The Quality of Evidence Revealing Subtle Gender Biases in Science is in the Eye of the Beholder

Scientists are trained to evaluate and interpret evidence without bias or subjectivity. Thus, growing evidence revealing a gender bias against women—or favoring men—within science, technology, engineering, and mathematics (STEM) settings is provocative and raises questions about the extent to which gender bias may contribute to women’s underrepresentation within STEM fields. To the extent that research illustrating gender bias in STEM is viewed as convincing, the culture of science can begin to address the bias. However, are men and women equally receptive to this type of experimental evidence? This question was tested with three randomized, double-blind experiments—two involving samples from the general public (n = 205 and 303, respectively) and one involving a sample of university STEM and non-STEM faculty (n = 205). In all experiments, participants read an actual journal abstract reporting gender bias in a STEM context (or an altered abstract reporting no gender bias in experiment 3) and evaluated the overall quality of the research. Results across experiments showed that men evaluate the gender-bias research less favorably than women, and, of concern, this gender difference was especially prominent among STEM faculty (experiment 2). These results suggest a relative reluctance among men, especially faculty men within STEM, to accept evidence of gender biases in STEM. This finding is problematic because broadening the participation of underrepresented people in STEM, including women, necessarily requires a widespread willingness (particularly by those in the majority) to acknowledge that bias exists before transformation is possible

No Significant Role for Smooth Muscle Cell Mineralocorticoid Receptors in Atherosclerosis in the Apolipoprotein-E Knockout Mouse Model

Objective: Elevated levels of the hormone aldosterone are associated with increased risk of myocardial infarction and stroke in humans and increased progression and inflammation of atherosclerotic plaques in animal models. Aldosterone acts through the mineralocorticoid receptor (MR) which is expressed in vascular smooth muscle cells (SMCs) where it promotes SMC calcification and chemokine secretion in vitro. The objective of this study is to explore the role of the MR specifically in SMCs in the progression of atherosclerosis and the associated vascular inflammation in vivo in the apolipoprotein E knockout (ApoE−/−) mouse model.Methods and Results: Male ApoE−/− mice were bred with mice in which MR could be deleted specifically from SMCs by tamoxifen injection. The resulting atheroprone SMC-MR-KO mice were compared to their MR-Intact littermates after high fat diet (HFD) feeding for 8 or 16 weeks or normal diet for 12 months. Body weight, tail cuff blood pressure, heart and spleen weight, and serum levels of glucose, cholesterol, and aldosterone were measured for all mice at the end of the treatment period. Serial histologic sections of the aortic root were stained with Oil Red O to assess plaque size, lipid content, and necrotic core area; with PicroSirius Red for quantification of collagen content; by immunofluorescent staining with anti-Mac2/Galectin-3 and anti-smooth muscle α-actin antibodies to assess inflammation and SMC marker expression; and with Von Kossa stain to detect plaque calcification. In the 16-week HFD study, these analyses were also performed in sections from the brachiocephalic artery. Flow cytometry of cell suspensions derived from the aortic arch was also performed to quantify vascular inflammation after 8 and 16 weeks of HFD. Deletion of the MR specifically from SMCs did not significantly change plaque size, lipid content, necrotic core, collagen content, inflammatory staining, actin staining, or calcification, nor were there differences in the extent of vascular inflammation between MR-Intact and SMC-MR-KO mice in the three experiments.Conclusion: SMC-MR does not directly contribute to the formation, progression, or inflammation of atherosclerotic plaques in the ApoE−/− mouse model of atherosclerosis. This indicates that the MR in non-SMCs mediates the pro-atherogenic effects of MR activation

VarSight: prioritizing clinically reported variants with binary classification algorithms.

BackgroundWhen applying genomic medicine to a rare disease patient, the primary goal is to identify one or more genomic variants that may explain the patient's phenotypes. Typically, this is done through annotation, filtering, and then prioritization of variants for manual curation. However, prioritization of variants in rare disease patients remains a challenging task due to the high degree of variability in phenotype presentation and molecular source of disease. Thus, methods that can identify and/or prioritize variants to be clinically reported in the presence of such variability are of critical importance.MethodsWe tested the application of classification algorithms that ingest variant annotations along with phenotype information for predicting whether a variant will ultimately be clinically reported and returned to a patient. To test the classifiers, we performed a retrospective study on variants that were clinically reported to 237 patients in the Undiagnosed Diseases Network.ResultsWe treated the classifiers as variant prioritization systems and compared them to four variant prioritization algorithms and two single-measure controls. We showed that the trained classifiers outperformed all other tested methods with the best classifiers ranking 72% of all reported variants and 94% of reported pathogenic variants in the top 20.ConclusionsWe demonstrated how freely available binary classification algorithms can be used to prioritize variants even in the presence of real-world variability. Furthermore, these classifiers outperformed all other tested methods, suggesting that they may be well suited for working with real rare disease patient datasets

Prevalence of anxiety, depression and associated factors among pregnant women of Hyderabad, Pakistan.

