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Background: The Comparison of Outcomes and Access to Care for Heart Failure (COACH) trial demonstrated that use of a point-of-care risk assessment tool and a rapid ambulatory transitional heart failure clinic led to significant reductions in death and cardiovascular hospitalisation among patients with acute heart failure. We report a process evaluation of COACH intervention and strategy implementation. Methods: We conducted longitudinal interviews with staff to assess barriers and facilitators to COACH implementation. Factors were coded according to the Theoretical Domains Framework (TDF) and the Consolidated Framework for Implementation Research (CFIR). Intervention mapping was conducted to identify theory-rooted strategies to address barriers and influence facilitators toward implementation. We used interviews, document reviews, and check-in calls with implementation teams to describe uptake of these strategies and their impact on implementation success over time. Results: A total of 29 interviews were conducted across 10 sites. We identified 10 factors that affected COACH implementation, which corresponded to 6 TDF and 5 CFIR domains. Some barriers were resolved within the study period, but others persisted over time. Seven implementation strategies were recommended to sites. Participants identified ample preparation time, site-specific personnel support, structural and social characteristics conducive to the intervention needs, and implementation experience as factors that facilitated implementation success. Conclusions: We supported implementation of the COACH intervention in 10 acute care hospital sites and describe the factors impacting implementation. We recommend a rapid implementation assessment to sites wishing to implement COACH, and suggest strategies that can be used to mitigate barriers and aid facilitators to improve implementation success. Résumé: Contexte: L’essai COACH (Comparison of Outcomes and Access to Care for Heart Failure) a démontré que l’utilisation d’un outil d’évaluation des risques aux points de service et l’accès à des soins de transition dans une clinique ambulatoire spécialisée en insuffisance cardiaque réduisaient considérablement le taux de mortalité et d’hospitalisation pour cause de maladie cardiovasculaire chez les patients atteints d’insuffisance cardiaque aiguë. Nous avons évalué le processus de mise en œuvre d’interventions et de stratégies COACH. Méthodologie: Nous avons réalisé des entrevues longitudinales avec des membres du personnel afin d’évaluer les facteurs influant positivement et négativement sur la mise en œuvre d’interventions COACH. Les facteurs ont été codés d’après le cadre TDF (Theoretical Domains Framework) et l’étude CFIR (Consolidated Framework for Implementation Research). Une cartographie des interventions a permis de dégager des stratégies ancrées dans la théorie visant à éliminer les obstacles et à favoriser la mise en œuvre. Nous avons réalisé des entrevues, étudié la documentation et fait des appels de suivi aux équipes de mise en œuvre afin de décrire l’adoption de ces stratégies et leur incidence sur le succès à long terme de leur mise en œuvre. Résultats: Nous avons réalisé au total 29 entrevues dans 10 centres. Nous avons relevé 10 facteurs ayant une incidence sur la mise en œuvre d’interventions COACH qui correspondaient à 6 domaines du cadre TDF et à 5 domaines de l’étude CFIR. Certains obstacles ont pu être éliminés durant la période de l’étude, tandis que d’autres ont persisté. Sept stratégies de mise en œuvre ont été recommandées aux centres. Parmi les facteurs favorisant la réussite de la mise en œuvre, les participants ont mentionné un délai de préparation suffisant, le soutien offert au personnel de chaque centre, des caractéristiques structurales et sociales adaptées aux besoins en matière d’intervention et l’expérience de mise en œuvre. Conclusions: Nous avons pu favoriser la mise en œuvre d’interventions COACH dans 10 hôpitaux de soins actifs et décrit les facteurs ayant une incidence sur leur mise en œuvre. Nous recommandons de faire une évaluation rapide de la mise en œuvre aux centres qui souhaitent adopter des interventions COACH, et suggérons des stratégies pour réduire les obstacles et favoriser la réussite de la mise en œuvre.

Background: Pediatric patients require pharmacological management of pain and agitation associated with mechanical ventilation. Pain and agitation may be refractory to opioids and alpha-2 agonists, prompting the use of adjunctive analgesics and sedatives with alternative mechanisms. The purpose of this study was to describe the use of phenobarbital as an adjunctive agent for refractory agitation in critically ill, mechanically ventilated pediatric patients. Subjects and Methods: This was a single-center, retrospective chart review at a pediatric intensive care unit (PICU) at a pediatric academic medical center in America between 2016 and 2021. Children aged 2 months to 18 years old were admitted to the PICU were mechanically ventilated and received phenobarbital for adjunct sedation. Sixty-three patients had phenobarbital dosing data evaluated, and the 38 patients who were not receiving continuous neuromuscular blockade were included in the primary and secondary outcome analysis of time within the goal sedation score. Descriptive statistics was used to assess baseline characteristics and the primary outcome. Wilcoxon signed-rank tests were used to evaluate secondary outcomes. Results: Patients spent significantly more time within the goal sedation score range after phenobarbital compared to before phenobarbital. The median number of rescue sedative boluses, morphine equivalents (MEs), and benzodiazepine equivalents (BZDE) significantly decreased 2 days after the first phenobarbital dose compared to the 2 days before the first phenobarbital dose. Conclusions: The use of phenobarbital as an adjunct sedative was associated with a statistically significant increase in time spent in the goal sedation score range and decrease in ME, BZDE, and concomitant sedative boluses.

