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In recent years, the explosion of genomic data and bioinformatic tools has been accompanied by a growing conversation around reproducibility of results and usability of software. However, the actual state of the body of bioinformatics software remains largely unknown. The purpose of this paper is to investigate the state of source code in the bioinformatics community, specifically looking at relationships between code properties, development activity, developer communities, and software impact. To investigate these issues, we curated a list of 1,720 bioinformatics repositories on GitHub through their mention in peer-reviewed bioinformatics articles. Additionally, we included 23 high-profile repositories identified by their popularity in an online bioinformatics forum. We analyzed repository metadata, source code, development activity, and team dynamics using data made available publicly through the GitHub API, as well as article metadata. We found key relationships within our dataset, including: certain scientific topics are associated with more active code development and higher community interest in the repository; most of the code in the main dataset is written in dynamically typed languages, while most of the code in the high-profile set is statically typed; developer team size is associated with community engagement and high-profile repositories have larger teams; the proportion of female contributors decreases for high-profile repositories and with seniority level in author lists; and, multiple measures of project impact are associated with the simple variable of whether the code was modified at all after paper publication. In addition to providing the first large-scale analysis of bioinformatics code to our knowledge, our work will enable future analysis through publicly available data, code, and methods. Code to generate the dataset and reproduce the analysis is provided under the MIT license at https://github.com/pamelarussell/github-bioinformatics. Data are available at https://doi.org/10.17605/OSF.IO/UWHX8.

Understanding the host pathways that define susceptibility to Severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2) infection and disease are essential for the design of new therapies. Oxygen levels in the microenvironment define the transcriptional landscape, however the influence of hypoxia on virus replication and disease in animal models is not well understood. In this study, we identify a role for the hypoxic inducible factor (HIF) signalling axis to inhibit SARS-CoV-2 infection, epithelial damage and respiratory symptoms in the Syrian hamster model. Pharmacological activation of HIF with the prolyl-hydroxylase inhibitor FG-4592 significantly reduced infectious virus in the upper and lower respiratory tract. Nasal and lung epithelia showed a reduction in SARS-CoV-2 RNA and nucleocapsid expression in treated animals. Transcriptomic and pathological analysis showed reduced epithelial damage and increased expression of ciliated cells. Our study provides new insights on the intrinsic antiviral properties of the HIF signalling pathway in SARS-CoV-2 replication that may be applicable to other respiratory pathogens and identifies new therapeutic opportunities.

Semen quality and fertility has declined over the last 50 years, corresponding to ever-increasing environmental stressors. However, the cellular mechanisms involved and their impact on sperm functions remain unknown. In a repeated sampling human cohort study, we identify a significant effect of prior perceived stress to increase sperm motility 2-3 months following stress, timing that expands upon our previous studies revealing significant stress-associated changes in sperm RNA important for fertility. We mechanistically examine this post-stress timing in mice using an in vitro stress model in the epididymal epithelial cells responsible for sperm maturation and find 7282 differentially H3K27me3 bound DNA regions involving genes critical for mitochondrial and metabolic pathways. Further, prior stress exposure significantly changes the composition and size of epithelial cell-secreted extracellular vesicles that when incubated with mouse sperm, increase mitochondrial respiration and sperm motility, adding to our prior work showing impacts on embryo development. Together, these studies identify a time-dependent, translational signaling pathway that communicates stress experience to sperm, ultimately affecting reproductive functions. Changes in semen quality over the last 50 years correspond with increasing environmental stressors. Here, Moon et al . causally identified stress-mediated changes in secreted extracellular vesicles as regulators of sperm motility in mice and men.