Background: Few studies have examined the relationship between antenatal depression, anxiety and domestic violence in pregnant women in developing countries, despite the World Health Organization\u27s estimates that depressive disorders will be the second leading cause of the global disease burden by 2020. There is a paucity of research on mood disorders, their predictors and sequelae among pregnant women in Pakistan. Aims: To determine the prevalence of anxiety and depression and evaluate associated factors, including domestic violence, among pregnant women in an urban community in Pakistan. Methods: All pregnant women living in identified areas of Hyderabad, Pakistan were screened by government health workers for an observational study on maternal characteristics and pregnancy outcomes. Of these, 1,368 (76%) of eligible women were administered the validated Aga Khan University Anxiety Depression Scale at 20-26 weeks of gestation. Results: Eighteen per cent of the women were anxious and/or depressed. Psychological distress was associated with husband unemployment (p = 0.032), lower household wealth (p = 0.027), having 10 or more years of formal education ( p = 0.002), a first (p = 0.002) and an unwanted pregnancy ( p \u3c 0.001). The strongest factors associated with depression/anxiety were physical/sexual and verbal abuse, 42% of women who were physically and/or sexually abused and 23% of those with verbal abuse had depression/anxiety compared to 8% of those who were not abused. Conclusions: Anxiety and depression commonly occur during pregnancy in Pakistani women, rates are highest in women experiencing sexual/physical as well as verbal abuse, but they are also increased among women with unemployed spouses and those with lower household wealth. These results suggest that developing a screening and treatment programme for domestic violence and depression/anxiety during pregnancy may improve the mental health status of pregnant Pakistani women

A successful search for intervening 21 cm HI absorption in galaxies at 0.4 < z <1.0 with the Australian Square Kilometre Array Pathfinder (ASKAP)

We have used the Australian Square Kilometre Array Pathfinder (ASKAP) radio telescope to search for intervening 21 cm neutral hydrogen (HI) absorption along the line of sight to 53 bright radio continuum sources. Our observations are sensitive to HI column densities typical of Damped Lyman Alpha absorbers (DLAs) in cool gas with an HI spin temperature below about 300-500 K. The six-dish Boolardy Engineering Test Array (BETA) and twelve-antenna Early Science array (ASKAP-12) covered a frequency range corresponding to redshift $0.4<z<1.0$ and $0.37<z<0.77$ respectively for the HI line. Fifty of the 53 radio sources observed have reliable optical redshifts, giving a total redshift path $\Delta z$ = 21.37. This was a spectroscopically-untargeted survey, with no prior assumptions about the location of the lines in redshift space. Four intervening HI lines were detected, two of them new. In each case, the estimated HI column density lies above the DLA limit for HI spin temperatures above 50-80 K, and we estimate a DLA number density at redshift $z\sim0.6$ of $n(z)=0.19\substack{+0.15 \\ -0.09}$. This value lies somewhat above the general trend of $n(z)$ with redshift seen in optical DLA studies. Although the current sample is small, it represents an important proof of concept for the much larger 21cm First Large Absorption Survey in HI (FLASH) project to be carried out with the full 36-antenna ASKAP telescope, probing a total redshift path $\Delta z\sim\,50,000$.Comment: 21 pages, 11 figures. Accepted for publication in MNRA

Observations of cold extragalactic gas clouds at z=0.45z = 0.45 towards PKS 1610-771

