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Background Social determinants of health (SDOH) have been associated with diabetes risk; however, their association with cardiovascular disease (CVD) events in individuals with diabetes is poorly described. We hypothesized that a greater number of SDOH among individuals with diabetes would be associated with a higher risk of CVD events. Methods The REasons for Geographic and Racial Differences in Stroke (REGARDS) study is a national, biracial cohort of 30,239 individuals ≥45 years old recruited in 2003–2007. We included 6,322 participants with diabetes at baseline, defined as healthcare professional diagnosis, diabetes medication use, or blood glucose values. Seven SDOH that were individually associated with CVD events were included (P

Abstract Background The use of real-world data has become increasingly popular, also in the field of infectious disease (ID), particularly since the COVID-19 pandemic emerged. While much useful data for research is being collected, these data are generally stored across different sources. Privacy concerns limit the possibility to store the data centrally, thereby also limiting the possibility of fully leveraging the potential power of combined data. Federated learning (FL) has been suggested to overcome privacy issues by making it possible to perform research on data from various sources without those data leaving local servers. In this review, we discuss existing applications of FL in ID research, as well as the most relevant opportunities and challenges of this method. Methods References for this review were identified through searches of MEDLINE/PubMed, Google Scholar, Embase and Scopus until July 2023. We searched for studies using FL in different applications related to ID. Results Thirty references were included and divided into four sub-topics: disease screening, prediction of clinical outcomes, infection epidemiology, and vaccine research. Most research was related to COVID-19. In all studies, FL achieved good accuracy when predicting diseases and outcomes, also in comparison to non-federated methods. However, most studies did not make use of real-world federated data, but rather showed the potential of FL by using data that was manually partitioned. Conclusions FL is a promising methodology which allows using data from several sources, potentially generating stronger and more generalisable results. However, further exploration of FL application possibilities in ID research is needed.

Abstract Background Fluoropyrimidine (FP) chemotherapies are commonly prescribed for upper and lower gastrointestinal, breast and head and neck malignancies. Over 16,000 people with cancer require FP chemotherapies per annum in Australia. Between 10 and 40% patients experience grade 3–4 (≥ G3) toxicities that require hospital-based management ± intensive care admission. Approximately 1% of patients die secondary to FP toxicities. Prospective screening for DPYD gene variants (encoding the key enzyme for FP catabolism) can identify patients at risk of ≥ G3 toxicity and allow for dose adjustment prior to first FP exposure. Evidence supports this as a cost-effective method of improving patient safety and reducing healthcare burden internationally; however, no Australian data confirms its feasibility on a large scale. Method This investigator-led, single-arm study will determine large scale feasibility of prospective DPYD genotyping, confirming patient safety and cost-effectiveness within the Australian health care system. 5000 patients aged 18 years and older with solid organ cancers requiring FP chemotherapy will be consented and genotyped prior to commencing treatment, and early toxicity (within 60 days) post-FP exposure will be determined. Toxicity data for DPYD variant carriers who have dose adjustments will be compared to the wild-type cohort and historical cohorts of carriers who did not undergo genotyping prior to FP exposure, and prospective variant carriers who do not undergo dose-adjustment. Prevalence of the four standard DPYD gene variants will be confirmed in an Australian population. Additionally, health economic analysis, implementation research via semi-structured interviews of patients and clinicians, and feasibility of UGT1A1 genotyping will be conducted. Discussion This study will determine the prevalence of DPYD gene variant status in Australia and its impact on FP-induced toxicity among Australians with cancer. Feasibility and cost-effectiveness for Australian health care system will be estimated to support national roll-out of prospective DPYD genotyping prior to FP administration. Additionally, feasibility will be confirmed with the intention of including UGT1A1 in future pharmacogenomic panels to aid chemotherapy prescribing. Trial registration This trial was registered with the Australian and New Zealand Cancer Trials Registry on 13th Dec 2023, ACTRN12623001301651.

Abstract “Medical scientists” are postgraduate investigators who are engaged in biomedical research, and either hold a biomedical PhD or are qualified in medicine but do not participate in patient care. Medical scientists constitute ~40% of staff at medical faculties and >90% at nonuniversity medical research institutions in Germany. However, medical scientists in Germany face limited long‐term career prospects and a lack of dedicated training and support programmes. They also face time limits on their career progression arising from national academic employment legislation, and imminent reforms by the German government are likely to make this worse. Nevertheless, recent developments in the educational landscape including the introduction of increasingly focused MSc, pre‐PhD, and doctoral programmes to train medically aware basic scientists, as well as improved general recognition of the roles and relevance of medical scientists in health research, are encouraging. Physiologists have taken essential steps to improve the recognition of medical scientists in Germany by introducing a “specialist physiologist” qualification; this initiative could be applied to support medical scientists in other fields and countries. In this review, we describe the particular challenges facing medical scientists in Germany and make recommendations that may apply to other academic systems.

Abstract The limited availability of therapeutic options for patients with triple-negative breast cancer (TNBC) contributes to the high rate of metastatic recurrence and poor prognosis. Ferroptosis is a type of cell death caused by iron-dependent lipid peroxidation and counteracted by the antioxidant activity of the selenoprotein GPX4. Here, we show that TNBC cells secrete an anti-ferroptotic factor in the extracellular environment when cultured at high cell densities but are primed to ferroptosis when forming colonies at low density. We found that secretion of the anti-ferroptotic factors, identified as monounsaturated fatty acid (MUFA) containing lipids, and the vulnerability to ferroptosis of single cells depends on the low expression of stearyl-CoA desaturase (SCD) that is proportional to cell density. Finally, we show that the inhibition of Sec-tRNAsec biosynthesis, an essential step for selenoprotein production, causes ferroptosis and impairs the lung seeding of circulating TNBC cells that are no longer protected by the MUFA-rich environment of the primary tumour.

Abstract Background: The COVID-19 pandemic has posed significant challenges to global healthcare systems, particularly impacting individuals with pre-existing conditions like hypertension. This study sought to assess the impact of the antihypertensive medications, losartan and enalapril maleate on SARS-CoV-2 infected cells. Vero E6 cells were infected and treated in vitro, evaluating cell viability via the MTT colorimetric assay. Additionally, the study measured relative levels of viral RNA and selected gene messenger RNAs using reverse transcriptase followed by quantitative real-time polymerase chain reaction. Results: The findings revealed that losartan substantially reduced nucleocapsid RNA levels of SARS-CoV-2 to nearly undetectable levels, while enalapril maleate did not demonstrate a significant effect. In response to viral infection, the expression of il-18, p53, p21, and p62 increased compared to uninfected-untreated cells. Notably, il-6 expression was upregulated by both infection and treatments. A comparison between infected cells treated with losartan or enalapril maleate highlighted the presence of distinct profiles in the expression of il-6, p53, p21, and p62. Conclusions: The data from our study suggest that these medications could interfere with certain effects triggered by SARS-CoV-2 infection in Vero E6 cells. However, their influence appears to vary both quantitatively and qualitatively in the modulation of metabolic and signal transduction pathways.

