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Introduction: We developed low-cost, portable paper-based diagnostic devices for detection of human immunoglobulin M (IgM) and immunoglobulin G (IgG) in serum without any sample preparation. These devices can be used to help identify presence of diseases, used to provide rapid results (<5 minutes), readily used by untrained personnel, employed in austere environments, configured to obtain multiplexed assays, and easily disposed of.Materials and Methods: We successfully accomplished colorimetric detection of human IgG and human IgM using a sandwich-style assay within the microfluidic paper device via vertical flow immunoassay configuration. The reaction zone in the wax printed paper layer is a small circular pattern. Gold nanoparticles conjugated with anti-human IgG and IgM antibodies have been used for colorimetric detection of IgG or IgM by naked eye. Colorimetric signal can be precisely quantified through implementation of image analysis software which can be developed as an app for a smartphone. The size of the device is 2 cm × 2 cm × 1 mm.Results: Colorimetric detection of human IgG was accomplished at 100 fg/mL concentration using a gold nanoparticle-conjugated anti-human IgG antibody. The developed platform has a dynamic range of IgM and IgG concentrations between 0.1 pg/mL and 100 μg/mL. These devices provided a color readout in <5 minutes using 20 µL of serum. We also demonstrated that the devices show a significant degree of ruggedness and temperature stability as they were able to provide satisfactory results (detection of 0.1 pg/mL IgG) after 14 days of long stability and shelf-life experiment at an elevated temperature of at least 50 ˚C-the shelf life can be as long as 180 days under ambient conditions for detection of 100 µg/mL IgG.Conclusions: Because of the inherent simplicity of the device operation and their ease of use, there is no variation between samples and users of the device. This low-cost approach enables multiplexing with >1 measurement performed in parallel at the same time. We anticipate that because of the sensitivity, specificity, ease of use, and overall reliability, this approach will become a standard for diagnosis of diseases and health conditions. [ABSTRACT FROM AUTHOR]

Although the fictional domain exhibits a prima facie freedom from real-world moral constraints, certain fictive imaginings seem to deserve moral criticism. Capturing both intuitions, this paper argues for double-standard moralism, the view that fictive imaginings are subject to different moral standards than their real-world counterparts. I show how no account has, thus far, offered compelling reasons to warrant the moral appropriateness of this discrepancy. I maintain that the normative discontinuity between fiction and the actual world is moderate, as opposed to one that leaves fictive engagements wholly exempt from moral evaluations. I propose a way of addressing the gamer's dilemma that is compatible with a moderate kind of discontinuity. Finally, I contend that the audience is justified in adopting deviant moral attitudes in fictional situations because their consequences largely differ from those that analogous real-world events would have. [ABSTRACT FROM AUTHOR]

The knowledge of the gestational age of the newborn is essential for management. In the absence of a dating scan, the postnatal assessment scores have drawbacks of being difficult to learn and administer in the community. The measurement of the foot length is easy, reproducible and offers an objective assessment. The objective of this study was to determine the correlation of postnatal (<48 h) foot length measurement (with calipers) with gestational age as determined by antenatal dating ultrasound, create a predictive model for the same and propose foot length measurement cutoffs for <37 and <34 weeks of gestation. Secondary objectives were to assess the correlation between foot length as measured with calipers and that measured with a ruler and a paper footprint. This was a hospital-based cross-sectional study. Among the 520 babies assessed, the correlation of foot length with gestational age was 0.89. Operational cutoffs for the categories of <37 and <34 weeks at a sensitivity of 95% were <70 and <65 mm, respectively. The Pearson's correlation between foot length as measured by caliper and ruler was 0.95 and between caliper and paper footprint was 0.87. This study correlating foot length and gestational age has the potential to help neonatal care providers make informed management decisions, particularly in resource-limited settings. [ABSTRACT FROM AUTHOR]

Study Question: Are there temporal trends of sperm concentration (SC) and total sperm count (TSC) in Chinese healthy males from 1981 to 2019?Summary Answer: Our result indicated a temporal decrease in SC and TSC among 327 373 healthy Chinese men in the recent four decades.What Is Known Already: A review of 61 papers reported a temporal decline in SC and TSC from 1938 to 1990. This trend was later confirmed by a systematic review of 185 published papers from 1981 to 2013. However, the majority of the included individuals were from western countries. In China, whether SC and TSC have declined remains controversial.Study Design, Size, Duration: This systematic review of published articles used data extracted from Pubmed, Science Direct, Embase, China-National-Knowledge-Infrastructure (CNKI) and Wanfang Data to assess changes in SC and TSC in China from 1981 to 2019.Participants/materials, Setting, Methods: A total of 111 studies including 327 373 individuals who provided semen samples from 1981 to 2019 were extracted for the present analysis. Study selection and data extraction were performed by two independent researchers. The trends in SC and TSC were analysed using liner-regression and meta-regression before and after adjusting for potential covariates. Moreover, subgroups, categorised based on geographic region, fertility status or recruitment source, were also analysed.Main Results and the Role Of Chance: SC declined significantly (slope liner-regression = -0.748 million/ml/year; P = 0.005; slope meta-regression = -0.824 million/ml/year; P < 0.001) between 1981 and 2019 in China. Trends for TSC was similar to that for SC (slope liner-regression = -2.073 million/year; P = 0.032; slope meta-regression = -2.188 million/year; P = 0.003). In subgroup meta-regression analyses, males with definite fertility had continuous declines in SC (slope northern group=-2.268, P = 0.009; slope southern group=-1.014, P = 0.009) and TSC (slope northern group=-9.675, P = 0.010; slope southern group=-3.215, P = 0.042). However, in the unselected group, where fertility status was unknown, the obvious downward trend in SC was only seen in males from Northern regions (slope = -0.836, P = 0.003). Another subgroup analysis demonstrated that obvious decreases in SC (slope = -1.432, P < 0.001) and TSC (slope=-4.315, P = 0.001) were only seen in volunteer groups but not in pre-pregnancy examination groups and other recruitment groups. The results changed minimally in multiple sensitivity analyses.Limitations, Reasons For Caution: The validity of the meta-analysis results was limited mainly by the quality of the included studies. Additionally, our study spanned many decades and the recommended criteria for some semen parameter assessments have significantly changed, which may bring about some unavoidable bias. Moreover, the data remain insufficient especially in some provinces of China.Wider Implications Of the Findings: The present study is the first study to report significant decreases in SC and TSC in 327 373 healthy Chinese men between 1981 and 2019, indicating a serious reproductive health warning. Further studies on the causes of the declines are urgently needed.Study Funding/competing Interest(s): D.Z. is supported by the National Natural Science Funding of China, Natural Science Funding of Shaanxi Province, Science Funding of Health Department, Shaanxi Province, Fundamental Research Funds for the Central University and the Project of Independent Innovative Experiment for Postgraduates in Medicine in Xi'an Jiaotong University. The authors have no conflicts of interests to declare.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Introduction: In India, 38.7% of adults are exposed to SHS at home and 30.2% at work. This paper estimates the direct economic costs of diseases attributable to secondhand smoking (SHS) in India for persons aged 15 years and above.Aims and Methods: Nationally representative data on healthcare expenditures, healthcare utilization, and SHS prevalence were used to estimate economic costs attributable to SHS. A prevalence-based attributable risk approach was used for estimating the attributable direct costs. To estimate the SHS-attributable fraction, the excess utilization of healthcare among SHS exposed non-smokers compared to unexposed non-smokers was estimated using a method of propensity score matching (PSM).Results: The annual direct economic costs attributable to SHS from all diseases in India in the year 2017 for persons aged more than 15 years amounted to INR 566.7 billion (USD 8.7 billion). This amounted to INR 705 per adult non-smoker. The SHS attributable costs were higher among the youngest age group 20 to 24, and women bear 71% of the direct medical costs attributable to SHS.Conclusions: The annual direct economic costs of SHS amount to approximately 0.33% of India's Gross Domestic Product (GDP), or 8.1% of total healthcare expenditures in India. It is also much larger than the total excise tax revenue from cigarettes and bidis. As bidi smoking is the most popular form of smoking in India and bidis are mostly consumed by the poor, a disproportionate burden of SHS is likely borne by poor households in India.Implications: In India, 38.7% of adults are exposed to SHS at home and 30.2% at work. However, there is no estimate of the economic burden of any kind from SHS exposure in India. This study used a prevalence-based attributable risk approach combined with a PSM technique to estimate excess healthcare utilization for SHS exposed non-smokers and the annual direct economic costs of SHS in India. Annual direct SHS-attributable costs in India is INR 566.7 billion (USD 8.7 billion) SHS costs constituted 0.33% of GDP and 8.1% of healthcare expenditures in India. [ABSTRACT FROM AUTHOR]

Introduction: The number and variety of alternative tobacco and nicotine products that can potentially provide reduced-risk choices for cigarette smokers who switch completely to such products instead of continued smoking have grown substantially in the past decade. Innovation and choice are likely to improve the prospects of smokers making the switch, but this provides challenges to regulators and manufacturers to ensure that changes to regulations and products promote and do not hinder contributions to tobacco harm reduction.Aims and Methods: This paper looks at where bridging data sets for tobacco heating products, closed system vaping products, and oral nicotine products might enable innovation while protecting the interests of consumers.Results: We review product data from chemical studies and a toxicological study showing how bridging can be applied and consider what product development changes might allow bridging from existing datasets or trigger the need for new ones.Conclusions: Bridging across specific product ranges can increase the speed of innovation, foster competition, and limit the burden of assessment for regulators while maintaining product safety and quality.Implications: Bridging partial data sets is an established practice within other industries, that aims to improve efficiency with regulatory approvals, accepts natural product variation, and supports product innovation. We review product data from chemical studies and a toxicological study showing how bridging can be applied and consider what product development changes might allow bridging from existing datasets or trigger the need for new ones. This in turn can increase the speed of innovation, foster competition, and limit the burden of assessment for regulators while maintaining product safety and quality. [ABSTRACT FROM AUTHOR]