Abstract The gut microbiota of infants in low- to middle-income countries is underrepresented in microbiome research. This study explored the faecal microbiota composition and faecal cytokine profiles in a cohort of infants in a rural province of Cambodia and investigated the impact of sample storage conditions and infant environment on microbiota composition. Faecal samples collected at three time points from 32 infants were analysed for microbiota composition using 16S rRNA amplicon sequencing and concentrations of faecal cytokines. Faecal bacterial isolates were subjected to whole genome sequencing and genomic analysis. We compared the effects of two sample collection methods due to the challenges of faecal sample collection in a rural location. Storage of faecal samples in a DNA preservation solution preserved Bacteroides abundance. Microbiota analysis of preserved samples showed that Bifidobacterium was the most abundant genus with Bifidobacterium longum the most abundant species, with higher abundance in breast-fed infants. Most infants had detectable pathogenic taxa, with Shigella and Klebsiella more abundant in infants with recent diarrhoeal illness. Neither antibiotics nor infant growth were associated with gut microbiota composition. Genomic analysis of isolates showed gene clusters encoding the ability to digest human milk oligosaccharides in B. longum and B. breve isolates. Antibiotic-resistant genes were present in both potentially pathogenic species and in Bifidobacterium. Faecal concentrations of Interlukin-1alpha and vascular endothelial growth factor were higher in breast-fed infants. This study provides insights into an underrepresented population of rural Cambodian infants, showing pathogen exposure and breastfeeding impact gut microbiota composition and faecal immune profiles.

Abstract Background Sickle cell anemia (SCA) prevalence remains high in sub-Saharan Africa. Long-term treatment with hydroxyurea (HU) increases survival, however, poor adherence to treatment could limit effectiveness. Whilst HU treatment adherence is currently high, this might decrease over time. Methods We conducted a single-center, randomized, open-label, parallel group phase 2 controlled clinical trial to determine whether mobile Directly Observed Therapy (m-DOT) increases HU treatment adherence (NCT02844673). Eligible participants were adults with homozygous SCA. People on a chronic blood transfusion program, with hemoglobin (Hb) A levels greater than 20% of the total Hb, total Hb less than 4 g/dL, pregnant or HIV positive were excluded. After a 3-month pre-treatment period participants were randomized to either m-DOT or standard monitoring arm. All participants received smart mobile phones and were treated with HU (15 mg/kg) daily for three months. In the m-DOT arm, drug intake was video recorded on cell phone by the participant and the video sent to the study team. The primary objective was to evaluate the effect of m-DOT on adherence to HU treatment by medication possession ratio (MPR). Results Of the 86 participants randomized, 76 completed the trial (26.13 ± 6.97 years, 63.5 % female). Adherence was high (MPR > 95 %) in both groups, 29 (80.6 %) in m-DOT versus 37 (94.9 %) in the standard monitoring arm (P = 0.079). No HU treatment was withheld from participants due to safety concerns. Conclusions m-DOT did not increase adherence to HU treatment. We recommend that further testing in larger trials with a longer follow up period be undertaken.

Abstract In biogeochemical phosphorus cycling, iron oxide minerals are acknowledged as strong adsorbents of inorganic and organic phosphorus. Dephosphorylation of organic phosphorus is attributed only to biological processes, but iron oxides could also catalyze this reaction. Evidence of this abiotic catalysis has relied on monitoring products in solution, thereby ignoring iron oxides as both catalysts and adsorbents. Here we apply high-resolution mass spectrometry and X-ray absorption spectroscopy to characterize dissolved and particulate phosphorus species, respectively. In soil and sediment samples reacted with ribonucleotides, we uncover the abiotic production of particulate inorganic phosphate associated specifically with iron oxides. Reactions of various organic phosphorus compounds with the different minerals identified in the environmental samples reveal up to twenty-fold greater catalytic reactivities with iron oxides than with silicate and aluminosilicate minerals. Importantly, accounting for inorganic phosphate both in solution and mineral-bound, the dephosphorylation rates of iron oxides were within reported enzymatic rates in soils. Our findings thus imply a missing abiotic axiom for organic phosphorus mineralization in phosphorus cycling.

Abstract Background Theories, models and frameworks (TMFs) are useful when implementing, evaluating and sustaining healthcare evidence-based interventions. Yet it can be challenging to identify an appropriate TMF for an implementation project. We developed and tested the usability of an online tool to help individuals who are doing or supporting implementation practice activities to identify appropriate models and/or frameworks to inform their work. Methods We used methods guided by models and evidence on implementation science and user-centered design. Phases of tool development included applying findings from a scoping review of TMFs and interviews with 24 researchers/implementers on barriers and facilitators to identifying and selecting TMFs. Based on interview findings, we categorized the TMFs by aim, stage of implementation, and target level of change to inform the tool’s algorithm. We then conducted interviews with 10 end-users to test the usability of the prototype tool and administered the System Usability Scale (SUS). Usability issues were addressed and incorporated into the tool. Results We developed Find TMF, an online tool consisting of 3–4 questions about the user’s implementation project. The tool’s algorithm matches key characteristics of the user’s project (aim, stage, target change level) with characteristics of different TMFs and presents a list of candidate models/frameworks. Ten individuals from Canada or Australia participated in usability testing (mean SUS score 84.5, standard deviation 11.4). Overall, participants found the tool to be simple, easy to use and visually appealing with a useful output of candidate models/frameworks to consider for an implementation project. Users wanted additional instruction and guidance on what to expect from the tool and how to use the information in the output table. Tool improvements included incorporating an overview figure outlining the tool steps and output, displaying the tool questions on a single page, and clarifying the available functions of the results page, including adding direct links to the glossary and to complementary tools. Conclusions Find TMF is an easy-to-use online tool that may benefit individuals who support implementation practice activities by making the vast number of models and frameworks more accessible, while also supporting a consistent approach to identifying and selecting relevant TMFs.

