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This article interrogates the scientific conference as a means by which the organizers of the World League for Sexual Reform's 1929 conference attempted to marshal the 'scientific spirit' in order to present progressive sexual reform as a rational and scientifically informed undertaking. The conference was carefully curated to make the sex reform movement (and the assorted characters that gathered under its banner) look serious, legitimate and, most importantly, scientific. The conference was also an attempt by organizer Norman Haire to exert control over the strategy of sexology, an enterprise that put him at odds with other prominent sexologists of the time. Crucially, Haire understood sexology as inherently intellectually interdisciplinary, but was strategically convinced that the only sound rubric through which to promote and gain acceptance for the movement was through medical science. This central debate, about how best to define the contested concept of sexology, continues among historians today. By examining how the 1929 conference organizers wrestled to define their sex-reforming remit and how they curated the conference to that end, this paper will offer a window onto the mechanisms via which adherents of intellectual communities contend with heterogeneity, how we judge forms of knowledge and, ultimately, what constitutes science.

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 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.

Objective To evaluate the relationship between infarct pattern, inferred stroke mechanism and risk of recurrence in patients with ischaemic stroke. The question is clinically relevant to optimise secondary stroke prevention investigations and treatment.Design We conducted a retrospective analysis of the dabigatran treatment of acute stroke II (DATAS II) trial (ClinicalTrials.gove NCT NCT02295826), in which patients underwent diffusion-weighted imaging (DWI) at baseline and 30 days after randomisation to one of two antithrombotic therapies. Patients were classified as embolic, isolated small subcortical infarcts or transient ischaemic attack TIA (no infarct) at baseline and day 30. Stroke mechanism was determined by traditional and modified (based on DWI lesion findings) Trial of Org 10 172 in Acute Stroke Treatment (TOAST) criteria (DWI-TOAST).Setting Multicentre (6) tertiary acute stroke treatment hospitals.Participants 305 adults with minor ischaemic stroke (National Institutes of Health Stroke Scale (NIHSS) score≤9).Results Of 305 patients, 148 had embolic pattern infarcts, 93 were isolated small subcortical infarcts and 64 had no infarct on baseline MRI (TIA). In the absence of DWI, TOAST classification indicated the mechanism was cryptogenic in 147 patients (48.2%), and small-vessel occlusion in 127 (41.6%). Using, DWI-TOAST, the number of cryptogenic strokes decreased to 123 (40.3%), and the number of small-vessel occlusion strokes increased to 151 (49.5%). Recurrent infarcts were seen in 13% of patients with an MRI-defined embolic infarct pattern and cryptogenic mechanism on DWI-TOAST. The relative risk of recurrent infarction in patients with undetermined aetiology was increased compared with other categories (standardised coefficient=1.0 (0.1, 1.9), p=0.029). The topography of recurrent infarcts was most often embolic (60.9%), but in 39.1% an isolated small subcortical infarct was seen.Conclusions Definitive identification of infarct topography with DWI has a significant impact on infarct mechanism classification. The variable relationship between baseline infarct patterns, clinical presentation and recurrent infarct distribution is a challenge to both the lacunar and embolic stroke of uncertain source (ESUS) concepts. Irrespective of aetiological classification, patients with MRI-defined cryptogenic embolic pattern infarcts are at high risk for recurrent events.Trial registration number Linked to the DATAS II trial. ClinicalTrials.gov ID NCT02295826.

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.

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.

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.

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.

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 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.

Rationale and objective Disease-specific health-related quality of life (HRQOL) instruments enable us to capture domains that are most relevant to specific patient populations and are useful when a more individualised approach to patient assessment is desired. In this study, we assessed the validity and reliability of the first instrument specifically developed to measure HRQOL in hypersensitivity pneumonitis (HP). Methods A 39-item HP-HRQOL instrument and several anchors were collected from a cohort of patients with HP. Exploratory factor analysis and item reduction were utilised to construct a shortened version of the instrument. Several validity and reliability analyses were conducted on this version of the HP-HRQOL. Measurements and main results 59 patients with HP completed the study. The revised HP-HRQOL instrument comprises 15 items composing two factors (domains): 1) impacts on daily life; and 2) mental wellbeing. Internal consistency reliability was strong for Factor 1 (Cronbach's α=0.94, 95% CI 0.92–0.96) and Factor 2 (Cronbach's α=0.89, 95% CI 0.85–0.94). Test–retest reliability was strong (ICC 0.94, 95% CI 0.89–0.97). The HP-HRQOL strongly correlated with other validated patient-reported outcome measures and moderately correlated with % predicted forced vital capacity. The HP-HRQOL distinguished between those with different severities of HP as determined by lung function and supplemental oxygen use. Conclusions The HP-HRQOL, the first patient-reported outcome instrument specific to adults with HP, possesses strong validity and reliability characteristics for measuring disease-specific HRQOL and distinguishes among patients with different severities of disease.

Abstract The invasive brown widow spider, Latrodectus geometricus (Araneae: Theridiidae), has spread in multiple locations around the world and, along with it, brought associated organisms such as endosymbionts. We investigated endosymbiont diversity and prevalence across putative native and invasive populations of this spider, predicting lower endosymbiont diversity across the invasive range compared to the native range. First, we characterized the microbial community in the putative native (South Africa) and invasive (Israel and the United States) ranges via high throughput 16S sequencing of 103 adult females. All specimens were dominated by reads from only 1–3 amplicon sequence variants (ASV), and most individuals were infected with an apparently uniform strain of Rhabdochlamydia. We also found Rhabdochlamydia in spider eggs, indicating that it is a maternally-inherited endosymbiont. Relatively few other ASV were detected, but included two variant Rhabdochlamydia strains and several Wolbachia, Spiroplasma and Enterobacteriaceae strains. We then diagnostically screened 118 adult female spiders from native and invasive populations specifically for Rhabdochlamydia and Wolbachia. We found Rhabdochlamydia in 86% of individuals and represented in all populations, which suggests that it is a consistent and potentially important associate of L. geometricus. Wolbachia was found at lower overall prevalence (14%) and was represented in all countries, but not all populations. In addition, we found evidence for geographic variation in endosymbiont prevalence: spiders from Israel were more likely to carry Rhabdochlamydia than those from the US and South Africa, and Wolbachia was geographically clustered in both Israel and South Africa. Characterizing endosymbiont prevalence and diversity is a first step in understanding their function inside the host and may shed light on the process of spread and population variability in cosmopolitan invasive species.