Abstract Background Connecting the composition and function of industrial microbiomes is a major aspiration in microbial biotechnology. Here, we address this question in wine fermentation, a model system where the diversity and functioning of fermenting yeast species are determinant of the flavor and quality of the resulting wines. Results First, we surveyed yeast communities associated with grape musts collected across wine appellations, revealing the importance of environmental (i.e., biogeography) and anthropic factors (i.e., farming system) in shaping community composition and structure. Then, we assayed the fermenting yeast communities in synthetic grape must under common winemaking conditions. The dominating yeast species defines the fermentation performance and metabolite profile of the resulting wines, and it is determined by the initial fungal community composition rather than the imposed fermentation conditions. Yeast dominance also had a more pronounced impact on wine meta-transcriptome than fermentation conditions. We unveiled yeast-specific transcriptomic profiles, leveraging different molecular functioning strategies in wine fermentation environments. We further studied the orthologs responsible for metabolite production, revealing modules associated with the dominance of specific yeast species. This emphasizes the unique contributions of yeast species to wine flavor, here summarized in an array of orthologs that defines the individual contribution of yeast species to wine ecosystem functioning. Conclusions Our study bridges the gap between yeast community composition and wine metabolite production, providing insights to harness diverse yeast functionalities with the final aim to producing tailored high-quality wines. Video Abstract

Abstract Background Regional variations in SARS-CoV-2 infection were observed in Canada and other countries. Studies have used multilevel analyses to examine how a context, such as a neighbourhood, can affect the SARS-CoV-2 infection rates of the people within it. However, few multilevel studies have quantified the magnitude of the general contextual effect (GCE) in SARS-CoV-2 infection rates and assessed how it may be associated with individual- and area-level characteristics. To address this gap, we will illustrate the application of the median rate ratio (MRR) in a multilevel Poisson analysis for quantifying the GCE in SARS-CoV-2 infection rates in Ontario, Canada. Methods We conducted a population-based, two-level multilevel observational study where individuals were nested into regions (i.e., forward sortation areas [FSAs]). The study population included community-dwelling adults in Ontario, Canada, between March 1, 2020, and May 1, 2021. The model included seven individual-level variables (age, sex, asthma, diabetes, hypertension, congestive heart failure, and chronic obstructive pulmonary disease) and four FSA census-based variables (household size, household income, employment, and driving to work). The MRR is a median value of the rate ratios comparing two patients with identical characteristics randomly selected from two different regions ordered by rate. We examined the attenuation of the MRR after including individual-level and FSA census-based variables to assess their role in explaining the variation in rates between regions. Results Of the 11 789 128 Ontario adult community-dwelling residents, 343 787 had at least one SARS-CoV-2 infection during the study period. After adjusting for individual-level and FSA census-based variables, the MRR was attenuated to 1.67 (39% reduction from unadjusted MRR). The strongest FSA census-based associations were household size (RR = 1.88, 95% CI: 1.71–1.97) and driving to work (RR = 0.68, 95% CI: 0.65–0.71). Conclusions The individual- and area-level characteristics in our study accounted for approximately 40% of the between-region variation in SARS-CoV-2 infection rates measured by MRR in Ontario, Canada. These findings suggest that population-based policies to address social determinants of health that attenuate the MRR may reduce the observed between-region heterogeneity in SARS-CoV-2 infection rates.

Abstract Background Five decades into the era of mass incarceration, a growing number of older adults have experienced criminal legal involvement (CLI) in their lifetime. Studies have shown that prior incarceration is associated with substantial disease burden, but little is known about the distinct needs and utilization patterns of middle-aged and older adults with lifetime CLI compared to those without. Using a nationally representative data set, we tested the association between lifetime CLI exposure and use of acute care services among middle-aged and older adults. Methods Our sample included 44,007 US adults (25,074 middle-aged-50-64 years; 18,709 older- ≥65 years) who participated in the National Survey of Drug Use and Health (2015–2019). The data is publicly available. Our independent variable was lifetime CLI. Using separate negative binomial regression models for middle-aged and older adults, we tested the association between lifetime CLI and acute healthcare utilization (ED visits and nights spent inpatient) controlling for relevant sociodemographic covariates. Results For middle-aged respondents, 19.1% reported lifetime CLI; for older adults, the rate of exposure was 9.6%. In multivariate models, CLI was associated with increased ED visits in middle-aged adults (IRR 1.18, 95% CI 1.06–1.31) but not older adults (IRR 0.99, 95% CI 0.85–1.16). CLI was associated with increased nights hospitalized in both groups (middle-aged: IRR 1.33, 95% CI 1.08–1.62; older adults: IRR 1.26, 95% CI 1.01, 1.57). Conclusion Middle-aged and older adults with lifetime CLI experience higher rates of acute care utilization than their peers with no lifetime CLI, even after adjustment for confounders. As the cohort of adults from the era of mass incarceration ages, understanding the mechanisms by which lifetime CLI impacts health outcomes is crucial in designing interventions to improve outcomes and reduce unnecessary acute healthcare utilization.

Abstract Background The natural light environment is far more complex than that experienced by animals under laboratory conditions. As a burrowing species, wild mice are able to self-modulate their light exposure, a concept known as light environment sampling behaviour. By contrast, under laboratory conditions mice have little opportunity to exhibit this behaviour. To address this issue, here we introduce a simple nestbox paradigm to allow mice to self-modulate their light environment. Dark nestboxes fitted with passive infrared sensors were used to monitor locomotor activity, circadian entrainment, decision making and light environment sampling behaviour. Results Under these conditions, mice significantly reduce their light exposure to an average of just 0.8 h across a 24 h period. In addition, mice show a distinct pattern of light environment sampling behaviour, with peaks at dawn and dusk under a ramped light dark cycle. Furthermore, we show that the timing of light environment sampling behaviour depends upon endogenous circadian rhythms and is abolished in mice lacking a circadian clock, indicating a feedback loop between light, the circadian clock and behaviour. Conclusions Our results highlight the important role of behaviour in modifying the light signals available for circadian entrainment under natural conditions.

The National Education Nature Park aims to involve every nursery, school, and college in England in enhancing the biodiversity on their site, whilst supporting young people’s wellbeing, pro-environmental behaviours, and green skills. Young people gather environmental data using citizen science research, and then through collaboration and collective decision-making, they design and implement their own nature recovery actions. But will this participation in community and citizen science lead to behaviour change and environmental action, and how can we build participants’ sense of agency to take environmental action through our programme? Here, we present our Theory of Change for the Nature Park and the design features of the programme that connect participation in citizen science with achieving two crucial types of change - environmental change in the form of biodiversity gain, and the behaviour change that underpins it.

Abstract Little is known about the effect of future weather and climate on municipal water demand in coastal communities with tourist-centric economies. To address this knowledge gap, we used an econometric model of monthly water demand that allowed for non-linear responses to weather variables to estimate temperature-response functions for demand from a sample of communities in the Oregon Mid-Coast. A main result is that local temperature was not a significant driver of variability in monthly water demand but that temperature in the Willamette Valley—the source of most tourists to the Oregon coast—was. We assumed that the increase in demand in response to higher Willamette Valley temperature arose from an increase in tourists escaping the heat in the Willamette Valley for cooler conditions on the coast. Applying the temperature response functions to scenarios of future climate to the year 2070 led to projected increases in water demand independent of other factors. Whether future tourism is either constrained by the local resident population that serves tourism or is constrained by the potential tourist population in the Willamette Valley, the climate-change contribution to projected water demand is generally of comparable magnitude to—if not greater than—the contribution from resident population change alone over the next 50 years. For communities where the population is projected to decline, the climate effect may more than offset the effect of declining population, resulting in a net positive change in demand.

