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Introduction: Healthcare professionals (HCPs) appear to be at increased risk for negative psychological outcomes [e.g. depression, anxiety, post-traumatic stress disorder (PTSD), moral distress] and associated impacts on functioning throughout the COVID-19 pandemic. HCPs working on designated COVID-19 units may be further impacted than their colleagues not on these units given added demands of patient care and risk of contracting COVID-19. Little is known, however, about the mental health and functioning of specific professional groups beyond nurses and physicians, including respiratory therapists (RTs), over the course of the pandemic. Accordingly, the purpose of the present study was to characterize the mental health and functioning of Canadian RTs and compare profiles between RTs working on and off designated COVID-19 units. Methods: Canadian RTs completed an online survey between February and June 2021, including demographic information (e.g. age, sex, gender,) and measures of depression, anxiety, stress, PTSD, moral distress and functional impairment. Descriptive statistics, correlation analyses and between-groups comparisons were conducted to characterize RTs and compare profiles between those on and off COVID-19 units. Results: Two hundred and eighteen (N = 218) RTs participated in this study. The estimated response rate was relatively low (6.2%) Approximately half of the sample endorsed clinically relevant symptoms of depression (52%), anxiety (51%) and stress (54%) and one in three (33%) screened positively for potential PTSD. All symptoms correlated positively with functional impairment (p's < .05). RTs working on COVID-19 units reported significantly greater patient-related moral distress compared to those not on these units (p < .05). Conclusion: Moral distress and symptoms of depression, anxiety, stress and PTSD were prevalent among Canadian RTs and were associated with functional impacts. These results must be interpreted with caution given a low response rate, yet raise concern regarding the long-term impacts of pandemic service among RTs. Research on RTs' mental health prior to and during the COVID-19 pandemic is scant, especially in comparison to other HCPs. RTs in the present study reported experiencing moral distress and clinically significant symptoms of depression, anxiety and PTSD, with associated functional impairment. One in three RTs screened positive for likely PTSD on the PCL-5. There is a need to provide RTs with adequate mental health supports and to understand the long-term impacts of pandemic service among RTs.

Respiratory therapists (RTs) faced morally distressing situations throughout the COVID-19 pandemic, including working with limited resources and facilitating video calls for families of dying patients. Moral distress is associated with a host of adverse psychological and functional outcomes (e.g. depression, anxiety, symptoms of posttraumatic stress disorder [PTSD] and functional impairment) and consideration of position departure. The purpose of this study was to understand the impact of moral distress and its associated psychological and functional outcomes on consideration to leave a clinical position among Canadian RTs during the COVID-19 pandemic. Canadian RTs (N = 213) completed an online survey between February and June 2021. Basic demographic information (e.g. age, sex, gender) and psychometrically validated measures of moral distress, depression, anxiety, stress, PTSD, dissociation, functional impairment, resilience and adverse childhood experiences were collected. One in four RTs reported considering leaving their position. RTs considering leaving reported elevated levels of moral distress and adverse psychological and functional outcomes compared to RTs not considering leaving. Over half (54.5%) of those considering leaving scored above the cut-off for potential diagnosis of PTSD. Previous consideration to leave a position and having left a position in the past each significantly increased the odds of currently considering leaving, along with system-related moral distress and symptoms of PTSD, but the contribution of these latter factors was small. Canadian RTs considering leaving their position reported elevated levels of distress and adverse psychological and functional outcomes, yet these individual-level factors appear unlikely to be the primary factors underlying RTs' consideration to leave, because their effects were small. Further research is required to identify broader, organizational factors that may contribute to consideration of position departure among Canadian RTs.

Introduction. Les thérapeutes respiratoires ont été confrontés à des situations moralement difficiles tout au long de la pandémie de COVID-19, en particulier le fait d’avoir peu de ressources pour effectuer leur travail ou encore la participation à des appels vidéo avec les familles de patients mourants. La détresse morale (c’est-à-dire la détresse psychologique résultant de l’interdiction de suivre un plan d’action reconnu et approprié d’un point de vue éthique) est associée à une foule de conséquences psychologiques et fonctionnelles négatives (dépression, anxiété, symptômes du trouble de stress post‑traumatique [TSPT], déficience fonctionnelle, etc.) et au fait d’envisager de quitter son poste. L’objectif de cette étude était de comprendre l’effet de la détresse morale et de ses conséquences psychologiques et fonctionnelles sur le fait que des thérapeutes respiratoires canadiens aient envisagé de quitter leur poste clinique pendant la pandémie de COVID‑19.Méthodologie.Des thérapeutes respiratoires canadiens (N = 213) ont répondu à un sondage en ligne entre février et juin 2021. Des caractéristiques inividuelles de base (âge, sexe/genre, etc.) ont été recueillies, ainsi que des mesures psychométriques validées de la détresse morale, de la dépression, de l’anxiété, du stress, du TSPT, de la dissociation, de la déficience fonctionnelle, de la résilience et des expériences négatives vécues durant l’enfance.Résultats. Un thérapeute respiratoire sur quatre a déclaré envisager de quitter son poste en raison d’une détresse morale. Ceux qui envisageaient de le faire ont fait état de niveaux élevés de détresse morale et de conséquences psychologiques et fonctionnelles négatives comparativement aux thérapeutes respiratoires qui n’envisageaient pas de quitter leur poste. Plus de la moitié (54,5 %) de ceux qui envisageaient de quitter leur poste ont obtenu un score supérieur au seuil indiquant un diagnostic potentiel de TSPT. Le fait d’avoir déjà envisagé de quitter un poste auparavant en raison d’une détresse morale et le fait d’avoir effectivement quitté un poste antérieur augmentaient significativement la probabilité d’envisager de quitter son poste, tout comme la détresse morale liée au système et les symptômes de TSPT, mais la contribution de ces derniers facteurs était faible.Conclusion.Les thérapeutes respiratoires canadiens qui envisageaient de quitter leur poste en raison d’une détresse morale ont signalé des niveaux élevés de détresse et de conséquences psychologiques et fonctionnelles négatives. Il semble néanmoins peu probable que ces facteurs individuels soient les principaux facteurs pour lesquels ils envisageaient de quitter leur poste, car les effets en étaient faibles. D’autres recherches sont nécessaires pour cerner les facteurs organisationnels plus vastes susceptibles d’inciter les thérapeutes respiratoires canadiens à vouloir quitter leur poste.