Abstract Background The impact of social frailty on older adults is profound including mortality risk, functional decline, falls, and disability. However, effective strategies that respond to the needs of socially frail older adults are lacking and few studies have unpacked how social determinants operate or how interventions can be adapted during periods requiring social distancing and isolation such as the COVID-19 pandemic. To address these gaps, we conducted a scoping review using JBI methodology to identify interventions that have the best potential to help socially frail older adults (age ≥65 years). Methods We searched MEDLINE, CINAHL (EPSCO), EMBASE and COVID-19 databases and the grey literature. Eligibility criteria were developed using the PICOS framework. Our results were summarized descriptively according to study, patient, intervention and outcome characteristics. Data synthesis involved charting and categorizing identified interventions using a social frailty framework. Results Of 263 included studies, we identified 495 interventions involving ~124,498 older adults who were mostly female. The largest proportion of older adults (40.5%) had a mean age range of 70-79 years. The 495 interventions were spread across four social frailty domains: social resource (40%), self-management (32%), social behavioural activity (28%), and general resource (0.4%). Of these, 189 interventions were effective for improving loneliness, social and health and wellbeing outcomes across psychological self-management, self-management education, leisure activity, physical activity, Information Communication Technology and socially assistive robot interventions. Sixty-three interventions were identified as feasible to be adapted during infectious disease outbreaks (e.g., COVID-19, flu) to help socially frail older adults. Conclusions Our scoping review identified promising interventions with the best potential to help older adults living with social frailty.

Rapid development and deployment of marine carbon dioxide removal (mCDR) approaches will be required to prevent the worst consequences of climate change and meet national treaty obligations under the Paris agreement. However, approaches to monitor the efficacy and environmental safety of mCDR are not being developed with the same intensity as the technology. Verification will be required to convince a sceptical public and regulatory community of the overall benefit of mCDR as well as provide the regulatory community a basis for risk assessments that will be required for at scale deployments. In this perspective, we posit that genomics-based approaches can be used to assess the efficacy of carbon sequestration and monitor for the possibility of unintended consequences. By adopting these approaches, it will be feasible to develop the evidence portfolio necessary to underpin assessments of the risks, benefits and trade-offs involved in responsible deployment of mCDR.

Summary: Background: Anaemia in sickle cell disease (SCD) is a significant cause of morbidity and mortality, but few studies have reported on the burden and outcome of very severe anaemia. This study described the epidemiology of very severe anaemia by determining the prevalence and incidence, investigating associated clinical and laboratory factors, and assessing outcomes in SCD. Methods: A 10-year prospective cohort study involving SCD patients of all ages was conducted at Muhimbili National Hospital in Tanzania between 2004 and 2013. SCD included Homozygous SS-Sickle cell anaemia and Sβ0 thalassemia at clinics and during hospitalization visits. Very severe anaemia was defined as Haemoglobin

Study region: Lake Bogoria and Lake Baringo, Rift Valley, Kenya Study focus: Starting around 2010, several of Kenya’s Rift Valley lakes experienced significant rises in water levels. There is presently fear of an ecological catastrophe should the water levels of the alkaline Lake Bogoria continue to rise and subsequently overflow into and cross-mix with the freshwater Lake Baringo, a hydrological situation witnessed ∼8 000–10 000 years ago. New hydrological insights into the region: In the last decade, data reveals significant meteorological and hydrological changes in the study region. Average annual rainfall has more than doubled, with substantial increases in variability. Despite a decrease in the number of rainy days within this period, intense rainfall days have increased by 318 %. Relative to the maximum water level observed in 2020, a 0.7 m increase in lake level would be sufficient for Lake Bogoria to reach the spill point located at about 1000.2 m, beyond which an overflow into Lake Baringo begins to occur. In 2023, the lake level declined by 1.5 m, resulting in a decreased risk of overflow of ∼20 %. Results indicate that mean annual rainfall after 2010 was high enough to provide an average annual flow of 500–1000 L/s from Lake Bogoria towards Baringo if lake levels were at spill point elevation.

Background: Magnetocardiography (MCG) may provide a rapid diagnostic option for patients presenting with chest pain in the emergency department (ED). Case summaries: This case series presents two instances from a multicenter study, where MCG could have served as a rapid, non-invasive diagnostic tool for chest pain patients. In both cases, multiple high-sensitivity troponin (hsTn) tests yielded incorrect evidence of ischemia. In the first case, multiple positive hsTn tests led to the patient requiring 23 h of observation care, while MCG rapidly ruled out acute coronary syndrome (ACS). In the second case, MCG revealed findings indicative of cardiac ischemia where serial ECGs did not indicate ischemia and serial hsTns were normal. Subsequent cardiac catheterization confirmed 99 % stenosis in the patient's left main and left anterior descending arteries, necessitating coronary artery bypass grafting (CABG). Conclusion: MCG offers a rapid, painless, non-invasive, radiation free assessment for patients presenting with acute chest pain. Integrating MCG into ED workflows has the potential to improve throughput, reduce the need for subsequent patient observation or inpatient admission, and minimize or eliminate the need for other more expensive non-invasive cardiac testing. MCG avoids some of the problems associated with other methods for diagnosing ischemia. MCG does not involve radiation or the use of pharmacologic agents which have a risk for allergic reactions and anaphylaxis, or the need for an intravenous line. Stress tests are frequently contraindicated or unable to be performed in patients on various medications, may require patient cooperation and in the case of exercise stress tests, the patient's capability to exercise. MCG requires no special patient preparation.

