitive grants, regardless of award amount, will be subject to the Congressional notification and release process.

FTA emphasizes that third-party procurement applies to all funding awards, as described in FTA Circular 4220.1F, “Third Party Contracting Guidance.” However, FTA may approve applications that include a specifically identified partnering organization(s) (2 CFR 200.302(f)). When included, the application, budget, and budget narrative should provide a clear understanding of how the selection of these organizations is critical for the project and give sufficient detail about the costs involved. C.

Planning FTA encourages applicants to engage the appropriate State Departments of Transportation, Regional Transportation Planning Organizations, or Metropolitan Planning Organizations in areas to be served by the project funds available under this program. D. Standard Assurances The applicant assures that it will comply with all applicable Federal statutes, regulations, executive orders, FTA circulars, and other Federal administrative requirements in carrying out any project supported by the FTA grant.

The applicant acknowledges that it is under a continuing obligation to comply with the terms and conditions of the grant agreement issued for its project with FTA. The applicant understands that Federal laws, regulations, policies, and administrative practices might be modified from time to time and may affect the implementation of the project. The applicant agrees that the most recent Federal requirements will apply to the project unless FTA issues a written determination otherwise.

The applicant must submit the Certifications and Assurances before receiving a grant if it does not have current certifications on file. E. Free Speech and Religious Liberty In connection with any program or activity conducted with or benefiting from funds awarded under this notice, recipients of funds must comply with all applicable requirements of Federal law, including, without limitation, the Constitution of the United States.

Statutory, regulatory, and public policy requirements, including without limitation, those protecting free speech, religious liberty, public welfare, the environment, and prohibiting discrimination. The conditions of performance, non-discrimination requirements, and other assurances made applicable to the award of funds in accordance with regulations of the Department of Transportation. And applicable Federal financial assistance and contracting principles promulgated by the Office of Management and Budget.

In complying with these requirements, recipients must ensure that no concession agreements are denied or other contracting decisions made on the basis of speech or other activities protected by the First Amendment. If the Department determines that a recipient has failed to comply with applicable Federal requirements, the Department may terminate the award of funds and disallow previously incurred costs, requiring the recipient to reimburse any expended award funds. (3) Reporting The post-award reporting requirements include submission of the Federal Financial Report (FFR) and Milestone Progress Report in TrAMS.

An evaluation of the grant will occur at various points in the demonstration process and at the end of the project. In addition, FTA is responsible for producing an Annual Report to Congress that compiles evaluation of selected projects, including an evaluation of the performance measures identified by the applicants. All applicants must develop an evaluation plan to measure the success or failure of their projects and describe any plans for broad-based implementation of successful projects.

FTA may request data and reports to support the evaluation and Annual Report. A. Independent Evaluation To achieve a comprehensive understanding of the impacts and implications of each proposed COVID-19 Research Demonstration Program, projects funded under this announcement will require the recipient to conduct a third party independent evaluation of their project.

Recipients will be required to contract with a third party independent evaluator to assist in developing an evaluation plan, and collecting, storing and managing data required to fulfill the evaluation requirement. No more than 10 percent of the Federal share of the project may be used to hire the third-party independent evaluator and the inclusion of a third-party independent evaluation should be described in the grant application. If the project duration is more than two years, an interim evaluation report would need to be submitted to FTA, otherwise the evaluation report should be included as part of the final project report.

B. COVID-19 Research Demonstration Grant Program Evaluation Projects funded under this announcement will be required to establish a set of performance metrics set by the third-party independent evaluator and shared with FTA. G.

Federal Awarding Agency Contacts Information For questions about applying, please contact Jamel El-Hamri email. Jamel.El-Hamri@dot.gov phone. 202-366-8985.

A TDD is available at 1-800-877-8339 (TDDFIRS). To ensure that applicants receive accurate information about eligibility or the program, applicants are encouraged to contact FTA directly with questions, rather than through intermediaries or third parties.Start Printed Page 63658 FTA staff also may conduct briefings on the competitive grants selection and award process upon request. Start Signature K.

Jane Williams, Deputy Administrator. End Signature End Supplemental Information [FR Doc. 2020-22316 Filed 10-7-20.

