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Abstract Increasing biological nitrogen (N) fixation (BNF) in maize production could reduce the environmental impacts of N fertilizer use, but reactive N in the rhizosphere of maize limits the BNF process. Using non-transgenic methods, we developed gene-edited strains of Klebsiella variicola (Kv137-2253) and Kosakonia sacchari (Ks6-5687) bacteria optimized for root-associated BNF and ammonium excretion in N-rich conditions. The aim of this research was to elucidate the mechanism of action of these strains. We present evidence from in vitro, in planta and field experiments that confirms that our genetic remodeling strategy derepresses BNF activity in N-rich systems and increases ammonium excretion by orders of magnitude above the respective wildtype strains. BNF is demonstrated in controlled environments by the transfer of labeled 15N2 gas from the rhizosphere to the chlorophyll of inoculated maize plants. This was corroborated in several 15N isotope tracer field experiments where inoculation with the formulated, commercial-grade product derived from the gene-edited strains (PIVOT BIO PROVEN® 40) provided on average 21 kg N ha-1 to the plant by the VT-R1 growth stages. Data from small-plot and on-farm trials suggest that this technology can improve crop N status pre-flowering and has potential to mitigate the risk of yield loss associated with a reduction in synthetic N fertilizer inputs.

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.

Electronic health records (EHRs) have emerged as resources for both the identification of adverse drug events (ADEs) and general population health surveillance, however questions remain around how best to utilize EHR data for drug safety signal identification. While the majority of signal identification research has utilized spontaneous reports and health insurance claims, these data also have limitations. Pharmacovigilance approaches combining EHR data with other data sources have the potential to address many of the shortcomings of individual sources. This mini-review seeks to provide an overview of some of the recent research leveraging EHR data in combination with spontaneous reports, claims data, and other pharmacovigilance data sources for drug safety signal identification. Studies have shown that combining EHR data with these and other sources is often beneficial compared to the use of a single source alone, however the synergism or friction introduced is insufficiently explored in current literature. Our review explores how EHR data benefits signal identification when used in combination with other sources, what methods have been applied, and what considerations have previously been noted. Finally, we identify gaps in current research and highlight important considerations for future work using multiple real world data sources for drug safety surveillance.

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.

ABSTRACTWe sought in-depth understanding on the evolution of factors influencing COVID-19 booster dose and bivalent vaccine hesitancy in a longitudinal semi-structured interview-based qualitative study. Serial interviews were conducted between July 25th and September 1st, 2022 (Phase I: univalent booster dose availability), and between November 21st, 2022 and January 11th, 2023 (Phase II: bivalent vaccine availability). Adults (≥18 years) in Canada who had received an initial primary series and had not received a COVID-19 booster dose were eligible for Phase I, and subsequently invited to participate in Phase II. Twenty-two of twenty-three (96%) participants completed interviews for both phases (45 interviews). Nearly half of participants identified as a woman (n = 11), the median age was 37 years (interquartile range: 32–48), and most participants were employed full-time (n = 12); no participant reported needing to vaccinate (with a primary series) for their workplace. No participant reported having received a COVID-19 booster dose at the time of their interview in Phase II. Three themes relating to the development of hesitancy toward continued vaccination against COVID-19 were identified: 1) effectiveness (frequency concerns; infection despite vaccination); 2) necessity (less threatening, low urgency, alternate protective measures); and 3) information (need for data, contradiction and confusion, lack of trust, decreased motivation). The data from interviews with individuals who had not received a COVID-19 booster dose or bivalent vaccine despite having received a primary series of COVID-19 vaccines highlights actionable targets to address vaccine hesitancy and improve public health literacy.

