European Journal of Pharmacology

Background: Deep brain stimulation (DBS) is a treatment option for Parkinson disease (PD). However, the effect of DBS on the arterial pressure (AP) remains unexplored. We aimed to develop an artificial baroreflex system for treating orthostatic hypotension (OH) due to central baroreflex failure in patients with PD. To achieve this, we developed an appropriate algorithm after estimating the dynamic responses of the AP to DBS using a white noise system identification method. Methods: We randomly performed DBS while measuring the AP tonometrically in 3 trials involving 3 patients with PD treated with DBS. We calculated the frequency response of the AP to the DBS using a fast Fourier transform algorithm. Finally, the feedback correction factors were determined via numerical simulation. Results: The frequency responses of the systolic AP to random DBS were identifiable in all 3 trials, and the steady state gain was 8.24 mmHg/STM. Based on these results, the proportional correction factor was set to 0.12, and the integral correction factor was set to 0.018. The computer simulation revealed that the system could quickly and effectively attenuate a sudden AP drop induced by external disturbances such as head-up tilting. Conclusion: An artificial baroreflex system with DBS may be a novel therapeutic approach for OH caused by central baroreflex failure.

Abstract Background: Despite widespread adoption of contemporary guideline-directed medical therapy (GDMT), patients with heart failure with reduced ejection fraction (HFrEF) continue to experience substantial residual morbidity and mortality. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated cardiometabolic benefits in diabetes and obesity, but their role in HFrEF remains uncertain. Objectives: To evaluate whether the addition of GLP-1RAs to optimized GDMT is associated with improved clinical outcomes in patients with HFrEF (NYHA class II-IV). Methods: We conducted a retrospective, multicenter cohort study using the TriNetX Research Network. Adults ([&ge;]18 years) with HFrEF (LVEF [&le;]40%) receiving GDMT between January 2020 and October 2024 were included. Patients treated with GLP-1RAs were compared with those on GDMT alone. After 1:1 propensity score matching, 1,518 patients were included in each cohort. Outcomes over 2 years included all-cause mortality, major adverse cardiovascular events (MACE), critical care utilization, and acute kidney failure. Time-to-event analyses were performed using Kaplan-Meier methods and Cox proportional hazards models. Results: In the matched cohort (mean age [~]63 years, [~]33% female), GLP-1RA use was associated with significantly lower all-cause mortality compared with GDMT alone (12.8% vs 23.8%; hazard ratio [HR] 0.48; 95% CI 0.40-0.57; p<0.001), corresponding to an absolute risk reduction of 11.0%. MACE was also reduced (35.8% vs 47.4%; HR 0.64; 95% CI 0.58-0.72; p<0.001). Additionally, GLP-1RA therapy was associated with lower critical care utilization (18.4% vs 28.9%; HR 0.55; 95% CI 0.47-0.64; p<0.001) and reduced acute kidney failure (29.2% vs 37.3%; HR 0.67; 95% CI 0.59-0.76; p<0.001). Rates of pancreatitis and substance-related disorders were low and not significantly different between groups. Conclusions: Among patients with HFrEF receiving contemporary GDMT, adjunctive GLP-1RA therapy was associated with significant reductions in mortality, cardiovascular events, and healthcare utilization. These findings support the potential role of GLP-1RAs as a novel, mechanism-complementary therapy in HFrEF. Prospective randomized trials are needed to confirm these observations and determine whether GLP-1RAs should be incorporated as a fifth pillar of GDMT.