Study objectives: Patients frequently present to the emergency department (ED) with chest pain requiring further risk stratification. Traditional cardiac diagnostics such as stress testing may expose patients to ionizing radiation, may not be readily available, may take significant time for testing and interpretation, and adds cost to the workup. Magnetocardiography (MCG) is an alternative approach to assess candidates more quickly and efficiently than routine downstream testing. Design: We created and ran 1000 trials of a Monte Carlo simulation. Using this simulation, we modeled the national annual impact by averting further cardiac diagnostics. Setting: All EDs in the United States. Participants: All ED adult patients with chest pain. Interventions: Simulated use of MCG to reduce avoidable downstream cardiac diagnostics. Main outcome measures: Our primary outcome was to estimate the impact of an MCG-first strategy on the annual national cost savings among eligible patients in the ED. Our secondary outcomes were the estimated reduction in short-stay hospitalizations, cancer cases, and cancer deaths due to radiation exposure. Results: An MCG-first strategy was estimated to save a mean (±SD) of $574 million (±$175 million) by avoiding 555,000 (±93,000) downstream cardiac diagnostic tests. This resulted in a national annual cumulative decrease of 500,000 (±84,000) hospitalizations, 7,600,000 (±1,500,000) bed hours, 409 (±110) new cancer diagnoses, and 210 (±56) new cancer deaths due to radiation exposure from avoidable cardiac diagnostics. Conclusions: If adopted widely and used consistently, an MCG-first strategy among eligible patients could yield substantial benefits by averting avoidable cardiac diagnostic testing.

Abstract Background Effective mentorship is an important contributor to academic success. Given the critical role of leadership in fostering mentorship, this study sought to explore the perspectives of departmental leadership regarding 1) current departmental mentorship processes; and 2) crucial components of a mentorship program that would enhance the effectiveness of mentorship. Methods Department Division Directors (DDDs), Vice-Chairs, and Mentorship Facilitators from the Department of Medicine at the University of Toronto Temerty Faculty of Medicine were interviewed between April and December 2021 using a semi-structured guide. Interviews were audio-recorded and transcribed verbatim, then coded. Analysis occurred in 2 steps: 1) codes were organized to identify emergent themes; then 2) the Social Ecological Model (SEM) was applied to interpret the findings. Results Nineteen interviews (14 DDDs, 3 Vice-Chairs, and 2 Mentorship Facilitator) were completed. Analysis revealed three themes: (1) a culture of mentorship permeated the department as evidenced by rigorous mentorship processes, divisional mentorship innovations, and faculty that were keen to mentor; (2) barriers to the establishment of effective mentoring relationships existed at 3 levels: departmental, interpersonal (mentee-mentor relationships), and mentee; and (3) strengthening the culture of mentorship could entail scaling up pre-existing mentorship processes and promoting faculty engagement. Application of SEM highlighted critical program features and determined that two components of interventions (creating tools to measure mentorship outcomes and systems for mentor recognition) were potential enablers of success. Conclusions Establishing ‘mentorship outcome measures’ can incentivize and maintain relationships. By tangibly delineating departmental expectations for mentorship and creating systems that recognize mentors, these measures can contribute to a culture of mentorship.

Abstract Background Various studies have demonstrated gender disparities in workplace settings and the need for further intervention. This study identifies and examines evidence from randomized controlled trials (RCTs) on interventions examining gender equity in workplace or volunteer settings. An additional aim was to determine whether interventions considered intersection of gender and other variables, including PROGRESS-Plus equity variables (e.g., race/ethnicity). Methods Scoping review conducted using the JBI guide. Literature was searched in MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, ERIC, Index to Legal Periodicals and Books, PAIS Index, Policy Index File, and the Canadian Business & Current Affairs Database from inception to May 9, 2022, with an updated search on October 17, 2022. Results were reported using Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension to scoping reviews (PRISMA-ScR), Sex and Gender Equity in Research (SAGER) guidance, Strengthening the Integration of Intersectionality Theory in Health Inequality Analysis (SIITHIA) checklist, and Guidance for Reporting Involvement of Patients and the Public (GRIPP) version 2 checklist. All employment or volunteer sectors settings were included. Included interventions were designed to promote workplace gender equity that targeted: (a) individuals, (b) organizations, or (c) systems. Any comparator was eligible. Outcomes measures included any gender equity related outcome, whether it was measuring intervention effectiveness (as defined by included studies) or implementation. Data analyses were descriptive in nature. As recommended in the JBI guide to scoping reviews, only high-level content analysis was conducted to categorize the interventions, which were reported using a previously published framework. Results We screened 8855 citations, 803 grey literature sources, and 663 full-text articles, resulting in 24 unique RCTs and one companion report that met inclusion criteria. Most studies (91.7%) failed to report how they established sex or gender. Twenty-three of 24 (95.8%) studies reported at least one PROGRESS-Plus variable: typically sex or gender or occupation. Two RCTs (8.3%) identified a non-binary gender identity. None of the RCTs reported on relationships between gender and other characteristics (e.g., disability, age, etc.). We identified 24 gender equity promoting interventions in the workplace that were evaluated and categorized into one or more of the following themes: (i) quantifying gender impacts; (ii) behavioural or systemic changes; (iii) career flexibility; (iv) increased visibility, recognition, and representation; (v) creating opportunities for development, mentorship, and sponsorship; and (vi) financial support. Of these interventions, 20/24 (83.3%) had positive conclusion statements for their primary outcomes (e.g., improved academic productivity, increased self-esteem) across heterogeneous outcomes. Conclusions There is a paucity of literature on interventions to promote workplace gender equity. While some interventions elicited positive conclusions across a variety of outcomes, standardized outcome measures considering specific contexts and cultures are required. Few PROGRESS-Plus items were reported. Non-binary gender identities and issues related to intersectionality were not adequately considered. Future research should provide consistent and contemporary definitions of gender and sex. Trial registration Open Science Framework https://osf.io/x8yae .