Abstract Background Fragmentation of care (that is, the use of multiple ambulatory providers without a dominant provider) may increase the risk of gaps in communication among providers. However, it is unclear whether people with fragmented care (as measured in claims) perceive more gaps in communication among their providers. It is also unclear whether people who perceive gaps in communication experience them as clinically significant (that is, whether they experience adverse events that they attribute to poor coordination). Methods We conducted a longitudinal study using data from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, including a survey on perceptions of healthcare (2017–2018) and linked fee-for-service Medicare claims (for the 12 months prior to the survey) (N = 4,296). We estimated correlation coefficients to determine associations between claims-based and self-reported numbers of ambulatory visits and ambulatory providers. We then used logistic regression to determine associations between claims-based fragmentation (measured with the reversed Bice-Boxerman Index [rBBI]) and self-reported gaps in care coordination and, separately, between claims-based fragmentation and self-reported adverse events that the respondent attributed to poor coordination. Results The correlation coefficient between claims-based and self-report was 0.37 for the number of visits and 0.38 for the number of providers (p

Abstract A sense of belonging to a community is a dimension of subjective well-being that is of growing population health interest. We evaluated sex-stratified associations between community belonging and risk of avoidable hospitalization. Adult men and women from the Canadian Community Health Survey (2000–2014) were asked to rate their sense of community belonging (N = 456,415) and were also linked to acute inpatient hospitalizations to 31 March 2018. We used Cox proportional hazards models to assess the association between community belonging and time to hospitalization related to ambulatory care sensitive conditions (ACSCs) and adjusted for a range of sociodemographic, health, and behavioural confounders. Compared to those who reported intermediate levels of belonging, both very weak and very strong sense of belonging were associated with greater risk of avoidable hospitalization for women (HR 1.29, 95% CI 1.12, 1.47, very weak; HR 1.15, 95% CI 1.03, 1.27, very strong), but not for men (HR 1.12, 95% CI 0.97, 1.29, very weak; HR 1.08, 95% CI 0.98, 1.19, very strong). This study suggests that community belonging is associated with risk of ACSC hospitalization for women and provides a foundation for further research on community belonging and population health.

Abstract Background While Human Factors (HF) methods have been applied to the design of decision support systems (DSS) to aid clinical decision-making, the role of HF to improve decision-support for population health outcomes is less understood. We sought to comprehensively understand how HF methods have been used in designing digital population health DSS. Materials and methods We searched English documents published in health sciences and engineering databases (Medline, Embase, PsychINFO, Scopus, Comendex, Inspec, IEEE Xplore) between January 1990 and September 2023 describing the development, validation or application of HF principles to decision support tools in population health. Results We identified 21,581 unique records and included 153 studies for data extraction and synthesis. We included research articles that had a target end-user in population health and that used HF. HF methods were applied throughout the design lifecycle. Users were engaged early in the design lifecycle in the needs assessment and requirements gathering phase and design and prototyping phase with qualitative methods such as interviews. In later stages in the lifecycle, during user testing and evaluation, and post deployment evaluation, quantitative methods were more frequently used. However, only three studies used an experimental framework or conducted A/B testing. Conclusions While HF have been applied in a variety of contexts in the design of data-driven DSSs for population health, few have used Human Factors to its full potential. We offer recommendations for how HF can be leveraged throughout the design lifecycle. Most crucially, system designers should engage with users early on and throughout the design process. Our findings can support stakeholders to further empower public health systems.

Abstract Introduction Psoriatic arthritis (PsA) is a chronic inflammatory disease requiring long-term treatment. Bimekizumab, a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A, has demonstrated tolerability and sustained clinical efficacy for up to 1 year for patients with PsA. Here, we report the longer-‍term safety and efficacy of bimekizumab up to 2 years. Methods BE OPTIMAL (biologic disease-modifying antirheumatic drug [bDMARD]-naïve) and BE COMPLETE (prior inadequate response/intolerance to tumor necrosis factor inhibitors [TNFi-IR]) assessed subcutaneous bimekizumab 160 mg every 4 weeks in patients with PsA. BE OPTIMAL included a reference arm (adalimumab 40 mg every 2 weeks); patients switched to bimekizumab at week 52 with no washout between treatments. BE OPTIMAL week 52 and BE COMPLETE week 16 completers were eligible for the BE VITAL open-label extension. Efficacy outcomes are reported to week 104/100 (BE OPTIMAL/BE COMPLETE). Results A total of 710/852 (83.3%) bDMARD-naïve and 322/400 (80.5%) TNFi-IR patients completed week 104/100. Up to 104 weeks, patients treated with bimekizumab in BE OPTIMAL and BE COMPLETE had treatment-emergent adverse event incidence rates (exposure-adjusted incidence rate/100 patient-years) of 179.9 (95% CI 166.9, 193.7) and 100.3 (89.2, ‍112.4), respectively. The proportion of patients achieving efficacy outcomes (≥ 50% improvement from baseline in American College of Rheumatology [ACR] response criteria, 100% improvement from baseline in Psorisis Area and Severity Index [PASI], minimal disease activity [MDA]) was sustained in all patients from week 52 to week 104/100. Conclusions Bimekizumab was well tolerated for up to 2 years of treatment and no new safety signals were observed. Sustained clinical efficacy was observed up to 2 years in bDMARD-naïve and TNFi-IR patients with active PsA. Patients switching from adalimumab to bimekizumab demonstrated further improvement in skin and nail symptoms, and sustained efficacy in joint symptoms. Trial Registration BE OPTIMAL (NCT03895203), BE COMPLETE (NCT03896581), BE VITAL (NCT04009499).

Abstract Introduction Risankizumab has demonstrated a favourable safety profile in patients with psoriatic disease (moderate-to-severe psoriasis [PsO] and psoriatic arthritis [PsA]). We evaluated the long-term safety of risankizumab in psoriatic disease. Methods Long-term safety was evaluated by analysing data from 20 (phase 1–4) clinical trials for plaque PsO and four (phase 2–3) trials for PsA. Treatment-emergent adverse events (TEAEs) and AEs in areas of special interest were reported among patients receiving ≥ 1 dose of risankizumab. Exposure-adjusted event rates were presented as events (E) per 100 patient-years (PY). Results The long-term safety data analyses included 3658 patients with PsO (13,329.3 PY) and 1542 patients with PsA (3803.0 PY). The median (range) treatment duration for patients with PsO and PsA was 4.1 (0.2–8.8) years and 2.8 (0.2–4.0) years, respectively. In the PsO population, rates of TEAEs, serious AEs and AEs leading to discontinuation were 145.5 E/100 PY, 7.4 E/100 PY and 1.9 E/100 PY, respectively; in the PsA population, these rates were 142.6 E/100 PY, 8.6 E/100 PY, and 1.8 E/100 PY, respectively. The rates of serious infections (excluding COVID-19-related infections) in the PsO and PsA populations were 1.2 and 1.4 E/100 PY, respectively. The rates of opportunistic infections (excluding tuberculosis and herpes zoster) were low (

Abstract Atmospheric mercury (Hg(0), Hg(II)) and riverine exported Hg (Hg(II)) are proposed as important Hg sources to the Arctic Ocean. As plankton cannot passively uptake Hg(0), gaseous Hg(0) has to be oxidized to be bioavailable. Here, we measured Hg isotope ratios in zooplankton, Arctic cod, total gaseous Hg, sediment, seawater, and snowpack from the Bering Strait, the Chukchi Sea, and the Beaufort Sea. The Δ200Hg, used to differentiate between Hg(0) and Hg(II), shows, on average, 70% of Hg(0) in all biota and differs with seawater Δ200Hg (Hg(II)). Since Δ200Hg anomalies occur via tropospheric Hg(0) oxidation, we propose that near-surface Hg(0) oxidation via terrestrial vegetation, coastally evaded halogens, and sea salt aerosols, which preserve Δ200Hg of Hg(0) upon oxidation, supply bioavailable Hg(II) pools in seawater. Our study highlights sources and pathways in which Hg(0) poses potential ecological risks to the Arctic Ocean biota.

Abstract A diverse antibody repertoire is essential for humoral immunity. Antibody diversification requires the introduction of deoxyuridine (dU) mutations within immunoglobulin genes to initiate somatic hypermutation (SHM) and class switch recombination (CSR). dUs are normally recognized and excised by the base excision repair (BER) protein uracil-DNA glycosylase 2 (UNG2). However, FAM72A downregulates UNG2 permitting dUs to persist and trigger SHM and CSR. How FAM72A promotes UNG2 degradation is unknown. Here, we show that FAM72A recruits a C-terminal to LisH (CTLH) E3 ligase complex to target UNG2 for proteasomal degradation. Deficiency in CTLH complex components result in elevated UNG2 and reduced SHM and CSR. Cryo-EM structural analysis reveals FAM72A directly binds to MKLN1 within the CTLH complex to recruit and ubiquitinate UNG2. Our study further suggests that FAM72A hijacks the CTLH complex to promote mutagenesis in cancer. These findings show that FAM72A is an E3 ligase substrate adaptor critical for humoral immunity and cancer development.

