The Ever Widening Gyre: Factors Affecting Change in Adult Education Graduate Programs

The purpose of this survey study was to understand the factors that have influenced recent changes in the size of adult education graduate programs. We found that integration has a significant effect on changes in student enrollment while leadership, innovation, and integration all significantly predict variance in faculty growth

First-in-Human Studies of MW01-6-189WH, a Brain-Penetrant, Antineuroinflammatory Small-Molecule Drug Candidate: Phase 1 Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Studies in Healthy Adult Volunteers

MW01-6-189WH (MW189) is a novel central nervous system-penetrant small-molecule drug candidate that selectively attenuates stressor-induced proinflammatory cytokine overproduction and is efficacious in intracerebral hemorrhage and traumatic brain injury animal models. We report first-in-human, randomized, double-blind, placebo-controlled phase 1 studies to evaluate the safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending intravenous doses of MW189 in healthy adult volunteers. MW189 was safe and well tolerated in single and multiple doses up to 0.25 mg/kg, with no clinically significant concerns. The most common drug-related treatment-emergent adverse event was infusion-site reactions, likely related to drug solution acidity. No clinically concerning changes were seen in vital signs, electrocardiograms, physical or neurological examinations, or safety laboratory results. PK analysis showed dose-proportional increases in plasma concentrations of MW189 after single or multiple doses, with approximately linear kinetics and no significant drug accumulation. Steady state was achieved by dose 3 for all dosing cohorts. A pilot pharmacodynamic study administering low-dose endotoxin to induce a systemic inflammatory response was done to evaluate the effects of a single intravenous dose of MW189 on plasma cytokine levels. MW189 treatment resulted in lower levels of the proinflammatory cytokine TNF-α and higher levels of the anti-inflammatory cytokine IL-10 compared with placebo treatment. The outcomes are consistent with the pharmacological mechanism of MW189. Overall, the safety profile, PK properties, and pharmacodynamic effect support further development of MW189 for patients with acute brain injury

Validation of the prognostic performance of Breast Cancer Index (BCI) in hormone receptor-positive (HR+) postmenopausal breast cancer patients in the TEAM trial

Purpose: Early-stage HR+ breast cancer patients face a prolonged risk of recurrence even after adjuvant endocrine therapy. The Breast Cancer Index (BCI) is significantly prognostic for overall (0-10 years) and late (5-10 years) distant recurrence risk (DR) in N0 and N1 patients. Here, BCI prognostic performance was evaluated in HR+ postmenopausal women from the TEAM trial.Experimental Design: 3544 patients were included in the analysis (N=1519 N0, N=2025 N+). BCI risk groups were calculated using pre-specified cut-points. Kaplan-Meier analyses and logranktests were used to assess the prognostic significance of BCI risk groups based on DR. Hazard ratios (HR) and confidence intervals (CI) were calculated using Cox models with and without clinical covariates.Results: For overall 10-year DR, BCI was significantly prognostic in N0 (N=1196) and N1 (N=1234) patients who did not receive prior chemotherapy (p<0.001). In patients who were DRfree for 5 years, 10-year late DR rates for low- and high-risk groups were 5.4% and 9.3% (N0 cohort, N=1285) and 4.8% and 12.2% (N1 cohort, N=1625) with multivariate HRs of 2.25 (95% CI: 1.30-3.88; p=0.004) and 2.67 (95% CI: 1.53-4.63; p=<0.001), respectively. Late DR performance was substantially improved using previously optimized cut-points, identifying BCIlow-risk groups with even lower 10-year late DR rates of 3.8% and 2.7% in N0 and N1 patients, respectively.Conclusions: The TEAM trial represents the largest prognostic validation study for BCI to date and provides a more representative assessment of late DR risk to guide individualized treatment decision-making for HR+ early-stage breast cancer patients