Abstract Survival from ovarian cancer depends on the resection status after primary surgery. We performed genome-wide association analyses for resection status of 7705 ovarian cancer patients, including 4954 with high-grade serous carcinoma (HGSOC), to identify variants associated with residual disease. The most significant association with resection status was observed for rs72845444, upstream of MGMT, in HGSOC (p = 3.9 × 10−8). In gene-based analyses, PPP2R5C was the most strongly associated gene in HGSOC after stage adjustment. In an independent set of 378 ovarian tumours from the AGO-OVAR 11 study, variants near MGMT and PPP2R5C correlated with methylation and transcript levels, and PPP2R5C mRNA levels predicted progression-free survival in patients with residual disease. MGMT encodes a DNA repair enzyme, and PPP2R5C encodes the B56γ subunit of the PP2A tumour suppressor. Our results link heritable variation at these two loci with resection status in HGSOC.

The northwestern Antarctic Peninsula is an important spawning, recruitment, and overwintering ground for Antarctic krill. The region is warming rapidly, and the current impacts of climate and environmental variability on the reproductive cycle of krill remain unclear. Here, we examine the reproductive stage of female krill in the austral winter from 2012 to 2016 in relation to climate and environmental data to assess what factors influence the timing of reproductive development. We observed significant interannual variability in the degree of maturation in female krill, ranging from 48% of female krill measured at a station in 2016 to a maximum of 94% of female krill measured at a station in 2014. On average, across all five years, three-quarters of the female krill sampled were in the stage known as previtellogenesis, the point at which the onset of sexual maturity begins. The preceding spring, summer, and autumn Southern Annular Mode and the Multivariate El Niño Index explained most of the variance in the data and indicated a strong, preconditioning storm-related effect on environmental conditions leading up to winter, affecting krill maturation status at the end of the winter season. Results from our study can be used to improve krill population models that are necessary for the management of the krill fishery and for conservation at the northwestern Antarctic Peninsula.

Summary: Background: Reducing cigarette addictiveness has the potential to avert millions of yearly tobacco-related deaths worldwide. Substantially reducing nicotine in cigarettes decreases cigarette consumption, but no large clinical trial has determined the effects of reduced-nicotine cigarettes when other nicotine-containing products are available. The aim of this study was to examine the effects of reduced-nicotine cigarettes in the context of the availability of alternative nicotine delivery systems. Methods: In a U.S. six-site, open-label, parallel-arm study, smokers were randomized for twelve weeks to an experimental marketplace containing cigarettes with either 0.4 mg or 15.8 mg nicotine per gram of tobacco; all had access to non-combusted alternative nicotine delivery systems (e.g., e-cigarettes; medicinal nicotine). Group differences in the primary outcomes (cigarettes per day, number of smoke-free days) were examined using linear and negative binomial regression, respectively (Trial Registration: NCT03272685). Findings: Among 438 randomized participants (mean [standard deviation (SD), range] age, 44.5 [11.9, 20–73] years, 225 [51.4%] women, 282 [64.4%] White and 339 [77.4%] trial completers), those in the 0.4 mg vs. 15.8 mg nicotine cigarette condition experienced significantly lower cigarettes per day at the end of intervention (mean [SD], 7.05 [7.88] vs. 12.95 [9.07], adjusted mean difference, −6.21 [95% CI, −7.66 to −4.75], P

Abstract Background Hypercytokinemia, the renin-angiotensin system, hypoxia, immune dysregulation, and vasculopathy with evidence of immune-related damage are implicated in brain morbidity in COVID-19 along with a wide variety of genomic and environmental influences. There is relatively little evidence of direct SARS-CoV-2 brain infection in COVID-19 patients. Methods Brain histopathology of 36 consecutive autopsies of patients who were RT-PCR positive for SARS-CoV-2 was studied along with findings from contemporary and pre-pandemic historical control groups. Immunostaining for serum and blood cell proteins and for complement components was employed. Microcirculatory wall complement deposition in the COVID-19 cohort was compared to historical control cases. Comparisons also included other relevant clinicopathological and microcirculatory findings in the COVID-19 cohort and control groups. Results The COVID-19 cohort and both the contemporary and historical control groups had the same rate of hypertension, diabetes mellitus, and obesity. The COVID-19 cohort had varying amounts of acute neutrophilic vasculitis with leukocytoclasia in the microcirculation of the brain in all cases. Prominent vascular neutrophilic transmural migration was found in several cases and 25 cases had acute perivasculitis. Paravascular microhemorrhages and petechial hemorrhages (small brain parenchymal hemorrhages) had a slight tendency to be more numerous in cohort cases that displayed less acute neutrophilic vasculitis. Tissue burden of acute neutrophilic vasculitis with leukocytoclasia was the same in control cases as a group, while it was significantly higher in COVID-19 cases. Both the tissue burden of acute neutrophilic vasculitis and the activation of complement components, including membrane attack complex, were significantly higher in microcirculatory channels in COVID-19 cohort brains than in historical controls. Conclusions Acute neutrophilic vasculitis with leukocytoclasia, acute perivasculitis, and associated paravascular blood extravasation into brain parenchyma constitute the first phase of an immune-related, acute small-vessel inflammatory condition often termed type 3 hypersensitivity vasculitis or leukocytoclastic vasculitis. There is a higher tissue burden of acute neutrophilic vasculitis and an increased level of activated complement components in microcirculatory walls in COVID-19 cases than in pre-pandemic control cases. These findings are consistent with a more extensive small-vessel immune-related vasculitis in COVID-19 cases than in control cases. The pathway(s) and mechanism for these findings are speculative.