Abstract Pituitary neuroendocrine tumors (PitNET) represent the vast majority of sellar masses. Some behave aggressively, growing rapidly and invading surrounding tissues, with high rates of recurrence and resistance to therapy. Our aim was to establish patterns of genomic, transcriptomic and methylomic evolution throughout time in primary and recurrent tumors from the same patient. Therefore, we performed transcriptome- and exome-sequencing and methylome microarrays of aggressive, primary, and recurrent PitNET from the same patient. Primary and recurrent tumors showed a similar exome profile, potentially indicating a stable genome over time. In contrast, the transcriptome of primary and recurrent PitNET was dissimilar. Gonadotroph, silent corticotroph, as well as metastatic corticotroph and a somatotroph PitNET expressed genes related to fatty acid biosynthesis and metabolism, phosphatidylinositol signaling, glycerophospholipid and phospholipase D signaling, respectively. Diacylglycerol kinase gamma (DGKG), a key enzyme in glycerophospholipid metabolism and phosphatidylinositol signaling pathways, was differentially expressed between primary and recurrent PitNET. These alterations did not seem to be regulated by DNA methylation, but rather by several transcription factors. Molecular docking showed that dasatinib, a small molecule tyrosine kinase inhibitor used in the treatment of chronic lymphocytic and acute lymphoblastic leukemia, could target DGKG. Dasatinib induced apoptosis and decreased proliferation in GH3 cells. Our data indicate that pituitary tumorigenesis could be driven by transcriptomically heterogeneous clones, and we describe alternative pharmacological therapies for aggressive and recurrent PitNET.

Abstract Purpose Blood-flow restriction (BFR) endurance training may increase endurance performance and muscle strength similar to traditional endurance training while requiring a lower training intensity. We aimed to compare acute cardiorespiratory responses to low-intensity interval exercise under BFR with moderate-intensity traditional interval exercise (TRA). Methods We conducted a randomized crossover study. The protocol involved three cycling intervals interspersed with 1 min resting periods. With a 48-h washout period, individuals performed the protocol twice in random order: once as BFR-50 (i.e., 50% incremental peak power output [IPPO] and 50% limb occlusion pressure [LOP]) and once as TRA-65 (65% IPPO without occlusion). TRA-65 intervals lasted 2 min, and time-matched BFR-50 lasted 2 min and 18 s. Respiratory parameters were collected by breath-by-breath analysis. The ratings of perceived breathing and leg exertion (RPE, 0 to 10) were assessed. Linear mixed models were used for analysis. Results Out of the 28 participants initially enrolled in the study, 24 healthy individuals (18 males and 6 females) completed both measurements. Compared with TRA-65, BFR-50 elicited lower minute ventilation (VE, primary outcome) (-3.1 l/min [-4.4 to -1.7]), oxygen consumption (-0.22 l/min [-0.28 to -0.16]), carbon dioxide production (-0.25 l/min [-0.29 to -0.20]) and RPE breathing (-0.9 [-1.2 to -0.6]). RPE leg was significantly greater in the BFR-50 group (1.3 [1.0 to 1.7]). Conclusion BFR endurance exercise at 50% IPPO and 50% LOP resulted in lower cardiorespiratory work and perceived breathing effort compared to TRA at 65% IPPO. BFR-50 could be an attractive alternative for TRA-65, eliciting less respiratory work and perceived breathing effort while augmenting perceived leg muscle effort. Trial registration NCT05163600; December 20, 2021.

Abstract Background The prevalence of cardiovascular disease is burgeoning in low- and middle-income countries (LMICs). In sub-Saharan Africa, the prevalence of cardiovascular risk factors is increasing, though rates of CVD diagnosis and management remain low. Awareness of the influence of social determinants of health (SDOH) on cardiovascular outcomes is growing, however, most work focuses on high-income countries. Material needs security is a measure of SDOH that may be particularly relevant for LMICs. This study investigated the relationship between material needs security and cardiovascular risk in older adults living in South Africa. Methods The analysis included 5059 respondents age ≥ 40 in the Health and Aging in Africa survey, an observational cohort study administered in 2014 in Mpumalanga Province, South Africa. Linear regression models tested the association between material needs and eight cardiovascular risk factors (waist-to-hip ratio, body mass index, blood pressure, glucose, cholesterol, LDL, and triglycerides). Adjusted linear regression models controlled for sociodemographic confounders. Results There were significant adjusted associations found between increased material needs security and four cardiovascular risk factors, including waist-to-hip ratio (β = 0.001; 95% CI [0.00002,0.002]), BMI (β = 0.19; 95%CI=[0.14,0.24]), glucose (β = 0.46; 95%CI=[0.02,0.90]), and triglycerides (β = 0.26; 95%CI=[0.02,0.49]). Conclusion Increased material needs security was associated with significantly increased cardiovascular risk in older adults in rural South Africa. These findings can inform the approach to treatment and management of cardiovascular disease in South Africa and similar LMICs. Future investigations should evaluate the implementation and efficacy of interventions that recognize the role of material needs security in cardiovascular risk.

Chronic hepatitis B (CHB) disease caused by persistent infection with hepatitis B virus (HBV) is a global health problem affecting almost 300 million people worldwide, resulting in up to 1 million deaths each year. The factors contributing to HBV mediated liver disease are yet to be fully resolved, however, multiple studies have suggested that HBV splice variants may be a contributing factor. Recent studies have indicated that novel fusion proteins encoded by splice variants, or the splice-derived RNA itself, may impact replication of wild-type HBV, although the direct mechanisms for these interactions are largely unknown. This review explores the latest knowledge regarding the contribution of splice variants to liver disease and their impact on HBV replication.

Objectives To prospectively evaluate the effect of guselkumab through 48 weeks across various clinical outcomes in subgroups of patients with psoriatic arthritis (PsA) and inadequate response to tumour necrosis factor inhibitors (TNFi-IR) from the phase 3b COSMOS trial. Subgroups were defined by baseline demographics, disease characteristics and prior/ongoing therapies.Methods Patients with active PsA (tender joint count (TJC) and swollen joint count (SJC) both ≥3) and TNFi-IR were randomised 2:1 to receive guselkumab 100 mg at week 0, week 4, then every 8 weeks through week 44 or to placebo with cross-over to guselkumab 100 mg at week 16 (early escape) or week 24 (planned). Guselkumab effect on joints (American College of Rheumatology (ACR) 20/50/70, enthesitis, dactylitis), skin (Psoriasis Area and Severity Index 90/100, Investigator’s Global Assessment 0/1), patient-reported outcomes (PROs) (Functional Assessment of Chronic Illness Therapy–Fatigue, Health Assessment Questionnaire–Disability Index) and composite outcome measures (PsA Disease Activity Score low disease activity, minimal disease activity) were evaluated by baseline patient age, sex, body mass index, SJC, TJC, PsA duration, %body surface area, C reactive protein, pain Visual Analogue Scale, number of prior TNFi and discontinuation reason, and conventional synthetic disease-modifying antirheumatic drug status. Results are descriptive only.Results Baseline characteristics were similar between guselkumab (n=189) and placebo (n=96) groups. The benefit of guselkumab over placebo in achieving ACR 20 (primary endpoint; 50% vs 28%) and ACR 50 (23% vs 8%) response at week 24 was observed within all subgroups. Furthermore, response rates in the guselkumab group increased between week 24 and week 48 within almost all subgroups. Similar response patterns at week 24 and through week 48 were observed across various clinical outcomes.Conclusions Guselkumab every 8 weeks led to consistent improvements through week 24 in joint, skin, PRO and composite outcomes versus placebo across diverse baseline-defined subgroups of TNFi-IR patients with PsA. Response rates increased or were durable through week 48 within most subgroups.