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

Background: Obesity disproportionately affects marginalized and low-income populations. Birth parent obesity from the prenatal period and childhood has been associated with child obesity. It is unknown whether prenatal or postnatal birth parent obesity has differential effects on subsequent changes in adiposity and metabolic health in children. Objectives: We evaluated how birth parent obesity 7 y after delivery was associated with child body composition changes and cardiometabolic health in midchildhood and further assessed the influence of the perinatal and postpartum period on associations. Methods: Black and Dominican pregnant individuals were enrolled, and dyads (n = 319) were followed up at child age 7 and 9 y. Measures included, height, weight, waist circumference (WC), and percent body fat (BF%). Multiple linear regression was used to relate postpartum weight status with child outcomes accounting for attrition, and a series of secondary analyses were conducted with additional adjustment for perinatal weight status, gestational weight gain (GWG), and/or long-term weight retention to evaluate how these factors influenced associations. Results: Almost one-quarter (23%) of birth parents and 24.1% children were classified with obesity at child age 7 y, while at 9 y, 30% of children had obesity. Birth parent obesity at child age 7 y was associated with greater changes, from ages 7 to 9 y, in child BMI z-score (β: 0.13; 95% CI: 0.02, 0.24) and BF% (β: 1.15; 95% CI: 0.22, 2.09) but not obesity at age 9 y. All observed associations crossed the null after additional adjustment for prenatal factors. Conclusions: Birth parent obesity at 7-y postpartum is associated with greater gains in child BMI z-score and BF% in midchildhood. These associations diminish after accounting for prenatal size, suggesting a lasting impact of the perinatal environment and that interventions supporting families from the prenatal period through childhood are needed.

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

Abstract Background The concept of intersectionality proposes that demographic and social constructs intersect with larger social structures of oppression and privilege to shape experiences. While intersectionality is a widely accepted concept in feminist and gender studies, there has been little attempt to use this lens in implementation science. We aimed to supplement the Consolidated Framework for Implementation Research (CFIR), a commonly used framework in implementation science, to support the incorporation of intersectionality in implementation science projects by (1) integrating an intersectional lens to the CFIR; and (2) developing a tool for researchers to be used alongside the updated framework. Methods Using a nominal group technique, an interdisciplinary framework committee (n = 17) prioritized the CFIR as one of three implementation science models, theories, and frameworks to supplement with intersectionality considerations; the modification of the other two frameworks are described in other papers. The CFIR subgroup (n = 7) reviewed the five domains and 26 constructs in the CFIR and prioritized domains and constructs for supplementation with intersectional considerations. The subgroup then iteratively developed recommendations and prompts for incorporating an intersectional approach within the prioritized domains and constructs. We developed recommendations and prompts to help researchers consider how personal identities and power structures may affect the facilitators and inhibitors of behavior change and the implementation of subsequent interventions. Results We achieved consensus on how to apply an intersectional lens to CFIR after six rounds of meetings. The final intersectionality supplemented CFIR includes the five original domains, and 28 constructs; the outer systems and structures and the outer cultures constructs were added to the outer setting domain. Intersectionality prompts were added to 13 of the 28 constructs. Conclusion Through an expert-consensus approach, we modified the CFIR to include intersectionality considerations and developed a tool with prompts to help implementation users apply an intersectional lens using the updated framework.

Abstract Background Caudal regression syndrome is a rare complex congenital anomaly with reduced penetrance and phenotypic variability characterized by osseous defects of the caudal spine, lower limb anomalies, and accompanying genitourinary, gastrointestinal/anorectal, and cardiac system soft tissue defects. We report a rare presentation of type 1 caudal regression syndrome in a pregnant woman with preexisting diabetes, in which early recognition of severe fetal anomalies on routine antenatal ultrasound facilitated confirmation with fetal magnetic resonance imaging to characterize extent of disease and prognosticate fetal outcome. Case presentation This case of type 1 caudal regression syndrome in the setting of maternal pregestational diabetes mellitus resulted in stillbirth. The mother was a 29-year-old Caucasian primigravida female with past medical history of poorly controlled type 2 diabetes managed with metformin prior to pregnancy, prompting admission for glucose management and initiation of insulin at 13 weeks. Baseline hemoglobin A1c was high at 8.0%. Fetal ultrasound at 22 weeks was notable for severe sacral agenesis, bilateral renal pelvis dilatation, single umbilical artery, and pulmonary hypoplasia. Fetal magnetic resonance imaging at 29 weeks showed absent lower two-thirds of the spine with corresponding spinal cord abnormality compatible with type 1 caudal regression syndrome. The mother delivered a male stillborn at 39 and 3/7 weeks. Minimally invasive postmortem magnetic resonance imaging and computed tomography autopsy were performed to confirm clinical findings when family declined conventional autopsy. Etiology of sacral agenesis was attributed to poorly controlled maternal diabetes early in gestation. Conclusion Maternal preexisting diabetes is a known risk factor for development of congenital malformations. This rare case of type 1 caudal regression syndrome in a mother with preexisting diabetes with elevated hemoglobin A1c highlights the importance of preconception glycemic control in diabetic women and the utility of fetal magnetic resonance imaging for confirmation of ultrasound findings to permit accurate prognostication. Additionally, minimally invasive postmortem magnetic resonance imaging and computed tomography autopsy can facilitate diagnostic confirmation of clinical findings in perinatal death due to complex congenital anomalies while limiting the emotional burden on bereaved family members who decline conventional autopsy.