ImportanceEpilepsy is one of the most common neurological disorders globally. A significant proportion of patients fail to achieve effective seizure control with medication and ultimately develop drug-resistant epilepsy, particularly mesial temporal lobe epilepsy (MTLE). While surgical resection and laser interstitial thermal therapy (LITT) are effective treatments for drug-resistant MTLE, these procedures may be associated with severe adverse events. In contrast, allogeneic induced pluripotent stem cell (iPSC)-based therapy is expected to offer a novel, potentially safer therapeutic approach with fewer side effects for patients with drug-resistant MTLE. ObjectiveTo evaluate the safety and preliminary efficacy of a single intracranial injection of ALC05 (iPSC-derived GABAergic interneurons) in patients with unilateral MTLE, and to assess the therapeutic effects of different dosage levels. Design, Setting, and ParticipantsThis single-center, randomized, double-blind, Phase 1 clinical trial will enroll 12 subjects with unilateral MTLE. All subjects will be randomly assigned to either the low-dose or high-dose group in a 1:1 ratio. To minimize risks at each dose level, the first subject in each dose group will be monitored for safety for at least 3 months following ALC05 injection and must demonstrate acceptable safety and tolerability before the remaining subjects are enrolled. The primary outcome will be the incidence and severity of adverse events (AEs) and serious adverse events (SAEs). Secondary outcomes include cell engraftment and survival, responder rate, and seizure frequency. The follow-up period for this study is 1 year. After completing the follow-up period within this study, subjects will enter a 15-year long-term safety follow-up. DiscussionMTLE remains a significant challenge in neurology. The results of this study will provide critical data regarding the feasibility and preliminary efficacy of ALC05 in treating MTLE and may offer a transformative therapeutic option for this condition.

Abstract Background: ST-elevation myocardial infarction (STEMI) is reported to be a leading cause of mortality worldwide. While cardiac troponins are the gold standard for myocardial injury detection but creatine kinase-MB (CK-MB) and total creatine phosphokinase (CPK) retain prognostic use in resource-limited settings. Objective: To evaluate the prognostic significance of admission CK-MB and CPK levels in STEMI patients and to assess their association with hematological parameters for integrated risk stratification. Methods: This cross-sectional study enrolled 15 consecutive STEMI patients from the Punjab Institute of Cardiology, Lahore, during January 2024. Comprehensive laboratory analysis including cardiac biomarkers (CK-MB, CPK, troponin-I, LDH), complete blood count, renal function, serum electrolytes, and metabolic parameters, was performed on admission. Pearson correlation and comparative statistical analyses were also conducted to assess the relationships between cardiac biomarkers and hematological indices. Results: The cohort includes 15 patients (mean age 50.1 +/- 12.2 years; 73.3% male). Cardiac biomarker elevation was prevalent: CK-MB was elevated in 12/15 (80%), CPK was elevated in 12/15 (80%), with concordant elevation in 11/15 (73.3%), which indicates extensive myocardial necrosis. Troponin-I showed the highest elevation rate at 13/15 (86.7%). Hematological abnormalities included anemia (60%), WBC elevation (53.3%), and RBC reduction (40%). Random glucose averaged 150.80 +/- 63.55 mg/dL, with 66.7% highlighted the hyperglycemia. Remarkably, electrolyte balance was preserved in all of the patients (0% sodium, potassium, and bicarbonate abnormalities), indicating maintained homeostasis. Pearson correlation analysis revealed a significant correlation between CK-MB and CPK (r = 0.615, p = 0.0126), while correlations between cardiac biomarkers and hematological parameters were weak (p > 0.05). Risk stratification identified 53.3% of patients as high-risk who required intensive management. Conclusions: CK-MB and CPK demonstrate significant concordance and retain prognostic value in STEMI patients, particularly in resource-limited settings where troponin access may be constrained. While troponin-I remains the most sensitive biomarker, combined assessment of conventional cardiac enzymes supports reliable evaluation of myocardial injury. Hematological parameters reflect systemic response but show limited correlation with cardiac biomarkers.