It is known that 25%–30% of individuals with cutaneous psoriasis (PsC) will develop psoriatic arthritis (PsA). To date, the reasons for the development of PsA in individuals with PsC have not been identified. Furthermore, there are considerable delays in the diagnosis and treatment of PsA, which lead to joint and bone deformation and chronic pain. It is therefore important to develop more precise diagnostic and screening tools. In this narrative review of the literature, clinical risk factors and novel molecular biomarkers (genetic markers, blood and inflammatory markers, lipid, metabolite and protein biomarkers) have been evaluated. The review included 38 publications that were reported between May 2020 and May 2024. Similar to previous reviews, nail involvement was one of the strongest clinical risk factors for the development of PsA, while molecular biomarkers did not provide a clear and robust differentiation between PsC and PsA groups. The seemingly poor performance of molecular markers may be largely attributed to small study populations and heterogeneity in study designs. Data and sample sharing in large consortia such as HIPPOCRATES (Health initiatives in Psoriasis and PsOriatic arthritis ConsoRTium European States) could help to overcome the limitations of small studies and enable the development of more robust diagnostic and screening tools for PsA.

Psoriasis is a chronic inflammatory autoimmune skin disease characterized by keratinocyte hyperproliferation, primarily driven by the IL-23/IL-17 axis. In addition to immune response, various skin components, including the epidermal barrier and the skin microbiota, have been individually implicated in the disease pathogenesis. Here, we aimed to investigate the interplay between epidermal tight junctions, Staphylococcus aureus enterotoxin B (SEB), and CD4 T cell-mediated immune responses. By immunofluorescence analyses of skin biopsies, we observed that claudin-1 distribution was significantly altered in psoriatic patients, which correlated with the localization of Staphylococcus aureus and SEB across skin layers and with disease severity. Furthermore, functional CD4 TCRvβ17 cells were associated with SEB presence in patients skin and positively correlated with psoriasis severity. Notably, in patients with SEB detected in the dermis, CD4 TCRvβ17 IL-17 cells were linked to barrier abnormalities.Unsupervised analysis stratified psoriasis patients into three groups based on SEB presence and location, supporting the previous findings. The patient group with SEB in the dermis exhibited improved responses to biological therapy, including reductions in PASI score, claudin-1 fragmentation, S. aureus and SEB presence, and CD4 TCRvβ17 cell percentages. Our findings emphasize the complex interplay between epidermal barrier distribution, SEB localization, and functional CD4 TCRvβ17 cells in psoriatic skin, highlighting their potential in patient stratification in association with the severity of the disease.

BackgroundInterest is emerging regarding the role of blood biomarkers in acute stroke. The aim of this pilot study was to determine the feasibility of biomarker acquisition in suspected acute stroke, using modern ultrasensitive immunoassay techniques, and explore their potential usefulness for stroke diagnosis and management.MethodsIn 62 patients with suspected acute stroke, blood samples were prospectively obtained upon arrival and prior to neuroimaging. Serum levels of glial fibrillary acidic protein (sGFAP) and neurofilament light chain (sNfL) were analyzed using a single molecule array (SIMOA®) method, according to time of symptom onset, neuroimaging, and final diagnosis.ResultsAcute ischemic stroke (AIS) was diagnosed in 35 patients, 10 with large-vessel occlusion (LVO). The remaining were diagnosed with intracerebral hemorrhage (ICH) (n = 12), transient ischemic attack (n = 4), and stroke mimics (n = 11). Median (IQR) sGFAP levels were significantly higher in ICH (2,877.8 [1,002.1–10,402.5] pg./mL) compared to others diagnoses. In AIS, GFAP levels appear to increase with longer delays since symptom onset and were higher in patients with more extensive ischemic changes on baseline CT (ASPECTS ≤7) than those without, particularly in LVO stroke. NfL values were similar across groups.ConclusionIn acute stroke, serum GFAP levels show potential as an adjunct tool for the distinction between ICH and AIS. Specific to AIS, GFAP may also offer insight into time from onset, and extent of ischemic tissue injury on neuroimaging, particularly in LVO stroke. These preliminary findings merit further study.

Background: Emergency service personnel perform roles associated with high levels of trauma exposure and stress, and not surprisingly experience greater risk for poor mental health including posttraumatic stress disorder (PTSD), depression, anxiety, and substance use relative to the general population. Although programs exist to minimise the risk of developing mental health problems, their efficacy to date has been limited or untested. We will test the efficacy of the three programs which form PEREI: Protecting Emergency Responders with Evidence-Based Interventions. PEREI consists of modified versions of internet-delivered cognitive training in resilience (iCT-R) for early career first responders, PEREI-S for supervisors, and Be Well for Significant Others (BW-SO).Method: Up to 450 members in their first 5 years of service across multiple agencies will be recruited, with their adult supports (significant others, friends) invited to participate. Up to 180 supervisors in the agencies will be recruited. Participants will be randomized to their respective program or to receive the standard practice for mental health offered by the service (or usual mental health support for significant others). Assessments will be conducted pre- and post-program, and at 6- and 12-month follow-up. Primary outcome is PTSD and depression severity and probable-diagnosis. Secondary measures will index hypothesized mediators and moderators of outcome and determine whether the programs are cost-effective.Conclusions: The results will provide evidence as to efficacious methods for reducing risk of mental health problems in high-risk occupations, a better understanding of how such interventions may work, and whether they are good value for money.Trial registration: www.anzctr.org.au (ACTRN12622001267741)

Objectives The widespread adoption of wearables, for example, smartphones and smartwatches in the daily lives of the general population, allows passive monitoring of physiological and behavioural data in the real world. This qualitative study explores the perspective of psoriatic arthritis (PsA) patients towards these so-called digital biomarkers (dBMs).Methods As part of a Design Thinking approach, six focus groups were conducted involving 27 PsA patients. The semistructured topic guide included disease activity, coping strategies, care needs, and potential advantages and disadvantages of dBMs. Thematic analysis followed an abductive coding method.Results PsA daily permeates patients’ lives, both physically and mentally. Participants discussed how their lives are focused on minimising the impact of the disease on their daily routines. Their attempts to gain control over their disease highly depend on trial and error. Flare-ups are related to physiological as well as behavioural micro and macro changes. Understanding these changes could enable the detection of (early) flare. Participants elicited pros and cons of the use of dBMs, discussed their intended use and made practical remarks. This led to three main themes: ‘Perceived dBM opportunities’, ‘Mapping Disease activity’ and ‘Perceived dBM barriers and pitfalls’.Conclusion PsA patients are receptive to dBMs for tracking the disease symptoms. Disease activity is regarded multifaceted and thus, dBMs should include a broad range of features to truly reflect the disease activity status. Reducing the time of trial and error in learning to manage the disease is regarded beneficial. Establishing and maintaining the relationship with their attending physicians is a prerequisite, even if remote patient monitoring becomes an alternative for some physical hospital visits.

Background: Certified peer recovery specialists (CPRS) and licensed clinical social workers (LCSWs) can facilitate substance use disorder (SUD) treatment engagement for emergency department (ED) patients at risk for overdose. Predictors of treatment engagement after such behavioral services are unknown. Methods: This secondary analysis included Rhode Island ED patients at high risk for opioid overdose participating in a randomized controlled trial comparing the effectiveness of CPRS and LCSWs services (2018–2021). SUD treatment engagement within 90 days post-discharge was identified using statewide administrative data. Potential predictors were obtained from baseline questionnaires. Classification and regression trees (CART) were used to identify predictors of treatment engagement. Results: In the ED, 323 and 325 participants received CPRS and LCSWs services, respectively, among whom 141 (43.7 %) and 137 (42.2 %) engaged in SUD treatment within 90 days post-discharge. For the CPRS group, predictors of treatment engagement included unhealthy alcohol use, prescription opioid or benzodiazepine use in past 6 months, and lifetime history of: unstable housing, barriers to treatment, bipolar disorder diagnosis, addiction treatment, and recovery services. In the LCSW group, predictors included health insurance, current pain, opioid overdose in past year, and lifetime history of anxiety disorder diagnosis and mental illness treatment. However, CART had low predictive accuracy (CPRS: 60.9 %, LCSW: 54.8 %). Conclusions: Among ED patients at high risk of opioid overdose receiving behavioral services, 90-day SUD treatment engagement was high. Sociobehavioral and clinical patient characteristics did not accurately predict treatment engagement. Behavioral services should be offered to all ED patients at high risk of opioid overdose.