Processes driving changes in sea-ice seasonality and sea-ice thickness were explored for a ‘warm-shelf’ region along the West Antarctic Peninsula using vertically coupled sea-ice-ocean thermodynamic simulations, with and without assimilated satellite sea-ice observations and moored ocean temperature observations. Simulations with assimilated sea-ice observations permitted investigation of surface [thermodynamic and dynamic (e.g., wind-driven)] processes affecting sea-ice thickness and seasonality. Assimilation of quasi-weekly variability in the depth and temperature of the deep warm pycnocline permitted examination of subsurface processes affecting sea-ice. Simulations using assimilated sea-ice observations (and implied motion) always produced greater surface heat fluxes and overall thinner sea ice. Assimilating seasonal and quasi-weekly variability in the depth and temperature of the pycnocline modified the start of the sea-ice season by −23 to +1 d, and also modified the sea ice thickness/seasonality to be thinner/shorter or thicker/longer at sub-seasonal and seasonal timescales, highlighting a mechanism where a shoaling pycnocline enhanced upward deep-water heat fluxes as transient surface-induced turbulence had a greater effect on a reduced mixed layer volume. The observed interplay of surface, subsurface, and sea-ice modulation of ocean-atmosphere heat transfer underscores the importance of representing the interaction between sea-ice concentration and upper ocean variability in climate projections.

Abstract Background Soil and water salinity are increasing problems worldwide, causing significantly reduced crop yields. Alfalfa (Medicago sativa L.) is often listed as salt‐sensitive, but field testing of improved cultivars is limited. Forage systems and improved high‐quality alfalfa varieties are needed to enable crop production under high salinity (HS) conditions. Methods The objective of this study was to measure the yield and quality response of alfalfa to high saline conditions in the field and to document the relative saline tolerance of its varieties. HS irrigation water (electrical conductivity of water, or ECw 8.0–11.0 dS m−1) was applied to 33 nondormant alfalfa cultivars and were compared with low salinity (LS) treatments (ECw 0.5–1.2 dS m−1) over 4 years in a Mediterranean environment on a clay loam soil utilizing a split‐plot design. Crops were harvested seven to eight times per year, and the forage quality was measured on selected harvests utilizing near‐infrared spectroscopy. Results The average yield loss due to HS treatment was 23.9% compared with LS treatment, but yields averaged 23.4 Mg ha−1 under HS over the 3 full years of production. This level of production is considered to be economically viable in this region. Differences in salinity tolerance between lines were identified in the field; individual cultivars lost 5%–35% of their LS yield when grown under HS conditions. Forage quality was significantly improved under HS versus LS conditions, but improvements were negatively correlated with biomass yield (R2 > 0.81), similar to responses observed in drought‐stressed alfalfa. Conclusions These yield results confirm greenhouse studies, indicating that alfalfa is highly salt tolerant once established in the field, with potential for further improvement with tolerant cultivars. Salinity tolerance should be chosen based on total biomass yield as well as on the salinity tolerance index (HS yield relative to LS yield). Agronomic practices to mitigate salinity and sodicity are critical, along with improved cultivars.