Introduction: The current study was designed to test the potential role of recombinant human MG53 (rhMG53) protein on protecting against alkaline-induced corneal injury in mice.Materials and Methods: A round filter paper with 2-mm diameter was soaked in 1 mol/L of NaOH solution. The mouse alkaline injury was generated by placing the filter paper directly on the cornea for 30 seconds and washed with 30-mL saline; 10 µL of rhMG53 solution (20 µg/mL) or saline control was topically administrated on the mouse corneas (twice per day for 10 days). Re-epithelialization was measured by fluorescein staining and imaged by a slit lamp equipped with a digital camera. Clinical neovascularization and opacity scores were measured every day after injury. Ten days after injury, mice were sacrificed and corneas were dissected out for flat mount staining of CD31 for neovascularization.Results: MG53 was present in both dog aqueous humor and human tears. mg53-/- corneas were more susceptible to alkaline-induced corneal injury. Topical treatment of rhMG53 improved re-epithelialization, suppressed neovascularization, and fibrosis induced by alkaline injury.Conclusions: rhMG53 may be an effective means to treat corneal wounding. [ABSTRACT FROM AUTHOR]

Introduction: The U.S. Army medics are often the first responders in the care of sick and injured soldiers on the battlefield, sick call in a Role 2 aid station and garrison clinics. Sick call medics are required to utilize the Algorithm Directed Troop Medical Care (ADTMC) to care for and then render a disposition for these soldiers. The current ADTMC manual is a thick, heavy paper manual. A desktop and smartphone application has been developed that contains the entire ADTMC manual algorithm-based content. Our goal is to enhance the medics' clinical learning and critical thinking skills while improving their evaluation, disposition, and documentation during patient encounters.Materials and Methods: The application was field-tested with the 173rd IBCT (A) while attending a field exercise at Grafenwoehr, Germany. At the unit's Role 2 tent setup, the use of the paper manual to the utilization of the same material via the ADTMC application was compared by observing the medics' workflows directly while they were caring for ill and injured soldiers.Results: Medics, while examining patients, would demonstrate 50% faster exam time using the application compared to medics using only the manual. Moreover, a 50% decrease in document processing time as a result of digitization of the paper documentation process was confirmed. The application ("app") enabled the medics to continue their screening assessments and patient disposition duties on a desktop computer or a smartphone without the need to refer to the paper manual.Conclusion: Medics, by adopting this tool, will become quicker, more efficient, and develop critical thinking skills. In other words, the ability to objectively evaluate patients in order to form a proper disposition of sick and injured soldiers during training, in the field, as well as in garrison. When utilized properly, the ADTMC application ensures that soldiers reporting to sick call are expeditiously routed to the appropriate level of care, and is a vehicle for further training for medics in the care of soldiers. [ABSTRACT FROM AUTHOR]

There has been substantial progress in the development of regenerative medicine strategies for CNS disorders over the last decade, with progression to early clinical studies for some conditions. However, there are multiple challenges along the translational pipeline, many of which are common across diseases and pertinent to multiple donor cell types. These include defining the point at which the preclinical data are sufficiently compelling to permit progression to the first clinical studies; scaling-up, characterization, quality control and validation of the cell product; design, validation and approval of the surgical device; and operative procedures for safe and effective delivery of cell product to the brain. Furthermore, clinical trials that incorporate principles of efficient design and disease-specific outcomes are urgently needed (particularly for those undertaken in rare diseases, where relatively small cohorts are an additional limiting factor), and all processes must be adaptable in a dynamic regulatory environment. Here we set out the challenges associated with the clinical translation of cell therapy, using Huntington's disease as a specific example, and suggest potential strategies to address these challenges. Huntington's disease presents a clear unmet need, but, importantly, it is an autosomal dominant condition with a readily available gene test, full genetic penetrance and a wide range of associated animal models, which together mean that it is a powerful condition in which to develop principles and test experimental therapeutics. We propose that solving these challenges in Huntington's disease would provide a road map for many other neurological conditions. This white paper represents a consensus opinion emerging from a series of meetings of the international translational platforms Stem Cells for Huntington's Disease and the European Huntington's Disease Network Advanced Therapies Working Group, established to identify the challenges of cell therapy, share experience, develop guidance and highlight future directions, with the aim to expedite progress towards therapies for clinical benefit in Huntington's disease. [ABSTRACT FROM AUTHOR]

Background: E-values are a recently introduced approach to evaluate confounding in observational studies. We aimed to empirically assess the current use of E-values in published literature.Methods: We conducted a systematic literature search for all publications, published up till the end of 2018, which cited at least one of two inceptive E-value papers and presented E-values for original data. For these case publications we identified control publications, matched by journal and issue, where the authors had not calculated E-values.Results: In total, 87 papers presented 516 E-values. Of the 87 papers, 14 concluded that residual confounding likely threatens at least some of the main conclusions. Seven of these 14 named potential uncontrolled confounders. 19 of 87 papers related E-value magnitudes to expected strengths of field-specific confounders. The median E-value was 1.88, 1.82, and 2.02 for the 43, 348, and 125 E-values where confounding was felt likely to affect the results, unlikely to affect the results, or not commented upon, respectively. The 69 case-control publication pairs dealt with effect sizes of similar magnitude. Of 69 control publications, 52 did not comment on unmeasured confounding and 44/69 case publications concluded that confounding was unlikely to affect study conclusions.Conclusions: Few papers using E-values conclude that confounding threatens their results, and their E-values overlap in magnitude with those of papers acknowledging susceptibility to confounding. Facile automation in calculating E-values may compound the already poor handling of confounding. E-values should not be a substitute for careful consideration of potential sources of unmeasured confounding. If used, they should be interpreted in the context of expected confounding in specific fields. [ABSTRACT FROM AUTHOR]

Good data curation is integral to cohort studies, but it is not always done to a level necessary to ensure the longevity of the data a study holds. In this opinion paper, we introduce the concept of data curation debt-the data curation equivalent to the software engineering principle of technical debt. Using the context of UK cohort studies, we define data curation debt-describing examples and their potential impact. We highlight that accruing this debt can make it more difficult to use the data in the future. Additionally, the long-running nature of cohort studies means that interest is accrued on this debt and compounded over time-increasing the impact a debt could have on a study and its stakeholders. Primary causes of data curation debt are discussed across three categories: longevity of hardware, software and data formats; funding; and skills shortages. Based on cross-domain best practice, strategies to reduce the debt and preventive measures are proposed-with importance given to the recognition and transparent reporting of data curation debt. Describing the debt in this way, we encapsulate a multi-faceted issue in simple terms understandable by all cohort study stakeholders. Data curation debt is not only confined to the UK, but is an issue the international community must be aware of and address. This paper aims to stimulate a discussion between cohort studies and their stakeholders on how to address the issue of data curation debt. If data curation debt is left unchecked it could become impossible to use highly valued cohort study data, and ultimately represents an existential risk to studies themselves. [ABSTRACT FROM AUTHOR]

Background: Changes in tobacco products, use patterns, and assessment technology in the last 15 years led the Society for Research on Nicotine and Tobacco (SRNT) Treatment Research Network to call for an update to the 2003 SRNT recommendations for assessing abstinence in clinical trials of smoking cessation interventions.Methods: The SRNT Treatment Research Network convened a group of investigators with decades of experience in conducting tobacco treatment clinical trials. To arrive at the updated recommendations, the authors reviewed the recommendations of the prior SRNT Workgroup as well as current literature. Ten additional experts in the field provided feedback on this paper and these recommendations.Results: With respect to defining abstinence, the authors recommend: (1) continuing to use the definition of no use of combustible tobacco products (regardless of use of noncombustible tobacco products [e.g., snus] and alternative products [e.g., e-cigarettes]) and collecting additional data to permit alternate abstinence definitions; (2) no use of combustible or smokeless tobacco products; and (3) no use of combustible or smokeless tobacco products or alternative products, as appropriate for the research question being addressed. The authors also recommend reporting point prevalence and prolonged abstinence at multiple timepoints (end of treatment, ≥3 months after the end of treatment, and ≥6 months postquit or posttreatment initiation).Conclusions: Defining abstinence requires specification of which products a user must abstain from using, the type of abstinence (i.e., point prevalence or continuous), and the duration of abstinence. These recommendations are intended to serve as guidelines for investigators as they collect the necessary data to accurately describe participants' abstinence during smoking cessation clinical trials.Implications: This paper provides updated recommendations for defining abstinence in the context of smoking cessation treatment clinical trials. [ABSTRACT FROM AUTHOR]

Background: The endocannabinoid system (ECS) consists of the cannabinoid receptors CB1 and CB2, the main endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) and their metabolic enzymes N-acylphosphatidylethanolamine-specific phospholipase D, fatty acid amide hydrolase, diacylglycerol lipase and monoacylglycerol lipase. This system is involved in the modulation of essential physiological processes. Its role in the reproductive system has become significantly important in recent years, given its major role in events such as gametogenesis, decidualisation, implantation and placentation.Objective and Rationale: In this paper, we review the literature and summarize the role of the ECS elements in reproduction and their potential as early markers for diagnosis of reproductive disorders or as pharmacological targets for treatment.Search Methods: Original research and review papers published from 1964 to June 2019 were selected in terms of relevance, reliability and quality by searching PubMed, MEDLINE and Web of Science, using the following search terms: endocannabinoid system and endometriosis; endocannabinoid system and ectopic pregnancy; endocannabinoid system and miscarriage; endocannabinoid system and pre-eclampsia; endocannabinoid system and endometrial cancer; endocannabinoid system and reproduction; endocannabinoid, endometrium; placenta; N-acylethanolamines; anandamide; 2-arachidonoylglycerol; and cannabinoids.Outcomes: This review demonstrates relevant information concerning ECS alterations in endometriosis, ectopic pregnancy, miscarriage, pre-eclampsia and endometrial cancer. We highlight the importance of the endocannabinoids in endometrial and placental physiology and pathophysiology, from studies in vitro and in vivo and in clinical observations. The most studied of the endogenous cannabinoids is AEA. The levels of AEA were increased in plasma of patients with endometriosis and miscarriage, as well as in the fallopian tube of women with ectopic pregnancy and in endometrial biopsies of endometrial cancer. Changes in the pattern of expression of the cannabinoid receptor CB1 were also observed in endometrial biopsies of endometriosis, fallopian tube and decidua of patients with ectopic pregnancy and pre-eclamptic placenta. Moreover, alterations in CB2 expression have been reported in association with endometrial cancer. In general, studies on the cannabinoid signalling through CB2 and on the biological activities of the other major endocannabinoid, namely 2-AG, as well as its metabolic enzymes are scarce and avidly required.Wider Implications: The pathophysiological mechanisms involved in the described endometrial and placental pathologies are still unclear and lack the means for an early diagnosis. Based on current evidence, though alterations in ECS are demonstrated at tissue level, it is difficult to associate plasmatic changes in AEA with specific endometrial and placental diseases. Thus, pairing alterations in AEA levels with 2-AG and/or other endocannabinoid-like molecules may provide more accurate and early diagnoses. In addition, patients may benefit from new therapies that target the ECS and endocannabinoid signalling. [ABSTRACT FROM AUTHOR]