STRUCTERED ABSTRACTO_ST_ABSBACKGROUNDC_ST_ABSCoronary artery bypass graft (CABG) is a widely performed procedure for coronary artery disease (CAD), yet its association with Impaired Cognition (IC), i.e., mild-cognitive impairment or all-cause dementia, while accounting for APO ({varepsilon}) genotype, remains unclear. METHODSWe analyzed AllofUS participants with CAD (Age[&ge;]60 yrs) from 2017-2023. We defined CAD as a history of angina/myocardial infarction/chronic ischemic heart disease or having percutaneous coronary intervention/CABG, and IC as mild cognitive impairment or all-cause dementia using ICD/SNOMED codes. We performed logistic regression analyses to assess the association between CABG and IC, adjusting for clinical factors (age, sex, hypertension, diabetes, hyperlipidemia, depression, stroke, smoking, alcohol use, statin/antihypertensive/antidiabetic use), social determinants (self-reported race/ethnicity, income, employment), and APO ({varepsilon}) genotypes. We further performed stratified analyses across APO ({varepsilon}) genotypes ({varepsilon}2/{varepsilon}2, {varepsilon}2/{varepsilon}3 {varepsilon}3/{varepsilon}3, {varepsilon}2/{varepsilon}4, {varepsilon}3/{varepsilon}4, {varepsilon}4/{varepsilon}4). We defined significance at p [&le;] 0.05. RESULTSWe included 22,349 with CAD and identified 908 with IC after CAD till 2023. 40% were females, 70% were White, 12% were Black, and 9% were Hispanic. The proportion of IC was higher (5.1% vs 3.5%, p=1e-08) in CABG (n=8,135) vs non-CABG (n=14,214). After adjusting for clinical factors, social determinants, and APO ({varepsilon}) genotypes, CABG (1.23;1.06-1.41, p = 0.005) was associated with IC. In APO ({varepsilon}) stratified analysis, the association of CABG with IC was strongest in the APO {varepsilon}2/{varepsilon}3 group (1.91;1.21-3.02, p = 0.005). CONCLUSIONIn the AllofUS cohort, we observed an association between CABG and IC in CAD participants, with the strongest association in the APO {varepsilon}2/{varepsilon}3 group. Key MessageO_ST_ABSWhat is already known on this topicC_ST_ABSCoronary artery disease (CAD) and Impaired Cognitive (IC) disease, i.e., mild cognitive impairment and all-cause dementia, share genetic, sociodemographic, and clinical factors, including cardiovascular conditions like coronary artery bypass grafting (CABG) procedure. What this study addsWe observed an association between CABG and IC in CAD participants after adjusting for sociodemographic, clinical factors, and APO ({varepsilon}) effects. Further, when CAD participants were stratified across APO ({varepsilon}) groups, CABG was significantly associated with IC in the APO {varepsilon}2/{varepsilon}3 group. How this study might affect research, practice or policyOur observations highlight the role of APO ({varepsilon}) genotype evaluation in CAD patients for IC risk assessment.

COVID-19 has spread rapidly and caused a global pandemic making it one of the deadliest in history. Early identification of patients with coronavirus disease 2019 who may develop critical illness is of immense importance. Therefore, novel biomarkers were needed to identify patients who will suffer rapid disease progression to severe complications and death. Many treatments were adopted including the antiviral Remdesivir, the antiretroviral Lopinavir /Ritonavir and Tocilizumab. Our study aimed not only to specify high-risk factors and biomarkers of fatal outcome in hospitalized subjects with coronavirus but also to compare the efficacy of the three considered treatments to help clinicians better choose a therapeutic strategy and reduce mortality. We divided the population (n=711) into four main groups based according to the WHO ordinal severity scale. The percentage of mortality, in and out the hospital, the length of stay in the hospital, the pulmonary inflammatory lesion and its distribution, the SARS-CoV-2 IgM and IgG variations at admission, the inflammatory markers, the complete blood count, the coagulation factors and enzymes, proteins and electrolytes profile, glucose and lipid profile, and other relevant markers were measured. The significance of the observed variation was assessed by multivariate and ANOVA analyses. We succeeded to establish a novel predictive scoring model of disease progression based on a cohort of Lebanese hospitalized patients relying on the pulmonary inflammatory lesions, inflammation biomarkers such as LDH, D-Dimer, CRP, IL-6 and the lymphocyte count, the number of comorbidities and the age of the patient which all were significantly correlated with the illness severity showing best outcomes with immunomodulatory and anticoagulant treatments by the results. As top tier, Tocilizumab was more efficient than the two other treatments in non-severe cases but none of the used treatments was insanely effective alone to reduce mortality in severe cases.