Abstract Study Objectives Cognitive behavioral insomnia therapy (CBT-I) combined with supervised open-label tapering is effective for helping hypnotic-dependent patients discontinue their hypnotics. This study tested whether slowing the tapering pace and blinding the tapering process enhance outcomes. Methods Seventy-eight benzodiazepines (BZD) or benzodiazepine receptor agonists (BZRA) users completed 4 CBT-I sessions, followed by a randomly assigned blinded tapering protocol wherein hypnotic dosage was: held constant, reduced by 10% every two weeks, or reduced by 25% every two weeks. After 20 weeks those who did not have their medications reduced were offered an open-label tapering protocol. Participants completed assessments 3 months after completing their respective tapering protocols. Outcomes included discontinuation rates, hypnotic withdrawal effects, and responder and remission rates determined by Insomnia Severity Index (ISI) scores. Results No differences were observed between the two tapering paces (10% vs. 25%). Blinded tapering had a consistent association with better outcomes that did not reach statistical significance. At 3-month follow-up the number of patients needed to be treated with blinded taper instead of open-label tapering in order for one additional individual to achieve desired endpoints was 7.7 for BZD/BZRA discontinuation, 3.4 for hypnotic withdrawal effects, 4.4 for ISI responder status, and 5.0 for insomnia remission. One-third (32.3%) of the sample was using benzo-related hypnotics at 3-month follow-up. Twice as many individuals (64.6%) were using some type of medication or substance for sleep at this time point. Conclusions Blinding tapering may enhance hypnotic discontinuation rates and insomnia treatment response and remission rates. Trial Registration: Clinicaltrials.gov Identifier: NCT02831894, “The Role of Tapering Pace and Selected Traits on Hypnotic Discontinuation;” URL:https://clinicaltrials.gov/ct2/show/NCT02831894?term=hypnotics&cond=Insomnia&cntry=US&state=US%3ACO&city=Denver&draw=2&rank=2

Tick bites, associated with the secretion of tick saliva containing the xenoglycan galactose-alpha-1, 3-galactose (alpha-gal or aGal), are recognized as the causal factors of alpha-Gal syndrome (AGS; or red meat allergy) in humans. AGS occurs after the increased production of IgE antibodies against aGal, which is found in most mammalian cells, except for the Old World monkey and humans. The aGal sensitization event has been linked to an initial tick bite, followed by consumption of red meat containing the aGal glycan, which triggers the onset of the allergic response resulting in urticaria, anaphylaxis, or even death. In North America, the lone star tick, Amblyomma americanum , has been identified as the main culprit for AGS. However, only a subset of the human population exposed to lone star tick bites develops AGS. This suggests the presence of unidentified variables associated with the sensitization event. To evaluate the quantitative variations of the aGal in ticks, we evaluated the differences in aGal levels in different strains of A. americanum ticks partially fed on different blood sources using an artificial feeding system and animal hosts. We found significantly higher aGal levels in the female ticks fed on human blood than those fed on the blood of other mammals with large variations among different tick populations and individuals. We propose that host-specific genetic components in the A. americanum ticks are involved in the production of high aGal epitope in the tick saliva, which provides a part of the explanation for the variables associated with the AGS sensitization event of the tick bite.

The current literature suggests that some women are uniquely vulnerable to negative effects of hormonal contraception (HC) on affective processes. However, little data exists as to which factors contribute to such vulnerability. The present study evaluated the impact of prepubertal adverse childhood experiences (ACEs) on reward processing in women taking HC (N = 541) compared to naturally cycling women (N = 488). Participants completed an online survey assessing current and past HC use and exposure to 10 different adverse childhood experiences (ACEs) before puberty (ACE Questionnaire), with participants categorized into groups of low (0–1) versus high (≥2) prepubertal ACE exposure. Participants then completed a reward task rating their expected and experienced valence for images that were either erotic, pleasant (non-erotic), or neutral. Significant interactions emerged between prepubertal ACE exposure and HC use on expected ( p = 0.028) and experienced ( p = 0.025) valence ratings of erotic images but not pleasant or neutral images. Importantly, follow-up analyses considering whether women experienced HC-induced decreases in sexual desire informed the significant interaction for expected valence ratings of erotic images. For current HC users, prepubertal ACEs interacted with HC-induced decreased sexual desire ( p = 0.008), such that high ACE women reporting decreased sexual desire on HC showed substantially decreased ratings for anticipated erotic images compared to both high prepubertal ACE women without decreased sexual desire ( p < 0.001) and low prepubertal ACE women also reporting decreased sexual desire ( p = 0.010). The interaction was not significant in naturally cycling women reporting previous HC use, suggesting that current HC use could be impacting anticipatory reward processing of sexual stimuli among certain women (e.g., high prepubertal ACE women reporting HC-induced decreases in sexual desire). The study provides rationale for future randomized, controlled trials to account for prepubertal ACE exposure to promote contraceptive selection informed by behavioral evidence.