Objectives: To assess the quality of evidence on the effectiveness of local US laws restricting the sale of flavored tobacco products.Methods: We conducted a systematic search and qualitative scoping review of English-language papers published through May 2020 that evaluated flavored tobacco sales policies implemented by US jurisdictions during 2010-2019. We constructed a conceptual model for flavored and menthol tobacco sales restriction outcomes, assigned GRADE quality of evidence ratings to policy outcomes evaluated through the included studies, and summarized factors that might explain weak or inconsistent findings.Results: We found moderate to high quality of evidence associating policy implementation with reduced availability, marketing, and sales of policy-restricted products, and decreased youth and adult tobacco use of these products; however, policy exclusions and exemptions, implementation challenges, tobacco industry actions (e.g., marketing of concept-named flavored products; exploiting policy exemptions for certain store types), and consumer responses (e.g., cross-border or illicit purchasing) might undermine or mitigate intended policy effects.Conclusions: Flavored and menthol tobacco product sales restrictions implemented and evaluated in US jurisdictions appear to have achieved some of their intended outcomes; however, deficiencies in study designs, methods, and metrics could contribute to equivocal findings on quality of evidence associating policy implementation and outcomes. Gaps in the evidence are beginning to be filled with research using more rigorous study designs, improved measurement and analytic methods, and longer-term follow-up.Implications: In the absence of comprehensive federal action, US jurisdictions have the obligation to restrict flavored and menthol product sales to protect vulnerable populations from tobacco-related harms. The considerable expenditure of financial resources, political will, and time dedicated to policy adoption and implementation argue for evaluation studies designed to maximize the quality of evidence. This review offers generalizable insights into evaluation findings that can inform efforts to enhance tobacco control policy implementation and impact in the US and globally. [ABSTRACT FROM AUTHOR]

Background: Convalescent plasma has been used to treat many viral diseases including Ebola. The manufacture of a purified anti-Ebola virus (EBOV) intravenous immunoglobulin (IVIG) from pooled convalescent plasma is described in this paper.Methods: An enzyme-linked immunosorbent assay (ELISA) targeting an EBOV surface glycoprotein antigen was used to determine the immunoglobulin titer of pooled plasma and purified anti-EBOV IVIG. Anti-EBOV IVIG was also tested in neutralization assays using a vesicular stomatitis virus pseudovirion expressing EBOV glycoprotein on its surface and with live EBOV. Finally, the efficacy of the anti-EBOV IVIG was assessed in a mouse model of EBOV infection.Results: In the ELISA, the anti-EBOV IVIG was shown to have a 7-fold increase in immunoglobulin G (IgG) titer over pooled convalescent plasma. In both the pseudovirion and live virus assays, the anti-EBOV IVIG showed approximately 5- to 6-fold increased potency over pooled plasma. Anti-EBOV IVIG also significantly improved survivability in mice infected with the virus when administered concurrently or 2 days after infection.Conclusions: These data support this purified anti-EBOV IVIG merits additional investigation and clinical trials for treatment and postexposure prophylaxis of Ebola virus disease. The experience gained can be applied to manufacture hyperimmune globulins against other emerging viruses. [ABSTRACT FROM AUTHOR]

Introduction: Diversification away from tobacco production has been identified as a priority for Malawi, historically one of the world's most tobacco-reliant countries.Methods: This paper refers to a nationally representative data set to characterize broad trends in production since 2000 to understand whether Malawi is shifting away from tobacco and how production has changed over time.Results: From 2004 to 2019, the share of Malawian crop farmers producing tobacco fell from 16% to 5%, and tobacco's share of the total value of crop production also declined sharply. Tobacco farms are generally growing larger (in size and scale of production) over time. However, land productivity remains low, with net returns of 93 000 MWK (128 USD) per hectare at the median. Farm-gate prices for tobacco have declined relative to the prices of maize or fertilizer, rendering tobacco a less lucrative avenue to generate the cash income needed to purchase these key items. In addition, the share of the export price received by farmers has also declined over time, with the median farm-gate price representing 32% of the export price in 2004 and 18% in 2019.Conclusions: In some respects, a transition away from tobacco has already occurred. Additional research is needed to understand why the farm-gate share of tobacco export prices has declined over this period and how the livelihoods of smallholder farm-households that exited tobacco production have been affected.Implications: To the extent that tobacco prices appear to be declining, there is a need to rigorously assess whether farmers have suitable crop alternatives (with established markets) and other livelihood options. Likely, investments are yet needed to foster strong alternatives to tobacco; such investments include research and development in on-farm technologies to raise the productivity of non-tobacco crops, as well as improvements in non-tobacco value chains to reduce transportation costs and promote private investment. [ABSTRACT FROM AUTHOR]

Background: Human male infertility has a notable genetic component, including well-established diagnoses such as Klinefelter syndrome, Y-chromosome microdeletions and monogenic causes. Approximately 4% of all infertile men are now diagnosed with a genetic cause, but a majority (60-70%) remain without a clear diagnosis and are classified as unexplained. This is likely in large part due to a delay in the field adopting next-generation sequencing (NGS) technologies, and the absence of clear statements from field leaders as to what constitutes a validated cause of human male infertility (the current paper aims to address this). Fortunately, there has been a significant increase in the number of male infertility NGS studies. These have revealed a considerable number of novel gene-disease relationships (GDRs), which each require stringent assessment to validate the strength of genotype-phenotype associations. To definitively assess which of these GDRs are clinically relevant, the International Male Infertility Genomics Consortium (IMIGC) has identified the need for a systematic review and a comprehensive overview of known male infertility genes and an assessment of the evidence for reported GDRs.Objective and Rationale: In 2019, the first standardised clinical validity assessment of monogenic causes of male infertility was published. Here, we provide a comprehensive update of the subsequent 1.5 years, employing the joint expertise of the IMIGC to systematically evaluate all available evidence (as of 1 July 2020) for monogenic causes of isolated or syndromic male infertility, endocrine disorders or reproductive system abnormalities affecting the male sex organs. In addition, we systematically assessed the evidence for all previously reported possible monogenic causes of male infertility, using a framework designed for a more appropriate clinical interpretation of disease genes.Search Methods: We performed a literature search according to the PRISMA guidelines up until 1 July 2020 for publications in English, using search terms related to 'male infertility' in combination with the word 'genetics' in PubMed. Next, the quality and the extent of all evidence supporting selected genes were assessed using an established and standardised scoring method. We assessed the experimental quality, patient phenotype assessment and functional evidence based on gene expression, mutant in-vitro cell and in-vivo animal model phenotypes. A final score was used to determine the clinical validity of each GDR, across the following five categories: no evidence, limited, moderate, strong or definitive. Variants were also reclassified according to the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines and were recorded in spreadsheets for each GDR, which are available at imigc.org.Outcomes: The primary outcome of this review was an overview of all known GDRs for monogenic causes of human male infertility and their clinical validity. We identified a total of 120 genes that were moderately, strongly or definitively linked to 104 infertility phenotypes.Wider Implications: Our systematic review curates all currently available evidence to reveal the strength of GDRs in male infertility. The existing guidelines for genetic testing in male infertility cases are based on studies published 25 years ago, and an update is far overdue. The identification of 104 high-probability 'human male infertility genes' is a 33% increase from the number identified in 2019. The insights generated in the current review will provide the impetus for an update of existing guidelines, will inform novel evidence-based genetic testing strategies used in clinics, and will identify gaps in our knowledge of male infertility genetics. We discuss the relevant international guidelines regarding research related to gene discovery and provide specific recommendations to the field of male infertility. Based on our findings, the IMIGC consortium recommend several updates to the genetic testing standards currently employed in the field of human male infertility, most important being the adoption of exome sequencing, or at least sequencing of the genes validated in this study, and expanding the patient groups for which genetic testing is recommended. [ABSTRACT FROM AUTHOR]

Background: Spermatozoa acquire their motility and fertilizing abilities during their maturation through the epididymis. This process is controlled by epididymal epithelial cells that possess features adapted to sense and respond to their surrounding environment and to communicate with spermatozoa. During the past decade, new intercellular communication processes have been discovered, including the secretion and transport of molecules from the epithelium to spermatozoa via extracellular vesicles (EVs), as well as sensing of the intraluminal milieu by cellular extensions.Objective and Rationale: This review addresses recent findings regarding epididymal epithelial cell features and interactions between spermatozoa and the epididymal epithelium as well as epigenetic modifications undergone by spermatozoa during transit through the epididymal microenvironment.Search Methods: A systematic search was conducted in Pubmed with the keyword 'epididymis'. Results were filtered on original research articles published from 2009 to 2021 and written in the English language. One hundred fifteen original articles presenting recent advancements on the epididymis contribution to sperm maturation were selected. Some additional papers cited in the primary reference were also included. A special focus was given to higher mammalian species, particularly rodents, bovines and humans, that are the most studied in this field.Outcomes: This review provides novel insights into the contribution of epididymal epithelium and EVs to post-testicular sperm maturation. First, new immune cell populations have been described in the epididymis, where they are proposed to play a role in protecting the environment surrounding sperm against infections or autoimmune responses. Second, novel epididymal cell extensions, including dendrites, axopodia and primary cilia, have been identified as sensors of the environment surrounding sperm. Third, new functions have been outlined for epididymal EVs, which modify the sperm epigenetic profile and participate in transgenerational epigenetic inheritance of paternal traits.Wider Implications: Although the majority of these findings result from studies in rodents, this fundamental research will ultimately improve our knowledge of human reproductive physiopathologies. Recent discoveries linking sperm epigenetic modifications with paternal environmental exposure and progeny outcome further stress the importance of advancing fundamental research on the epididymis. From this, new therapeutic options for infertile couples and better counseling strategies may arise to increase positive health outcomes in children conceived either naturally or with ART. [ABSTRACT FROM AUTHOR]