GREAT FALLS, how to get floxin over the counter Mont. €” For months, the jail in central Montana’s Cascade County was free of the coronavirus, which seemed as distant a threat as it did in much of the nation’s rural Mountain West.Then a few people who had the virus were arrested. By the time how to get floxin over the counter Paul Krogue, the jail’s medical director, realized there was a problem, nearly 50 inmates were infected in the jail, where some had been sleeping on mats on an overcrowded floor. After several weeks, Mr. Krogue got a call that infections were spreading to a side of the jail that had been virus-free.He hung up the phone and put his head in his hands.“I just kind of lost how to get floxin over the counter it, like, ‘My God, I don’t know how much longer I can do this,’” Mr.

Krogue, a nurse practitioner, recalled. €œI was just scared that I’m not going to be able to see it through, that I’m going to get sick — you just feel so exhausted and it’s just a lot.”The Mountain West, which for months avoided the worst of the pandemic, has rapidly devolved into one of the most alarming hot spots in a country that recorded its eight millionth confirmed case on Thursday, a day when more than 65,000 cases were announced nationwide, the most in a single day since July.Seventeen states, including many in the Mountain West, have added more cases in the past week than any other week of the pandemic. And the spread through sparsely populated areas of rural America has created problems in small towns that lack critical resources — including doctors how to get floxin over the counter — even in ordinary times.Wyoming, which did not have 1,000 total cases until June, recently added more than 1,000 in a single week. Reports of new infections have recently reached record levels in Alaska, Colorado and Idaho. And Montana, where more than half of the state’s cases have been announced since August, is averaging more than 500 cases per day.In Cascade County, more than 300 inmates and staff members have been infected in a facility meant to hold 365 people, the county’s first major outbreak in a region where the virus is suddenly surging.The county seat, Great Falls, is seeing its worst how to get floxin over the counter case numbers yet.

The local hospital and its 27-bed Covid-19 unit is at capacity. The county health department is racing to hire new contact tracers. And Mr how to get floxin over the counter. Krogue, who also teaches nursing at Montana State University’s Great Falls campus, has seen attendance in his classes dwindle as students fall ill or quarantine.“I was just scared that I’m not going to be able to see it through, that I’m going to get sick,” said Paul Krogue, the jail’s medical director.Credit...Tailyr Irvine for The New York TimesOne place where the infections have spread has been local jails, which are confined, often crowded spaces. Jails are staples of local communities and tend to have people coming and going how to get floxin over the counter more quickly than prisons.

Jails can hold everyone from people awaiting criminal trials for months to those picked up for a suspended driver’s license for a few hours. With so many people filtering in and out, jails pose extra risks for the virus’s spread — not only inside facilities but in potentially feeding outbreaks in the rest of the community.Nationally, jails and prisons have seen disproportionate rates of infection and death, with a mortality rate twice as high as in the general population and an infection rate more than four times as high, according to recent data.A how to get floxin over the counter New York Times database has tracked clusters of at least 50 coronavirus cases in a dozen rural jails in Montana, Idaho, Utah and New Mexico during the pandemic. Among them. The Purgatory Correctional Center in Hurricane, Utah, with 166 infections. The jail how to get floxin over the counter in Twin Falls, Idaho, with 279.

And, in New Mexico, the Cibola County Correctional Center, which has reported 357 cases.In Cascade County, infections at the jail make up about a quarter of all known virus cases in the county. Health authorities say how to get floxin over the counter that the jail’s outbreak, which began in mid-August, was not believed to be the main cause of the community’s recent surge, but that it had led to some cases. In the past two months, Mr. Krogue said, the jail released 29 people who were considered actively infected.Infections at the jail make up about a quarter of Cascade County’s known virus cases.Credit...Tailyr Irvine for The New York TimesGreat Falls, home to about 58,000 residents, is in the less mountainous part of Montana, with the Missouri River flowing through and a large oil refinery on its banks. The Cascade County Detention Center sits how to get floxin over the counter along a highway at the edge of town.

Drive five miles in any direction and you are surrounded by wide-open plains.Montana requires that masks be worn inside businesses and indoor public spaces, and many people in Great Falls wear them when walking around downtown’s Central Avenue, where shops and cafes are still recovering from shutting down in the spring. Others go without masks, citing the open space and lack of crowds.Bob Kelly, the mayor, said people had not been overly worried about how the jail outbreak might affect the rest of town when it started.“I think that by the very definition of a jail, hopefully, the disease how to get floxin over the counter will be incarcerated, as well as the patients,” he said. €œIs there concern?. Sure, there’s how to get floxin over the counter concern. But is there overreaction?.