Background and Aims: Acute myocarditis (AM) is a T cell-mediated myocardial disease with clinical manifestations ranging from mild chest pain to cardiogenic shock. Reliable biomarkers to stratify patients and guide therapy are currently lacking. In particular, the extent of the dysregulation of inflammatory pathways, and the impact on myocardial dysfunction, remain elusive. Methods: Serum analyses were performed in prospectively recruited AM patients (n = 103) from two independent cohorts. Multimodal data integration combining profiling of cytokine and chemokine dysregulation with clinical biomarkers was used to define clinical phenotypes with distinct inflammatory signatures. Machine-learning and regression models were applied to determine biomarkers that indicate clinical severity. Results: Immuno-proteomic profiling revealed conserved inflammatory patterns across AM cohorts, dominated by T cell-related cytokines and chemokines. In addition, AM patients showed dysregulation of fibroblast-derived cytokines, including hepatocyte growth factor (HGF), bone morphogenic protein 4 (BMP4) and the BMP4 inhibitors Gremlin-1 (GREM1) and Gremlin-2 (GREM2). Data integration and unsupervised clustering revealed two immuno-clinical phenotypes, linking T cell activation and fibroblast dysregulation to disease severity. Machine learning-based analysis identified CXCL10, GREM2 and LVEF as critical parameters for stratifying disease severity. Conclusions: These findings highlight a systemic T cell activation signature as diagnostic hallmark of AM. In addition, dysregulation of fibroblast-derived tissue cytokines serves as an indicator for distinct immuno-clinical phenotypes in myocardial inflammatory disease. Thus, the clinically relevant link between T cell-driven immune activation, myocardial inflammation and fibroblast-driven remodelling provides a versatile set of parameters to identify severe manifestations of AM.

Background | Angina with nonobstructive coronary arteries (ANOCA) is a heterogeneous condition encompassing distinct endotypes representing different underlying pathophysiological mechanisms. Endothelial dysfunction is considered a central hallmark of ANOCA. However, studying patient-derived endothelial cells (ECs) remains challenging due to the limited availability of disease-specific endothelial samples. We therefore aimed to assess the feasibility of isolating and culturing ECs from catheterization material obtained during routine coronary function testing in ANOCA patients. Methods | Catheterization material was collected from 79 ANOCA patients (84% female, age 58{+/-}10 years) undergoing coronary function testing. ECs were isolated, expanded and characterized using immunostaining, flow cytometry, gene expression profiling and functional assays. Results | EC isolation was successful in 43% of cases and resulted in 34 primary EC cultures that were expanded up to passage 10. Isolation success was independent of clinical or procedural characteristics. Isolated cells exhibited typical EC morphology and expressed EC markers confirmed by immunostaining, flow cytometry and gene expression analyses. EC marker gene expression remained largely stable over passages. However, stress- and defense-related gene expression programs increased over time, while proliferation-related processes decreased. Functional assays demonstrated that the coronary catheterization-derived ECs showed typical properties of wound healing, angiogenesis, activation responses upon stimuli and monocyte adhesion. Conclusions | This study demonstrates the feasibility of isolating and expanding ECs directly from catheterization material collected during routine coronary function testing in ANOCA patients. These patient-derived ECs retain characteristic endothelial features and functionality. This approach offers primary EC cultures to study the mechanisms underlying endothelial dysfunction in ANOCA.

Schizophrenia (SCZ) and type 2 diabetes mellitus (T2DM) are common comorbid disorders that severely impair patient prognosis and quality of life. This study aimed to explore the association between the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism and MTHFR promoter methylation in patients with comorbid SCZ and T2DM. A total of 120 participants were enrolled from Liaocheng Fourth Peoples Hospital between January 2025 and June 2025, comprising 30 subjects in each of the four groups: SCZ group, T2DM group, SCZ-T2DM comorbid (SCZ+T2DM) group, and healthy control (CTL) group. Corresponding primers were designed for genetic analysis, and methylation-specific PCR (MSP) was performed to detect the methylation level of the MTHFR promoter. Genotype distribution of the MTHFR C677T polymorphism was consistent with Hardy-Weinberg equilibrium (HWE) (p>0.05). The C677T polymorphism was significantly associated with an elevated risk of SCZ and T2DM comorbidity (p<0.05). Notably, the methylation rate of the MTHFR promoter in the SCZ+T2DM group (95.00%) was not significantly higher than that in the CTL group (90.00%) (p>0.05). In conclusion, the MTHFR gene may serve as a susceptibility gene for SCZ-T2DM comorbidity, whereas MTHFR promoter methylation is not associated with the pathogenesis of this comorbid condition. These results indicate that genetic variation in MTHFR, rather than promoter methylation, contributes critically to the comorbidity of SCZ and T2DM in the Han Chinese population. Our findings may provide novel molecular insights into their shared pathophysiology and inform future clinical strategies for patients with this complex phenotype.