Investigation of potential gender bias in the peer review system at Reproduction

This study examined whether publication outcome was affected by the gender of author, handling associate editor (AE), or reviewer, and whether there was gender bias in reviewer selection, in the journal Reproduction. Analyses were carried out on 4289 original research manuscripts submitted to the journal between 2007 and 2019. Both female and male AEs appointed more male reviewers than female reviewers, but female AEs were significantly more likely to appoint female reviewers than male AEs were (p < 0.001). When examining the gender of either first or last author manuscripts, those with female authors that were reviewed by female reviewers received better scores than those with male authors that were reviewed by female reviewers (p < 0.05): where the reviewer was male, no such effect was observed. Acceptance rates of manuscripts were similar for both female and male authors, whether first or last, regardless of AE gender. Overall, there was no significant correlation between gender of first or last author, or of AE, on the likelihood of acceptance of a research paper. These data suggest no bias against female authors during the peer review process in this reproductive biology journal

Incorporating conceptual site models into national-scale environmental risk assessments for legacy waste in the coastal zone

Solid wastes deposited in the coastal zone that date from an era of lax environmental regulations continue to pose significant challenges for regulators and coastal managers worldwide. The increasing risk of contaminant release from these legacy disposal sites, due to a range of factors including rising sea levels, associated saline intrusion, and greater hydrological extremes, have been highlighted by many researchers. Given this widespread challenge, and the often-limited remedial funds available, there is a pressing need for the development of new advanced site prioritization protocols to limit potential pollution risks to sensitive ecological or human receptors. This paper presents a multi-criteria decision analysis that integrates the principles of Conceptual Site Models (Source-Pathway-Receptor) at a national scale in England and Wales to identify legacy waste sites where occurrence of pollutant linkages are most likely. A suite of spatial data has been integrated in order to score potential risks associated with waste type (Source), likelihood of pollutant release relating to current and future flood and erosion climate projections, alongside current management infrastructure (Pathway), and proximity to sensitive ecological features or proxies of human use in coastal areas (Receptors). Of the 30,281 legacy waste deposits identified in England and Wales, 3,219 were located within the coastal zone, with coastal areas containing a density of legacy wastes (by area) 10.5 times higher than inland areas. Of these, 669 were identified as priority sites in locations without existing coastal defences or flood management infrastructure, with 2550 sites identified in protected areas where contaminant transfer risks could still be apparent. The majority (63%) of the priority sites have either undefined source terms, or are classified as mixed wastes. Mining and industrial wastes were also notable waste categories, and displayed strong regional distributions in the former mining areas of north-east and south-west of England, south Wales, and post-industrial estuaries. The large-scale screening process presented here could be used by environmental managers as a foundation to direct more high-resolution site assessment and remedial work at priority sites, and can be used as a tool by governments for directing funding to problematic sites

Estimates of adherence and error analysis of physical activity data collected via accelerometry in a large study of free-living adults

<p>Abstract</p> <p>Background</p> <p>Activity monitors (AM) are small, electronic devices used to quantify the amount and intensity of physical activity (PA). Unfortunately, it has been demonstrated that data loss that occurs when AMs are not worn by subjects (removals during sleeping and waking hours) tend to result in biased estimates of PA and total energy expenditure (TEE). No study has reported the degree of data loss in a large study of adults, and/or the degree to which the estimates of PA and TEE are affected. Also, no study in adults has proposed a methodology to minimize the effects of AM removals.</p> <p>Methods</p> <p>Adherence estimates were generated from a pool of 524 women and men that wore AMs for 13 – 15 consecutive days. To simulate the effect of data loss due to AM removal, a reference dataset was first compiled from a subset consisting of 35 highly adherent subjects (24 HR; minimum of 20 hrs/day for seven consecutive days). AM removals were then simulated during sleep and between one and ten waking hours using this 24 HR dataset. Differences in the mean values for PA and TEE between the 24 HR reference dataset and the different simulations were compared using paired <it>t</it>-tests and/or coefficients of variation.</p> <p>Results</p> <p>The estimated average adherence of the pool of 524 subjects was 15.8 ± 3.4 hrs/day for approximately 11.7 ± 2.0 days. Simulated data loss due to AM removals during sleeping hours in the 24 HR database (n = 35), resulted in biased estimates of PA (p < 0.05), but not TEE. Losing as little as one hour of data from the 24 HR dataset during waking hours results in significant biases (p < 0.0001) and variability (coefficients of variation between 7 and 21%) in the estimates of PA. Inserting a constant value for sleep and imputing estimates for missing data during waking hours significantly improved the estimates of PA.</p> <p>Conclusion</p> <p>Although estimated adherence was good, measurements of PA can be improved by relatively simple imputation of missing AM data.</p