We present results from MUSE observations of a 21-cm HI absorption system detected with the Australian Square Kilometre Array Pathfinder radio telescope at redshift $z = 0.4503$ towards the $z = 1.71$ quasar PKS 1610-771. We identify four galaxies (A, B, X and Y) at the same redshift as the 21-cm H I Damped Lyman-{\alpha} (DLA) absorption system, with impact parameters ranging from less than 10 kpc to almost 200 kpc from the quasar sightline. Ca II and Na I absorption is seen in the MUSE spectrum of the background QSO, with velocities coinciding with the initial HI 21-cm detection, but tracing less dense and warmer gas. This metal-line component aligns with the rotating ionised disc of galaxy B (impact parameter 18 kpc from the QSO) and appears to be co-rotating with the galaxy disc. In contrast, the 21-cm HI absorber is blueshifted relative to the galaxies nearest the absorber and has the opposite sign to the velocity field of galaxy B. Since galaxies A and B are separated by only 17 kpc on the sky and $70$ km s$^{-1}$ in velocity, it appears likely that the 21-cm detection traces extragalactic clouds of gas formed from their interaction. This system reveals that the cold 100 K neutral gas critical for star formation can be associated with complex structures beyond the galaxy disc, and is a first case study made in preparation for future large 21-cm absorption surveys like the ASKAP First Large Absorption Survey in HI.Comment: Accepted. 13 pages, 7 figure

Clinical actionability of comprehensive genomic profiling for management of rare or refractory cancers

Background. The frequency with which targeted tumor sequencing results will lead to implemented change in care is unclear. Prospective assessment of the feasibility and limitations of using genomic sequencing is critically important. Methods. A prospective clinical study was conducted on 100 patients with diverse-histology, rare, or poor-prognosis cancers to evaluate the clinical actionability of a Clinical Laboratory Improvement Amendments (CLIA)-certified, comprehensive genomic profiling assay (FoundationOne), using formalin-fixed, paraffin-embedded tumors. The primary objectives were to assess utility, feasibility, and limitations of genomic sequencing for genomically guided therapy or other clinical purpose in the setting of a multidisciplinary molecular tumor board. Results. Of the tumors from the 92 patients with sufficient tissue, 88 (96%) had at least one genomic alteration (average 3.6, range 0–10). Commonly altered pathways included p53 (46%), RAS/RAF/MAPK (rat sarcoma; rapidly accelerated fibrosarcoma; mitogen-activated protein kinase) (45%), receptor tyrosine kinases/ligand (44%), PI3K/AKT/mTOR (phosphatidylinositol-4,5-bisphosphate 3-kinase; protein kinase B; mammalian target of rapamycin) (35%), transcription factors/regulators (31%), and cell cycle regulators (30%). Many low frequency but potentially actionable alterations were identified in diverse histologies. Use of comprehensive profiling led to implementable clinical action in 35% of tumors with genomic alterations, including genomically guided therapy, diagnostic modification, and trigger for germline genetic testing. Conclusion. Use of targeted next-generation sequencing in the setting of an institutional molecular tumor board led to implementable clinical action in more than one third of patients with rare and poor-prognosis cancers. Major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access. Early and serial sequencing in the clinical course and expanded access to genomically guided early-phase clinical trials and targeted agents may increase actionability. Implications for Practice: Identification of key factors that facilitate use of genomic tumor testing results and implementation of genomically guided therapy may lead to enhanced benefit for patients with rare or difficult to treat cancers. Clinical use of a targeted next-generation sequencing assay in the setting of an institutional molecular tumor board led to implementable clinical action in over one third of patients with rare and poor prognosis cancers. The major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access both on trial and off label. Approaches to increase actionability include early and serial sequencing in the clinical course and expanded access to genomically guided early phase clinical trials and targeted agents

Hunter-gatherer environments at the Late Pleistocene sites of Mwanganda's Village and Bruce, northern Malawi

Mwanganda's Village (MGD) and Bruce (BRU) are two open-air site complexes in northern Malawi with deposits dating to between 15 and 58 thousand years ago (ka) and containing Middle Stone Age (MSA) lithic assemblages. The sites have been known since 1966 and 1965, respectively, but lacked chronometric and site formation data necessary for their interpretation. The area hosts a rich stone artifact record, eroding from and found within alluvial fan deposits exhibiting poor preservation of organic materials. Although this generally limits opportunities for site-based environmental reconstructions, MGD and BRU are located at the distal margins of the alluvial fan, where lacustrine lagoonal deposits were overprinted by a calcrete paleosol. This has created locally improved organic preservation and allowed us to obtain ecological data from pollen, phytoliths, and pedogenic carbonates, producing a regional- to site-scale environmental context for periods of site use and abandonment. Here, we integrate the ecological data into a detailed site formation history, based on field observations and micromorphology, supplemented by cathodoluminescence microscopy and μ-XRF. By comparing local, on-site environmental proxies with more regional indicators, we can better evaluate how MSA hunter-gatherers made decisions about the use of resources across the landscape. Our data indicate that while tree cover similar to modern miombo woodland and evergreen gallery forest prevailed at most times, MSA hunter-gatherers chose more locally open environments for activities that resulted in a lithic artifact record at multiple locations between 51 and 15 ka.publishedVersio

Does a radio jet drive the massive multi-phase outflow in the ultra-luminous infrared galaxy IRAS 10565+2448?