As therapeutic options emerge for hereditary spastic paraplegias (HSP), clinical trials require outcome measures that reflect disease aspects most important to patients. Patient priorities in HSP remain poorly defined. This study aimed to develop a regulatory-compliant framework of patient-prioritised health domains to evaluate treatment response in clinical trials. Patient-reported data on health impacts were collected via two multinational, multilingual online surveys conducted sequentially, including 616 and 504 patients across the clinical and genetic spectrum of HSP. Using a staged approach, we examined prevalence, relevance, and severity, focusing on health impacts that were (i) common (ii) sensitive to disease progression, (iii) highly relevant to patients, and (iv) showed strong severity-relevance correlation. Patient representatives contributed centrally to study design and prioritisation. Our patient-focused analysis yielded five highly prevalent and relevant core health domains: mobility, lower body function, autonomic dysregulation, pain, and psychosocial aspects. Ambulation and lower body function ranked highest across all disease stages. Among non-motor impacts, reduced ability to work, bladder incontinence, and fatigue were most relevant. In mild disease stages, reduced walking distance, reduced walking speed, and the urgency to empty the bladder were the most frequent and most relevant health impact. This work provides the most comprehensive patient-reported and disease stage specific profiling of HSP health impacts to date. It lays the necessary groundwork for developing patient-focused outcome tools capable of capturing treatment effects in future trials.

Study ObjectivesIdiopathic hypersomnia (IH) is a central nervous system hypersomnia frequently accompanied by autonomic symptoms, yet objective physiological data are limited. We sought to characterize autonomic nervous system (ANS) dysfunction in IH using nocturnal heart rate variability (HRV) and diurnal autonomic reflex testing (ART), compared to individuals with type 1 narcolepsy (NT1) and healthy controls (HCs). MethodsTwenty-four adults with IH, 10 with NT1, and 14 HCs underwent overnight video polysomnography with HRV analyses in time and frequency domains during stable slow-wave sleep and REM sleep. Comprehensive ART included sympathetic adrenergic (head-up tilt (HUT), Valsalva BP responses), parasympathetic cardiovagal (HRV to deep breathing, Valsalva ratio), and sudomotor (Q-Sweat) measures. ResultsIH participants were predominantly female, with over half reporting long sleep duration. Compared to NT1 and HC, participants with IH demonstrated a greater magnitude of orthostatic tachycardia on tilt ({Delta}HR 41.0 {+/-} 16.3 vs. 26.3 {+/-} 9.3 vs. 30.8 {+/-} 9.3 bpm, p = 0.0086), as well as frequent sudomotor dysfunction (64.3%). IH participants demonstrated greater nocturnal and REM HR with reduced parasympathetic indices during REM, indicating diminished vagal modulation compared with HCs ConclusionsIH is characterized by a distinct pattern of autonomic dysfunction, including pronounced orthostatic tachycardia, frequent sudomotor abnormalities, and reduced parasympathetic activity during sleep. These findings provide objective physiological evidence of ANS involvement in IH and delineate features that distinguish IH from NT1 and HCs.