Slaughterhouses may be hotspots for the transmission of antimicrobial resistant (AMR) pathogens. To obtain information on the AMR landscape in Kenyan slaughterhouses, we collected swabs of the environment, animal carcasses, and workers. Bacterial isolates were identified in 101/193 (52.3 %) samples, and most showed resistance to streptomycin (68.7 %), ampicillin (48.7 %), and tetracycline (42.5 %). Multi drug resistance was exhibited by 35/80 isolates (43.8 %; 95 % CI: 33.2–54.9 %), while Extended Spectrum Beta Lactamase was expressed in 5/80 isolates (6.3 %; 95 % CI: 2.6–14.3 %). These findings illustrate the presence of resistant bacteria throughout the slaughterhouse environment, posing a risk to workers and meat consumers and highlighting the need for an integrated surveillance system along the food chain.

The ongoing panzootic of highly pathogenic H5 clade 2.3.4.4b avian influenza (HPAI) spread to North America in late 2021, with detections of HPAI viruses in Alaska beginning in April 2022. HPAI viruses have since spread across the state, affecting many species of wild birds as well as domestic poultry and wild mammals. To better understand the dissemination of HPAI viruses spatiotemporally and among hosts in Alaska and adjacent regions, we compared the genomes of 177 confirmed HPAI viruses detected in Alaska during April–December 2022. Results suggest multiple viral introductions into Alaska between November 2021 and August or September 2022, as well as dissemination to areas within and outside of the state. Viral genotypes differed in their spatiotemporal spread, likely influenced by timing of introductions relative to population immunity. We found evidence for dissemination of HPAI viruses between wild bird species, wild birds and domestic poultry, as well as wild birds and wild mammals. Continued monitoring for and genomic characterization of HPAI viruses in Alaska can improve our understanding of the evolution and dispersal of these economically costly and ecologically relevant pathogens.

Background: Risk factors for cardiovascular disease (CVD) and sleep health are well-known to be sex- and race-specific. To build on the established relationship between sleep duration and CVD risk, this cross-sectional study aimed to describe sex-specific associations between CVD risk and other sleep characteristics (sleep quality, sleep timing and sleep onset latency) in low-income adults of African descent. Methods: Self-reported sleep (Pittsburgh Sleep Quality Index [PSQI], Epworth Sleepiness Scale [ESS], Insomnia Severity Index [ISI]), demographic and lifestyle data were collected in 412 adults (56 % women, 35.0 ± 7.6y, 40 % employed) living in an informal settlement in South Africa. CVD risk was determined using the BMI-modified Framingham 10-year CVD risk formula. Results: Logistic regression analyses, adjusted for employment, alcohol use and physical activity, indicated that men reporting poor sleep quality (OR: 1.95[95 %CI: 1.07–3.51], p=0.025) and earlier bedtimes (0.54[0.39–0.74], p

This study examines the allocation of COVID-19 funding for Indigenous Peoples in Canada, Australia, New Zealand, and the United States during the pandemic’s first wave. Indigenous communities, already facing health disparities, systemic discrimination, and historical forces of colonisation, found themselves further vulnerable to the virus. Analysing the funding policies of these countries, we employed a Health Equity Impact Assessment (HEIA) tool and an Indigenous Lens Tool supplement to evaluate potential impacts. Our results identify three major funding equity issues: unique health and service needs, socioeconomic disparities, and limited access to community and culturally safe health services. Despite efforts for equitable funding, a lack of meaningful consultation led to shortcomings, as seen in Canada’s state of emergency declaration and legal disputes in the United States. New Zealand stood out for integrating Māori perspectives, showcasing the importance of consultation. The study calls for a reconciliation-minded path, aligning with Truth and Reconciliation principles, the UN Declaration on the Rights of Indigenous Peoples, and evolving government support. The paper concludes that co-creating equitable funding policies grounded in Indigenous knowledge requires partnership, meaningful consultation, and organisational cultural humility. Even in emergencies, these measures ensure responsiveness and respect for Indigenous self-determination.

Introduction Second to motor vehicles, bicycles contribute to more childhood injuries than any other consumer product. Youth bicycling safety education programmes are one avenue of prevention, but despite a plethora of programmes, little is known about their impact on bicycling safety behaviour. This paper summarises a cluster-randomised trial to evaluate the impact of a bicycle safety education programme for young adolescents.Methods and analysis Adolescents aged 9–12 years old who bike at least two times per week and a parent/guardian are recruited via email listservs, flyers and word of mouth. Participants are screened for eligibility before they are consented/assented into the study. Adolescent-parent dyads are randomised to one of the three study arms (Control, Bike Club, Bike Club Plus) based on the school they attend. The Bike Club intervention arm evaluates the bicycle safety club programme and the Bike Club Plus intervention arm evaluates the addition of an active parent engagement component. Control group participants receive no intervention, but they are told that other participants in the study will receive the education intervention so that they understand why they are asked to record their bicycling trips for two separate weeks. The intervention involves 12 hours of classroom and on-bike lessons covering a variety of bike safety skills for independent riding in mixed traffic. Adolescents record their bike rides using a Global Positioning System (GPS)/video camera system for 2 weeks, 1 week before and 1 week after the education programme for participants in the intervention arms and approximately 1 month between data collection weeks for participants in the control group. All participants complete baseline and follow-up surveys. Primary outcomes include rates safety-relevant events (eg, crashes, near crashes) and safety behaviours (eg, helmet use, traffic law violations, hazard avoidance) per 100 miles/min ridden, and the proportion of positive and negative behaviours relative to the overall number of instances of a given event behaviour. Secondary outcomes include differences in knowledge test scores, mean ratings of perceptions, mean ratings of self-efficacy, and identification and recall of cues to action related to bicycling safety.Ethics and dissemination This study has ethical approval from the University of Iowa Institutional Review Board (IRB# 202105148). Study results will be disseminated through presentations at national and international scientific conferences, peer-reviewed manuscripts, outreach to stakeholders and digital media outlets.Trial registration number NCT05265689.

PurposeThe aims of this study were to evaluate and compare fibroblast activation protein (FAP) expression and localization in surgically resected cholangiocarcinoma (CCA), primary and metastatic hepatocellular carcinoma (HCC), hepatocellular adenoma (HCA), and focal nodular hyperplasia (FNH), and to identify any association between CCA clinical or pathologic features and FAP expression.Materials and methodsFAP immunostaining from surgically resected CCA (N = 58), primary intrahepatic and extrahepatic metastatic HCC (N = 148), HCA (N26), and FNH (N = 19) was scored (negative, weak positive, moderate positive or strong positive) from tissue microarrays. FAP expression was compared between groups. CCA FAP expression was compared to clinical and tumor pathology features.ResultsModerate-strong FAP expression in the tumor stroma was present in 93.1% of CCA, 60.7% of extrahepatic metastatic HCC, 29.6% of primary HCC, 21.1% of FNH, and 11.6% of HCA. Moderate-strong FAP expression in tumor stroma was significantly more prevalent in CCA than HCC (p 0.05, all).ConclusionFAP is expressed in the stroma of a high proportion (93%) of primary CCA independent of patient clinical or tumor pathology features. As such, these data provide the tissue basis for systematically evaluating FAP as a theranostic target across a broad range of CCA subtypes.