No.”The mayor of Great Falls said that residents had considered the jail’s outbreak a distant concern at first.Credit...Tailyr Irvine for The New York TimesSome residents’ nonchalance about the risks of the virus, said Mr. Krogue, the jail’s medical director, can be traced to a spring and early summer when almost no one in Cascade County knew anyone who had been sickened.“We benefited from that early on,” he said how to get floxin over the counter. €œBut in some ways, I think it did us a disservice, too, because it also created a certain level of complacency.”That has quickly shifted now, he said, as cases have spiked.The number of active cases known to county officials on any given day has risen sharply to about 600, according to Trisha Gardner, Cascade County’s health officer. The county how to get floxin over the counter has seen 1,261 cases and six deaths during the pandemic, a Times database shows. Some of the cases have been tied to the jail outbreak, she said, and others have been connected to bars and restaurants.

Even figuring out what has led to some cases has been complex, she said, as residents have been reluctant to cooperate with contact tracers.“Our hospitals are at capacity, our public health system is at capacity,” she said. €œIt’s not sustainable at this rate.”When the outbreak at the jail began, social distancing how to get floxin over the counter was impossible, the authorities said. Three inmates shared cells designed for two. At night, men slept how to get floxin over the counter on thin blue pads in every available space. On the floor in the day room, in shower stalls, in stairwells, in hallways outside of cells.Inmates did not receive masks until August, and jail officials said many have refused to wear them.In interviews with more than a dozen inmates and their family members, inmates described the jail during the outbreak as chaotic and unsanitary.

They said their pleas for help often went unanswered by nurses and guards.Newly arriving inmates were not always quarantined from one another before their test results were known because of a lack of space, inmates and jail officials said.Owen Hawley, 30, said every inmate in his living area of 38 men had tested positive for the virus. He said he had been unable to eat how to get floxin over the counter for three days, had intensive body aches and suffered from a headache so powerful it felt as if it was “behind my eyes.”“After the fourth day of like, not eating and stuff, I just shut off, you know?. € he said.A jail area set aside for quarantining new inmates.Credit...Tailyr Irvine for The New York TimesAt one point, Mr. Hawley said, he and other prisoners protested the way the virus was being handled how to get floxin over the counter by refusing to leave their living areas and by blocking new inmates from entering. Everyone was ultimately tested, Mr.

Hawley said, and how to get floxin over the counter each prisoner was given a disposable mask.Sierra Jasmine Wells, 25, another inmate, said women in her dormitory had grown ill, one after the next.“Everyone around me was getting sick and it was tough on me,” she said. €œBy then, I had already accepted the fact that I was going to get sick.”When she became infected, she said, she was given cough syrup and Tylenol.“I kind of was just left alone to deal with it,” she said.Jesse Slaughter, the county sheriff who oversees the jail, said that the jail’s medical staff was doing everything it could, and that he had been seeking health care assistance from other counties. Officials defended their handling of the outbreak, noting that all inmates received standard medications including Tylenol twice a day and were taken to area hospitals when they needed added care. Seven inmates, as well as some staff members, were how to get floxin over the counter hospitalized. No one from the jail has died from the virus, officials said.Sheriff Jesse Slaughter, who oversees the jail, said he had been seeking health care assistance from other counties.Credit...Tailyr Irvine for The New York TimesMr.

Krogue said that since the start of the how to get floxin over the counter outbreak he had been working up to 16 hours each day and sleeping in his basement, away from his wife and children. He remains healthy but says he fears bringing the virus home. The virus has slowed some in the jail, and officials have moved some inmates to other facilities, but other prisons and jails in the state are now seeing outbreaks.“You can start to see what some of these other places experienced much earlier on, and we just didn’t have that experience, but it’s certainly happening now,” Mr. Krogue said how to get floxin over the counter. €œIt’s just real in a way that it wasn’t.”Lucy Tompkins reported from Great Falls, Maura Turcotte from Chicago and Libby Seline from Lincoln, Neb.