Background: Stanniocalcin-1 (STC-1) is a widely expressed glycoprotein hormone involved in a diverse spectrum of physiological and pathophysiological processes including angiogenesis, mineral homeostasis, cell proliferation, inflammation and apoptosis. Over the last 20 years, numerous studies have reported STC-1 expression within female reproductive tissues including the uterus, ovaries and placenta and implicated STC-1 in processes such as ovarian follicular development, blastocyst implantation, vascular remodelling in early pregnancy and placental development. Notably, dysregulation of STC-1 within reproductive tissues has been linked to the onset of severe reproductive disorders including endometriosis, polycystic ovary syndrome, poor trophoblast invasion and placental perfusion in early pregnancy. Furthermore, significant changes in tissue expression and in maternal systemic concentration take place throughout pregnancy and further substantiate the vital role of this protein in reproductive health and disease.Objective and Rationale: Our aim is to provide a comprehensive overview of the existing literature, to summarise the expression profile and roles of STC-1 within the female reproductive system and its associated pathologies. We highlight the gaps in the current knowledge and suggest potential avenues for future research.Search Methods: Relevant studies were identified through searching the PubMed database using the following search terms: 'stanniocalcin-1', 'placenta', 'ovary', 'endometrium', 'pregnancy', 'reproduction', 'early gestation'. Only English language papers published between 1995 and 2020 were included.Outcomes: This review provides compelling evidence of the vital function that STC-1 plays within the female reproductive system. The literature presented summarise the wide expression profile of STC-1 within female reproductive organs, as well as highlighting the putative roles of STC-1 in various functions in the reproductive system. Moreover, the observed link between altered STC-1 expression and the onset of various reproductive pathologies is presented, including those in pregnancy whose aetiology occurs in the first trimester. This summary emphasises the requirement for further studies on the mechanisms underlying the regulation of STC-1 expression and function.Wider Implications: STC-1 is a pleiotropic hormone involved in the regulation of a number of important biological functions needed to maintain female reproductive health. There is also growing evidence that dysregulation of STC-1 is implicated in common reproductive and obstetric disorders. Greater understanding of the physiology and biochemistry of STC-1 within the field may therefore identify possible targets for therapeutic intervention and/or diagnosis. [ABSTRACT FROM AUTHOR]

Background: Worldwide, the prevalence of obesity in women of reproductive age is increasing. Bariatric surgery is currently viewed as the most effective, long-term solution for this problem. Preconception bariatric surgery can reduce the prevalence of obesity-related subfertility and adverse maternal, pregnancy and birth outcomes. Maternal health during the periconception period is crucial for optimal gametogenesis and for embryonic and fetal development which also affects health in the later lives of both mother and offspring. Although preconception bariatric surgery improves several pregnancy outcomes, it can also increase the prevalence of pregnancy complications due to excessive and rapid weight loss. This can lead to iatrogenic malnutrition with vitamin deficiencies and derangements in metabolic and endocrine homeostasis. Thus, bariatric surgery can greatly influence periconception maternal health with consequences for reproduction, pregnancy and health in later life. However, its influence on periconception maternal health itself has never been reviewed systematically.Objective and Rationale: The aim of this review was to investigate associations between bariatric surgery and determinants of periconception maternal health such as endocrine changes, fertility, vitamin status, irregular menstrual cycles, miscarriages and congenital malformations.Search Methods: Medline, Embase, PubMed, Web of Science, Google Scholar and the Cochrane databases were used for the literature search until 1 November 2020. The search strategy terms included, among others, bariatric surgery, hormones, fertility, malformations, miscarriages and vitamin status. We searched for human studies that were written in English. Abstracts, reviews, meta-analyses and conference papers were excluded. The ErasmusAGE score was used to assess the quality of the included studies.Outcomes: A total of 51 articles were analysed. The mean quality score was 5 (range 2-8). After bariatric surgery, hormonal axes normalized and menstrual cycle regularity was restored, resulting in increased fertility. Overall, there were no short-term risks for reproductive outcomes such as the increased risk of miscarriages or congenital malformations. However, the risk of vitamin deficiencies was generally increased after bariatric surgery. A meta-analysis of 20 studies showed a significant decrease in infertility (risk difference (RD) -0.24, 95% confidence interval (CI) -0.42, -0.05) and menstrual cycle irregularities (RD -0.24, 95% CI -0.34, -0.15) with no difference in rates of miscarriage (RD 0.00, 95% CI -0.09, 0.10) and congenital malformations (RD 0.01, 95% CI -0.02, 0.03).Wider Implications: The current systematic review and meta-analysis show associations between bariatric surgery and periconception maternal health and underlines the need for providing and personalizing preconception care for women after bariatric surgery. We recommend preconception care including the recommendation of postponing pregnancy until weight loss has stabilized, irrespective of the surgery-to-pregnancy interval, and until vitamin status is normalized. Therefore, regular monitoring of vitamin status and vitamin supplementation to restore deficiencies is recommended. Furthermore, this systematic review emphasizes the need for a long-term follow-up research of these women from the periconception period onwards as well as their pregnancies and offspring, to further improve care and outcomes of these mothers and children. [ABSTRACT FROM AUTHOR]

Background: Rigorously designed longitudinal studies can inform how best to reduce the widening health gap between Indigenous and non-Indigenous children.Methods: A systematic review was performed to identify and present the breadth and depth of longitudinal studies reporting the health and well-being of Indigenous children (aged 0-18 years) globally. Databases were searched up to 23 June 2020. Study characteristics were mapped according to domains of the life course model of health. Risk of bias was assessed using the National Institutes of Health (NIH) Study Quality Assessment Tools. Reported level of Indigenous involvement was also appraised; PROSPERO registration CRD42018089950.Results: From 5545 citations, 380 eligible papers were included for analysis, representing 210 individual studies. Of these, 41% were located in Australia (n = 88), 22.8% in the USA (n = 42), 11.9% in Canada (n = 25) and 10.9% in New Zealand (n = 23). Research tended to focus on either health outcomes (50.9%) or health-risk exposures (43.8%); 55% of studies were graded as 'good' quality; and 89% of studies made at least one reference to the involvement of Indigenous peoples over the course of their research.Conclusions: We identified gaps in the longitudinal assessment of cultural factors influencing Indigenous child health at the macrosocial level, including connection to culture and country, intergenerational trauma, and racism or discrimination. Future longitudinal research needs to be conducted with strong Indigenous leadership and participation including holistic concepts of health. This is critical if we are to better understand the systematic factors driving health inequities experienced by Indigenous children globally. [ABSTRACT FROM AUTHOR]

Introduction: Smokeless tobacco (ST) is a significant South Asian public health problem. This paper reports a qualitative study of a sample of South Asian ST users.Methods: Interviews, using a piloted topic guide, with 33 consenting, urban dwelling adult ST users explored their ST initiation, continued use, and cessation attempts. Framework data analysis was used to analyze country specific data before a thematic cross-country synthesis was completed.Results: Participants reported long-term ST use and high dependency. All reported strong cessation motivation and multiple failed attempts because of ease of purchasing ST, tobacco dependency, and lack of institutional support.Conclusions: Interventions to support cessation attempts among consumers of South Asian ST products should address the multiple challenges of developing an integrated ST policy, including cessation services.Implications: This study provides detailed understanding of the barriers and drivers to ST initiation, use, and cessation for users in Bangladesh, India, and Pakistan. It is the first study to directly compare these three countries. The insight was then used to adapt an existing behavioral support intervention for ST cessation for testing in these countries. [ABSTRACT FROM AUTHOR]

Introduction: Smoking rates are alarmingly high among young people experiencing homelessness (YEH), yet there are no evidence-based cessation programs for this population. This paper presents results from a pilot evaluation of a text messaging-based smoking cessation treatment, as an adjunct to brief group cessation counseling, to improve abstinence rates among 18-25-year-old smokers experiencing homelessness. The goal of this study was to estimate effect sizes for a larger trial and it was not powered to detect group differences.Aims and Methods: YEH smokers who had a working cell phone with them at recruitment were randomized to receive a group counseling session, nicotine patches, and written material on quitting (n = 37) or a similar program that also included a 6-week automated text messaging intervention (TMI) to provide ongoing support for quitting (n = 40). Smoking outcomes were evaluated through a 90-day follow-up.Results: Seven-day point prevalence abstinence at 90-day follow-up was higher in the TMI condition than standard condition (17.50% vs. 8.11%, respectively; Cohen's h = .37); however, the 90-day continuous abstinence rate was not statistically different from zero in either condition. Reductions in the number of days smoked in the past 30 days from baseline to follow-up were greater in the TMI condition than the standard condition (-14.24 vs. -8.62, respectively; Cohen's d = .49).Conclusions: Adding a 6-week TMI support to a brief group counseling and pharmacotherapy protocol holds promise for smoking reduction and abstinence among YEH smokers. Results indicate that further development and evaluation of the TMI in this population is warranted.Trial Registration: ClinicalTrials.gov Identifier NCT03874585. Registered March 14, 2019, https://clinicaltrials.gov/ct2/show/record/NCT03874585.Implications: This is the first study to evaluate the feasibility of using a text messaging-based intervention (TMI) for behavior change with 18-25 year olds experiencing homelessness, and more specifically, the first to test a TMI to provide ongoing support for smoking cessation. Small to medium effect sizes for the TMI are promising in terms of implementing a TMI using participants' own cell phones, as well as the efficacy of this approach as an adjunct to standard care (brief group counseling and pharmacotherapy) for smoking cessation among YEH. [ABSTRACT FROM AUTHOR]