Abstract Background People with diabetes mellitus (DM) have an estimated two- to three-times greater risk of adverse tuberculosis (TB) treatment outcomes compared to those without DM. Blood glucose control is a primary aim of managing DM during TB treatment, yet TB programmes are not generally adapted to provide DM services. The purpose of this study was to understand perceptions and the lived experiences of diabetic patients in TB treatment in the Philippines, with a view to informing the development of disease co-management strategies. Methods This mixed methods study was conducted within a prospective cohort of adults newly-starting treatment for drug-sensitive and drug-resistant TB at 13 public TB clinics in three regions of the Philippines. Within the subset of 189 diabetic persons who self-reported a prior DM diagnosis, or were diagnosed by screenings conducted through the TB clinic, longitudinal blood glucose data were used to ascertain individuals’ glycaemic control (controlled or uncontrolled). Univariable logistic regression analyses exploring associations between uncontrolled glycaemia and demographic and clinical factors informed purposive sampling of 31 people to participate in semi-structured interviews. All audio-recorded data were transcribed and thematic analysis performed. Results Participants — both with controlled and uncontrolled blood glucose — were knowledgeable about diabetes and its management. However, a minority of participants were aware of the impact of DM on TB treatment and outcomes. Many participants newly-diagnosed with DM at enrolment in TB treatment had not perceived any diabetic symptoms prior and would have likely not sought clinical consult otherwise. Access to free glucose-lowering medications through TB clinics was a key enabling resource. However, participants expressed fear of side effects and interrupted access to glucose-lowering medications, and a preference for phytotherapy. Many participants felt that physical and financial impacts of TB and its treatment were challenges to DM management. Conclusions and recommendations Results of this study indicate that public TB clinics can provide diabetic patients with additional health care resources and education to address co-morbidity. TB programmes might consider identifying patients with complicated DM, and offering diabetic monitoring and management, as DM and diabetic complications may compound the burden of TB and its treatment.

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.

Abstract Background Few training opportunities or resources for non-expert implementers focus on the “practice” as opposed to the “science” of knowledge translation (KT). As a guide for novice implementers, we present an open-access, fillable workbook combining KT theories, models, and frameworks (TMFs) that are commonly used to support the implementation of evidence-based practices. We describe the process of creating and operationalizing our workbook. Methods Our team has supported more than 1000 KT projects and 300 teams globally to implement evidence-based interventions. Our stakeholders have consistently highlighted their need for guidance on how to operationalize various KT TMFs to support novice implementers in “practising” KT. In direct response to these requests, we created a pragmatic, fillable KT workbook. The workbook was designed by KT scientists and experts in the fields of adult education, graphic design, and usability and was piloted with novice implementers. It is rooted in an integrated KT approach and applies an intersectionality lens, which prompts implementers to consider user needs in the design of implementation efforts. Results The workbook is framed according to the knowledge-to-action model and operationalizes each stage of the model using appropriate theories or frameworks. This approach removes guesswork in selecting appropriate TMFs to support implementation efforts. Implementers are prompted to complete fillable worksheets that are informed by the Theoretical Domains Framework, the Consolidated Framework for Implementation Research, the Behaviour Change Wheel, the Effective Practice and Organization of Care framework, Proctor’s operationalization framework, the Durlak and DuPre process indicators, and the Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) framework. As they complete the worksheets, users are guided to apply theoretically rooted approaches in planning the implementation and evaluation of their evidence-based practice. Conclusions This workbook aims to support non-expert implementers to use KT TMFs to select and operationalize implementation strategies to facilitate the implementation of evidence-based practices. It provides an accessible option for novice implementers who wish to use KT methods to guide their work.

Abstract Background Chronic disease management (CDM) through sustained knowledge translation (KT) interventions ensures long-term, high-quality care. We assessed implementation of KT interventions for supporting CDM and their efficacy when sustained in older adults. Methods Design: Systematic review with meta-analysis engaging 17 knowledge users using integrated KT. Eligibility criteria: Randomized controlled trials (RCTs) including adults (> 65 years old) with chronic disease(s), their caregivers, health and/or policy-decision makers receiving a KT intervention to carry out a CDM intervention for at least 12 months (versus other KT interventions or usual care). Information sources: We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from each database’s inception to March 2020. Outcome measures: Sustainability, fidelity, adherence of KT interventions for CDM practice, quality of life (QOL) and quality of care (QOC). Data extraction, risk of bias (ROB) assessment: We screened, abstracted and appraised articles (Effective Practice and Organisation of Care ROB tool) independently and in duplicate. Data synthesis: We performed both random-effects and fixed-effect meta-analyses and estimated mean differences (MDs) for continuous and odds ratios (ORs) for dichotomous data. Results We included 158 RCTs (973,074 participants [961,745 patients, 5540 caregivers, 5789 providers]) and 39 companion reports comprising 329 KT interventions, involving patients (43.2%), healthcare providers (20.7%) or both (10.9%). We identified 16 studies described as assessing sustainability in 8.1% interventions, 67 studies as assessing adherence in 35.6% interventions and 20 studies as assessing fidelity in 8.7% of the interventions. Most meta-analyses suggested that KT interventions improved QOL, but imprecisely (36 item Short-Form mental [SF-36 mental]: MD 1.11, 95% confidence interval [CI] [− 1.25, 3.47], 14 RCTs, 5876 participants, I 2 = 96%; European QOL-5 dimensions: MD 0.01, 95% CI [− 0.01, 0.02], 15 RCTs, 6628 participants, I 2 = 25%; St George’s Respiratory Questionnaire: MD − 2.12, 95% CI [− 3.72, − 0.51] 44 12 RCTs, 2893 participants, I 2 = 44%). KT interventions improved QOC (OR 1.55, 95% CI [1.29, 1.85], 12 RCTS, 5271 participants, I 2 = 21%). Conclusions KT intervention sustainability was infrequently defined and assessed. Sustained KT interventions have the potential to improve QOL and QOC in older adults with CDM. However, their overall efficacy remains uncertain and it varies by effect modifiers, including intervention type, chronic disease number, comorbidities, and participant age. Systematic review registration PROSPERO CRD42018084810.