BackgroundFamily-based HIV index case testing identifies family members with unknown HIV status and links them to care. Data are limited in southern Ethiopia. MethodsA facility-based cross-sectional study was conducted among 377 adults on antiretroviral therapy (ART) in Wolaita Zone, Southern Ethiopia, from November 2022 to May 2023. Participants were selected using systematic random sampling. Data were collected via interviewer-administered semi-structured questionnaire. Multivariable logistic regression identified factors associated with index case family testing. Adjusted odds ratios (AOR) with 95% confidence intervals (CI) were calculated, and statistical significance was declared at p < 0.05. ResultsThe proportion of index case family testing for HIV was 84.9% (95% CI: 81.2- 88.6). In multivariable analysis, urban residence (AOR = 2.8; 95% CI: 1.16-6.75), duration on ART greater than 12 months (AOR = 13.0; 95% CI: 4.6-36.9), disclosure of HIV status to family members (AOR = 5.6; 95% CI: 1.9-16.5), discussion of HIV status with family members (AOR = 6.6; 95% CI: 1.9-23.2), and being counselled by health professionals to bring families for testing (AOR = 6.3; 95% CI: 2.1-19.0) were significantly associated with index case family testing. ConclusionThe prevalence of family-based HIV index case testing in Wolaita Zone was 84.9%, below the national 95% target. Health professionals should strengthen counselling on ART adherence, status disclosure, family discussion, and active referral to improve testing uptake among family members of people living with HIV.

Background: Dengue is rapidly emerging in parts of Europe. How households value vector control attributes, and whether inferences depend on decision models or message framing, is unclear. Methods: We conducted a split-ballot online experiment among adults in Italy and France, as well as a hotspot subsample from Marche, Italy. National samples included 1,505 respondents in Italy and 1,501 in France; 183 respondents were recruited in Marche. Participants were randomised to a discrete choice experiment (random utility maximisation) or a regret-based choice experiment (random regret minimisation) and to one of three pre-task messages (control, loss aversion, community values). Each respondent completed 12 choice tasks comparing two dengue control programmes and an opt-out. We estimated mixed logit and mixed random-regret models with random parameters and treatment effects. Results: Across frameworks, nearby cases and high mosquito prevalence were the dominant drivers of programme uptake, whereas cost and operational burden were secondary. In pooled analyses, loss-aversion messaging increased the weight on high mosquito prevalence in both models (from 0.483 to 0.547 in the utility model; from 0.478 to 0.557 in the regret model). Cost effects were small nationally but larger in the hotspot subsample. Conclusions: Risk salience dominates preferences for dengue vector control in these European settings. Random utility and random regret models yield consistent rankings of attributes but differ in behavioural interpretation and some secondary effects; messaging effects were modest and context dependent.

BackgroundAccelerometer-derived behavioral phenotype captures multidimensional aspects of human behavior extending well beyond physical activity, encompassing light exposure, step counts, physical activity patterns, sleep, and circadian rhythms. Whether these five domains constitute a unified behavioral architecture underlying cancer risk and whether circadian organization and light exposure confer incremental predictive value beyond movement volume alone remains to be comprehensively established. MethodsWe conducted an accelerometer-wide association study (AWAS) encompassing the complete accelerometer-derived behavioral exposome across five behavioral domains in UK Biobank participants with valid wrist accelerometry data. Incident solid cancers were designated as the primary endpoint, with prespecified site-specific solid cancers and hematological malignancy as secondary outcomes. Cox proportional hazards models with age as the timescale were used. The minimal covariate set served as the primary reporting tier, followed by sensitivity analyses additionally adjusting for adiposity/metabolic factors, independent activity patterns, shift work history, and accelerometry measurement quality. Nominal statistical significance was defined as two-sided P < 0.05 ResultsAmong 89,080 participants, 6,598 incident solid cancer events were observed over a median follow-up of 8.39 years. In the minimally adjusted model, the pan-solid-tumor association atlas was dominated by signals from activity volume, inactivity fragmentation, and circadian rhythm. Higher overall acceleration (HR per SD: 0.91, 95% CI: 0.89-0.94) and higher daily step counts (HR: 0.93, 95% CI: 0.90-0.95) were independently associated with reduced solid cancer risk, while inactivity fragmentation metrics were consistently linked to higher risk. Notably, circadian rhythms, most prominently cosinor mesor (Midline Estimating Statistic of Rhythm under cosinor model), emerged as leading inverse risk signals, underscoring the independent contribution of circadian behavioral architecture. Site-specific analyses revealed pronounced heterogeneity across tumor sites. Lung cancer exhibited a robust inverse activity-risk gradient, while breast cancer showed reproducible associations with MVPA. Most strikingly, nocturnal light exposure demonstrated a tumor-site-specific association confined to pancreatic cancer, a signal absent across all other sites examined. Associations for uterine cancer were predominantly inactivity-related and substantially attenuated following adjustment for adiposity and metabolic factors. ConclusionsAcross five accelerometer-derived behavioral domains, solid cancers as a whole were most consistently associated with a high-movement, low-fragmentation, and circadian-coherent behavioral profile. While site-specific heterogeneity exists, the broad cancer risk landscape is dominated by movement volume, inactivity fragmentation, and circadian rhythmicity. Light exposure, although more localized in its contribution, demonstrates a potentially novel and specific association with pancreatic cancer risk. These findings support a five-domain behavioral exposome framework for cancer epidemiology and, importantly, position circadian rhythm integrity and nocturnal light exposure as critically understudied dimensions warranting dedicated mechanistic investigation.