Teaching that supports ideas of social justice is often difficult to enact, particularly for teachers who may have few models for the process of developing such instruction. In this dissertation, I address the development and analysis of three semester-long partnerships between myself and three high school teachers interested in improving their social justice practice. The design of these partnerships, and of the work teachers and I did within them, was highly collaborative and drew primarily on teachers’ ideas and understandings rather than privileging my own. Teachers were asked to conceptualize and define social justice with respect to their own classroom context, to consider ways in which they might respond through their practice to the issues they identified, and to design and implement changes that addressed these issues. My own role was that of a dynamic resource, available to support teachers and to discuss, observe, comment, assess, and challenge as per their preferences. My use of the methodology of portraiture enabled me to tell the story of our work together in order to demonstrate the process through which these teachers worked to improve their social justice practice. Further, by drawing on interviews with a principal and district leader in addition to teacher data, I was able to contextualize teachers’ work within the functioning of the school and district in which they operate, with a focus on all participants’ understandings of work being done at their own and other levels, the context of their school and district and its impact on teachers’ work, and the relationship between teachers’ classroom practice and the policies that support or constrain it. My analysis demonstrates that these teachers have substantial knowledge of their students and classroom context that supported our work together, and teachers themselves suggested both that they found our partnerships to be impactful and that they had a desire for further feedback and discussion around their practice. I found that teachers had different ways of linking issues of social justice to their work, sometimes addressing connections between these issues and the curriculum, sometimes incorporating social justice ideas into their relationships with students, and sometimes focusing on these issues through the ways in which they supported students in interacting with one another. Further, teachers identified discussion in our work together as far more helpful for improving their practice than the simple provision of external resources and expressed a desire for further constructive conversation about their practice. My interviews with teachers and administrators suggested that future opportunities for learning might be complicated by disconnects both among teachers and between teachers and the administration in ways in which concepts like social justice, equity, equality, and fairness, as well as classroom issues like gender and politics, were taken up. I conclude with recommendations for researchers, school and district leaders, and other educational stakeholders around improving dialogue and focusing on what is good in others’ practice in order to better support social justice work in education.

Mepolizumab (anti-IL5 therapy) reduces asthma exacerbations in urban children with exacerbation-prone eosinophilic asthma. We previously utilized nasal transcriptomics to identify inflammatory pathways (gene co-expression modules) associated with asthma exacerbations despite this therapy. In this study, we applied differential gene correlation analysis on these targeted gene co-expression modules to gain better insight into the treatment effects on correlation structure within gene networks. Mepolizumab treatment resulted in loss of correlation amongst eosinophil-specific genes but conservation and even strengthening of correlation amongst mast cell-specific genes, T2 cytokines, and airway epithelial inflammatory genes. Notably, mepolizumab induced significant gain in correlation of genes associated with multiple aspects of airway epithelial inflammation including those related to extracellular matrix production and nitric oxide synthesis, and this change was associated with a poor clinical response to mepolizumab. These findings highlight that using differential gene correlation analysis offers insight into the molecular regulatory effects of treatment on gene interactions and may lead to better understanding of disease mechanisms and therapeutic responses. ClinicalTrials.gov ID: NCT03292588. Mepolizumab (anti-IL-5 therapy) has been shown to reduce type 2 inflammation in asthma. Here the authors use bulk transcriptomics from nasal samples before and after mepolizumab treatment to assess the changes and associations with treatment outcomes.