Abstract Documentary climate data describe evidence of past climate arising from predominantly written historical documents such as diaries, chronicles, newspapers, or logbooks. Over the past decades, historians and climatologists have generated numerous document-based time series of local and regional climates. However, a global dataset of documentary climate time series has never been compiled, and documentary data are rarely used in large-scale climate reconstructions. Here, we present the first global multi-variable collection of documentary climate records. The dataset DOCU-CLIM comprises 621 time series (both published and hitherto unpublished) providing information on historical variations in temperature, precipitation, and wind regime. The series are evaluated by formulating proxy forward models (i.e., predicting the documentary observations from climate fields) in an overlapping period. Results show strong correlations, particularly for the temperature-sensitive series. Correlations are somewhat lower for precipitation-sensitive series. Overall, we ascribe considerable potential to documentary records as climate data, especially in regions and seasons not well represented by early instrumental data and palaeoclimate proxies.

Abstract Background Demand for rapid evidence-based syntheses to inform health policy and systems decision-making has increased worldwide, including in low- and middle-income countries (LMICs). To promote use of rapid syntheses in LMICs, the WHO’s Alliance for Health Policy and Systems Research (AHPSR) created the Embedding Rapid Reviews in Health Systems Decision-Making (ERA) Initiative. Following a call for proposals, four LMICs were selected (Georgia, India, Malaysia and Zimbabwe) and supported for 1 year to embed rapid response platforms within a public institution with a health policy or systems decision-making mandate. Methods While the selected platforms had experience in health policy and systems research and evidence syntheses, platforms were less confident conducting rapid evidence syntheses. A technical assistance centre (TAC) was created from the outset to develop and lead a capacity-strengthening program for rapid syntheses, tailored to the platforms based on their original proposals and needs as assessed in a baseline questionnaire. The program included training in rapid synthesis methods, as well as generating synthesis demand, engaging knowledge users and ensuring knowledge uptake. Modalities included live training webinars, in-country workshops and support through phone, email and an online platform. LMICs provided regular updates on policy-makers’ requests and the rapid products provided, as well as barriers, facilitators and impacts. Post-initiative, platforms were surveyed. Results Platforms provided rapid syntheses across a range of AHPSR themes, and successfully engaged national- and state-level policy-makers. Examples of substantial policy impact were observed, including for COVID-19. Although the post-initiative survey response rate was low, three quarters of those responding felt confident in their ability to conduct a rapid evidence synthesis. Lessons learned coalesced around three themes – the importance of context-specific expertise in conducting reviews, facilitating cross-platform learning, and planning for platform sustainability. Conclusions The ERA initiative successfully established rapid response platforms in four LMICs. The short timeframe limited the number of rapid products produced, but there were examples of substantial impact and growing demand. We emphasize that LMICs can and should be involved not only in identifying and articulating needs but as co-designers in their own capacity-strengthening programs. More time is required to assess whether these platforms will be sustained for the long-term.