African-American patients who visit physicians of the same race rate their medical visits as more satisfying and participatory than do those who see physicians of other races. Little research has investigated the communication process in race-concordant and race-discordant medical visits. To compare patient-physician communication in race-concordant and race-discordant visits and examine whether communication behaviors explain differences in patient ratings of satisfaction and participatory decision making. Cohort study with follow-up using previsit and postvisit surveys and audiotape analysis. 16 urban primary care practices. 252 adults (142 African-American patients and 110 white patients) receiving care from 31 physicians (of whom 18 were African-American and 13 were white). Audiotape measures of patient-centeredness, patient ratings of physicians' participatory decision-making styles, and overall satisfaction. Race-concordant visits were longer (2.15 minutes [95% CI, 0.60 to 3.71]) and had higher ratings of patient positive affect (0.55 point, [95% CI, 0.04 to 1.05]) compared with race-discordant visits. Patients in race-concordant visits were more satisfied and rated their physicians as more participatory (8.42 points [95% CI, 3.23 to 13.60]). Audiotape measures of patient-centered communication behaviors did not explain differences in participatory decision making or satisfaction between race-concordant and race-discordant visits. Race-concordant visits are longer and characterized by more patient positive affect. Previous studies link similar communication findings to continuity of care. The association between race concordance and higher patient ratings of care is independent of patient-centered communication, suggesting that other factors, such as patient and physician attitudes, may mediate the relationship. Until more evidence is available regarding the mechanisms of this relationship and the effectiveness of intercultural communication skills programs, increasing ethnic diversity among physicians may be the most direct strategy to improve health care experiences for members of ethnic minority groups.

OBJECTIVES:  To determine: 1) whether racial and ethnic differences exist in patients’ perceptions of primary care provider (PCP) and general health care system–related bias and cultural competence; and 2) whether these differences are explained by patient demographics, source of care, or patient‐provider communication variables. DESIGN:  Cross‐sectional telephone survey. SETTING:  The Commonwealth Fund 2001 Health Care Quality Survey. SUBJECTS:  A total of 6,299 white, African‐American, Hispanic, and Asian adults. MEASUREMENTS AND MAIN RESULTS:  Interviews were conducted using random‐digit dialing; oversampling respondents from communities with high racial/ethnic minority concentrations; and yielding a 54.3% response rate. Main outcomes address respondents’ perceptions of their PCPs’ and health care system–related bias and cultural competence; adjusted probabilities (Pr) are reported for each ethnic group. Most racial/ethnic differences in perceptions of PCP bias and cultural competence were explained by demographics, source of care, and patient–physician communication variables. In contrast, racial/ethnic differences in patient perceptions of health care system–wide bias and cultural competence persisted even after controlling for confounders: African Americans, Hispanics, and Asians remained more likely than whites (P < .001) to perceive that: 1) they would have received better medical care if they belonged to a different race/ethnic group (Pr 0.13, Pr 0.08, Pr 0.08, and Pr 0.01, respectively); and 2) medical staff judged them unfairly or treated them with disrespect based on race/ethnicity (Pr 0.06, Pr 0.04, Pr 0.06, and Pr 0.01, respectively) and how well they speak English (Pr 0.09, Pr 0.06, Pr 0.06, and Pr 0.03, respectively). CONCLUSION:  While demographics, source of care, and patient–physician communication explain most racial and ethnic differences in patient perceptions of PCP cultural competence, differences in perceptions of health care system–wide bias and cultural competence are not fully explained by such factors. Future research should include closer examination of the sources of cultural bias in the US medical system.