Abstract Background Tumor regression following immune checkpoint blockade (ICB) is often associated with immune-related adverse events (irAEs), marked by inflammation in non-cancerous tissues. This study was undertaken to investigate the functional relationship between anti-tumor and anti-self immunity, to facilitate irAE management while promoting anti-tumor immunity. Methods Multiple biopsies from tumor and inflamed tissues were collected from a patient with melanoma experiencing both tumor regression and irAEs on ICB, who underwent rapid autopsy. Immune cells infiltrating melanoma lesions and inflamed normal tissues were subjected to gene expression profiling with multiplex qRT-PCR for 122 candidate genes. Subsequently, immunohistochemistry was conducted to assess the expression of 14 candidate markers of immune cell subsets and checkpoints. TCR-beta sequencing was used to explore T cell clonal repertoires across specimens. Results While genes involved in MHC I/II antigen presentation, IFN signaling, innate immunity and immunosuppression were abundantly expressed across specimens, irAE tissues over-expressed certain genes associated with immunosuppression (CSF1R, IL10RA, IL27/EBI3, FOXP3, KLRG1, SOCS1, TGFB1), including those in the COX-2/PGE2 pathway (IL1B, PTGER1/EP1 and PTGER4/EP4). Immunohistochemistry revealed similar proportions of immunosuppressive cell subsets and checkpoint molecules across samples. TCRseq did not indicate common TCR repertoires across tumor and inflammation sites, arguing against shared antigen recognition between anti-tumor and anti-self immunity in this patient. Conclusions This comprehensive study of a single patient with melanoma experiencing both tumor regression and irAEs on ICB explores the immune landscape across these tissues, revealing similarities between anti-tumor and anti-self immunity. Further, it highlights expression of the COX-2/PGE2 pathway, which is known to be immunosuppressive and potentially mediates ICB resistance. Ongoing clinical trials of COX-2/PGE2 pathway inhibitors targeting the major COX-2 inducer IL-1B, COX-2 itself, or the PGE2 receptors EP2 and EP4 present new opportunities to promote anti-tumor activity, but may also have the potential to enhance the severity of ICB-induced irAEs.

Abstract Organisms vary in the timing of energy acquisition and use for reproduction. Thus, breeding strategies exist on a continuum, from capital breeding to income breeding. Capital breeders acquire and store energy for breeding before the start of the reproductive season, while income breeders finance reproduction using energy acquired during the reproductive season. Latitude and its associated environmental drivers are expected to heavily influence breeding strategy, potentially leading to latitudinal variation in breeding strategies within a single species. We examined the breeding strategy of the Asian shore crab Hemigrapsus sanguineus at five sites spanning nearly 10° of latitude across its invaded United States range. We hypothesized that the primary breeding strategy of this species would shift from income breeding to capital breeding as latitude increases. We found that though this species’ breeding strategy is dominated by capital breeding throughout much of the range, income breeding increases in importance at lower latitudes. This latitudinal pattern is likely heavily influenced by the duration of the foraging and breeding seasons, which also vary with latitude. We also found that reproductive characteristics at the northern and southern edges of the invaded range were consistent with continued range expansion. We suggest that the reproductive flexibility of the Asian shore crab is a key facilitator of its continued invasion success. Our results highlight the influence of latitude on the breeding strategy of a species and emphasize the need for further research regarding the ecological importance and implications of flexibility in breeding strategies within species.

Abstract South Africans living in low socioeconomic areas have self-reported unusually long sleep durations (approximately 9–10 h). One hypothesis is that these long durations may be a compensatory response to poor sleep quality as a result of stressful environments. This study aimed to investigate whether fear of not being safe during sleep is associated with markers of sleep quality or duration in men and women. South Africans (n = 411, 25–50 y, 57% women) of African-origin living in an urban township, characterised by high crime and poverty rates, participated in this study. Participants are part of a larger longitudinal cohort study: Modelling the Epidemiologic Transition Study (METS)–Microbiome. Customised questions were used to assess the presence or absence of fears related to feeling safe during sleep, and the Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index were used to assess daytime sleepiness, sleep quality and insomnia symptom severity respectively. Adjusted logistic regression models indicated that participants who reported fears related to safety during sleep were more likely to report poor sleep quality (PSQI > 5) compared to participants not reporting such fears and that this relationship was stronger among men than women. This is one of the first studies outside American or European populations to suggest that poor quality sleep is associated with fear of personal safety in low-SES South African adults.

Objectives Long-term sickness absence from employment has negative consequences for the economy and can lead to widened health inequalities. Sick notes (also called ‘fit notes’) are issued by general practitioners when a person cannot work for health reasons for more than 7 days. We quantified the sick note rate in people with evidence of COVID-19 in 2020, 2021 and 2022, as an indication of the burden for people recovering from COVID-19.Design Cohort study.Setting With National Health Service (NHS) England approval, we used routine clinical data (primary care, hospital and COVID-19 testing records) within the OpenSAFELY-TPP database.Participants People 18–64 years with a recorded positive test or diagnosis of COVID-19 in 2020 (n=365 421), 2021 (n=1 206 555) or 2022 (n=1 321 313); general population matched in age, sex and region in 2019 (n=3 140 326), 2020 (n=3 439 534), 2021 (n=4 571 469) and 2022 (n=4 818 870); people hospitalised with pneumonia in 2019 (n=29 673).Primary outcome measure Receipt of a sick note in primary care.Results Among people with a positive SARS-CoV-2 test or COVID-19 diagnosis, the sick note rate was 4.88 per 100 person-months (95% CI 4.83 to 4.93) in 2020, 2.66 (95% CI 2.64 to 2.67) in 2021 and 1.73 (95% CI 1.72 to 1.73) in 2022. Compared with the age, sex and region-matched general population, the adjusted HR for receipt of a sick note over the entire follow-up period (up to 10 months) was 4.07 (95% CI 4.02 to 4.12) in 2020 decreasing to 1.57 (95% CI 1.56 to 1.58) in 2022. The HR was highest in the first 30 days postdiagnosis in all years. Among people hospitalised with COVID-19, after adjustment, the sick note rate was lower than in people hospitalised with pneumonia.Conclusions Given the under-recording of postacute COVID-19-related symptoms, these findings contribute a valuable perspective on the long-term effects of COVID-19. Despite likely underestimation of the sick note rate, sick notes were issued more frequently to people with COVID-19 compared with those without, even in an era when most people are vaccinated. Most sick notes occurred in the first 30 days postdiagnosis, but the increased risk several months postdiagnosis may provide further evidence of the long-term impact.

Slaughterhouses are hotspots for the transmission of antimicrobial-resistant pathogens. We conducted stakeholder discussions on antimicrobial-resistant pathogens within the slaughterhouse setting. Butchers were described as powerful stakeholders; challenges included limited funding and staff, inadequate infrastructure, and limited laboratory capacity. Slaughterhouse workers understood that their work increased their risk for exposure.