When is computer-mediated intergroup contact most promising? Examining the effect of out-group members' anonymity on prejudice

Computer-mediated intergroup contact (CMIC) is a valuable strategy to reduce negative sentiments towards members of different social groups. We examined whether characteristics of communication media that facilitate intergroup encounters shape its effect on out-group attitudes. Specifically, we propose that concealing individuating cues about out-group members during CMIC increases prejudice, as interaction partners are perceived as less socially present. To assess these hypotheses, we conducted two mixed-factorial experiments. Participants engaged in synchronous intergroup contact via text-chat with out-group members (Study 1) and a confederate (Study 2) who either shared or concealed their name and photo. Overall, CMIC reduced negative out-group sentiments. Study 2 showed, however, that out-group members' anonymity decreased perceived social presence, which was associated with less positive evaluations of the CMIC and higher prejudice. In conclusion, CMIC can contribute to conflict resolution interventions, preparing individuals for direct intergroup contact, if its affordances or conversation topics enhance interaction partners' social presence

Downregulation of histone H2A and H2B pathways is associated with anthracycline sensitivity in breast cancer

Abstract Background Drug resistance in breast cancer is the major obstacle to effective treatment with chemotherapy. While upregulation of multidrug resistance genes is an important component of drug resistance mechanisms in vitro, their clinical relevance remains to be determined. Therefore, identifying pathways that could be targeted in the clinic to eliminate anthracycline-resistant breast cancer remains a major challenge. Methods We generated paired native and epirubicin-resistant MDA-MB-231, MCF7, SKBR3 and ZR-75-1 epirubicin-resistant breast cancer cell lines to identify pathways contributing to anthracycline resistance. Native cell lines were exposed to increasing concentrations of epirubicin until resistant cells were generated. To identify mechanisms driving epirubicin resistance, we used a complementary approach including gene expression analyses to identify molecular pathways involved in resistance, and small-molecule inhibitors to reverse resistance. In addition, we tested its clinical relevance in a BR9601 adjuvant clinical trial. Results Characterisation of epirubicin-resistant cells revealed that they were cross-resistant to doxorubicin and SN-38 and had alterations in apoptosis and cell-cycle profiles. Gene expression analysis identified deregulation of histone H2A and H2B genes in all four cell lines. Histone deacetylase small-molecule inhibitors reversed resistance and were cytotoxic for epirubicin-resistant cell lines, confirming that histone pathways are associated with epirubicin resistance. Gene expression of a novel 18-gene histone pathway module analysis of the BR9601 adjuvant clinical trial revealed that patients with low expression of the 18-gene histone module benefited from anthracycline treatment more than those with high expression (hazard ratio 0.35, 95 % confidence interval 0.13–0.96, p = 0.042). Conclusions This study revealed a key pathway that contributes to anthracycline resistance and established model systems for investigating drug resistance in all four major breast cancer subtypes. As the histone modification can be targeted with small-molecule inhibitors, it represents a possible means of reversing clinical anthracycline resistance. Trial registration ClinicalTrials.gov identifier NCT00003012 . Registered on 1 November 1999

Understanding the burden of interstitial lung disease post-COVID-19: the UK Interstitial Lung Disease-Long COVID Study (UKILD-Long COVID)