Reporting was contributed by Izzy Colón from Columbia, Mo., Brendon Derr from Phoenix, Rebecca Griesbach from Tuscaloosa, Ala., Danya Issawi and Timothy Williams from how to get floxin over the counter New York, Ann Hinga Klein from Des Moines, K.B. Mensah from Silver Spring, Md., and Mitch Smith from Chicago.Start Preamble Federal Transit Administration (FTA), DOT. Notice of funding how to get floxin over the counter opportunity. The Coronavirus Disease 2019 (COVID-19) public health emergency Start Printed Page 63654has had a significant impact on transit operations. During a series of FTA listening sessions held over the last three months, transit agencies asked FTA to support research to identify solutions to address the operational challenges that they are facing as a result of COVID-19.

In response, FTA how to get floxin over the counter makes available through this Notice of Funding Opportunity (NOFO) funding to support research demonstration grants to public transit agencies to develop, deploy, and demonstrate innovative solutions that improve the operational efficiency of transit agencies, as well as enhance the mobility of transit users affected by the COVID-19 public health emergency. Demonstration grants under this NOFO are authorized under FTA's Public Transportation Innovation Program (49 U.S.C. 5312). Eligible projects will demonstrate innovative solutions to improve the operational efficiencies of transit systems and enhance mobility for their communities in four major areas. (1) Vehicle, facility, equipment and infrastructure cleaning and disinfection.

(2) exposure mitigation measures. (3) innovative mobility such as contactless payments. And (4) measures that strengthen public confidence in transit services. The total funding available for awards under this NOFO is $10,000,000. FTA may supplement this amount if additional funding becomes available.

Applicants must submit completed proposals for funding opportunity FTA-2020-015-TRI through the GRANTS.GOV “APPLY” function by 11:59 p.m. Eastern Time on November 2, 2020. Prospective applicants should register as soon as possible on the GRANTS.GOV website to ensure they can complete the application process before the submission deadline. Application instructions are available on FTA's website at http://transit.dot.gov/​howtoapply and in the “FIND” module of GRANTS.GOV. FTA will not accept mail and fax submissions.

Start Further Info Please send any questions on this notice to Jamel El-Hamri email. Jamel.El-Hamri@dot.gov phone. 2020-366-8985. A Telecommunication Device for the Deaf (TDD) is available for individuals who are deaf or hard of hearing at 1-800-877-8339. End Further Info End Preamble Start Supplemental Information Table of Contents A.

Program Description B. Federal Award Information C. Eligibility Information D. Application and Submission Information E. Application Review Information F.

Federal Award Administration Information G. Federal Awarding Agency Contact Information A. Program Description The Public Transportation COVID-19 Research Demonstration Grant Program is funded through the Public Transportation Innovation Program (49 U.S.C. 5312), with the goal to develop, deploy, and demonstrate innovative solutions that improve the operational efficiency of transit agencies, as well as enhance the mobility of transit users affected by the COVID-19 public health emergency. Eligible projects will propose to develop and deploy innovative solutions in four major areas.

(1) Vehicle, facility, equipment and infrastructure cleaning and disinfection. (2) exposure mitigation measures. (3) innovative mobility such as contactless payments. And (4) measures that strengthen public confidence in transit. As required by 49 U.S.C.

5312(e)(4), projects funded under this NOFO must participate in an evaluation by an independent outside entity that will conduct a comprehensive evaluation of the success or failure of the projects funded under this subsection and any plan for broad-based implementation of the innovation promoted by successful projects. B. Federal Award Information FTA makes available $10,000,000 in fiscal year (FY) 2020 funds under the Public Transportation Innovation Program (49 U.S.C. 5312) to finance the Public Transportation COVID-19 Research Demonstration Grant Program. FTA may supplement the total funds available if additional funding becomes available at the time project selections are made.

FTA will grant pre-award authority starting on the date of the project award announcement for selected projects and should be completed within 24 months from the date of award. Funds are available only for eligible expenses incurred after the announcement of project selections. C. Eligibility Information (1) Eligible Applicants Eligible applicants include State and local governmental authorities, direct recipients of Urbanized Area (49 U.S.C. 5307) and Rural Area (49 U.S.C.