Introduction Buprenorphine is a highly effective treatment for opioid use disorder (OUD). However, provider observations and preliminary research suggest that the current standard maintenance dose may be insufficient for suppressing withdrawal and preventing cravings among people who use or have used fentanyl. Buprenorphine dosing guidelines were based on studies among people who use heroin and have not been formally re-evaluated since fentanyl became predominant in the unregulated drug supply. We aim to compare the effectiveness of a high (24 mg) vs standard (16 mg) maintenance daily dose of buprenorphine for improving retention in treatment, decreasing the use of non-prescribed opioids, preventing cravings and reducing opioid overdose risk in patients.Methods and analysis Adults who are initiating or continuing buprenorphine for moderate to severe OUD and have a recent history of fentanyl use (n=250) will be recruited at four outpatient substance use treatment clinics in Rhode Island. Patients continuing buprenorphine must be on doses of 16 mg or less and have ongoing fentanyl use to be eligible. Participants will be randomly assigned 1:1 to receive either a high (24 mg) or standard (16 mg) maintenance daily dose, each with usual care, and followed for 12 months to evaluate outcomes. Providers will determine the buprenorphine initiation strategy, with the requirement that participants reach the study maintenance dose within 7 days of randomisation. Providers may adjust the maintenance dose, if clinically needed, for participant safety. The primary study outcome is retention in buprenorphine treatment at 6 months postrandomisation, measured using clinical and statewide administrative data. Other outcomes include non-prescribed opioid use and opioid cravings (secondary), as well as non-fatal or fatal opioid overdose (exploratory).Ethics and dissemination This protocol was approved by the Brown Institutional Review Board (STUDY00000075). Results will be presented at conferences and published in peer-reviewed journals.Trial registration number NCT06316830.

Background: Psoriatic arthritis (PsA) is a chronic inflammatory disease that causes pain and fatigue, reduces physical function, and negatively impacts health-related quality of life (HRQoL). In the phase III BE OPTIMAL and BE COMPLETE studies, bimekizumab demonstrated clinical efficacy and meaningful improvements in patient-reported outcome (PRO) measures in biologic disease-modifying antirheumatic drug (bDMARD)-naïve patients, and those who had prior inadequate response/intolerance to tumor necrosis factor inhibitors (TNFi-IR). Objectives: To examine the association between achieving increasingly stringent clinical disease control criteria and improvements in PRO measures in patients with active PsA receiving bimekizumab. Design: Post hoc analysis of two phase III studies. Methods: BE OPTIMAL and BE COMPLETE assessed subcutaneous bimekizumab 160 mg every 4 weeks in bDMARD-naïve and TNFi-IR patients with active PsA. Disease control was assessed using American College of Rheumatology (ACR) response criteria, Minimal Disease Activity, Disease Activity Index for Psoriatic Arthritis, and the composite outcome of ACR50 and 100% improvement in Psoriasis Area and Severity Index. Associations between clinical disease control criteria and PRO measures of pain, fatigue, physical function, and HRQoL were assessed at week 16 and week 52/40 (BE OPTIMAL/BE COMPLETE). Results: Achievement of increasingly stringent clinical disease control criteria was generally associated with sequentially greater improvements in all PRO measures, including pain. At week 52/40, 94.7% of bDMARD-naïve and 97.6% of TNFi-IR patients achieving ACR70 reported ⩾50% improvements in pain from baseline, and the greatest numerical improvements (−48.5 bDMARD-naïve; −54.7 TNFi-IR). This pattern was evident as early as week 16 and sustained when assessed at week 52/40 across the majority of clinical disease control criteria and PRO measures reported. Conclusion: The achievement of increasingly stringent thresholds of disease control was associated with corresponding greater improvements in PROs, for patients receiving bimekizumab treatment, irrespective of prior TNFi use. Trial registration ClinicalTrials.gov: NCT03895203, NCT03896581, and NCT04009499.

Abstract Introduction We evaluated the impact of gender on disease severity, health-related quality of life (HRQoL), treatment management, and patient–healthcare professional (HCP) interactions from the perspectives of patients with psoriatic arthritis (PsA). Methods Data were collected from a global online patient survey conducted by The Harris Poll (November 2, 2017 to March 12, 2018). Eligible patients were aged ≥ 18 years, with a self-reported diagnosis of PsA for > 1 year, had visited a rheumatologist/dermatologist in the past 12 months, and had reported previously using ≥ 1 conventional synthetic or biologic disease-modifying antirheumatic drug. Data were stratified by gender and analyzed descriptively, inferentially by binomial (chi-square) tests, and by multivariate logistic regression models. Results Data from 1286 patients who participated were included: 52% were female, 48% were male. Varying perceptions of disease severity between males and females were indicated by differences in symptoms leading to a diagnosis of PsA, and in symptoms reported despite treatment; more females than males reported joint tenderness, skin patches/plaques, and enthesitis. More females than males reported a major/moderate impact of PsA on their physical activity and emotional/mental well-being. Reasons for switching medication differed between genders, with more females switching because they perceived their medication to not be effective enough related to their joint symptoms. More females than males were very satisfied with their communication with their rheumatologist and were more likely to discuss the impact of PsA on their daily lives, their treatment satisfaction, and treatment goals with their rheumatologist. Conclusions Patients’ perceptions of the impact of PsA on HRQoL, treatment management, and interactions with HCPs varied between males and females. More females than males reported major/moderate physical and emotional impacts of PsA. When treating patients, it is important for HCPs to consider the potential impact of gender on patients’ experience of PsA and its symptoms. Graphical plain language summary available for this article. Graphical Abstract

Resilience is defined as the maintenance or relatively quick recovery of mental health during and after adversity. Rather than focusing on psychopathology and its causes, resilience research aims to understand what protective mechanisms shield individuals against developing such disorders and translate these insights to improve psychosocial care. This resilience approach seems especially promising for the field of oncology because patients face stressor after stressor from diagnosis to survivorship. Helping patients to learn how they can best use the resources and abilities available to them can empower patients to handle subsequent stressors. In the past few decades, resilience has increasingly been considered as a dynamic process of adaptation. While researchers use this definition, resilience has not yet been studied as a dynamic process in the field of oncology. As a result, the potential of resilience research to gain insight into what helps protect cancer patients from developing psychopathology is limited. We discuss conceptual and methodological proposals to advance resilience research in oncology. Most importantly, we propose applying prospective longitudinal designs to capture the dynamic resilience process. By gaining insight in how cancer patients engage in protective factors, resilience research can come to its full potential and help prevent psychopathology.

Abstract Disparities in healthcare delivery and design are deeply-rooted within healthcare systems globally. Many researchers have developed methods to measure inequity; however, there currently exists no accepted measurement approach implemented consistently across health systems. We applied the model-based Relative Index of Inequality (RII) as a measure of inequity at one of Canada’s largest health systems, Trillium Health Partners, across two service types: planned and outpatient. Our RII estimates suggest that the lowest-SES individuals received planned and outpatient services at rates 2.4 times and 2.5 times lower than the highest-SES individuals, respectively. Across both service types, the largest disparity was for breast cancer screening, where patients from the lowest-SES neighbourhoods were 5.4 times less likely to use this service at THP. These findings further underscore the importance of consistently measuring and monitoring inequities to develop effective strategies to address the health needs of patients from lower SES neighbourhoods. The approach used within this study should be considered for widespread integration into health system reporting metrics.