The Royal Society of Canada Working Group on Health Research System Recovery developed actionable recommendations for organizations to implement to strengthen Canada’s health research system. Recommendations were based on input from participants from G7 countries and Australia and New Zealand. Participants included health research funding agency leaders; research institute leaders; health, public health, and social care policy-makers; researchers; and members of the public. The recommendations were categorized using the World Health Organization’s framework for health research systems and include governance/stewardship: (1) Outline research logistics as part of emergency preparedness to streamline research in future pandemics. (2) Embed equity and inclusion in all research processes. (3) Facilitate streamlined, inclusive, and rigorous processes for grant application preparation and review. (4) Create knowledge mobilization infrastructure to support the generation and use of evidence. (5) Coordinate research efforts across local, provincial, national, and international entities. Financing: (6) Reimagine the funding of health research. Capacity building: (7) Invest in formative training opportunities rooted in equity, diversity, and anti-racism. (8) Support researchers’ career development throughout their career span. (9) Support early career researchers to establish themselves. Producing and using research: (10) Strengthen Indigenous health research and break down systemic barriers to its conduct. (11) Develop mechanisms to produce novel research. (12) Enhance research use across the health research ecosystem.

IntroductionThere is no useful method to discriminate between latent tuberculosis infection (LTBI) and active pulmonary tuberculosis (PTB). This study aimed to investigate the potential of cytokine profiles to discriminate between LTBI and active PTB using whole-blood stimulation with Mycobacterium tuberculosis (MTB) antigens, including latency-associated antigens.Materials and methodsPatients with active PTB, household contacts of active PTB patients and community exposure subjects were recruited in Manila, the Philippines. Peripheral blood was collected from the participants and used for whole-blood stimulation (WBS) with either the early secretory antigenic target and the 10-kDa culture filtrate protein (ESAT-6/CFP-10), Rv3879c or latency-associated MTB antigens, including mycobacterial DNA-binding protein 1 (MDP-1), α-crystallin (Acr) and heparin-binding hemagglutinin (HBHA). Multiple cytokine concentrations were analyzed using the Bio-Plex™ multiplex cytokine assay.ResultsA total of 78 participants consisting of 15 active PTB patients, 48 household contacts and 15 community exposure subjects were eligible. The MDP-1-specific IFN-γ level in the active PTB group was significantly lower than that in the household contact group (p < 0.001) and the community exposure group (p < 0.001). The Acr-specific TNF-α and IL-10 levels in the active PTB group were significantly higher than those in the household contact (TNF-α; p = 0.001, IL-10; p = 0.001) and community exposure (TNF-α; p < 0.001, IL-10; p = 0.01) groups. However, there was no significant difference in the ESAT-6/CFP-10-specific IFN-γ levels among the groups.ConclusionThe patterns of cytokine profiles induced by latency-associated MTB antigens using WBS have the potential to discriminate between LTBI and active PTB. In particular, combinations of IFN-γ and MDP-1, TNF-α and Acr, and IL-10 and Acr are promising. This study provides the first demonstration of the utility of MDP-1-specific cytokine responses in WBS.

Background: Diagnosing ischemia in emergency department (ED) patients with suspected acute coronary syndrome (sACS) is challenging with equivocal disposition of intermediate risk patients. Objective: Compare sensitivity and specificity of magnetocardiography (MCG) versus standard of care (SOC) stress testing in diagnosing myocardial ischemia. Methods: Multicenter, prospective, observational cohort study. ED patients with sACS and HEART score ≥ 3 underwent 90 s noninvasive MCG to detect myocardial ischemia. Results were blinded to the patient's clinicians. MCGs were read independently by 3 physicians blinded to clinical data. Myocardial ischemia was ≥70 % epicardial coronary artery stenosis, revascularization within 30 days, or 30-day major adverse cardiac events (MACE). Time to first test (TTT) and patient satisfaction for MCG and SOC were compared. Results: Of enrolled patients (N = 390) (mean age 59 ± 12 years, 45 % female), 99 (25 %) underwent a non-invasive stress test: 42 (14 %) diagnosed with ischemia. MCG sensitivity was 66.7 % (50.5–80.4 %, 95 % CI) and specificity 57.1 % (50.0–63.3 %, 95 % CI) for detecting coronary ischemia. Noninvasive stress testing (stress echo, nuclear stress, and exercise stress) had the same sensitivity 66.7 % (95 % CI 29.9 % to 92.5 %) and a specificity of 89.9 % (95 % CI 81.7–95.3 %). Mean TTT was shorter for MCG, 3.18 h (SD 1.91) vs. SOC stress testing 22.71 (SD 15.23), p

Good zoos have four aims—to conserve species, educate the public, engage in research, and provide recreation—all of which can only be achieved when underpinned by high animal welfare standards. In this paper, we share the approach that The Royal Zoological Society of Scotland’s (RZSS) Edinburgh Zoo and Highland Wildlife Park take to animal welfare. We highlight the role that animal welfare research, in collaboration with universities, has had in enabling the zoo to take an evidence-based approach to welfare and to put findings into practice. We share the collaborative process through which we developed and piloted the current animal welfare assessment tools, how they were validated, and how they were tested for reliability as part of a long-term collaboration between the Royal Zoological Society of Scotland and the University of Stirling: (1) the RZSS Welfare Assessment Tool, a 50-question animal welfare assessment adapted from the British and Irish Association of Zoos and Aquariums (BIAZA) Toolkit; and (2) the Stirling Toolkit, a package of evidence-based resources for behavioural-data collection. Our aim is to facilitate standardised, evidence-based approaches to assessing animal welfare which, when finalised, can be used collaboratively across zoos.