5311) formula funds, and Indian tribes. Eligible applicants are limited to FTA grantees or subrecipients who would be the primary beneficiaries of the innovative products and services that are developed—typically public transit agencies. Except for projects proposed by Indian tribes, proposals for projects in rural (non-urbanized) areas must be submitted as part of a consolidated State proposal. States and other eligible applicants also may submit consolidated proposals for projects in urbanized areas. The submission of the Statewide application will not preclude the submission and consideration of any application from other eligible recipients in an urbanized area in a State.

Proposals may contain projects to be implemented by the recipient or its subrecipients. Eligible subrecipients include public agencies, private nonprofit organizations, and private providers engaged in public transportation. Eligible applicants may submit consolidated proposals for projects. (2) Cost Sharing or Matching The maximum Federal share of project costs is 100 percent. FTA may give additional consideration to applicants that propose a local share and may view these applicants as more competitive.

The applicant must document the source(s) of the local match, if any, in the grant application. For any applicants proposing match, eligible local match sources include the following. Cash from non-Government sources other than revenues from providing public transportation services. Revenues derived from the sale of advertising and concessions. Revenues generated from value capture financing mechanisms.

Funds from an undistributed cash surplus. Replacement or depreciation cash fund or reserve. New capital. Or in-kind contributions. (3) Eligible Projects Eligible projects will propose innovative solutions to improve operational efficiencies of transit agencies and enhance the mobility of transit users, through projects that demonstrate innovative solutions for.

Vehicle, facility, equipment and infrastructure cleaning and disinfection. Exposure mitigation measures such a real-time notification of rail and bus passenger loads. New multi-modal payment innovative mobility systems such as contactless payments. And measures that strengthen public confidence in transit. Each applicant may only submit one proposal.Start Printed Page 63655 D.

Application and Submission Information (1) Address and Form of Application Submission Applications must be submitted through GRANTS.GOV. Applicants can find general information for submitting applications through GRANTS.GOV at www.fta.dot.gov/​howtoapply, along with specific instructions for the forms and attachments required for submission. Mail and fax submissions will not be accepted. (2) Content and Form of Application Submission a. Proposal Submission A complete proposal submission consists of at least two forms.

1. The SF-424 Mandatory Form (downloadable from GRANTS.GOV) and 2. The supplemental form for the FY 2020 COVID-19 Demonstration Program (downloadable from GRANTS.GOV), which is available on FTA's website at (placeholder for FTA COVID-19 Demonstration Program). The application must include responses to all sections of the SF-424 mandatory form and the supplemental form unless a section is indicated as optional. FTA will use the information on the supplemental form to determine applicant and project eligibility for the program and to evaluate the proposal against the selection criteria described in part E of this notice.

FTA will accept only one supplemental form per SF-424 submission. FTA encourages applicants to consider submitting a single supplemental form that includes multiple activities to be evaluated as a consolidated proposal. Applicants may attach additional supporting information to the SF-424 submission, including but not limited to letters of support, project budgets, or excerpts from relevant planning documents. Supporting documentation must be described and referenced by file name in the appropriate response section of the supplemental form, or it may not be reviewed. Information such as applicant name, Federal amount requested, local match amount, description of areas served, etc., may be requested in varying degrees of detail on both the SF-424 form and supplemental form.

Applicants must fill in all fields unless stated otherwise on the forms. If applicants copy information into the supplemental form from another source, they should verify that the supplemental form has fully captured pasted text and that it has not truncated the text due to character limits built into the form. Applicants should use both the “Check Package for Errors” and the “Validate Form” validation buttons on both forms to check all required fields. Applicants should also ensure that the Federal and local amounts specified are consistent. Addressing the deteriorating conditions and disproportionately high fatality rates on our rural transportation infrastructure is of critical interest to the Department, as rural transportation networks face unique challenges in safety, infrastructure condition, and passenger and freight usage.

Consistent with the R.O.U.T.E.S. Initiative, the Department encourages applicants to consider how the project will address the challenges faced by rural areas. B. Application Content The SF-424 Mandatory Form and the supplemental form will prompt applicants for the required information, including. I.

Applicant Name ii. Dun and Bradstreet (D&B) Data Universal Numbering System (DUNS) number iii. Key contact information (contact name, address, email address, and phone number) iv. Congressional district(s) where project will take place v. Project Information (title, executive summary, and type) vi.

A detailed description of the need for the project vii. A detailed description of how the project will support the Program objectives viii. Evidence that the applicant can provide the local cost shares ix. A description of the technical, legal, and financial capacity of the applicant x. A detailed project budget xi.