Abstract Early detection of atrial fibrillation (AF) enables initiation of anticoagulation and early rhythm control therapy to reduce stroke, cardiovascular death, and heart failure. In a cross-sectional, observational study, we aimed to identify a combination of circulating biomolecules reflecting different biological processes to detect prevalent AF in patients with cardiovascular conditions presenting to hospital. Twelve biomarkers identified by reviewing literature and patents were quantified on a high-precision, high-throughput platform in 1485 consecutive patients with cardiovascular conditions (median age 69 years [Q1, Q3 60, 78]; 60% male). Patients had either known AF (45%) or AF ruled out by 7-day ECG-monitoring. Logistic regression with backward elimination and a neural network approach considering 7 key clinical characteristics and 12 biomarker concentrations were applied to a randomly sampled discovery cohort (n = 933) and validated in the remaining patients (n = 552). In addition to age, sex, and body mass index (BMI), BMP10, ANGPT2, and FGF23 identified patients with prevalent AF (AUC 0.743 [95% CI 0.712, 0.775]). These circulating biomolecules represent distinct pathways associated with atrial cardiomyopathy and AF. Neural networks identified the same variables as the regression-based approach. The validation using regression yielded an AUC of 0.719 (95% CI 0.677, 0.762), corroborated using deep neural networks (AUC 0.784 [95% CI 0.745, 0.822]). Age, sex, BMI and three circulating biomolecules (BMP10, ANGPT2, FGF23) are associated with prevalent AF in unselected patients presenting to hospital. Findings should be externally validated. Results suggest that age and different disease processes approximated by these three biomolecules contribute to AF in patients. Our findings have the potential to improve screening programs for AF after external validation.

Introduction. For over a century, Sporothrix schenckii was considered the sole species responsible for sporotrichosis. In 2007, scientific community confirmed the disease could be caused by various Sporothrix species. These species differed in their virulence factors and their antifungal sensitivity. Objective. This study aims to characterize 42 Colombian clinical isolates of Sporothrix spp. phenotypically and genotypically. Material and methods. Forty-two clinical isolates were characterized using phenotypic methods. It involved various culture media to determine their growth range at different temperatures and to assess the type and distribution of pigment and colony texture. Microscopic morphology was evaluated through microcultures, as well as the conidia diameter, type of sporulation, and morphology. Additionally, the assimilation of carbohydrates was selected as a physiological trait for species identification. Genotyping of 40 isolates was performed through partial amplification of the calmodulin gene, followed by sequence analysis. Results. Molecular studies enabled the identification of 32 isolates of S. schenckii and 8 isolates of S. globosa. The combination of phenotypic and genotypic methods eased these species characterizations and the recognition keys development based on parameters such as growth diameter at 25 and 30 ºC, colony texture (membranous or velvety) on potato dextrose agar, and microscopic morphology with predominance of pigmented triangular, elongated oval globose, or subglobose conidia. Conclusions. Confirmation of the phenotypic characteristics and molecular analysis is crucial for identifying Sporothrix species and determining adequate treatment. This study represents the first phenotypical and genotypical characterization of clinical isolates of Sporothrix spp. reported in Colombia.

Abstract Background Tuberous sclerosis complex (TSC) is a rare and complex genetic disorder, associated with tumor growth in various organ systems, epilepsy, and a range of neuropsychiatric manifestations including intellectual disability. With improving patient-centered care and targeted therapies, patient-reported outcome measures (PROMs) are needed to measure the impact of TSC manifestations on daily functioning. The aim of this study was to develop a TSC-specific PROM for adults that captures the impact of TSC on physical functions, mental functions, activity and participation, and the social support individuals with TSC receive, called the TSC-PROM. Methods COSMIN methodology was used to develop a self-reported and proxy-reported version. Development and validation consisted of the following studies: PROM development, content validity, structural validity, internal consistency, and construct validity. The International Classification of Functioning and Disability was used as a framework. Content validity was examined by a multidisciplinary expert group and cognitive interview study. Structural and construct validity, and internal consistency were examined in a large cohort, using confirmatory factor analysis, hypotheses testing, and Cronbach’s alpha. Results The study resulted in an 82-item self version and 75-item proxy version of the TSC-PROM with four subscales (physical functions 18 and 19 items, mental functions 37 and 28 items, activities and participation 13 and 14 items, social support 13 items, for self version and proxy version respectively). Sufficient results were found for structural validity with sufficient unidimensionality for each subscale. With regard to construct validity, 82% of the hypotheses were met for the self version and 59% for the proxy version. The PROM showed good internal consistency (Cronbach’s alpha 0.78–0.97). Conclusions We developed a PROM for adults with TSC, named TSC-PROM, showing sufficient evidence for reliability and validity that can be used in clinical and research settings to systematically gain insight into their experiences. It is the first PROM in TSC that addresses the impact of specific TSC manifestations on functioning, providing a valuable, patient-centered addition to the current clinical outcomes.

BackgroundType 2 diabetes disproportionately affects South Asian subgroups. Lifestyle prevention programs help prevent and manage diabetes; however, there is a need to tailor these programs for mobile health (mHealth). ObjectiveThis study examined technology access, current use, and preferences for health communication among South Asian immigrants diagnosed with or at risk for diabetes, overall and by sex. We examined factors associated with interest in receiving diabetes information by (1) text message, (2) online (videos, voice notes, online forums), and (3) none or skipped, adjusting for sociodemographic characteristics and technology access. MethodsWe used baseline data collected in 2019-2021 from two clinical trials among South Asian immigrants in New York City (NYC), with one trial focused on diabetes prevention and the other focused on diabetes management. Descriptive statistics were used to examine overall and sex-stratified impacts of sociodemographics on technology use. Overall logistic regression was used to examine the preference for diabetes information by text message, online (videos, voice notes, or forums), and no interest/skipped response. ResultsThe overall sample (N=816) had a mean age of 51.8 years (SD 11.0), and was mostly female (462/816, 56.6%), married (756/816, 92.6%), with below high school education (476/816, 58.3%) and limited English proficiency (731/816, 89.6%). Most participants had a smartphone (611/816, 74.9%) and reported interest in receiving diabetes information via text message (609/816, 74.6%). Compared to male participants, female participants were significantly less likely to own smartphones (317/462, 68.6% vs 294/354, 83.1%) or use social media apps (Viber: 102/462, 22.1% vs 111/354, 31.4%; WhatsApp: 279/462, 60.4% vs 255/354, 72.0%; Facebook: Messenger 72/462, 15.6% vs 150/354, 42.4%). A preference for receiving diabetes information via text messaging was associated with male sex (adjusted odds ratio [AOR] 1.63, 95% CI 1.01-2.55; P=.04), current unemployment (AOR 1.62, 95% CI 1.03-2.53; P=.04), above high school education (AOR 2.17, 95% CI 1.41-3.32; P