Introduction The COVID-19 pandemic has led to over 100 million cases worldwide. The UK has had over 4 million cases, 400 000 hospital admissions and 100 000 deaths. Many patients with COVID-19 suffer long-term symptoms, predominantly breathlessness and fatigue whether hospitalised or not. Early data suggest potentially severe long-term consequence of COVID-19 is development of long COVID-19-related interstitial lung disease (LC-ILD). Methods and analysis The UK Interstitial Lung Disease Consortium (UKILD) will undertake longitudinal observational studies of patients with suspected ILD following COVID-19. The primary objective is to determine ILD prevalence at 12 months following infection and whether clinically severe infection correlates with severity of ILD. Secondary objectives will determine the clinical, genetic, epigenetic and biochemical factors that determine the trajectory of recovery or progression of ILD. Data will be obtained through linkage to the Post-Hospitalisation COVID platform study and community studies. Additional substudies will conduct deep phenotyping. The Xenon MRI investigation of Alveolar dysfunction Substudy will conduct longitudinal xenon alveolar gas transfer and proton perfusion MRI. The POST COVID-19 interstitial lung DiseasE substudy will conduct clinically indicated bronchoalveolar lavage with matched whole blood sampling. Assessments include exploratory single cell RNA and lung microbiomics analysis, gene expression and epigenetic assessment. Ethics and dissemination All contributing studies have been granted appropriate ethical approvals. Results from this study will be disseminated through peer-reviewed journals. Conclusion This study will ensure the extent and consequences of LC-ILD are established and enable strategies to mitigate progression of LC-ILD

Dipeptidyl peptidase-1 inhibition in patients hospitalised with COVID-19: a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial

Background Neutrophil serine proteases are involved in the pathogenesis of COVID-19 and increased serine protease activity has been reported in severe and fatal infection. We investigated whether brensocatib, an inhibitor of dipeptidyl peptidase-1 (DPP-1; an enzyme responsible for the activation of neutrophil serine proteases), would improve outcomes in patients hospitalised with COVID-19. Methods In a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial, across 14 hospitals in the UK, patients aged 16 years and older who were hospitalised with COVID-19 and had at least one risk factor for severe disease were randomly assigned 1:1, within 96 h of hospital admission, to once-daily brensocatib 25 mg or placebo orally for 28 days. Patients were randomly assigned via a central web-based randomisation system (TruST). Randomisation was stratified by site and age (65 years or ≥65 years), and within each stratum, blocks were of random sizes of two, four, or six patients. Participants in both groups continued to receive other therapies required to manage their condition. Participants, study staff, and investigators were masked to the study assignment. The primary outcome was the 7-point WHO ordinal scale for clinical status at day 29 after random assignment. The intention-to-treat population included all patients who were randomly assigned and met the enrolment criteria. The safety population included all participants who received at least one dose of study medication. This study was registered with the ISRCTN registry, ISRCTN30564012. Findings Between June 5, 2020, and Jan 25, 2021, 406 patients were randomly assigned to brensocatib or placebo; 192 (47·3%) to the brensocatib group and 214 (52·7%) to the placebo group. Two participants were excluded after being randomly assigned in the brensocatib group (214 patients included in the placebo group and 190 included in the brensocatib group in the intention-to-treat population). Primary outcome data was unavailable for six patients (three in the brensocatib group and three in the placebo group). Patients in the brensocatib group had worse clinical status at day 29 after being randomly assigned than those in the placebo group (adjusted odds ratio 0·72 [95% CI 0·57–0·92]). Prespecified subgroup analyses of the primary outcome supported the primary results. 185 participants reported at least one adverse event; 99 (46%) in the placebo group and 86 (45%) in the brensocatib group. The most common adverse events were gastrointestinal disorders and infections. One death in the placebo group was judged as possibly related to study drug. Interpretation Brensocatib treatment did not improve clinical status at day 29 in patients hospitalised with COVID-19