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

Objective To describe patterns of virtual and in-person outpatient mental health service use and factors that may influence the choice of modality in a child and adolescent service.Design A pragmatic mixed-methods approach using routinely collected administrative data between 1 April 2020 and 31 March 2022 and semi-structured interviews with clients, caregivers, clinicians and staff. Interview data were coded according to the Consolidated Framework for Implementation Research (CFIR) and examined for patterns of similarity or divergence across data sources, respondents or other relevant characteristics.Setting Child and adolescent outpatient mental health service, Nova Scotia, Canada.Participants IWK Health clinicians and staff who had participated in virtual mental healthcare following its implementation in March 2020 and clients (aged 12–18 years) and caregivers of clients (aged 3–18 years) who had received treatment from an IWK outpatient clinic between 1 April 2020 and 31 March 2022 (n=1300). Participants (n=48) in semi-structured interviews included nine clients aged 13–18 years (mean 15.7 years), 10 caregivers of clients aged 5–17 years (mean 12.7 years), eight Community Mental Health and Addictions booking and registration or administrative staff and 21 clinicians.Results During peak pandemic activity, upwards of 90% of visits (first or return) were conducted virtually. Between waves, return appointments were more likely to be virtual than first appointments. Interview participants (n=48) reported facilitators and barriers to virtual care within the CFIR domains of ‘outer setting’ (eg, external policies, client needs and resources), ‘inner setting’ (eg, communications within the service), ‘individual characteristics’ (eg, personal attributes, knowledge and beliefs about virtual care) and ‘intervention characteristics’ (eg, relative advantage of virtual or in-person care).Conclusions Shared decision-making regarding treatment modality (virtual vs in-person) requires consideration of client, caregiver, clinician, appointment, health system and public health factors across episodes of care to ensure accessible, safe and high-quality mental healthcare.

American institutions of nursing education have integrated cultural competence as a pillar approach to addressing health disparities. The theoretical frameworks, priorities, and solutions that national organizations pursue and endorse have far-reaching implications. The American Association of Colleges of Nursing (AACN) is one such organization. The purpose of this project was to critically analyze the AACN’s Tool Kit of Resources for Cultural Competent Education for Baccalaureate Nurses to excavate dynamics related to language, power, and inequality. Findings of this critical discourse analysis indicate: (1) the centrality of the AACN’s assumed authority and lack of relationality with readers, (2) nursing insularity and narrow theorization of culture and power, and (3) the harm of whiteness and colonialism as pedagogy. Accountability and repair include transparency, taking note of resources and viewpoints available and endorsed on organization websites, and updating (or refuting) outdated and harmful approaches.

Abstract Background Evidence has shown that private industry-sponsored randomized controlled trials (RCTs) and meta-analyses are more likely to report intervention-favourable results compared with other sources of funding. However, this has not been assessed in network meta-analyses (NMAs). Objectives To (a) explore the recommendation rate of industry-sponsored NMAs on their company’s intervention, and (b) assess reporting in NMAs of pharmacologic interventions according to their funding type. Methods Design: Scoping review of published NMAs with RCTs. Information Sources: We used a pre-existing NMA database including 1,144 articles from MEDLINE, EMBASE and Cochrane Database of Systematic Reviews, published between January 2013 and July 2018. Study Selection: NMAs with transparent funding information and comparing pharmacologic interventions with/without placebo. Synthesis: We captured whether NMAs recommended their own or another company’s intervention, classified NMAs according to their primary outcome findings (i.e., statistical significance and direction of effect), and according to the overall reported conclusion. We assessed reporting using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension to NMA (PRISMA-NMA) 32-item checklist. We matched and compared industry with non-industry NMAs having the same research question, disease, primary outcome, and pharmacologic intervention against placebo/control. Results We retrieved 658 NMAs, which reported a median of 23 items in the PRISMA-NMA checklist (interquartile range [IQR]: 21–26). NMAs were categorized as 314 publicly-sponsored (PRISMA-NMA median 24.5, IQR 22–27), 208 non-sponsored (PRISMA-NMA median 23, IQR 20–25), and 136 industry/mixed-sponsored NMAs (PRISMA-NMA median 21, IQR 19–24). Most industry-sponsored NMAs recommended their own manufactured drug (92%), suggested a statistically significant positive treatment-effect for their drug (82%), and reported an overall positive conclusion (92%). Our matched NMAs (25 industry vs 25 non-industry) indicated that industry-sponsored NMAs had favourable conclusions more often (100% vs 80%) and were associated with larger (but not statistically significantly different) efficacy effect sizes (in 61% of NMAs) compared with non–industry-sponsored NMAs. Conclusions Differences in completeness of reporting and author characteristics were apparent among NMAs with different types of funding. Publicly-sponsored NMAs had the best reporting and published their findings in higher impact-factor journals. Knowledge users should be mindful of this potential funding bias in NMAs.