Details on the local matching funds xii. A detailed project timeline xiii. Whether the project impacts an Opportunity Zone (3) Unique Entity Identifier and System for Award Management (SAM) Each applicant is required to. (1) Be registered in SAM before submitting an application. (2) provide a valid unique entity identifier in its application.

And (3) continue to maintain an active SAM registration with current information at all times during which the applicant has an active Federal award or an application or plan under consideration by FTA. These requirements do not apply if the applicant. (1) Is excepted from the requirements under 2 CFR 25.110(b) or (c). Or (2) has an exception approved by FTA under 2 CFR 25.110(d). FTA may not make an award until the applicant has complied with all applicable unique entity identifier and SAM requirements.

If an applicant has not fully complied with the requirements by the time FTA is ready to make an award, FTA may determine that the applicant is not qualified to receive an award and use that determination as a basis for making a Federal award to another applicant. All applicants must provide a unique entity identifier provided by SAM. Registration in SAM may take as little as 3-5 business days, but there can be unexpected steps or delays. For example, the applicant may need to obtain an Employer Identification Number. FTA recommends allowing ample time, up to several weeks, to complete all steps.

For additional information on obtaining a unique entity identifier, please visit www.sam.gov. (4) Submission Dates and Times Project proposals must be submitted electronically through GRANTS.GOV by 11:59 p.m. Eastern on November 2, 2020. Mail and fax submissions will not be accepted. FTA urges applicants to submit applications at least 72 hours prior to the due date to allow time to correct any problems that may have caused either GRANTS.GOV or FTA systems to reject the submission.

Proposals submitted after the deadline will only be considered under extraordinary circumstances not within the applicant's control. Deadlines will not be extended due to scheduled website maintenance. GRANTS.GOV scheduled maintenance and outage times are announced on the GRANTS.GOV website. Within 48 hours after submitting an electronic application, the applicant should receive two email messages from GRANTS.GOV. (1) Confirmation of successful transmission to GRANTS.GOV.

And (2) confirmation of successful validation by GRANTS.GOV. If the applicant does not receive confirmation of successful validation or receives a notice of failed validation or incomplete materials, the applicant must address the reason for the failed validation, as described in the email notice, and resubmit before the submission deadline. If making a resubmission for any reason, applicants must include all original attachments regardless of which attachments were updated and check the box on the supplemental form indicating this is a resubmission. Applicants are encouraged to begin the process of registration on the GRANTS.GOV site well in advance of the submission deadline. Registration is Start Printed Page 63656a multi-step process, which may take several weeks to complete before an application can be submitted.

Registered applicants may still be required to update their registration before submitting an application. Registration in SAM is renewed annually and persons making submissions on behalf of the Authorized Organization Representative (AOR) must be authorized in GRANTS.GOV by the AOR to make submissions. (5) Funding Restrictions Funds may be used for post-award expenditures only. Funds under this NOFO cannot be used to reimburse projects for otherwise eligible expenses incurred prior to the date of project award announcements. (6) Other Submission Requirements FTA encourages applicants to identify scaled funding options in case insufficient funding is available to fund a project at the full requested amount.

If an applicant indicates that a project is scalable, the applicant must provide an appropriate minimum funding amount that will fund an eligible project that achieves the objectives of the program and meets all relevant program requirements. The applicant must provide a clear explanation of how a reduced award would affect the project budget and scope. FTA may award a lesser amount whether or not the applicant provides a scalable option. E. Application Review Information (1) Project Evaluation Criteria Addressing the deteriorating conditions and disproportionately high fatality rates on our rural transportation infrastructure is of critical interest to the Department, as rural transportation networks face unique challenges in safety, infrastructure condition, and passenger and freight usage.

Consistent with the R.O.U.T.E.S. Initiative, the Department will consider how the project will address the challenges faced by rural areas. In addition, the Department will review and consider applications for funding pursuant to this Notice in accordance with the President's September 2, 2020 memorandum, entitled Memorandum on Reviewing Funding to State and Local Government Recipients of Federal Funds that Are Permitting Anarchy, Violence, and Destruction in American Cities, consistent with guidance from the Office of Management and Budget and the Attorney General and with all applicable laws. FTA will evaluate proposals submitted according to the following criteria. (a) Project Innovation and Impact.