Abstract Health inequalities amplified by the COVID-19 pandemic have disproportionately affected racialized and equity-deserving communities across Canada. In the Municipality of Peel, existing data, while limited, illustrates that individuals from racialized and equity-deserving communities continue to suffer, receive delayed care, and die prematurely. In response to these troubling statistics, grassroots community advocacy has called on health systems leaders in Peel to work with community and non-profit organizations to address the critical data and infrastructure gaps that hinder addressing the social determinants of health in the region. To support these advocacy efforts, we used a community-based participatory research approach to understand how we might build a data collection ecosystem across sectors, alongside community residents and service providers, to accurately capture the data about the social determinants of health. This approach involved developing a community engagement council, defining the problem with the community, mapping what data is actively collected and what is excluded, and understanding experiences of sociodemographic data collection from community members and service providers. Guided by community voices, our study focused on sociodemographic data collection in the primary care context and identified which service providers use and collect these data, how data are used in their work, the facilitators and barriers to data use and collection. Additionally, we gained insight into how sociodemographic data collection could be respectful, safe, and properly governed from the perspectives of community members. From this study, we identify a set of eight recommendations for sociodemographic data collection and highlight limitations. This foundational community-based work will inform future research in establishing data governance in partnership with diverse and equity-deserving communities.

Abstract The increasing incidence of oropharyngeal squamous cell carcinoma (OPSCC) is primarily due to human papillomavirus, and understanding the tumor biology caused by the virus is crucial. Our goal was to investigate the proteins present in the serum of patients with OPSCC, which were not previously studied in OPSCC tissue. We examined the difference in expression of these proteins between HPV-positive and -negative tumors and their correlation with clinicopathological parameters and patient survival. The study included 157 formalin-fixed, paraffin-embedded tissue samples and clinicopathological data. Based on the protein levels in the sera of OPSCC patients, we selected 12 proteins and studied their expression in HPV-negative and HPV-positive OPSCC cell lines. LRG1, SDR16C5, PIP4K2C and MVD proteins were selected for immunohistochemical analysis in HPV-positive and -negative OPSCC tissue samples. These protein´s expression levels were compared with clinicopathological parameters and patient survival to investigate their clinical relevance. LRG1 expression was strong in HPV-negative whereas SDR16C5 expression was strong in HPV-positive tumors. Correlation was observed between LRG1, SDR16C5, and PIP4K2C expression and patient survival. High expression of PIP4K2C was found to be an independent prognostic factor for overall survival and expression correlated with HPV-positive tumor status. The data suggest the possible role of LRG1, SDR16C5 and PIP4K2C in OPSCC biology.

Abstract Objective To compare how different imputation methods affect the estimates and performance of a prediction model for premature mortality. Study Design and Setting Sex-specific Weibull accelerated failure time survival models were run on four separate datasets using complete case, mode, single and multiple imputation to impute missing values. Six performance measures were compared to access predictive accuracy (Nagelkerke R2, integrated brier score), discrimination (Harrell’s c-index, discrimination slope) and calibration (calibration in the large, calibration slope). Results The highest proportion of missingness for a single variable was 10.86% for the female model and 8.24% for the male model. Comparing the performance measures for complete case, mode, single and multiple imputation: the Nagelkerke R2 values for the female model was 0.1084, 0.1116, 0.1120 and 0.111–0.1120 with the male model exhibited similar variation of 0.1050, 0.1078, 0.1078 and 0.1078–0.1081. Harrell’s c-index also demonstrated small variation with values of 0.8666, 0.8719, 0.8719 and 0.8711–0.8719 for the female model and 0.8549, 0.8548, 0.8550 and 0.8550–0.8553 for the male model. Conclusion In the scenarios examined in this study, mode imputation performed well when using a population health survey compared to single and multiple imputation when predictive performance measures is the main model goal. To generate unbiased hazard ratios, multiple imputation methods were superior. This study shows the need to consider the best imputation approach for a predictive model development given the conditions of missing data and the goals of the analysis.

Abstract Carboxy terminal fragments (CTFs) of TDP-43 contain an intrinsically disordered region (IDR) and form cytoplasmic condensates containing amyloid fibrils. Such condensates are toxic and associated with pathogenicity in amyotrophic lateral sclerosis. However, the molecular details of how the domain of TDP-43 CTFs leads to condensation and cytotoxicity remain elusive. Here, we show that truncated RNA/DNA-recognition motif (RRM) at the N-terminus of TDP-43 CTFs leads to the structural transition of the IDR, whereas the IDR itself of TDP-43 CTFs is difficult to assemble even if they are proximate intermolecularly. Hetero-oligomers of TDP-43 CTFs that have recruited other proteins are more toxic than homo-oligomers, implicating loss-of-function of the endogenous proteins by such oligomers is associated with cytotoxicity. Furthermore, such toxicity of TDP-43 CTFs was cell-nonautonomously affected in the nematodes. Therefore, misfolding and oligomeric characteristics of the truncated RRM at the N-terminus of TDP-43 CTFs define their condensation properties and toxicity.

Abstract Background Global progress on malaria control has stalled recently, partly due to challenges in universal access to malaria diagnosis and treatment. Community health workers (CHWs) can play a key role in improving access to malaria care for children under 5 years (CU5), but national policies rarely permit them to treat older individuals. We conducted a two-arm cluster randomized trial in rural Madagascar to assess the impact of expanding malaria community case management (mCCM) to all ages on health care access and use. Methods Thirty health centers and their associated CHWs in Farafangana District were randomized 1:1 to mCCM for all ages (intervention) or mCCM for CU5 only (control). Both arms were supported with CHW trainings on malaria case management, community sensitization on free malaria care, monthly supervision of CHWs, and reinforcement of the malaria supply chain. Cross-sectional household surveys in approximately 1600 households were conducted at baseline (Nov–Dec 2019) and endline (Nov–Dec 2021). Monthly data were collected from health center and CHW registers for 36 months (2019–2021). Intervention impact was assessed via difference-in-differences analyses for survey data and interrupted time-series analyses for health system data. Results Rates of care-seeking for fever and malaria diagnosis nearly tripled in both arms (from less than 25% to over 60%), driven mostly by increases in CHW care. Age-expanded mCCM yielded additional improvements for individuals over 5 years in the intervention arm (rate ratio for RDTs done in 6–13-year-olds, RRRDT6–13 years = 1.65; 95% CIs 1.45–1.87), but increases were significant only in health system data analyses. Age-expanded mCCM was associated with larger increases for populations living further from health centers (RRRDT6–13 years = 1.21 per km; 95% CIs 1.19–1.23). Conclusions Expanding mCCM to all ages can improve universal access to malaria diagnosis and treatment. In addition, strengthening supply chain systems can achieve significant improvements even in the absence of age-expanded mCCM. Trial registration The trial was registered at the Pan-African Clinical Trials Registry (#PACTR202001907367187).

Abstract The objective of this study is to use statistical techniques for the identification of transition points along the life course, aiming to identify fundamental changes in patient multimorbidity burden across phases of clinical care. This retrospective cohort analysis utilized 5.2 million patient encounters from 2013 to 2022, collected from a large academic institution and its affiliated hospitals. Structured information was systematically gathered for each encounter and three methodologies - clustering analysis, False Nearest Neighbor, and transitivity analysis - were employed to pinpoint transitions in patients’ clinical phase. Clustering analysis identified transition points at age 2, 17, 41, and 66, FNN at 4.27, 5.83, 5.85, 14.12, 20.62, 24.30, 25.10, 29.08, 33.12, 35.7, 38.69, 55.66, 70.03, and transitivity analysis at 7.27, 23.58, 29.04, 35.00, 61.29, 67.03, 77.11. Clustering analysis identified transition points that align with the current clinical gestalt of pediatric, adult, and geriatric phases of care. Notably, over half of the transition points identified by FNN and transitivity analysis were between ages 20 and 40, a population that is traditionally considered to be clinically homogeneous. Few transition points were identified between ages 3 and 17. Despite large social and developmental transition at those ages, the burden of multimorbidities may be consistent across the age range. Transition points derived through unsupervised machine learning approaches identify changes in the clinical phase that align with true differences in underlying multimorbidity burden. These transitions may be different from conventional pediatric and geriatric phases, which are often influenced by policy rather than clinical changes.