Abstract Background Preliminary evidence suggests that people who inject drugs (PWID) may be at an increased risk of developing infective endocarditis (IE), hepatitis C virus (HCV) infection, and/or human immunodeficiency virus (HIV) infection from hydromorphone controlled-release formulation. The hypothesized mechanism is related to insolubility of the drug, which promotes reuse, leading to contamination of injecting equipment. However, this relationship has not been confirmed. We aimed to conduct a systematic review including adult PWID exposed to controlled-release hydromorphone and the risk of acquiring IE, HCV, and HIV. Methods We searched MEDLINE, EMBASE, and Evidence Based Medicine reviews from inception until September 2021. Following pilot testing, two reviewers conducted all screening of citations and full-text articles, as well as abstracted data, and appraised risk of bias using the Newcastle–Ottawa scale and Effective Practice and Organization of Care tool. Equity issues were examined using the PROGRESS-PLUS framework. Discrepancies were resolved consistently by a third reviewer. Meta-analysis was not feasible due to heterogeneity across the studies. Results After screening 3,231 citations from electronic databases, 722 citations from unpublished sources/reference scanning, and 626 full-text articles, five studies were included. Five were cohort studies, and one was a case–control study. The risk of bias varied across the studies. Two studies reported on gender, as well as other PROGRESS-PLUS criteria (race, housing, and employment). Three studies focused specifically on the controlled-release formulation of hydromorphone, whereas two studies focused on all formulations of hydromorphone. One retrospective cohort study found an association between controlled-release hydromorphone and IE, whereas a case–control study found no evidence of an association. One retrospective cohort study found an association between the number of hydromorphone controlled-release prescriptions and prevalence of HCV. None of the studies specifically reported on associations with HIV. Discussion Very few studies have examined the risk of IE, HCV, and HIV infection after exposure to controlled-release hydromorphone. Very low-quality and scant evidence suggests uncertainty around the risks of blood-borne infections, such as HCV and IE to PWID using this medication.

Abstract Background The COVID-19 pandemic accelerated the spread of misinformation worldwide. The purpose of this study was to explore perceptions of misinformation and preferred sources of obtaining COVID-19 information from those living in Canada. In particular, we sought to explore the perceptions of East Asian individuals in Canada, who experienced stigma related to COVID-19 messaging. Methods We conducted a qualitative thematic analysis study. Interviews were offered in English, Mandarin and Cantonese. Interviewers probed for domains related to knowledge about COVID-19, preferred sources of information, perceived barriers and facilitators of misinformation, and preferences for communication during a health emergency. Interviews were recorded, translated, transcribed verbatim and analyzed using a framework approach. Transcripts were independently double-coded until > 60% agreement was reached. This study received research ethics approval. Results Fifty-five interviews were conducted. The majority of participants were women (67%); median age was 52 years. 55% of participants were of East-Asian descent. Participants obtained information about COVID-19 from diverse English and non-English sources including news media, government agencies or representatives, social media, and personal networks. Challenges to seeking and understanding information included: encountering misinformation, making sense of evolving or conflicting public health guidance, and limited information on topics of interest. 65% of participants reported encountering COVID-19 misinformation. East Asian participants called on government officials to champion messaging to reduce stigmatizing and racist rhetoric and highlighted the importance of having accessible, non-English language information sources. Participants provided recommendations for future public health communications guidance during health emergencies, including preferences for message content, information messengers, dissemination platforms and format of messages. Almost all participants preferred receiving information from the Canadian government and found it helpful to utilize various mediums and platforms such as social media and news media for future risk communication, urging for consistency across all platforms. Conclusions We provide insights on Canadian experiences navigating COVID-19 information, where more than half perceived encountering misinformation on platforms when seeking COVID-19 information . We provide recommendations to inform public health communications during future health emergencies.