Introduction: To review the geographic exposure measures used to characterize the tobacco environment in terms of density of tobacco outlets and proximity to tobacco outlets, and its association with smoking-related outcomes.Methods: We used PubMed and Google Scholar to find articles published until December 2019. The search was restricted to studies that (1) measured the density of and/or proximity to tobacco outlets and (2) included associations with smoking outcomes. The extraction was coordinated by several observers. We gathered data on the place of exposure, methodological approaches, and smoking outcomes.Results: Forty articles were eligible out of 3002 screened papers. Different density and proximity measures were described. 47.4% density calculations were based on simple counts (number of outlets within an area). Kernel density estimations and other measures weighted by the size of the area (outlets per square kilometer), population, and road length were identified. 81.3% of the articles which assessed proximity to tobacco outlets used length distances estimated through the street network. Higher density values were mostly associated with higher smoking prevalence (76.2%), greater tobacco use and smoking initiation (64.3%), and lower cessation outcomes (84.6%). Proximity measures were not associated with any smoking outcome except with cessation (62.5%).Conclusion: Associations between the density of tobacco outlets and smoking outcomes were found regardless of the exposure measure applied. Further research is warranted to better understand how proximity to tobacco outlets may influence the smoking outcomes. This systematic review discusses methodological gaps in the literature and provides insights for future studies exploring the tobacco environment.Implications: Our findings pose some methodological lessons to improve the exposure measures on the tobacco outlet environment. Solving these methodological gaps is crucial to understand the influence of the tobacco environment on the smoking outcomes. Activity spaces should be considered in further analyses because individuals are exposed to tobacco beyond their residence or school neighborhood. Further studies in this research area demand density estimations weighted by the size of the area, population, or road length, or measured using Kernel density estimations. Proximity calculations should be measured through the street network and should consider travel times apart from the length distance. [ABSTRACT FROM AUTHOR]

China has launched a series of talent-recruitment policies in the last years, in order to attract back Chinese nationals who stayed abroad. Yet, little is known about the effect of such policies. This paper examines whether researchers recruited in one of the Chinese flagship talent-recruitment policies—the 'Young Thousand Talents' policy (Y1000T)—had, in the following years after recruitment, better research performance. We compare these recipients against other Chinese nationals who got PhDs in equally prestigious non-Chinese universities but continued to work abroad (mostly in the USA). Results of difference-in-differences regressions show that returning to China has an effect of positioning returnees both at the bottom and at the very summit of the distribution of quality of publications. Nevertheless, some Y1000T researchers seem to have prioritized the quantity of outputs, arguably to the detriment of quality. This is probably due to certain research evaluation criteria in place until recent times. [ABSTRACT FROM AUTHOR]

Background: A nudge corresponds to any procedure that influences choice architecture, without using persuasion or financial incentives. Nudges are effective in increasing vaccination with heterogeneous levels of acceptability.Objective: To evaluate the effectiveness and acceptability of a nudge promoting influenza vaccination for general practice trainees, also called residents.Methods: The hypothesis was that a reminder would be efficient and accepted and that prior exposure to a nudge increases its acceptability. Residents were randomly divided into three parallel experimental arms: a nudge group, a no-nudge group and a control group in order to evaluate the Hawthorne effect. The nudge consisted of providing a paper form for the free delivery of the vaccine and contacts for occupational health services.Results: The analysis included 161 residents. There was a strong consensus among the residents that it is very acceptable to nudge their peers and patients. Acceptability was better with residents exposed to the nudge and with residents included in step 1 (Hawthorne effect). The nudge did not increase vaccination coverage.Conclusion: The failure of this nudge highlights the importance of matching an intervention to the population's needs. The experimental approach is innovative in this context and deserves further attention.Clinicaltrials.gov Pre-registration: NCT03768596. [ABSTRACT FROM AUTHOR]

Globally, prisoners tend to come from marginalized and socially disadvantaged sections of the society and exhibit a high incidence of ill health, linked to social exclusion and multiple complex needs. Prisons therefore offer an important opportunity to tackle inequality and injustice, through promoting health, reducing reoffending and facilitating community reintegration.This paper reports on and critically discusses findings from an evaluative research study, which aimed to identify and explore impacts of prisoners' participation in an innovative social and therapeutic horticultural programme, 'Greener on the Outside for Prisons' (GOOP), delivered in prisons in North West England. Focus groups with 16 prisoners and semi-structured interviews with six prison staff were conducted at five sites. Presented under three overarching themes (health and well-being; skills development, employability, and work preparedness; and relationships), findings suggest that engagement with and participation in GOOP were important in improving positive mental well-being, increasing physical activity and knowledge about healthier eating; developing skills and work readiness; and building relationships and catalysing and strengthening prosocial behaviours, important for good citizenship and effective resettlement. The paper concludes that – in the context of the current UK prison reform agenda and concern about the high incidence of violence, substance misuse, self-harm and suicide – prison-based horticulture can offer multiple benefits and make a significant contribution to the creation of safe, secure, supportive and health-enhancing environments. Furthermore, it contends that by joining up health and justice agendas, programmes such as GOOP have the potential to serve as powerful catalysts for wider systemic change, thereby helping tackle inequalities and social exclusion within societies across the globe. [ABSTRACT FROM AUTHOR]

Study Question: How many twins are born in human populations and how has this changed over recent decades?Summary Answer: Since the 1980s, the global twinning rate has increased by a third, from 9.1 to 12.0 twin deliveries per 1000 deliveries, to about 1.6 million twin pairs each year.What Is Known Already: It was already known that in the 1980s natural twinning rates were low in (East) Asia and South America, at an intermediate level in Europe and North America, and high in many African countries. It was also known that in recent decades, twinning rates have been increasing in the wealthier parts of our world as a result of the rise in medically assisted reproduction (MAR) and delayed childbearing.Study Design, Size, Duration: We have brought together all information on national twinning rates available from statistical offices, demographic research institutes, individual survey data and the medical literature for the 1980-1985 and the 2010-2015 periods.Participants/materials, Setting, Methods: For 165 countries, covering over 99% of the global population, we were able to collect or estimate twinning rates for the 2010-2015 period. For 112 countries, we were also able to obtain twinning rates for 1980-1985.Main Results and the Role Of Chance: Substantial increases in twinning rates were observed in many countries in Europe, North America and Asia. For 74 out of 112 countries the increase was more than 10%. Africa is still the continent with highest twinning rates, but Europe, North America and Oceania are catching up rapidly. Asia and Africa are currently home to 80% of all twin deliveries in the world.Limitations, Reasons For Caution: For some countries, data were derived from reports and papers based on hospital registrations which are less representative for the country as a whole than data based on public administrations and national surveys.Wider Implications Of the Findings: The absolute and relative number of twins for the world as a whole is peaking at an unprecedented level. An important reason for this is the tremendous increase in medically assisted reproduction in recent decades. This is highly relevant, as twin deliveries are associated with higher infant and child mortality rates and increased complications for mother and child during pregnancy and during and after delivery.Study Funding/competing Interest(s): The contribution of CM was partially supported by the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Programme (grant No 681546, FAMSIZEMATTERS), Nuffield College, and the Leverhulme Trust. The contribution of GP was partially supported by the French Agence Nationale de la Recherche (grant No ANR-18-CE36-0007-07). The authors declare no conflict of interest.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Introduction: In the United States, firearm suicide represents a major cause of preventable, premature death among veterans. The purpose of this systematic review was to characterize the body of literature on veteran firearm suicide and identify areas for future research, which may facilitate the development of firearm suicide interventions in Veterans Health Administration (VHA) and non-Veterans Health Administration clinical settings.Materials and Methods: All randomized controlled trials, quasi-experimental, naturalistic, observational, and case study designs published between January 1, 1990 and February 21, 2019 were included in our review. Following title and abstract review, 65 papers were included in our full-text review and 37 studies were included in our analysis. We based our approach on a modification of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Studies were grouped into broad, nonmutually exclusive categories: (1) heterogeneity of datasets and veteran status determination for inclusion, (2) service histories, (3) firearm ownership, storage, behaviors, and risk perceptions, (4) patient and clinician attitudes toward firearm restriction interventions, (5) firearm suicide risk factors by study population, and (6) assessments of clinical firearm interventions.Results: This body of literature consists predominately of cross-sectional studies with mixed definitions and validation of veteran status, which revealed high concordance of increased risk of firearm suicide compared with nonveterans. Veterans have higher rates of firearm ownership than the general population, primarily citing personal protection as the reason for gun ownership. Veterans often exhibit risky firearm usage and storage behaviors but tend to favor measures that limit access to firearms by at-risk individuals. Despite this, there remains persistent hesitation among clinicians to screen and counsel veterans on firearm safety.Conclusions: This systematic review highlights an urgent need to produce higher quality evidence and new data with standard definitions that are critical to inform clinical practice and enhance public health measures to reduce firearm suicide among veterans. [ABSTRACT FROM AUTHOR]

Background: Directed acyclic graphs (DAGs) are of great help when researchers try to understand the nature of causal relationships and the consequences of conditioning on different variables. One fundamental feature of causal relations that has not been incorporated into the standard DAG framework is interaction, i.e. when the effect of one variable (on a chosen scale) depends on the value that another variable is set to. In this paper, we propose a new type of DAG-the interaction DAG (IDAG), which can be used to understand this phenomenon.Methods: The IDAG works like any DAG but instead of including a node for the outcome, it includes a node for a causal effect. We introduce concepts such as confounded interaction and total, direct and indirect interaction, showing that these can be depicted in ways analogous to how similar concepts are depicted in standard DAGs. This also allows for conclusions on which treatment interactions to account for empirically. Moreover, since generalizability can be compromised in the presence of underlying interactions, the framework can be used to illustrate threats to generalizability and to identify variables to account for in order to make results valid for the target population.Conclusions: The IDAG allows for a both intuitive and stringent way of illustrating interactions. It helps to distinguish between causal and non-causal mechanisms behind effect variation. Conclusions about how to empirically estimate interactions can be drawn-as well as conclusions about how to achieve generalizability in contexts where interest lies in estimating an overall effect. [ABSTRACT FROM AUTHOR]