Black and Hispanic children living in urban environments in the USA have an excess burden of morbidity and mortality from asthma. Therapies directed at the eosinophilic phenotype reduce asthma exacerbations in adults, but few data are available in children and diverse populations. Furthermore, the molecular mechanisms that underlie exacerbations either being prevented by, or persisting despite, immune-based therapies are not well understood. We aimed to determine whether mepolizumab, added to guidelines-based care, reduced the number of asthma exacerbations during a 52-week period compared with guidelines-based care alone. This is a randomised, double-blind, placebo-controlled, parallel-group trial done at nine urban medical centres in the USA. Children and adolescents aged 6–17 years, who lived in socioeconomically disadvantaged neighbourhoods and had exacerbation-prone asthma (defined as ≥two exacerbations in the previous year) and blood eosinophils of at least 150 cells per μL were randomly assigned 1:1 to mepolizumab (6–11 years: 40 mg; 12–17 years: 100 mg) or placebo injections once every 4 weeks, plus guideline-based care, for 52 weeks. Randomisation was done using a validated automated system. Participants, investigators, and the research staff who collected outcome measures remained masked to group assignments. The primary outcome was the number of asthma exacerbations that were treated with systemic corticosteroids during 52 weeks in the intention-to-treat population. The mechanisms of treatment response were assessed by study investigators using nasal transcriptomic modular analysis. Safety was assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03292588. Between Nov 1, 2017, and Mar 12, 2020, we recruited 585 children and adolescents. We screened 390 individuals, of whom 335 met the inclusion criteria and were enrolled. 290 met the randomisation criteria, were randomly assigned to mepolizumab (n=146) or placebo (n=144), and were included in the intention-to-treat analysis. 248 completed the study. The mean number of asthma exacerbations within the 52-week study period was 0·96 (95% CI 0·78–1·17) with mepolizumab and 1·30 (1·08–1·57) with placebo (rate ratio 0·73; 0·56–0·96; p=0·027). Treatment-emergent adverse events occurred in 42 (29%) of 146 participants in the mepolizumab group versus 16 (11%) of 144 participants in the placebo group. No deaths were attributed to mepolizumab. Phenotype-directed therapy with mepolizumab in urban children with exacerbation-prone eosinophilic asthma reduced the number of exacerbations. US National Institute of Allergy and Infectious Diseases and GlaxoSmithKline.

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections are characterized by early peaks of viraemia that decline as strong cellular immune responses develop 1 , 2 . Although it has been shown that virus-specific CD8-positive cytotoxic T lymphocytes (CTLs) exert selective pressure during HIV and SIV infection 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , the data have been controversial 12 , 13 . Here we show that Tat-specific CD8-positive T-lymphocyte responses select for new viral escape variants during the acute phase of infection. We sequenced the entire virus immediately after the acute phase, and found that amino-acid replacements accumulated primarily in Tat CTL epitopes. This implies that Tat-specific CTLs may be significantly involved in controlling wild-type virus replication, and suggests that responses against viral proteins that are expressed early during the viral life cycle might be attractive targets for HIV vaccine development.

A community computational challenge generates algorithms to predict activity of drug combinations. Recent therapeutic successes have renewed interest in drug combinations, but experimental screening approaches are costly and often identify only small numbers of synergistic combinations. The DREAM consortium launched an open challenge to foster the development of in silico methods to computationally rank 91 compound pairs, from the most synergistic to the most antagonistic, based on gene-expression profiles of human B cells treated with individual compounds at multiple time points and concentrations. Using scoring metrics based on experimental dose-response curves, we assessed 32 methods (31 community-generated approaches and SynGen), four of which performed significantly better than random guessing. We highlight similarities between the methods. Although the accuracy of predictions was not optimal, we find that computational prediction of compound-pair activity is possible, and that community challenges can be useful to advance the field of in silico compound-synergy prediction.

High-dose-rate brachytherapy (HDR-BT) delivered in a single fraction as monotherapy is a potential treatment modality for low- and intermediate-risk prostate cancer (LIR-PC); however, outcome data with this technique remain limited. Here we describe our institutional HDR monotherapy experience and report the efficacy and toxicity of this treatment. LIR-PC patients who received a definitive single fraction HDR-BT during 2013-2017 were retrospectively identified. The intended HDR monotherapy dose was 19 Gy in one fraction. Acute (< 90 days) and late (≥ 90 days) toxicity was assessed using CTCAE version 4.03. Trends in prostate-specific antigen (PSA) and American Urological Association (AUA) symptom scores after treatment were assessed using Bayesian linear mixed models. The Kaplan-Meier method was used to evaluate biochemical failure-free survival (BFFS). 28 patients with median follow-up of 23.6 months were identified. The median age at treatment was 65 years (48-83). The NCCN risk groups were low in 14, favorable intermediate in 10, and unfavorable intermediate in 4 patients. There were 5 (18%) and 0 (0%) acute grade 2 genitourinary (GU) and gastrointestinal (GI) toxicities, respectively, and one (4%) acute grade 3 GU toxicity. There were no late grade 3 toxicities, and 5 (18%) and 0 (0%) late grade 2 GU and GI toxicities respectively. PSA values and AUA symptom scores decreased significantly after treatment. There were 3 biochemical failures with the two- and three-year BFFS of 90.7% and 80.6%, respectively. Early results from a single institution suggest that single fraction HDR-BT with 19 Gy has limited toxicity, although with suboptimal biochemical control.