Objectives To identify, chart and analyse the literature on recent initiatives to improve long-term care (LTC) coverage, financial protection and financial sustainability for persons aged 60 and older.Design Rapid scoping review.Data sources Four databases and four sources of grey literature were searched for reports published between 2017 and 2022. After using a supervised machine learning tool to rank titles and abstracts, two reviewers independently screened sources against inclusion criteria.Eligibility criteria Studies published from 2017–2022 in any language that captured recent LTC initiatives for people aged 60 and older, involved evaluation and directly addressed financing were included.Data extraction and analysis Data were extracted using a form designed to answer the review questions and analysed using descriptive qualitative content analysis, with data categorised according to a prespecified framework to capture the outcomes of interest.Results Of 24 reports, 22 were published in peer-reviewed journals, and two were grey literature sources. Study designs included quasi-experimental study, policy analysis or comparison, qualitative description, comparative case study, cross-sectional study, systematic literature review, economic evaluation and survey. Studies addressed coverage based on the level of disability, income, rural/urban residence, employment and citizenship. Studies also addressed financial protection, including out-of-pocket (OOP) expenditures, copayments and risk of poverty related to costs of care. The reports addressed challenges to financial sustainability such as lack of service coordination and system integration, insufficient economic development and inadequate funding models.Conclusions Initiatives where LTC insurance is mandatory and accompanied by commensurate funding are situated to facilitate ageing in place. Efforts to expand population coverage are common across the initiatives, with the potential for wider economic benefits. Initiatives that enable older people to access the services needed while avoiding OOP-induced poverty contribute to improved health and well-being. Preserving health in older people longer may alleviate downstream costs and contribute to financial sustainability.

ObjectiveDiabetes is a risk factor for TB mortality and relapse. The Philippines has a high TB incidence with co-morbid diabetes. This study assessed the pre- and post-TB diagnosis costs incurred by people with TB and diabetes (TB-DM) and their households in the Philippines.MethodsLongitudinal data was collected for costs, income, and coping mechanisms of TB-affected households in Negros Occidental and Cebu, the Philippines. Data collection was conducted four times during TB treatment. The data collection tools were developed by adapting WHO's cross-sectional questionnaire in the Tuberculosis Patient Cost Surveys: A Handbook into a longitudinal study design. Demographic and clinical characteristics, self-reported household income, number of facility visits, patient costs, the proportion of TB-affected households facing catastrophic costs due to TB (>20% of annual household income before TB), coping mechanisms, and social support received were compared by diabetes status at the time of TB diagnosis.Results530 people with TB were enrolled in this study, and 144 (27.2%) had TB-DM based on diabetes testing at the time of TB diagnosis. 75.4% of people with TB-DM were more than 45 years old compared to 50.3% of people with TB-only (pConclusionPeople with TB-DM in the Philippines face extensive health service use. However, this does not translate into substantial differences in the incidence of catastrophic cost. Further study is required to understand the incidence of catastrophic costs due to diabetes-only in the Philippines.

Purpose: Clinical variant analysis pipelines likely have poor sensitivity to the effects on splicing from variants beyond 10 to 20 bases of exon-intron boundaries. Here, we demonstrate the value of SpliceAI to inform curation of rare variants previously classified as benign/likely benign (B/LB) under current guidelines. Methods: Exome sequencing data from 576 pediatric cancer patients enrolled in the Texas KidsCanSeq study were filtered for intronic or synonymous variants absent from population databases, predicted to alter splicing via SpliceAI (>0.20), and scored >10 by combined annotation-dependent depletion. Rare synonymous or intronic B/LB variants in 61 genes submitted to ClinVar were also evaluated and RNA further assessed in monocyte-derived messenger RNA and/or an in vitro splice reporter assay in HEK-293T cells. Results: SpliceAI-supplemented analysis of the KidsCanSeq cohort revealed a DICER1 intronic variant that resulted in missplicing in RNA from a proband with a personal and family history of pleuropulmonary blastoma but negative clinical exome and panel reports. Analysis of 34,188 B/LB ClinVar variants yielded 18 variants predicted to cause disrupted reading frames. Assessment of 8 variants (DICER1 n = 4, CDH1 n = 2, PALB2 n = 2) by in vitro splicing assay demonstrated abnormal splice products (mean 66%; range 6% to 100%). When available, phenotypic information from submitting laboratories demonstrated DICER1-associated tumors in 2 families (1 variant) and breast cancer in 3 families (2 PALB2 variants). Conclusion: Incorporation of SpliceAI in variant curation pipelines may improve classification of B/LB intronic and synonymous variants and highlight putative pathogenic variants for functional assays and RNA analysis, thereby increasing diagnostic yield for rare diseases.

Poor TB treatment outcomes are observed in patients with type 2 diabetes mellitus (DM) comorbidity and glycemic control throughout treatment may play a role. The objective of this study was to investigate glycemic control longitudinally among Filipino adults undergoing TB treatment using mixed-effects linear and logistic regression. Analyses were conducted in 188 DM-TB patients out of 901 enrolled in the Starting Anti-TB Treatment (St-ATT) cohort, with a median baseline glycosylated hemoglobin (HbA1c) of 8.2% (range 4.5-13.3%). Previous versus new DM diagnosis was associated with higher mean HbA1c (worse glycemic control) during treatment, with a smaller effect amongst those with central obesity (coefficient 0.80, 95% confidence interval [CI] 0.26, 1.57, P = 0.043) than amongst those without central obesity (coefficient 3.48, 95% CI 2.16, 4.80, P

This scoping review provides an overview of the relationship between physical activity, physical fitness, cognition, and academic outcomes in Latino school-aged children and identifies areas for future research. A primary search was conducted in PubMed, PsycINFO, Web of Science, and ERIC for original-research articles meeting the inclusion criteria; the search results were uploaded into PICO Portal and assessed by two independent reviewers. Of the 488 initial search results, 50 articles were eligible for full-text review, and 38 were included in this review. Most studies were cross-sectional, conducted in the United States or Chile, and included children 5–18 years old. Overall, the majority of articles reported positive associations between physical activity or physical fitness and cognitive outcomes (n = 11/12; 91.7%), and physical activity or physical fitness and academic outcomes (n = 22/28; 78.6%). In sum, this review provided consistent evidence for higher amounts of physical activity and greater physical fitness to be associated with various positive cognitive and academic outcomes in a school-aged Latino population. This scoping review also elucidated a substantial gap in the research regarding study design, with a discernible lack of interventional efforts. Future studies should test physical activity interventional strategies to optimize cognitive and academic outcomes in school-aged Latino populations.