(b) Project Approach. (c) National Applicability. (d) Commercialization and/or Knowledge Transfer. And (e) Technical, Legal and Financial Capacity. FTA encourages each applicant to demonstrate how a project supports all criteria with the most relevant information the applicant can provide, regardless of whether such information has been specifically requested or identified in this notice.

A. Project Innovation and Impact i. Effectiveness of the project in achieving and demonstrating the specific objectives of this program. Ii. Demonstration of benefits in addressing the needs of the transit agency and industry and impacts to infrastructure, equipment, transit workforce, and riders.

Iii. Degree of improvement over current and existing technologies, designs, and/or practices applicable to the transit industry. B. Project Approach i. Quality of the project approach such as existing partnerships, collaboration strategies and level of commitment of the project partners.

Ii. Proposal is realistic in its approach to fulfill the milestones/deliverables, schedule and goals. C. National Applicability i. Degree to which the project could be replicated by other transit agencies regionally or nationally.

Ii. Ability to evaluate technologies, designs and/or practices in a wide variety of conditions and locales. Iii. Degree to which the technology, designs and/or practices can be replicated by other transportation modes. D.

Commercialization and/or Knowledge Transfer i. Demonstrates a realistic plan for moving the results of the project into the transit marketplace (patents, conferences, articles in trade magazines, webinar, site visits, etc.). Ii. How the project team plans to work with the industry on improving best practices, guidance and/or standards, if applicable. Iii.

Demonstrate a clear understanding and robust approach to data collection, access and management. E. Technical, Legal and Financial Capacity Capacity of the applicant and any partners to successfully execute the project effort. There should be no outstanding legal, technical, or financial issues with the applicant that would make this a high-risk project. (2) Review and Selection Process An FTA technical evaluation committee will evaluate proposals based on the published project evaluation criteria.

Members of the technical evaluation committee will rate the applications and may seek clarification about any statement in an application. The FTA Administrator will determine the final selection and amount of funding for each project after consideration of the findings of the technical evaluation committee. Geographic diversity, diversity of the project type, the amount of local match to be provided, and the applicant's receipt and management of other Federal transit funds may be considered in FTA's award decisions. Prior fare payment innovation efforts may receive priority consideration. The FTA Administrator will consider the following key DOT objectives.

A. Utilizing alternative funding sources and innovative financing models to attract non-Federal sources of investment. B. Whether the project is located in or supports public transportation service in a qualified opportunity zone designated pursuant to 26.U.S.C. 1400Z-1.

And c. The extent to which the project addresses challenges specific to the provision of rural public transportation. (3) FAPIIS Review Prior to making a grant award, FTA is required to review and consider any information about the applicant that is in the Federal Awardee Performance and Integrity Information System (FAPIIS) accessible through SAM. An applicant may review and comment on information about itself that a Federal awarding agency previously entered. FTA will consider any comments by the applicant, in addition to the other information in FAPIIS, in making a judgment about the applicant's integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 2 CFR 200.205 Federal Awarding Agency Review of Risk Posed by Applicants.

F. Federal Award Administration Information (1) Federal Award Notices FTA will announce the final project selections on the FTA website. Project recipients should contact their FTA Regional Office for additional information regarding allocations for Start Printed Page 63657projects. At the time project selections are announced, FTA will extend pre-award authority for the selected projects. There is no blanket pre-award authority for these projects before announcement.

There is no minimum or maximum grant award amount, but FTA intends to fund as many meritorious projects as possible. FTA only will consider proposals from eligible recipients for eligible activities. Due to funding limitations, projects selected for funding may receive less than the amount originally requested. In those cases, applicants must be able to demonstrate that the proposed projects are still viable and can be completed with the amount awarded. (2) Administrative and National Policy Requirements a.

Pre-Award Authority FTA will issue specific guidance to recipients regarding pre-award authority at the time of selection. FTA does not provide pre-award authority for competitive funds until projects are selected, and there are Federal requirements that must be met before costs are incurred. For more information about FTA's policy on pre-award authority, see the FY 2020 Apportionments Notice published on June 3, 2020, at https://www.govinfo.gov/​content/​pkg/​FR-2020-06-03/​pdf/​2020-11946.pdf. b. Grant Requirements Selected applicants will submit a grant application through FTA's electronic grant management system and adhere to the customary FTA grant requirements for research project (insert Circular name).