Objective Many clinically extremely vulnerable rheumatology patients have only recently ceased shielding from COVID-19, while some continue to minimise in-person contact. The objective of this study was to understand the impact of shielding and associated support needs in patients with rheumatic conditions and to understand how rheumatology teams can meet these needs both currently and in future pandemics.Design, participants and setting The study was conducted in the Southwest of England using a case-study design. The participants were 15 patients with rheumatic conditions who were advised to shield and/or chose to shield at any time during the COVID-19 pandemic.Methods Qualitative data collected via telephone and online semi-structured interviews and analysed using reflexive thematic analysis.Results Fifteen interviews were conducted. Three main themes represent the data:‘Just shove them over there in the corner’ captures changes in patients’ self-perception. They felt different to most other people, vulnerable and left behind. The initial sense of shock was followed by a sense of loss as changes became long term.‘A long and lonely road’ captures patients’ psychological isolation due to a perceived lack of understanding and support. This included having to prove their health status and justify their shielding behaviours, which impacted their relationships. At times, they felt abandoned by their healthcare providers.‘You can’t just flip a switch’ captures the difficulty of getting back to pre-pandemic normal after shielding. Patients did not recognise themselves physically and mentally. They wanted to collaborate with health professionals and identified the need for specific guidance to support their recovery.Conclusion Patients are dealing with lasting physical and mental effects from shielding and consequences of delayed healthcare. Health professionals need time and resources to ask about patients’ well-being, identify their health needs and refer/signpost to appropriate sources of support.

Objectives To investigate psychometric performance of the 12-item Psoriatic Arthritis Impact of Disease (PsAID-12) total and individual item scores in patients with psoriatic arthritis (PsA) and to estimate score change thresholds and scores corresponding to different levels of symptom/impact severity.Methods Data up to week 16 from 1252 patients with active PsA enrolled in two randomised controlled trials of bimekizumab (BE OPTIMAL (NCT03895203) and BE COMPLETE (NCT03896581)) were used to assess construct validity (correlations with other patient-reported outcomes), known-groups validity (based on Minimal Disease Activity index, Disease Activity Index for Psoriatic Arthritis and Psoriatic Arthritis Disease Activity Score), reliability (Cronbach’s alpha and intraclass correlation coefficients (ICCs)) and responsiveness (sensitivity to change). Clinically meaningful within-patient improvement thresholds were estimated by anchor-based and distribution-based analyses, and symptom/impact severity thresholds were estimated by receiver operating characteristic curve analyses.Results The mean (SD) PsAID-12 total score at baseline was 4.19 (1.94). PsAID-12 scores demonstrated good convergent validity and good known-groups validity. Internal consistency reliability (Cronbach’s alpha 0.95) and test–retest reliability (ICC ≥ 0.70) were also good. Responsiveness was acceptable (correlations ≥0.30 for most scores). Improvement thresholds were estimated at 1.5–2 points for the PsAID-12 total score and 2 or 3 points for item scores. Thresholds for different levels of symptom/impact severity could be derived for most PsAID-12 items.Conclusions The PsAID-12 demonstrated robust psychometric properties in a large sample of patients with active PsA, supporting its use as a fit-for-purpose patient-reported outcome in this population. Furthermore, thresholds for score interpretation were derived.

Objective Evaluate long-term guselkumab effectiveness across Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)-recognised domains/related conditions of psoriatic arthritis (PsA).Methods Post hoc analyses used data from DISCOVER-2 (NCT03158285) biologic/Janus-kinase inhibitor-naïve participants with active PsA (≥5 swollen/≥5 tender joints, C-reactive protein ≥0.6 mg/dL), randomised (1:1:1) to guselkumab every 4 or 8 weeks (Q4W/Q8W) or placebo with crossover to guselkumab. Outcomes aligned with key GRAPPA-recognised domains of overall disease activity, peripheral arthritis, axial disease, enthesitis/dactylitis and skin psoriasis (nail psoriasis was not evaluated). PsA-related conditions (inflammatory bowel disease (IBD)/uveitis) were assessed via adverse events through W112. Least squares mean changes from baseline through W100 in continuous outcomes employed repeated measures mixed-effects models adjusting for baseline scores. Binary measure response rates were determined with non-responder imputation for missing data.Results 442/493 (90%) of guselkumab-randomised patients completed treatment through W100. Following early reductions in disease activity with guselkumab, durable improvements were observed across key PsA domains (swollen/tender joints, psoriasis, spinal pain, enthesitis/dactylitis) through W100. Response rates of therapeutically relevant targets generally increased through W100 with guselkumab Q4W/Q8W: Disease Activity Index for PsA low disease activity (LDA) 62%/59%, enthesitis resolution 61%/70%, dactylitis resolution 72%/83%, 100% improvement in Psoriasis Area and Severity Index 59%/53%, Psoriatic Arthritis Disease Activity Score LDA 51%/49% and minimal disease activity 38%/40%. Through W112, no cases of IBD developed among guselkumab-randomised patients and one case of uveitis was reported.Conclusion In biologic-naïve patients with active PsA, guselkumab provided early and durable improvements in key GRAPPA-recognised domains through 2 years, with substantial proportions achieving important treatment targets.

Objectives To assess 52-week safety and efficacy of bimekizumab in patients with active psoriatic arthritis (PsA) and prior inadequate response/intolerance to tumour necrosis factor inhibitors.Methods Patients completing the 16-week phase III double-blind, placebo-controlled BE COMPLETE (NCT03896581) study entered the open-label extension, BE VITAL (NCT04009499). All patients in BE VITAL received 160 mg bimekizumab every 4 weeks. Safety and efficacy are reported to week 52.Results A total of 347/400 (86.8%) patients completed week 52. To week 52, the exposure-adjusted incidence rate/100 patient-years for ≥1 treatment-emergent adverse event (TEAE) was 126.0, and was 7.0 for serious TEAEs. The most frequent TEAEs were SARS-CoV-2 (COVID-19), oral candidiasis, nasopharyngitis and urinary tract infection. All fungal infections were mild or moderate in severity and localised; two patients discontinued the study due to oral candidiasis. No cases of active tuberculosis, uveitis or inflammatory bowel disease were reported. One sudden death occurred. Sustained efficacy was observed with bimekizumab from week 16 to ‍52 across clinical and patient-reported outcomes. At week 52, 51.7% bimekizumab-randomised and 40.6% placebo/bimekizumab patients (receiving bimekizumab from week 16 to 52) had ≥50% improvement in the American College of Rheumatology criteria. Complete skin clearance (Psoriasis Area and Severity Index 100) was achieved by 65.9% bimekizumab and 60.2% placebo/bimekizumab patients at week 52. Minimal disease activity was achieved by 47.2% bimekizumab and 33.1% placebo/bimekizumab patients at week 52.Conclusions Bimekizumab demonstrated a safety profile consistent with previous reports; no new safety signals were identified. Sustained efficacy was observed from week 16 to 52.