The main purpose of research in mice is to explore metabolic changes in animal models and then predict or propose potential translational benefits in humans. Although some researchers in the brain research field have mentioned that the mouse experiments results still lack the complex neuroanatomy of humans, caution is required to interpret the findings. In mice, we observed in article seventeenth of the series of the effects of graded levels of calorie restriction, metabolomic changes in the cerebellum indicated activation of hypothalamocerebellar connections driven by hunger responses. Therefore, the purpose of the current perspective is to set this latest paper into a wider context of the physiological, behavioral, and molecular changes seen in these mice and to compare and contrast them with previous human studies. [ABSTRACT FROM AUTHOR]

Study Question: Is it possible to evaluate the methylome of individual oocytes to investigate the DNA methylome alterations in metaphase II (MII) oocytes with reduced embryo developmental potential?Summary Answer: The DNA methylome of each human first polar body (PB1) closely mirrored that of its sibling MII oocyte; hypermethylated long interspersed nuclear element (LINE) and long terminal repeats (LTRs) and methylation aberrations in PB1 promoter regions may indicate poor embryo development.What Is Known Already: The developmental potential of an embryo is determined by the oocyte's developmental competence, and the PB1 is a good substitute to examine the chromosomal status of the corresponding oocyte. However, DNA methylation, a key epigenetic modification, also regulates gene expression and embryo development.Study Design, Size, Duration: Twelve pairs of PB1s and sibling MII oocytes were biopsied and sequenced to compare their methylomes. To further investigate the methylome of PB1s and the potential epigenetic factors that may affect oocyte quality, MII oocytes (n = 74) were fertilized through ICSI, while PB1s were biopsied and profiled to measure DNA methylation. The corresponding embryos were further cultured to track their development potential. The oocytes and sperm samples used in this study were donated by healthy volunteers with signed informed consent.Participants/materials, Setting, Methods: Single-cell methylome sequencing was applied to obtain the DNA methylation profiles of PB1s and oocytes. The DNA methylome of PB1s was compared between the respective group of oocytes that progressed to blastocysts and the group of oocytes that failed to develop. DNA methylation levels of corresponding regions and differentially methylated regions were calculated using customized Perl and R scripts. RNA-seq data were downloaded from a previously published paper and reanalysed.Main Results and the Role Of Chance: The results from PB1-MII oocyte pair validated that PB1 contains nearly the same methylome (average Pearson correlation is 0.92) with sibling MII oocyte. LINE and LTR expression increased markedly after fertilization. Moreover, the DNA methylation levels in LINE (including LINE1 and LINE2) and LTR were significantly higher in the PB1s of embryos that could not reach the blastocyst stage (Wilcoxon-Matt-Whitney test, P < 0.05). DNA methylation in PB1 promoters correlated negatively with gene expression of MII oocyte. Regarding the methylation status of the promoter regions, 66 genes were hypermethylated in the developmental arrested group, with their related functions (significantly enriched in several Gene Ontology terms) including transcription, positive regulation of adenylate cyclase activity, mitogen-activated protein kinase (MAPK) cascade and intracellular oestrogen receptor signalling pathway.Large Scale Data: N/A.Limitations, Reasons For Caution: Data analysis performed in this study focused on the competence of human oocytes and compared them with maternal genetic and epigenetic profiles. Therefore, data regarding the potential regulatory roles of paternal genomes in embryo development are lacking.Wider Implications Of the Findings: The results from PB1-oocyte pairs demonstrated that PB1s shared similar methylomes with their sibling oocytes. The selection of the good embryos for transfer should not only rely on morphology but also consider the DNA methylation of the corresponding PB1 and therefore MII oocyte. The application of early-stage analysis of PB1 offers an option for high-quality oocyte and embryo selection, which provides an additional tool for elective single embryo transfer in assisted reproduction.Study Funding/competing Interest(s): This study was supported by the National Key Research and Development Program of China (2018YFC1004003, 2017YFA0103801), the National Natural Science Foundation of China (81730038, 3187144, 81521002) and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16020703). The authors have no conflicts of interest to declare. [ABSTRACT FROM AUTHOR]

The Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK) were developed to address widespread deficiencies in the reporting of such studies. The REMARK checklist consists of 20 items to report for published tumor marker prognostic studies. A detailed paper was published explaining the rationale behind checklist items, providing positive examples and giving empirical evidence of the quality of reporting. REMARK provides a comprehensive overview to educate on good reporting and provide a valuable reference for the many issues to consider when designing, conducting, and analyzing tumor marker studies and prognostic studies in medicine in general. Despite support for REMARK from major cancer journals, prognostic factor research studies remain poorly reported. To encourage dissemination and uptake of REMARK, we have produced this considerably abridged version of the detailed explanatory manuscript, which may also serve as a brief guide to key issues for investigators planning tumor marker prognostic studies. To summarize the current situation, more recent papers investigating the quality of reporting and related reporting guidelines are cited, but otherwise the literature is not updated. Another important impetus for this paper is that it serves as a basis for literal translations into other languages. Translations will help to bring key information to a larger audience world-wide. Many more details can be found in the original paper. [ABSTRACT FROM AUTHOR]

Background: Point-of-care tests (POCT) can assist general practitioners (GPs) in diagnosing and treating patients with acute cardiopulmonary symptoms, but it is currently unknown if POCT impact relevant clinical outcomes in these patients.Objective: To assess whether using POCT in primary care patients with acute cardiopulmonary symptoms leads to more accurate diagnosis and impacts clinical management.Methods: We performed a systematic review in four bibliographic databases. Articles published before February 2016 were screened by two reviewers. Studies evaluating the effect of GP use of POCT on clinical diagnostic accuracy and/or effect on treatment and referral rate in patients with cardiopulmonary symptoms were included.Results: Our search yielded nine papers describing data from seven studies, on the clinical diagnostic accuracy of POCT in a total of 2277 primary care patients with acute cardiopulmonary symptoms. Four papers showed data on GP use of D-dimer POCT in pulmonary embolism (two studies); two studies on Troponin T in acute coronary syndrome; one on heart-type fatty acid-binding protein (H-FABP) in acute coronary syndrome; one on B-type natriuretic peptide (BNP) in heart failure; one on 3-in-1 POCT (Troponin T, BNP, D-dimer) in acute coronary syndrome, heart failure and/or pulmonary embolism. Only one study assessed the effect of GP use of POCT on treatment initiation and one on actual referral rates.Conclusion: There is currently limited and inconclusive evidence that actual GP use of POCT in primary care patients with acute cardiopulmonary symptoms leads to more accurate diagnosis and affects clinical management. However, some studies show promising results, especially when a POCT is combined with a clinical decision rule. [ABSTRACT FROM AUTHOR]

Background: Systematic reviews of prenatal alcohol exposure effects generally only include conventional observational studies. However, estimates from such studies are prone to confounding and other biases.Objectives: To systematically review the evidence on the effects of prenatal alcohol exposure from randomized controlled trials (RCTs) and observational designs using alternative analytical approaches to improve causal inference.Search Strategy: Medline, Embase, Web of Science, PsychINFO from inception to 21 June 2018. Manual searches of reference lists of retrieved papers.Selection Criteria: RCTs of interventions to stop/reduce drinking in pregnancy and observational studies using alternative analytical methods (quasi-experimental studies e.g. Mendelian randomization and natural experiments, negative control comparisons) to determine the causal effects of prenatal alcohol exposure on pregnancy and longer-term offspring outcomes in human studies.Data Collection and Analysis: One reviewer extracted data and another checked extracted data. Risk of bias was assessed using customized risk of bias tools. A narrative synthesis of findings was carried out and a meta-analysis for one outcome.Main Results: Twenty-three studies were included, representing five types of study design, including 1 RCT, 9 Mendelian randomization and 7 natural experiment studies, and reporting on over 30 outcomes. One study design-outcome combination included enough independent results to meta-analyse. Based on evidence from several studies, we found a likely causal detrimental role of prenatal alcohol exposure on cognitive outcomes, and weaker evidence for a role in low birthweight.Conclusion: None of the included studies was judged to be at low risk of bias in all domains, results should therefore be interpreted with caution.Systematic Review Registration: This study is registered with PROSPERO, registration number CRD42015015941. [ABSTRACT FROM AUTHOR]

Causal inference requires theory and prior knowledge to structure analyses, and is not usually thought of as an arena for the application of prediction modelling. However, contemporary causal inference methods, premised on counterfactual or potential outcomes approaches, often include processing steps before the final estimation step. The purposes of this paper are: (i) to overview the recent emergence of prediction underpinning steps in contemporary causal inference methods as a useful perspective on contemporary causal inference methods, and (ii) explore the role of machine learning (as one approach to 'best prediction') in causal inference. Causal inference methods covered include propensity scores, inverse probability of treatment weights (IPTWs), G computation and targeted maximum likelihood estimation (TMLE). Machine learning has been used more for propensity scores and TMLE, and there is potential for increased use in G computation and estimation of IPTWs. [ABSTRACT FROM AUTHOR]

Interrupted time series designs are a valuable quasi-experimental approach for evaluating public health interventions. Interrupted time series extends a single group pre-post comparison by using multiple time points to control for underlying trends. But history bias-confounding by unexpected events occurring at the same time of the intervention-threatens the validity of this design and limits causal inference. Synthetic control methodology, a popular data-driven technique for deriving a control series from a pool of unexposed populations, is increasingly recommended. In this paper, we evaluate if and when synthetic controls can strengthen an interrupted time series design. First, we summarize the main observational study designs used in evaluative research, highlighting their respective uses, strengths, biases and design extensions for addressing these biases. Second, we outline when the use of synthetic controls can strengthen interrupted time series studies and when their combined use may be problematic. Third, we provide recommendations for using synthetic controls in interrupted time series and, using a real-world example, we illustrate the potential pitfalls of using a data-driven approach to identify a suitable control series. Finally, we emphasize the importance of theoretical approaches for informing study design and argue that synthetic control methods are not always well suited for generating a counterfactual that minimizes critical threats to interrupted time series studies. Advances in synthetic control methods bring new opportunities to conduct rigorous research in evaluating public health interventions. However, incorporating synthetic controls in interrupted time series studies may not always nullify important threats to validity nor improve causal inference. [ABSTRACT FROM AUTHOR]