All competitive grants, regardless of award amount, will be subject to the Congressional notification and release process. FTA emphasizes that third-party procurement applies to all funding awards, as described in FTA Circular 4220.1F, “Third Party Contracting Guidance.” However, FTA may approve applications that include a specifically identified partnering organization(s) (2 CFR 200.302(f)). When included, the application, budget, and budget narrative should provide a clear understanding of how the selection of these organizations is critical for the project and give sufficient detail about the costs involved. C. Planning FTA encourages applicants to engage the appropriate State Departments of Transportation, Regional Transportation Planning Organizations, or Metropolitan Planning Organizations in areas to be served by the project funds available under this program.

D. Standard Assurances The applicant assures that it will comply with all applicable Federal statutes, regulations, executive orders, FTA circulars, and other Federal administrative requirements in carrying out any project supported by the FTA grant. The applicant acknowledges that it is under a continuing obligation to comply with the terms and conditions of the grant agreement issued for its project with FTA. The applicant understands that Federal laws, regulations, policies, and administrative practices might be modified from time to time and may affect the implementation of the project. The applicant agrees that the most recent Federal requirements will apply to the project unless FTA issues a written determination otherwise.

The applicant must submit the Certifications and Assurances before receiving a grant if it does not have current certifications on file. E. Free Speech and Religious Liberty In connection with any program or activity conducted with or benefiting from funds awarded under this notice, recipients of funds must comply with all applicable requirements of Federal law, including, without limitation, the Constitution of the United States. Statutory, regulatory, and public policy requirements, including without limitation, those protecting free speech, religious liberty, public welfare, the environment, and prohibiting discrimination. The conditions of performance, non-discrimination requirements, and other assurances made applicable to the award of funds in accordance with regulations of the Department of Transportation.

And applicable Federal financial assistance and contracting principles promulgated by the Office of Management and Budget. In complying with these requirements, recipients must ensure that no concession agreements are denied or other contracting decisions made on the basis of speech or other activities protected by the First Amendment. If the Department determines that a recipient has failed to comply with applicable Federal requirements, the Department may terminate the award of funds and disallow previously incurred costs, requiring the recipient to reimburse any expended award funds. (3) Reporting The post-award reporting requirements include submission of the Federal Financial Report (FFR) and Milestone Progress Report in TrAMS. An evaluation of the grant will occur at various points in the demonstration process and at the end of the project.

In addition, FTA is responsible for producing an Annual Report to Congress that compiles evaluation of selected projects, including an evaluation of the performance measures identified by the applicants. All applicants must develop an evaluation plan to measure the success or failure of their projects and describe any plans for broad-based implementation of successful projects. FTA may request data and reports to support the evaluation and Annual Report. A. Independent Evaluation To achieve a comprehensive understanding of the impacts and implications of each proposed COVID-19 Research Demonstration Program, projects funded under this announcement will require the recipient to conduct a third party independent evaluation of their project.

Recipients will be required to contract with a third party independent evaluator to assist in developing an evaluation plan, and collecting, storing and managing data required to fulfill the evaluation requirement. No more than 10 percent of the Federal share of the project may be used to hire the third-party independent evaluator and the inclusion of a third-party independent evaluation should be described in the grant application. If the project duration is more than two years, an interim evaluation report would need to be submitted to FTA, otherwise the evaluation report should be included as part of the final project report. B. COVID-19 Research Demonstration Grant Program Evaluation Projects funded under this announcement will be required to establish a set of performance metrics set by the third-party independent evaluator and shared with FTA.

G. Federal Awarding Agency Contacts Information For questions about applying, please contact Jamel El-Hamri email. Jamel.El-Hamri@dot.gov phone. 202-366-8985. A TDD is available at 1-800-877-8339 (TDDFIRS).

To ensure that applicants receive accurate information about eligibility or the program, applicants are encouraged to contact FTA directly with questions, rather than through intermediaries or third parties.Start Printed Page 63658 FTA staff also may conduct briefings on the competitive grants selection and award process upon request. Start Signature K. Jane Williams, Deputy Administrator. End Signature End Supplemental Information [FR Doc. 2020-22316 Filed 10-7-20.

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