Abstract Functional lung imaging modalities such as hyperpolarized gas MRI ventilation enable visualization and quantification of regional lung ventilation; however, these techniques require specialized equipment and exogenous contrast, limiting clinical adoption. Physiologically-informed techniques to map proton (1H)-MRI ventilation have been proposed. These approaches have demonstrated moderate correlation with hyperpolarized gas MRI. Recently, deep learning (DL) has been used for image synthesis applications, including functional lung image synthesis. Here, we propose a 3D multi-channel convolutional neural network that employs physiologically-informed ventilation mapping and multi-inflation structural 1H-MRI to synthesize 3D ventilation surrogates (PhysVENeT). The dataset comprised paired inspiratory and expiratory 1H-MRI scans and corresponding hyperpolarized gas MRI scans from 170 participants with various pulmonary pathologies. We performed fivefold cross-validation on 150 of these participants and used 20 participants with a previously unseen pathology (post COVID-19) for external validation. Synthetic ventilation surrogates were evaluated using voxel-wise correlation and structural similarity metrics; the proposed PhysVENeT framework significantly outperformed conventional 1H-MRI ventilation mapping and other DL approaches which did not utilize structural imaging and ventilation mapping. PhysVENeT can accurately reflect ventilation defects and exhibits minimal overfitting on external validation data compared to DL approaches that do not integrate physiologically-informed mapping.

Abstract The Japanese rhinoceros beetle Trypoxylus dichotomus is a giant beetle with distinctive exaggerated horns present on the head and prothoracic regions of the male. T. dichotomus has been used as a research model in various fields such as evolutionary developmental biology, ecology, ethology, biomimetics, and drug discovery. In this study, de novo assembly of 615 Mb, representing 80% of the genome estimated by flow cytometry, was obtained using the 10 × Chromium platform. The scaffold N50 length of the genome assembly was 8.02 Mb, with repetitive elements predicted to comprise 49.5% of the assembly. In total, 23,987 protein-coding genes were predicted in the genome. In addition, de novo assembly of the mitochondrial genome yielded a contig of 20,217 bp. We also analyzed the transcriptome by generating 16 RNA-seq libraries from a variety of tissues of both sexes and developmental stages, which allowed us to identify 13 co-expressed gene modules. We focused on the genes related to horn formation and obtained new insights into the evolution of the gene repertoire and sexual dimorphism as exemplified by the sex-specific splicing pattern of the doublesex gene. This genomic information will be an excellent resource for further functional and evolutionary analyses, including the evolutionary origin and genetic regulation of beetle horns and the molecular mechanisms underlying sexual dimorphism.

Porcine reproductive and respiratory syndrome (PRRS) remains a formidable challenge for the global pig industry. Caused by PRRS virus (PRRSV), this disease primarily affects porcine reproductive and respiratory systems, undermining effective host interferon and other immune responses, resulting in vaccine ineffectiveness. In the absence of specific antiviral treatments for PRRSV, vaccines play a crucial role in managing the disease. The current market features a range of vaccine technologies, including live, inactivated, subunit, DNA, and vector vaccines, but only modified live virus (MLV) and killed virus (KV) vaccines are commercially available for PRRS control. Live vaccines are promoted for their enhanced protective effectiveness, although their ability to provide cross-protection is modest. On the other hand, inactivated vaccines are emphasized for their safety profile but are limited in their protective efficacy. This review updates the current knowledge on PRRS vaccines’ interactions with the host interferon system, and other immunological aspects, to assess their current status and evaluate advents in PRRSV vaccine development. It presents the strengths and weaknesses of both live attenuated and inactivated vaccines in the prevention and management of PRRS, aiming to inspire the development of innovative strategies and technologies for the next generation of PRRS vaccines.

The environmental tenacity of influenza A viruses (IAVs) in the environment likely plays a role in their transmission; IAVs are able to remain infectious in aquatic habitats and may have the capacity to seed outbreaks when susceptible wild bird hosts utilize these same environments months or even seasons later. Here, we aimed to assess the persistence of low-pathogenicity IAVs from naturally infected ducks in Northwestern Minnesota through a field experiment. Viral infectivity was measured using replicate samples maintained in distilled water in a laboratory setting as well as in filtered water from four natural water bodies maintained in steel perforated drums (hereafter, mesocosms) within the field from autumn 2020 to spring 2021. There was limited evidence for the extended persistence of IAVs held in mesocosms; from 65 initial IAV-positive samples, only six IAVs persisted to at least 202 days in the mesocosms compared to 17 viruses persisting at least this long when held under temperature-controlled laboratory settings in distilled water. When accounting for the initial titer of samples, viruses detected at a higher concentration at the initiation of the experiment persisted longer than those with a lower starting titer. A parallel experimental laboratory model was used to further explore the effects of water type on viral persistence, and the results supported the finding of reduced tenacity of IAVs held in mesocosms compared to distilled water. The results of this investigation provide evidence that many factors, including temperature and physicochemical properties, impact the duration of viral infectivity in natural settings, further extending our understanding of the potential and limitations of environmental-based methodologies to recover infectious IAVs.

IntroductionHistorically, university students demonstrate poor movement behaviours that could negatively impact current and future health. Recent literature has focused on identifying determinants of physical activity (PA) and sedentary behaviour (SB) in this population to inform the development of intervention strategies. However, the COVID-19 pandemic substantially restricted movement behaviours in this population, meaning findings of previous research may no longer be applicable within the current societal context. The present study explored the longitudinal relationships between pre-pandemic psychological, behavioural and anthropometric factors, and the movement behaviours of UK university students nine months following the outbreak of COVID-19.MethodsMental wellbeing (MWB), perceived stress (PS), body mass index (BMI), SB, and PA were assessed using an online self-report survey in 255 students prior to (October 2019) and nine months following (October 2020) the first confirmed case of COVID-19 in the UK. Path analysis was utilised to test relationships between pre-COVID mental wellbeing, perceived stress and BMI, and movement behaviours during the pandemic.ResultsThe fit of the path analysis model was good (χ2 = 0.01; CMIN = 0.10, CFI = 1.00, RMSEA = 0.00). Pre-covid MWB and PS positively influenced PA (β = 0.29; β = 0.24; P < 0.01) but not SB (β = -0.10; β = 0.00; P = 0.79) during the pandemic. Additionally, pre-pandemic SB and PA positively influenced SB and PA during the pandemic respectively (SB: β = 0.26; P < 0.01) (PA: β = 0.55; P < 0.01). Pre-pandemic BMI did not influence any measured variable during the pandemic (PA: β = 0.03 and P = 0.29; SB: β = 0.06 and P = 0.56), and there was no mediating effect of PA on SB during the pandemic (β = -0.26; P = 0.14).ConclusionThese findings indicate that pre-covid mental health and movement behaviours had a direct positive influence on PA during the pandemic, but not SB. This longitudinal study demonstrates the influence that prior psychological and behavioural factors have in determining university students' response to periods of elevated stress and uncertainty, furthering our understanding of determinants of health-related behaviours in students.