Abstract Background Doulas have been instrumental in providing breastfeeding support to nursing mothers before and during the COVID-19 pandemic, as they can significantly impact a mother's ability to initiate and maintain breastfeeding. However, the COVID-19 pandemic, subsequent lockdowns, and social isolation created challenges for nursing mothers to access doulas' services, usually provided in person. In this study, we examined the role of doulas in providing breastfeeding support during the COVID-19 pandemic, exploring adaptation to COVID-19 guidelines and the challenges doulas face in providing breastfeeding support during the pandemic. Methods A systematic review was conducted following the PRISMA guidelines. Thirteen scientific databases and twenty peer-reviewed journals were searched for journal articles published in English between January 2020 and March 2022 using key search terms (e.g., Doula, Breastfeeding, COVID-19). Studies evaluating the role of doulas in providing breastfeeding support during COVID-19, and the impact of COVID-19 Guidelines on doula services, were included. Two reviewers independently performed the risk of bias assessment and data extraction. Summative content analysis was used to analyze the data. Results The majority of studies were conducted in developed nations. This systematic review includes eight articles, four qualitative, one survey, two mixed-methods studies, and one prospective research study. Seven of the eight studies were conducted in the United States, and the eighth was conducted in multiple countries. These studies have three main themes: (1) virtual breastfeeding support provided by doulas during the pandemic; (2) remote social support provided by doulas to breastfeeding mothers during the pandemic; and (3) barriers to doula service delivery due to COVID-19 restrictions, primarily the exclusion of doulas as essential workers. The eight studies showed that doulas found innovative ways to serve the needs of birthing and nursing mothers during the difficulties brought on by the pandemic. Conclusion Doulas provided breastfeeding support during the COVID-19 pandemic by utilizing innovative service delivery methods while navigating changes in COVID-19 guidance. However, system-level integration of doulas' work and the acknowledgment of doulas as essential healthcare providers are needed to enhance doula service delivery capacity, especially during a pandemic, to help improve maternal health outcomes.

Abstract Background Validating new algorithms, such as methods to disentangle intrinsic treatment risk from risk associated with experiential learning of novel treatments, often requires knowing the ground truth for data characteristics under investigation. Since the ground truth is inaccessible in real world data, simulation studies using synthetic datasets that mimic complex clinical environments are essential. We describe and evaluate a generalizable framework for injecting hierarchical learning effects within a robust data generation process that incorporates the magnitude of intrinsic risk and accounts for known critical elements in clinical data relationships. Methods We present a multi-step data generating process with customizable options and flexible modules to support a variety of simulation requirements. Synthetic patients with nonlinear and correlated features are assigned to provider and institution case series. The probability of treatment and outcome assignment are associated with patient features based on user definitions. Risk due to experiential learning by providers and/or institutions when novel treatments are introduced is injected at various speeds and magnitudes. To further reflect real-world complexity, users can request missing values and omitted variables. We illustrate an implementation of our method in a case study using MIMIC-III data for reference patient feature distributions. Results Realized data characteristics in the simulated data reflected specified values. Apparent deviations in treatment effects and feature distributions, though not statistically significant, were most common in small datasets (n

Sucking lice live in intimate association with their hosts and often display a high degree of host specificity. The present study investigated sucking lice of the genus Lemurpediculus from six mouse lemur (Microcebus) and two dwarf lemur (Cheirogaleus) species endemic to the island of Madagascar, considered a biodiversity hotspot. Louse phylogenetic trees were created based on cytochrome C oxidase subunit I (COI), elongation factor 1α (EF1α) and internal transcribed spacer 1 (ITS1) sequences. While clustering according to host species was generally observed for COI and ITS1, suggesting high host specificity of the examined lice, EF1α sequences alone did not distinguish between lice of different Microcebus species, possibly due to rather recent divergence. As bootstrap support for basal tree structure was rather low, further data are necessary to resolve the evolutionary history of louse-mouse lemur associations. Three new species of sucking lice are described: Lemurpediculus zimmermanni sp. Nov. From Microcebus ravelobensis, Lemurpediculus gerpi sp.nov. from Microcebus gerpi, and Lemurpediculus tsimanampesotsae sp. nov. from Microcebus griseorufus. These new species are compared with all known congeneric species and identifying features are illustrated for all known species of Lemurpediculus.

Abstract Background The global spread of COVID-19 created an explosion in rapid tests with results in