Background The mechanisms by which parental early life stress can be transmitted to the next generation, in some cases in a sex-specific manner, are unclear. Maternal preconception stress may increase susceptibility to suboptimal health outcomes via in utero programming of the fetal hypothalamic–pituitary–adrenal (HPA) axis. Methods We recruited healthy pregnant women ( N  = 147), dichotomized into low (0 or 1) and high (2+) adverse childhood experience (ACE) groups based on the ACE Questionnaire, to test the hypothesis that maternal ACE history influences fetal adrenal development in a sex-specific manner. At a mean (standard deviation) of 21.5 (1.4) and 29.5 (1.4) weeks gestation, participants underwent three-dimensional ultrasounds to measure fetal adrenal volume, adjusting for fetal body weight ( wa FAV). Results At ultrasound 1, wa FAV was smaller in high versus low ACE males ( b  = − 0.17; z  = − 3.75; p  < .001), but females did not differ significantly by maternal ACE group ( b  = 0.09; z = 1.72; p  = .086). Compared to low ACE males, wa FAV was smaller for low ( b  = − 0.20; z  = − 4.10; p  < .001) and high ACE females ( b  = − 0.11; z  = 2.16; p  = .031); however, high ACE males did not differ from low ( b  = 0.03; z  = .57; p  = .570) or high ACE females ( b  = − 0.06; z  = − 1.29; p  = .196). At ultrasound 2, wa FAV did not differ significantly between any maternal ACE/offspring sex subgroups ( p s ≥ .055). Perceived stress did not differ between maternal ACE groups at baseline, ultrasound 1, or ultrasound 2 ( p s ≥ .148). Conclusions We observed a significant impact of high maternal ACE history on wa FAV, a proxy for fetal adrenal development, but only in males. Our observation that the wa FAV in males of mothers with a high ACE history did not differ from the wa FAV of females extends preclinical research demonstrating a dysmasculinizing effect of gestational stress on a range of offspring outcomes. Future studies investigating intergenerational transmission of stress should consider the influence of maternal preconception stress on offspring outcomes. Highlights Three-dimensional ultrasound serves as a non-invasive way to measure fetal adrenal volume as a proxy for development of the fetal hypothalamic–pituitary–adrenal axis. Weight-adjusted fetal adrenal volume ( wa FAV) differed between subgroups based on offspring sex and the mother’s history of adverse childhood experiences (ACEs). In males of mothers with a high ACE history, wa FAV was significantly smaller than in males of mothers with a low ACE history but indistinguishable from the wa FAV of females from either maternal ACE group; however, males of mothers with a low ACE history had larger wa FAV than females from either maternal ACE group. These findings suggest male vulnerability to dysmasculinization of wa FAV in response to maternal preconception stress in line with previous animal studies showing a dysmasculinizing effect of gestational stress on a range of offspring outcomes.

Background Progesterone administration has therapeutic effects in tobacco use disorder (TUD), with females benefiting more than males. Conversion of progesterone to the neurosteroid allopregnanolone is hypothesized to partly underlie the therapeutic effects of progesterone; however, this has not been investigated clinically. Methods Smokers ( n  = 18 males, n  = 21 females) participated in a randomized, double-blind, placebo-controlled crossover study of 200 mg progesterone daily across 4 days of abstinence. The ratio of allopregnanolone:progesterone was analyzed in relationship to nicotine withdrawal, smoking urges, mood states, subjective nicotine effects, and neural response to smoking cues. Results Allopregnanolone:progesterone ratio interacted with sex to predict withdrawal symptoms ( p  = 0.047), such that females with higher allopregnanolone:progesterone ratios reported lower withdrawal severity ( b  = − 0.98 [− 1.95, − 0.01]; p  = 0.048). In addition, allopregnanolone:progesterone ratio interacted with sex to predict confusion ( p  = 0.014) and fatigue ( p  = 0.034), such that females with higher allopregnanolone:progesterone ratios reported less confusion ( b  = − 0.45 [− 0.78, − 0.12]; p  = 0.008) and marginally lower fatigue ( b  = − 0.50 [− 1.03, 0.02]; p  = 0.062. Irrespective of sex, higher ratios of allopregnanolone:progesterone were associated with stronger “good effects” of nicotine ( b  = 8.39 [2.58, 14.20]); p  = 0.005) and weaker “bad effects” of nicotine ( b  = − 7.13 [− 13.53, − 0.73]; p  = 0.029). Conclusions Conversion of progesterone to allopregnanolone correlated with smoking-related outcomes in both sex-dependent and sex-independent ways. Sex-dependent effects suggest that conversion of progesterone to allopregnanolone may contribute to greater therapeutic benefits in females but not males with TUD. Trial registration Clinicaltrials.gov registration, retrospectively registered: NCT01954966; https://clinicaltrials.gov/ct2/show/NCT01954966 \\ Highlights Progesterone has sex-dependent effects on smoking measures in individuals with Tobacco Use Disorder. Higher conversion of progesterone to allopregnanolone (as indicated by the allopregnanolone:progesterone ratio) was associated with lower nicotine withdrawal in female but not male smokers during a brief abstinence. Higher conversion of progesterone to allopregnanolone was associated with lower ratings of confusion and marginally lower ratings of fatigue in female but not male smokers. Irrespective of sex, higher conversion of progesterone to allopregnanolone was associated with stronger “good effects” and weaker “bad effects” of nicotine during active smoking.