Objective: To compare preparation for transition in adolescents in the United States prior to and during the COVID-19 pandemic. Study Design: We used data from the 2019 and 2021 National Survey of Children’s Health to compare transition preparation before and after the COVID-19 pandemic among adolescents who had a medical care visit within the preceding year, controlled for relevant potential confounders. The association of demographic factors and survey year with a composite measure of adequate transition preparation was evaluated using univariable analysis and multivariable logistic regression. Results: The difference in transition preparation was not significant when comparing 2019 to 2021 (9.25 % in 2019 vs. 8.67 % in 2021, p = .556), despite changes in potential confounders, such as worse caregiver mental or emotional health and fewer adolescents having insurance or a usual source of preventive care. Older adolescents (odds ratio for each year 1.321, 95 % confidence interval 1.196 – 1.459), females (odds ratio 1.153, 95 % confidence interval 1.02 – 1.304) were more likely to have received adequate transition preparation. Adolescents from Spanish-speaking homes were less likely than adolescents from English-speaking homes to have received adequate transition preparation (odds ratio 0.529, 95 % confidence interval 0.329 – 0.849). Conclusions: The proportion of adolescents in the United States who received adequate preparation to transition to adult care did not change during the COVID-19 pandemic. However, in both years studied, only a small minority of adolescents in the United States were adequately prepared.

Objectives In the first year of the COVID-19 pandemic, health systems implemented programmes to manage outpatients with COVID-19. The goal was to expedite patients’ referral to acute care and prevent overcrowding of medical centres. We sought to evaluate the impact of such a programme, the COVID-19 Home Care Team (CHCT) programme.Design Retrospective cohort.Setting Kaiser Permanente Northern California.Participants Adult members before COVID-19 vaccine availability (1 February 2020–31 January 2021) with positive SARS-CoV-2 tests.Intervention Virtual programme to track and treat patients with ‘CHCT programme’.Outcomes The outcomes were (1) COVID-19-related emergency department visit, (2) COVID-19-related hospitalisation and (3) inpatient mortality or 30-day hospice referral.Measures We estimated the average effect comparing patients who were and were not treated by CHCT. We estimated propensity scores using an ensemble super learner (random forest, XGBoost, generalised additive model and multivariate adaptive regression splines) and augmented inverse probability weighting.Results There were 98 585 patients with COVID-19. The majority were followed by CHCT (n=80 067, 81.2%). Patients followed by CHCT were older (mean age 43.9 vs 41.6 years, p

Background Data on right ventricular (RV) exercise adaptation following acute intermediate and high-risk pulmonary embolism (PE) remain limited. This study aimed to evaluate the symptom burden, RV functional recovery during exercise and cardiopulmonary exercise parameters in survivors of intermediate and high-risk acute PE.Methods We prospectively recruited patients following acute intermediate and high-risk PE at four sites in Australia and UK. Study assessments included stress echocardiography, cardiopulmonary exercise testing (CPET) and ventilation–perfusion (VQ) scan at 3 months follow-up.Results Thirty patients were recruited and 24 (median age: 55 years, IQR: 22) completed follow-up. Reduced peak oxygen consumption (VO2) and workload was seen in 75.0% (n=18), with a persistent high symptom burden (mean PEmb-QoL Questionnaire 48.4±21.5 and emPHasis-10 score 22.4±8.8) reported at follow-up. All had improvement in RV-focused resting echocardiographic parameters. RV systolic dysfunction and RV to pulmonary artery (PA) uncoupling assessed by stress echocardiography was seen in 29.2% (n=7) patients and associated with increased ventilatory inefficiency (V̇E/V̇CO2 slope 47.6 vs 32.4, p=0.03), peak exercise oxygen desaturation (93.2% vs 98.4%, p=0.01) and reduced peak oxygen pulse (p=0.036) compared with controls. Five out of seven patients with RV–PA uncoupling demonstrated persistent bilateral perfusion defects on VQ scintigraphy consistent with chronic thromboembolic pulmonary vascular disease.Conclusion In our cohort, impaired RV adaptation on exercise was seen in almost one-third of patients. Combined stress echocardiography and CPET may enable more accurate phenotyping of patients with persistent symptoms following acute PE to allow timely detection of long-term complications.

Abstract Prevalence estimates are critical for malaria programming efforts but generating these from non-malaria surveys is not standard practice. Malaria prevalence estimates for 6–59-month-old Nigerian children were compared between two national household surveys performed simultaneously in 2018: a Demographic and Health Survey (DHS) and the Nigeria HIV/AIDS Indicator and Impact Survey (NAIIS). DHS tested via microscopy (n = 8298) and HRP2-based rapid diagnostic test (RDT, n = 11,351), and NAIIS collected dried blood spots (DBS) which were later tested for histidine-rich protein 2 (HRP2) antigen (n = 8029). National Plasmodium falciparum prevalence was 22.6% (95% CI 21.2– 24.1%) via microscopy and 36.2% (34.6– 37.8%) via RDT according to DHS, and HRP2 antigenemia was 38.3% (36.7–39.9%) by NAIIS DBS. Between the two surveys, significant rank-order correlation occurred for state-level malaria prevalence for RDT (Rho = 0.80, p

Abstract Individuals often face dilemmas in which non-cooperation serves their self-interest and cooperation favors society at large. Cooperation is often considered the moral choice because it creates equality and fairness among citizens. Accordingly, individuals whose political ideology attaches greater value to equality than to agency and self-reliance should not only cooperate on more rather than less efficient public goods, but also more on public goods from which individuals benefit equally rather than unequally. We examine this possibility by comparing ideologically left-leaning and right-leaning individuals’ cooperation on multiple public goods that varied in efficiency and (in)equality in returns. We find that left-leaning individuals cooperate more than right-leaning ones, but only on public goods that benefit everyone equally, and not more on public goods that generate inequalities. Left-leaning individuals also trust and expect others to cooperate more on equal- versus unequal-returns public goods, while self-identified right-leaning individuals do not differentiate between these. Interestingly, ideology does not predict which public good is deemed more morally appropriate to cooperate on. Results combined specify when and why self-identified leftists can(not) be expected to cooperate more than rightists and reveal how moral decision-making depends on structural elements of the public good provision problems that citizens face.