We present new upgraded Giant Metrewave Radio Telescope (uGMRT) HI 21-cm observations of the ultra-luminous infrared galaxy IRAS 10565+2448, previously reported to show blueshifted, broad, and shallow HI absorption indicating an outflow. Our higher spatial resolution observations have localised this blueshifted outflow, which is $\sim$ 1.36 kpc southwest of the radio centre and has a blueshifted velocity of $\sim 148\,\rm km\,s^{-1}$ and a full width at half maximum (FWHM) of $\sim 581\,\rm km\,s^{-1}$. The spatial extent and kinematic properties of the HI outflow are consistent with the previously detected cold molecular outflows in IRAS 10565+2448, suggesting that they likely have the same driving mechanism and are tracing the same outflow. By combining the multi-phase gas observations, we estimate a total outflowing mass rate of at least $140\, \rm M_\odot \,yr^{-1}$ and a total energy loss rate of at least $8.9\times10^{42}\,\rm erg\,s^{-1}$, where the contribution from the ionised outflow is negligible, emphasising the importance of including both cold neutral and molecular gas when quantifying the impact of outflows. We present evidence of the presence of a radio jet and argue that this may play a role in driving the observed outflows. The modest radio luminosity $L_{\rm1.4GHz}$ $\sim1.3\times10^{23}\,{\rm W\,Hz^{-1}}$ of the jet in IRAS 10565+2448 implies that the jet contribution to driving outflows should not be ignored in low radio luminosity AGN.Comment: 12 pages, 9 figures, accepted for publication in MNRA

A CFTR Potentiator in Patients with Cystic Fibrosis and the G551D Mutation

BACKGROUND: Increasing the activity of defective cystic fibrosis transmembrane conductance regulator (CFTR) protein is a potential treatment for cystic fibrosis. METHODS: We conducted a randomized, double-blind, placebo-controlled trial to evaluate ivacaftor (VX-770), a CFTR potentiator, in subjects 12 years of age or older with cystic fibrosis and at least one G551D-CFTR mutation. Subjects were randomly assigned to receive 150 mg of ivacaftor every 12 hours (84 subjects, of whom 83 received at least one dose) or placebo (83, of whom 78 received at least one dose) for 48 weeks. The primary end point was the estimated mean change from baseline through week 24 in the percent of predicted forced expiratory volume in 1 second (FEV(1)). RESULTS: The change from baseline through week 24 in the percent of predicted FEV(1) was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (P<0.001). Effects on pulmonary function were noted by 2 weeks, and a significant treatment effect was maintained through week 48. Subjects receiving ivacaftor were 55% less likely to have a pulmonary exacerbation than were patients receiving placebo, through week 48 (P<0.001). In addition, through week 48, subjects in the ivacaftor group scored 8.6 points higher than did subjects in the placebo group on the respiratory-symptoms domain of the Cystic Fibrosis Questionnaire–revised instrument (a 100-point scale, with higher numbers indicating a lower effect of symptoms on the patient’s quality of life) (P<0.001). By 48 weeks, patients treated with ivacaftor had gained, on average, 2.7 kg more weight than had patients receiving placebo (P<0.001). The change from baseline through week 48 in the concentration of sweat chloride, a measure of CFTR activity, with ivacaftor as compared with placebo was −48.1 mmol per liter (P<0.001). The incidence of adverse events was similar with ivacaftor and placebo, with a lower proportion of serious adverse events with ivacaftor than with placebo (24% vs. 42%). CONCLUSIONS: Ivacaftor was associated with improvements in lung function at 2 weeks that were sustained through 48 weeks. Substantial improvements were also observed in the risk of pulmonary exacerbations, patient-reported respiratory symptoms, weight, and concentration of sweat chloride