The Surviving Sepsis Campaign recommends immediate antibiotics for all patients with suspected sepsis and septic shock, ideally within 1 hour of recognition. Immediate antibiotic treatment is lifesaving for some patients, but a substantial fraction of patients initially diagnosed with sepsis have noninfectious conditions. Aggressive time-to-antibiotic targets risk promoting antibiotic overuse and antibiotic-associated harms for this subset of the population. An accurate understanding of the precise relationship between time-to-antibiotics and mortality for patients with possible sepsis is therefore critical to finding the best balance between assuring immediate antibiotics for those patients who truly need them versus allowing clinicians some time for rapid investigation to minimize the risk of overtreatment and antibiotic-associated harms for patients who are not infected. More than 30 papers have been published assessing the relationship between time-to-antibiotics and outcomes, almost all of which are observational cohort studies. Most report significant associations but all have important limitations. Key limitations include focusing just on the sickest subset of patients (only patients requiring intensive care and/or patients with septic shock), blending together mortality estimates from patients with very long intervals until antibiotics with patients with shorter intervals and reporting a single blended (and thus inflated) estimate for the average increase in mortality associated with each hour until antibiotics, and failure to control for large potential confounders including patients' presenting signs and symptoms and granular measures of comorbidities and severity of illness. In this study, we elaborate on these potential sources of bias and try to distill a better understanding of what the true relationship between time-to-antibiotics and mortality may be for patients with suspected sepsis or septic shock. [ABSTRACT FROM AUTHOR]

Background: In the UK, general practitioners (GPs) are the most commonly used providers of care for emotional concerns.Objective: To update and synthesize literature on barriers and facilitators to GP-patient communication about emotional concerns in UK primary care.Design: Systematic review and qualitative synthesis.Method: We conducted a systematic search on MEDLINE (OvidSP), PsycInfo and EMBASE, supplemented by citation chasing. Eligible papers focused on how GPs and adult patients in the UK communicated about emotional concerns. Results were synthesized using thematic analysis.Results: Across 30 studies involving 342 GPs and 720 patients, four themes relating to barriers were: (i) emotional concerns are difficult to disclose; (ii) tension between understanding emotional concerns as a medical condition or arising from social stressors; (iii) unspoken assumptions about agency resulting in too little or too much involvement in decisions and (iv) providing limited care driven by little time. Three facilitative themes were: (v) a human connection improves identification of emotional concerns and is therapeutic; (vi) exploring, explaining and negotiating a shared understanding or guiding patients towards new understandings and (vii) upfront information provision and involvement manages expectations about recovery and improves engagement in treatment.Conclusion: The findings suggest that treatment guidelines should acknowledge: the therapeutic value of a positive GP-patient relationship; that diagnosis is a two-way negotiated process rather than an activity strictly in the doctor's domain of expertise; and the value of exploring and shaping new understandings about patients' emotional concerns and their management. [ABSTRACT FROM AUTHOR]

Study Question: Is an MRI classification of deep pelvic endometriosis (DE) able to correctly predict the risk of DE surgery.Summary Answer: A new radiological classification, that we have called the deep pelvic endometriosis index (dPEI) classification, is accurate and reproducible to assess the extension of the disease in central and lateral compartments and well correlated with operating time, hospital stay duration and the risk of voiding dysfunction.What Is Known Already: Few imaging classifications are currently available to predict the extent of DE to help preoperative assessment of surgical outcomes and provide the patient with objective information about the risk of surgical complications.Study Design, Size, Duration: Retrospective monocentric observational study was conducted between 01 January 2017 and 31 December 2018 and included 150 women (mean age = 34.5 years, 20-52 years) with DE on MRI and who subsequently underwent surgery.Participants/materials, Setting, Methods: Two radiologists independently graded the disease according to MRI-based Enzian classification (A (rectovaginal septum and vagina locations), B (uterosacral locations) and C (rectosigmoid locations)) and a new radiological classification, that we have called the dPEI, that grades the severity of DE as: mild, moderate or severe DE. MRI findings and classification were correlated with surgical and pathological results.Main Results and the Role Of Chance: MRI-based and surgical Enzian classifications were concordant for A lesions in 78.7% (118/150), for B lesions in 34.7% (52/150) and for C lesions in 82.7% (124/150). Operating time and hospital stays were longer in Group A2 (rectovaginal septum and vagina, 1-3 cm) compared to A0, B2 (uterosacral, 1-3 cm) compared to B0, C3 (rectosigmoid >3 cm) compared to C2 (rectosigmoid 1-3 cm) or C0 (P < 0.001), in severe compared to moderate DE patients, and in moderate compared to mild extensive patients (P < 0.01). Patients with vaginal or rectosigmoid involvement were respectively six and three times more likely to experience high-grade complications according to Clavien-Dindo classification than patients without vaginal or rectosigmoid disease (P < 0.001). Postoperative voiding dysfunction was correlated with A lesions (odds ratio (OR) = 6.82, 95% CI 2.34-20.5), moderate or severe DE (OR = 4.15, 95% CI 1.26-17.9), the presence of at least unilateral lateral pelvic involvement (OR = 3.6, 95% CI 1.14-11.2, P = 0.03) and C lesions (OR = 2.6, 95% CI 1.03-6.8, P < 0.01).Limitations, Reasons For Caution: The study was conducted in an expert center and needs to be validated in a multicenter study. There is a limited number of patients with lateral pelvic endometriosis beyond the parietal fascia, probably due to the low prevalence of this disease presentation.Wider Implications Of the Findings: MRI imaging can be used to accurately predict postoperative complications for women with DE. This may help the clinician to preoperatively inform a patient about the risks of surgery. Larger clinical studies are required to validate these results.Study Funding/competing Interest(s): No external funding was used for this study. I.T.N.: Remunerated lecture GE, Hologic, Guerbet, Canon; Advisory board: Siemens - These relationships are on the topic of breast imaging, not related to the topic of this paper. Other coauthors have no conflict of interest to declare.Trial Registration Number: Not applicable. [ABSTRACT FROM AUTHOR]

It has long been recognized that sample size calculations for cluster randomized trials require consideration of the correlation between multiple observations within the same cluster. When measurements are taken at anything other than a single point in time, these correlations depend not only on the cluster but also on the time separation between measurements and additionally, on whether different participants (cross-sectional designs) or the same participants (cohort designs) are repeatedly measured. This is particularly relevant in trials with multiple periods of measurement, such as the cluster cross-over and stepped-wedge designs, but also to some degree in parallel designs. Several papers describing sample size methodology for these designs have been published, but this methodology might not be accessible to all researchers. In this article we provide a tutorial on sample size calculation for cluster randomized designs with particular emphasis on designs with multiple periods of measurement and provide a web-based tool, the Shiny CRT Calculator, to allow researchers to easily conduct these sample size calculations. We consider both cross-sectional and cohort designs and allow for a variety of assumed within-cluster correlation structures. We consider cluster heterogeneity in treatment effects (for designs where treatment is crossed with cluster), as well as individually randomized group-treatment trials with differential clustering between arms, for example designs where clustering arises from interventions being delivered in groups. The calculator will compute power or precision, as a function of cluster size or number of clusters, for a wide variety of designs and correlation structures. We illustrate the methodology and the flexibility of the Shiny CRT Calculator using a range of examples. [ABSTRACT FROM AUTHOR]

The stepped-wedge cluster randomized trial (SW-CRT) involves the sequential transition of clusters (such as hospitals, public health units or communities) from control to intervention conditions in a randomized order. The use of the SW-CRT is growing rapidly. Yet the SW-CRT is at greater risks of bias compared with the conventional parallel cluster randomized trial (parallel-CRT). For this reason, the CONSORT extension for SW-CRTs requires that investigators provide a clear justification for the choice of study design. In this paper, we argue that all other things being equal, the SW-CRT is at greater risk of bias due to misspecification of the secular trends at the analysis stage. This is particularly problematic for studies randomizing a small number of heterogeneous clusters. We outline the potential conditions under which an SW-CRT might be an appropriate choice. Potentially appropriate and often overlapping justifications for conducting an SW-CRT include: (i) the SW-CRT provides a means to conduct a randomized evaluation which otherwise would not be possible; (ii) the SW-CRT facilitates cluster recruitment as it enhances the acceptability of a randomized evaluation either to cluster gatekeepers or other stakeholders; (iii) the SW-CRT is the only feasible design due to pragmatic and logistical constraints (for example the roll-out of a scare resource); and (iv) the SW-CRT has increased statistical power over other study designs (which will include situations with a limited number of clusters). As the number of arguments in favour of an SW-CRT increases, the likelihood that the benefits of using the SW-CRT, as opposed to a parallel-CRT, outweigh its risks also increases. We argue that the mere popularity and novelty of the SW-CRT should not be a factor in its adoption. In situations when a conventional parallel-CRT is feasible, it is likely to be the preferred design. [ABSTRACT FROM AUTHOR]

Background: Many studies examined gender inequalities in research, but only a few data are available for general biomedical journals. We assessed the prevalence of female first authorship in general biomedical journals and examined its variations across a number of author, article and journal characteristics.Methods: This study was nested within a larger project designed to analyze the bibliometric characteristics of scientific articles. We retrieved 767 randomly selected articles published in 2016 in high impact factor journals of primary healthcare (n = 9) and general internal medicine (n = 9). We extracted the following data: author (gender, number of publications and affiliation of the first author), paper (number of authors, number of participants and study design) and journal characteristics (journal discipline and 2015 impact factor). We compared the proportion of articles authored by women and men using univariate and multivariate logistic regressions adjusted for intra-cluster correlations.Results: The female authorship proportion was 48% (63% for primary healthcare and 33% for general internal medicine, P-value < 0.001). In multivariate analysis, women published fewer articles (<5 versus >15 publications: OR 1.6 [95% CI 1.1-2.4]), were more often affiliated with institutions in the Western world (OR 2.2 [95% CI 1.2-3.9]), were more likely to publish qualitative studies (versus systematic reviews or experiments: OR 2.7 [95% CI 1.5-4.8]) and to publish in primary healthcare journals (OR 1.7 [95% CI 1.1-2.7]).Conclusions: The underrepresentation of women in articles published by general internal medicine journals, in articles from the non-Western world and in systematic reviews and trials should be addressed. [ABSTRACT FROM AUTHOR]