Abstract Laboratory and field-based studies of the invasive mosquito Aedes albopictus demonstrate its competency to transmit over twenty different pathogens linked to a broad range of vertebrate hosts. The vectorial capacity of Ae. albopictus to transmit these pathogens remains unclear, partly due to knowledge gaps regarding its feeding behavior. Blood meal analyses from field-captured specimens have shown vastly different feeding patterns, with a wide range of anthropophagy (human feeding) and host diversity. To address this knowledge gap, we asked whether differences in innate host preference may drive observed variation in Ae. albopictus feeding patterns in nature. Low generation colonies (F2–F4) were established with field-collected mosquitoes from three populations with high reported anthropophagy (Thailand, Cameroon, and Florida, USA) and three populations in the United States with low reported anthropophagy (New York, Maryland, and Virginia). The preference of these Ae. albopictus colonies for human versus non-human animal odor was assessed in a dual-port olfactometer along with control Ae. aegypti colonies already known to show divergent behavior in this assay. All Ae. albopictus colonies were less likely (p

Purpose Concomitant autoimmune rheumatic diseases (ARD) can add morbidity and complicate treatment decisions for patients with lung cancer. We evaluated the tumour characteristics at diagnosis and clinical outcomes in lung cancer patients with or without ARD.Methods This retrospective cohort study included 10 963 patients with lung cancer, treated at Johns Hopkins. Clinical data including tumour characteristics and outcomes were extracted from the cancer registry. Data on patients’ history of 20 ARD were extracted from the electronic medical record. Logistic regression was used to compare tumour characteristics between those with and without ARD; Kaplan-Meier curves and Cox proportional hazards models were performed to compare survival outcomes.Results ARD was present in 3.6% of patients (n=454). The mean age at diagnosis was 69 (SD 10) and 68 (SD 12) in patients with and without ARD (p=0.02). Female sex and smoking history were significantly associated with a history of ARD (OR: 1.75, OR: 1.46, p

Introduction Psoriatic arthritis (PsA) affects around 150 000 people in the UK of whom around 50% require treatment with biologics. The most used biologics for PsA target tumour necrosis factor (TNF) or interleukin-17A (IL-17A). About 50% of patients respond to each, but it is not currently possible to predict response for individual patients, necessitating sequential treatment steps. A recent proof of concept study in PsA suggested that using peripheral immunophenotype to choose therapy could improve time to treatment response.This study will test the hypothesis, within an open-label parallel-group biomarker-stratified multicentre randomised controlled trial, which the baseline proportion of CD4+T cells with an activated type 17 immunophenotype (Th17 levels) predicts response to IL-17A or TNF inhibitors in PsA. Additional analyses will identify if the model can be refined by combining additional clinical and immunophenotypic factors. Statistical modelling will be used to predict the likely effectiveness of these approaches compared with standard care.Methods and analysis Patients with PsA eligible to start their first biologic as part of standard care are recruited and baseline blood tests are taken for immunophenotyping. Participants are stratified equally by Th17 levels and randomised 1:1 to receive either TNF (adalimumab) or IL-17A (secukinumab) inhibitors. The primary analysis will establish the interaction between baseline immunophenotype and treatment on the primary outcome (achievement of minimal disease activity criteria at week 24). In secondary analysis, modelling will identify if this prediction model can be optimised further by incorporating clinical phenotypes and additional immunophenotyping techniques.Ethics and dissemination Ethical approval for the study was granted by the North West Preston Research Ethics Committee (ref 21/NW/0016). Dissemination will be via conference presentations and peer-reviewed publications, aiming to impact on treatment guidelines.Trial registration number ISRCTN17228602.

Expanding β cell mass is a critical goal in the fight against diabetes. CDK4, an extensively characterized cell cycle activator, is required to establish and maintain β cell number. β cell failure in the IRS2-deletion mouse type 2 diabetes model is, in part, due to loss of CDK4 regulator cyclin D2. We set out to determine whether replacement of endogenous CDK4 with the inhibitor-resistant mutant CDK4-R24C rescued the loss of β cell mass in IRS2-deficient mice. Surprisingly, not only β cell mass but also β cell dedifferentiation was effectively rescued, despite no improvement in whole body insulin sensitivity. Ex vivo studies in primary islet cells revealed a mechanism in which CDK4 intervened downstream in the insulin signaling pathway to prevent FOXO1-mediated transcriptional repression of critical β cell transcription factor Pdx1. FOXO1 inhibition was not related to E2F1 activity, to FOXO1 phosphorylation, or even to FOXO1 subcellular localization, but rather was related to deacetylation and reduced FOXO1 abundance. Taken together, these results demonstrate a differentiation-promoting activity of the classical cell cycle activator CDK4 and support the concept that β cell mass can be expanded without compromising function.

Abstract Gulf War Illness is a chronic multi-symptom disorder with severe cognitive impairments which may be related to glutamate excitotoxicity and central nervous system dysfunction. The low glutamate diet has been proposed as a comprehensive intervention for Gulf War Illness. We examined the effects of the low glutamate diet on verbal working memory using a fMRI N-back task. Accuracy, whole-brain blood oxygen level dependency (BOLD) response, and task-based functional connectivity were assessed at baseline and after 1 month on the diet (N = 24). Multi-voxel pattern analysis identified regions of whole-brain BOLD pattern differences after the diet to be used as seeds for subsequent seed-to-voxel functional connectivity analyses. Verbal working memory accuracy improved after the diet (+ 13%; p = 0.006). Whole-brain BOLD signal changes were observed, revealing lower activation within regions of the frontoparietal network and default mode network after the low glutamate diet. Multi-voxel pattern analysis resulted in 3 clusters comprising parts of the frontoparietal network (clusters 1 and 2) and ventral attention network (cluster 3). The seed-to-voxel analyses identified significant functional connectivity changes post-diet for clusters 1 and 2 (peak p

Abstract Nonlethal injury is a pervasive stress on individual animals that can affect large portions of a population at any given time. Yet most studies examine snapshots of injury at a single place and time, making the implicit assumption that the impacts of nonlethal injury are constant. We sampled Asian shore crabs Hemigrapsus sanguineus throughout their invasive North American range and from the spring through fall of 2020. We then documented the prevalence of limb loss over this space and time. We further examined the impacts of limb loss and limb regeneration on food consumption, growth, reproduction, and energy storage. We show that injury differed substantially across sites and was most common towards the southern part of their invaded range on the East Coast of North America. Injury also varied idiosyncratically across sites and through time. It also had strong impacts on individuals via reduced growth and reproduction, despite increased food consumption in injured crabs. Given the high prevalence of nonlethal injury in this species, these negative impacts of injury on individual animals likely scale up to influence population level processes (e.g., population growth), and may be one factor acting against the widespread success of this invader.