The exquisite angular resolution and sensitivity of JWST are opening a new window for our understanding of the Universe. In nearby galaxies, JWST observations are revolutionizing our understanding of the first phases of star formation and the dusty interstellar medium. Nineteen local galaxies spanning a range of properties and morphologies across the star-forming main sequence have been observed as part of the PHANGS-JWST Cycle 1 Treasury program at spatial scales of ∼5–50 pc. Here, we describe pjpipe , an image-processing pipeline developed for the PHANGS-JWST program that wraps around and extends the official JWST pipeline. We release this pipeline to the community as it contains a number of tools generally useful for JWST NIRCam and MIRI observations. Particularly for extended sources, pjpipe products provide significant improvements over mosaics from the MAST archive in terms of removing instrumental noise in NIRCam data, background flux matching, and calibration of relative and absolute astrometry. We show that slightly smoothing F2100W MIRI data to 0.″9 (degrading the resolution by about 30%) reduces the noise by a factor of ≈3. We also present the first public release (DR1.1.0) of the pjpipe processed eight-band 2–21 μ m imaging for all 19 galaxies in the PHANGS-JWST Cycle 1 Treasury program. An additional 55 galaxies will soon follow from a new PHANGS-JWST Cycle 2 Treasury program.

Theories of spiral structure traditionally separate into tight-winding Lin–Shu spiral density waves and the swing-amplified material patterns of Goldreich & Lynden-Bell and Julian & Toomre. In this paper we consolidate these two types of spirals into a unified description, treating density waves beyond the tight-winding limit, in the regime of shearing and nonsteady open spirals. This shearing wave scenario novelly captures swing amplification that enables structure formation above conventional Q thresholds. However, it also highlights the fundamental role of spiral forcing on the amplification process in general, whether the wave is shearing or not. Thus it captures resonant and nonresonant mode growth through the donkey effect described by Lynden-Bell & Kalnajs and, critically, the cessation of growth when donkey behavior is no longer permitted. Our calculations predict growth exclusive to trailing spirals above the Jeans length, the prominence of spirals across a range of orientations that increases with decreasing arm multiplicity, and a critical orientation where growth is fastest that is the same for both modes and material patterns. Predicted structures are consistent with highly regular, high-multiplicity gaseous spur features and long filaments spaced close to the Jeans scale in spirals and bars. Applied to stellar disks, conditions favor low multiplicity ( m < 5) open trailing spirals with pitch angles in the observed range 10° < i _p < 50°. The results of this work serve as a basis for describing spirals as a unified class of transient waves, abundantly stimulated but narrowly selected for growth depending on local conditions.

Survival from ovarian cancer depends on the resection status after primary surgery. We performed genome-wide association analyses for resection status of 7705 ovarian cancer patients, including 4954 with high-grade serous carcinoma (HGSOC), to identify variants associated with residual disease. The most significant association with resection status was observed for rs72845444, upstream of MGMT, in HGSOC (p = 3.9 × 10-8). In gene-based analyses, PPP2R5C was the most strongly associated gene in HGSOC after stage adjustment. In an independent set of 378 ovarian tumours from the AGO-OVAR 11 study, variants near MGMT and PPP2R5C correlated with methylation and transcript levels, and PPP2R5C mRNA levels predicted progression-free survival in patients with residual disease. MGMT encodes a DNA repair enzyme, and PPP2R5C encodes the B56γ subunit of the PP2A tumour suppressor. Our results link heritable variation at these two loci with resection status in HGSOC.

IntroductionLesbian, gay, bisexual, transgender, and queer/questioning (LGBTQ) individuals use tobacco at disproportionately high rates but are as likely as straight tobacco users to want to quit and to use quitlines. Little is known about the demographics and geographic distribution of LGBTQ quitline participants, their engagement with services, or their long-term outcomes.Aims and methodsCalifornians (N = 333 429) who enrolled in a statewide quitline 2010-2022 were asked about their sexual and gender minority (SGM) status and other baseline characteristics. All were offered telephone counseling. A subset (n = 19 431) was followed up at seven months. Data were analyzed in 2023 by SGM status (LGBTQ vs. straight) and county type (rural vs. urban).ResultsOverall, 7.0% of participants were LGBTQ, including 7.4% and 5.4% of urban and rural participants, respectively. LGBTQ participants were younger than straight participants but had similar cigarette consumption. Fewer LGBTQ participants reported a physical health condition (42.1% vs. 48.4%) but more reported a behavioral health condition (71.1% vs. 54.5%; both p's < .001). Among both LGBTQ and straight participants, nearly 9 in 10 chose counseling and both groups completed nearly three sessions on average. The groups had equivalent 30-day abstinence rates (24.5% vs. 23.2%; p = .263). Similar patterns were seen in urban and rural subgroups.ConclusionsLGBTQ tobacco users engaged with and appeared to benefit from a statewide quitline even though it was not LGBTQ community-based. A quitline with staff trained in LGBTQ cultural competence can help address the high prevalence of tobacco use in the LGBTQ community and reach members wherever they live.ImplicationsThis study describes how participants of a statewide tobacco quitline broke down by sexual orientation and gender. It compares participants both by SGM status and by type of county to provide a more complete picture of quitline participation both in urban areas where LGBTQ community-based cessation programs may exist and in rural areas where they generally do not. To our knowledge, it is the first study to compare LGBTQ and straight participants on their use of quitline services and quitting aids, satisfaction with services received, and rates of attempting quitting and achieving prolonged abstinence from smoking.