The behavioural variant of frontotemporal dementia (bvFTD) is a frequent cause of early-onset dementia. The diagnosis of bvFTD remains challenging because of the limited accuracy of neuroimaging in the early disease stages and the absence of molecular biomarkers, and therefore relies predominantly on clinical assessment. BvFTD shows significant symptomatic overlap with non-degenerative primary psychiatric disorders including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders and even personality disorders. To date, ∼50% of patients with bvFTD receive a prior psychiatric diagnosis, and average diagnostic delay is up to 5-6 years from symptom onset. It is also not uncommon for patients with primary psychiatric disorders to be wrongly diagnosed with bvFTD. The Neuropsychiatric International Consortium for Frontotemporal Dementia was recently established to determine the current best clinical practice and set up an international collaboration to share a common dataset for future research. The goal of the present paper was to review the existing literature on the diagnosis of bvFTD and its differential diagnosis with primary psychiatric disorders to provide consensus recommendations on the clinical assessment. A systematic literature search with a narrative review was performed to determine all bvFTD-related diagnostic evidence for the following topics: bvFTD history taking, psychiatric assessment, clinical scales, physical and neurological examination, bedside cognitive tests, neuropsychological assessment, social cognition, structural neuroimaging, functional neuroimaging, CSF and genetic testing. For each topic, responsible team members proposed a set of minimal requirements, optimal clinical recommendations, and tools requiring further research or those that should be developed. Recommendations were listed if they reached a ≥ 85% expert consensus based on an online survey among all consortium participants. New recommendations include performing at least one formal social cognition test in the standard neuropsychological battery for bvFTD. We emphasize the importance of 3D-T1 brain MRI with a standardized review protocol including validated visual atrophy rating scales, and to consider volumetric analyses if available. We clarify the role of 18F-fluorodeoxyglucose PET for the exclusion of bvFTD when normal, whereas non-specific regional metabolism abnormalities should not be over-interpreted in the case of a psychiatric differential diagnosis. We highlight the potential role of serum or CSF neurofilament light chain to differentiate bvFTD from primary psychiatric disorders. Finally, based on the increasing literature and clinical experience, the consortium determined that screening for C9orf72 mutation should be performed in all possible/probable bvFTD cases or suspected cases with strong psychiatric features. [ABSTRACT FROM AUTHOR]

Introduction: Genital human papillomavirus (HPV) is the most common sexually transmitted infection in the United States. The Center for Disease Control Advisory Committee on Immunization Practices (ACIP) has recognized the potential benefits of immunizing young men beginning at age 11 or 12 years and continuing through age 21 years. The maximum age of immunization is extended through age 26 for men who have sex with men, transgender individuals, and immunocompromised men. In spite of these recommendations, vaccination of young men is currently limited by numerous patient and provider variables. The authors sought to delineate these variables as they pertain to members of the U.S. Air Force in order to guide future interventions.Methods: The study consisted of two cross-sectional surveys at a single Air Force Base in California. The protocol was approved by the Institutional Review Board at David Grant Medical Center. The physician survey consisted of 10 questions that were formatted and designed to assess physicians' knowledge about the quadrivalent HPV vaccine (Gardasil) and 6 questions that were formatted and designed to assess physicians' counseling practices regarding Gardasil. The physician survey was distributed electronically via email in January 2017 to all 48 Family Medicine physicians, including both residents and staff, within the Family Medicine Residency Clinic at Travis Air Force Base. The email contained a link via Microsoft Share-point to an anonymous online survey. The patient survey was distributed in paper form to all male service members between the ages of 18 and 30 years who attended Commander's Calls over a 90-day period between January 2017 and March 2017. The patient survey included the primary outcome: proportion of respondents who had completed the HPV vaccination series. Descriptive statistics, including frequencies and percentages, were used to summarize the data. Contingency tables were constructed and the chi-square test or Fisher's Exact Test were performed to determine if particular demographic variables were associated with correct answers to individual knowledge questions.Results: The majority of the Family Medicine physicians surveyed have adequate knowledge of HPV and the vaccine but do not routinely offer the vaccine to their male patients. Inadequate time during the office visit was cited as the major limitation to vaccine promotion. Of the Active Duty Air Force males surveyed, only 27% completed the vaccine series. A lack of knowledge regarding the personal benefits of the vaccine and failure to remember to receive subsequent doses were cited as barriers to completion. Only one-quarter of all surveyed males were interested in speaking with a healthcare provider about HPV and/or the HPV vaccine.Conclusion: Deficiencies in public knowledge and insufficient provider practices are likely contributing to the suboptimal rates of HPV vaccination among eligible males. Additionally, eligible males are not interested in speaking with their healthcare providers about either HPV or the HPV vaccine. If the rates of HPV vaccination within the male population are to increase, health educators, public health proponents, and vaccine advocates need to devise a more effective approach to disseminate this information to eligible male recipients. [ABSTRACT FROM AUTHOR]

Epidemiologists are often confronted with datasets to analyse which contain measurement error due to, for instance, mistaken data entries, inaccurate recordings and measurement instrument or procedural errors. If the effect of measurement error is misjudged, the data analyses are hampered and the validity of the study's inferences may be affected. In this paper, we describe five myths that contribute to misjudgments about measurement error, regarding expected structure, impact and solutions to mitigate the problems resulting from mismeasurements. The aim is to clarify these measurement error misconceptions. We show that the influence of measurement error in an epidemiological data analysis can play out in ways that go beyond simple heuristics, such as heuristics about whether or not to expect attenuation of the effect estimates. Whereas we encourage epidemiologists to deliberate about the structure and potential impact of measurement error in their analyses, we also recommend exercising restraint when making claims about the magnitude or even direction of effect of measurement error if not accompanied by statistical measurement error corrections or quantitative bias analysis. Suggestions for alleviating the problems or investigating the structure and magnitude of measurement error are given. [ABSTRACT FROM AUTHOR]

In the 1980s debate intensified over whether there was a protective effect of high-density lipoprotein cholesterol (HDL-C) or an adverse effect of triglycerides on coronary heart disease (CHD) risk. In a 1991 paper reprinted in the IJE we suggested that the high degree of correlation between the two, together with plausible levels of measurement error, made it unlikely that conventional epidemiological approaches could contribute to causal understanding. The consensus that HDL-C was protective, popularly reified in the notion of 'good cholesterol', strengthened over subsequent years. Reviewing the biostatistical and epidemiological literature from before and after 1991 we suggest that within the observational epidemiology pantheon only Mendelian randomization studies-that began to appear at the same time as the initial negative randomized controlled trials-made a meaningful contribution. It is sobering to realize that many issues that appear suitable targets for epidemiological investigation are simply refractory to conventional approaches. The discipline should surely revisit this and other high-profile cases of consequential epidemiological failure-such as that with respect to vitamin E supplementation and CHD risk-rather than pass them over in silence. [ABSTRACT FROM AUTHOR]

Introduction: Youth with autism spectrum disorder (ASD) face high rates of unemployment, with unique challenges for military-dependent and -connected youth with ASD. This paper reports preliminary findings from Year One of a randomized waitlist controlled trial investigating the efficacy of the Project SEARCH + ASD Supports (PS + ASD) intervention model for military-dependent and -connected youth with ASD.Methods: Treatment group participants (n = 6) participated in internships at a military installation in the southeastern United States; waitlist group participants (n = 8) received special education transition services at their local high schools. Employment outcome data were collected at 12 months for both groups.Results: Fourteen unique internship experiences were developed across seven business partner organizations on the military installation during Year One. Five of six PS + ASD treatment group participants obtained competitive integrated employment for an overall employment rate of 83.3%. Four of the positions were federal jobs. None of the waitlist group participants obtained competitive integrated employment during the same period.Conclusions: Initial results are promising and suggest that the PS + ASD model may help to meet the transition needs of military-dependent and -connected youth with ASD and the employment needs of local military communities. [ABSTRACT FROM AUTHOR]

Background: Anti-cancer therapy is often a cause of premature ovarian insufficiency and infertility since the ovarian follicle reserve is extremely sensitive to the effects of chemotherapy and radiotherapy. While oocyte, embryo and ovarian cortex cryopreservation can help some women with cancer-induced infertility achieve pregnancy, the development of effective methods to protect ovarian function during chemotherapy would be a significant advantage.Objective and Rationale: This paper critically discusses the different damaging effects of the most common chemotherapeutic compounds on the ovary, in particular, the ovarian follicles and the molecular pathways that lead to that damage. The mechanisms through which fertility-protective agents might prevent chemotherapy drug-induced follicle loss are then reviewed.Search Methods: Articles published in English were searched on PubMed up to March 2019 using the following terms: ovary, fertility preservation, chemotherapy, follicle death, adjuvant therapy, cyclophosphamide, cisplatin, doxorubicin. Inclusion and exclusion criteria were applied to the analysis of the protective agents.Outcomes: Recent studies reveal how chemotherapeutic drugs can affect the different cellular components of the ovary, causing rapid depletion of the ovarian follicular reserve. The three most commonly used drugs, cyclophosphamide, cisplatin and doxorubicin, cause premature ovarian insufficiency by inducing death and/or accelerated activation of primordial follicles and increased atresia of growing follicles. They also cause an increase in damage to blood vessels and the stromal compartment and increment inflammation. In the past 20 years, many compounds have been investigated as potential protective agents to counteract these adverse effects. The interactions of recently described fertility-protective agents with these damage pathways are discussed.Wider Implications: Understanding the mechanisms underlying the action of chemotherapy compounds on the various components of the ovary is essential for the development of efficient and targeted pharmacological therapies that could protect and prolong female fertility. While there are increasing preclinical investigations of potential fertility preserving adjuvants, there remains a lack of approaches that are being developed and tested clinically. [ABSTRACT FROM AUTHOR]