Abstract Background Malaria remains a leading cause of morbidity and mortality worldwide, with progress in malaria control stalling in recent years. Proactive community case management (pro-CCM) has been shown to increase access to diagnosis and treatment and reduce malaria burden. However, lack of experimental evidence may hinder the wider adoption of this intervention. We conducted a cluster randomized community intervention trial to assess the efficacy of pro-CCM at decreasing malaria prevalence in rural endemic areas of Madagascar. Methods Twenty-two fokontany (smallest administrative unit) of the Mananjary district in southeast Madagascar were selected and randomized 1:1 to pro-CCM (intervention) or conventional integrated community case management (iCCM). Residents of all ages in the intervention arm were visited by a community health worker every 2 weeks from March to October 2017 and screened for fever; those with fever were tested by a rapid diagnostic test (RDT) and treated if positive. Malaria prevalence was assessed using RDTs on all consenting study area residents prior to and following the intervention. Hemoglobin was measured among women of reproductive age. Intervention impact was assessed via difference-in-differences analyses using logistic regressions in generalized estimating equations. Results A total of 27,087 and 20,475 individuals participated at baseline and endline, respectively. Malaria prevalence decreased from 8.0 to 5.4% in the intervention arm for individuals of all ages and from 6.8 to 5.7% in the control arm. Pro-CCM was associated with a significant reduction in the odds of malaria positivity in children less than 15 years (OR = 0.59; 95% CI [0.38–0.91]), but not in older age groups. There was no impact on anemia among women of reproductive age. Conclusion This trial suggests that pro-CCM approaches could help reduce malaria burden in rural endemic areas of low- and middle-income countries, but their impact may be limited to younger age groups with the highest malaria burden. Trial registration NCT05223933. Registered on February 4, 2022

Critical syndromes are conditions that carry a high global burden of disease. Scoring systems are practical and reproducible aids that allow patients with more severe disease to be quickly identified and admitted to intensive care and to initiate structured and aggressive therapy. The Sequential Organ Failure Assessment (SOFA) score is one of the most widely used in the world, as there are several versions and it is simple. However, with the appearance of the COVID-19, several studies showed that there was a disparity in the estimation of mortality and associated outcomes, with respect to race, which culminated in an excess of preventable mortality in certain racial groups. Constant evaluation of the performance of these scoring systems must be performed due to definitional updates, which may vary the accuracy of the predictive value. There is a very large evidence gap in this regard, as the existing studies are from high-income countries where the predominant racial group is Caucasian, which should draw attention to the magnitude of the problem. Based on the above, the objective of this review is to discuss evidence on the performance of critical care scoring systems, particularly SOFA, and the impact that race has had on its predictive value.

Abstract Concentrations of the hormone leptin, which is produced by adipose tissue, increase with increasing BMI, whereas leptin sensitivity often declines with higher BMI. Thus, altered leptin signaling may play a role in reproductive health risks observed with increasing BMI, which include later onset and slow progression of labor. Conflicting evidence from clinical, animal and in vitro studies have suggested that leptin either promotes or inhibits labor. We hypothesized that serum leptin concentrations or serum leptin: body mass index (BMI) ratios in women may be associated with the initiation and progression of labor. Following informed consent, serum samples were collected from 90 women with singleton pregnancies at the time of routine glucose-challenge testing, for measurement of leptin. The potential influence of leptin on gestation length and cervical dilation timing were examined by multiple linear regression. Data were analyzed from 63 participants who met exclusion and inclusion criteria. Leptin concentrations (log-transformed) at 24–28 weeks gestation were not significantly correlated with first trimester BMI . Log serum leptin and leptin: BMI ratio each were significantly associated with shorter total gestation length in uncomplicated, term pregnancies. In contrast, the mid-pregnancy leptin concentrations were not associated with progression of labor, assessed by cervical dilation over time. The association between higher serum leptin and shorter gestation length is consistent with the hypothesis that leptin promotes, or is permissive for, the onset of labor.

Abstract Reflecting the first wave COVID-19 pandemic in Central Europe (i.e. March 16th–April 15th, 2020) the neurosurgical community witnessed a general diminution in the incidence of emergency neurosurgical cases, which was impelled by a reduced number of traumatic brain injuries (TBI), spine conditions, and chronic subdural hematomas (CSDH). This appeared to be associated with restrictions imposed on mobility within countries but also to possible delayed patient introduction and interdisciplinary medical counseling. In response to one year of COVID-19 experience, also mapping the third wave of COVID-19 in 2021 (i.e. March 16 to April 15, 2021), we aimed to reevaluate the current prevalence and outcomes for emergency non-elective neurosurgical cases in COVID-19-negative patients across Austria and the Czech Republic. The primary analysis was focused on incidence and 30-day mortality in emergency neurosurgical cases compared to four preceding years (2017–2020). A total of 5077 neurosurgical emergency cases were reviewed. The year 2021 compared to the years 2017–2019 was not significantly related to any increased odds of 30 day mortality in Austria or in the Czech Republic. Recently, there was a significant propensity toward increased incidence rates of emergency non-elective neurosurgical cases during the third COVID-19 pandemic wave in Austria, driven by their lower incidence during the first COVID-19 wave in 2020. Selected neurosurgical conditions commonly associated with traumatic etiologies including TBI, and CSDH roughly reverted to similar incidence rates from the previous non-COVID-19 years. Further resisting the major deleterious effects of the continuing COVID-19 pandemic, it is edifying to notice that the neurosurgical community´s demeanor to the recent third pandemic culmination keeps the very high standards of non-elective neurosurgical care alongside with low periprocedural morbidity. This also reflects the current state of health care quality in the Czech Republic and Austria.

Objectives We aimed to evaluate whether obese patients with psoriatic arthritis (PsA) were less likely to be in remission/low disease activity (LDA).Methods We used data from the ReFlaP, an international multi-centre cohort study (NCT03119805), which recruited consecutive adults with definite PsA (disease duration ≥ 2 years) from 14 countries. Demographics, clinical data, comorbidities, and patient-reported outcomes were collected. Remission/LDA was defined as Very Low Disease Activity (VLDA)/minimal disease activity (MDA), Disease Activity in PSoriatic Arthritis (DAPSA) ≤4/≤14, or by patients’ opinion. Obesity was defined as physician-reported and/or body mass index ≥30 kg/m2. We evaluated the association between obesity and the presence of remission/LDA, with adjustment in multivariable regression models.Results Among 431 patients (49.3% women), 136 (31.6%) were obese. Obese versus non-obese patients were older, more frequently women, had higher tender joint and enthesitis counts and worse pain, physical function and health-related quality of life. Obese patients were less likely to be in VLDA; DAPSA remission and MDA, with adjusted ORs of 0.31 (95% CI 0.13 to 0.77); 0.39 (95% CI 0.19 to 0.80) and 0.61 (95% CI 0.38 to 0.99), respectively. Rates of DAPSA-LDA and patient-reported remission/LDA were similar for obese and non-obese patients.Conclusion PsA patients with comorbid obesity were 2.5–3 folds less likely to be in remission/LDA by composite scores compared with non-obese patients; however, remission/LDA rates were similar based on the patients’ opinion. PsA patients with comorbid obesity may have different disease profiles and require individualised management.