Childhood socioeconomic position (SEP) can have lifelong effects on health. Many studies have used adult height as a surrogate marker for early-life conditions. In this study, we derived the non-genetic component of height, calculated as the residual from sex-specific standardized height regressed on genetically predicted height, as a surrogate for childhood SEP, using data from the Hispanic Community Healthy Study/Study of Latinos (2008-2011). A positive residual would indicate favorable early-life conditions promoting growth, while a negative residual indicates early-life adversity that may stunt the development. The height residual was associated with early-life variables such as parental education, year of birth, US nativity and age at first migration to the US (50 states/DC), supporting the validity of height residual as a surrogate for early-life conditions. Furthermore, a height residual was positively associated with better cardiovascular health (CVH) and cognitive function among middle-aged and older adults. Interestingly, among <35 years old, the height residual was negatively associated with the "Lifes Essential 8" clinical CVH scores. These results suggest the non-genetic component of height as a surrogate for childhood environment, with predictive value for CVH and cognitive function.

Wearable-derived physiological features have been associated with disease risk, but most current studies focus on single conditions, limiting understanding of cross-disease patterns. This study adopts a trans-diagnostic approach to examine whether wearable data capture shared and condition-specific physiological signatures across multiple chronic conditions spanning physical and mental health, and then evaluates the utility of these features for disease classification. A total of 9,301 patients with at least 21 days of consecutive FitBit data from the All of Us Controlled Tier Dataset version 8 were analyzed. Disease subcohorts included cardiovascular disease (CVD), diabetes, obstructive sleep apnea (OSA), major depressive disorder (MDD), anxiety, bipolar disorder, and attention-deficit/ hyperactivity disorder (ADHD), chosen based on prevalence and relevance. Logistic regression and XGBoost models were fitted for each disease subcohort versus the control cohort. We found that compared to using just baseline demographic and lifestyle features, incorporating wearable-derived features enabled improved classification performance in all subcohorts for both models, except for ADHD where improvement was mainly observed for ROC-AUC in logistic regression model likely due to the smaller sample size in ADHD subcohort. The largest performance gains were observed in MDD (increase in ROC-AUC of 0.077 for Logistic regression, 0.071 for XGBoost; p < 0.001) and anxiety (increase in ROC-AUC of 0.077 for logistic regression, 0.108 for XGBoost; p < 0.001). This study provides one of the first comprehensive transdiagnostic evaluations of wearable-derived features for disease classification, highlighting their potential to enhance risk stratification in the real-world setting as a practical complement to clinical assessments and providing a foundation to explore more fine-grained wearable data. Author summaryWearable devices such as fitness trackers and smartwatches are becoming increasingly popular and affordable, providing continuous measurements of heart rate, physical activity, and sleep. Alongside the growing digitization of health records, this creates new opportunities for large-scale, real-world health studies. In this study, we analyzed wearable-derived physiological patterns across a range of chronic conditions spanning both physical and mental health to better understand how these signals relate to disease risk. We found that incorporating wearable-derived heart rate, activity and sleep features improved disease risk classification across several conditions, with particularly strong gains for major depressive disorder and anxiety. By examining how individual features contributed to model predictions, we also identified meaningful associations between physiological signals and disease risk. For example, both duration and day-to-day variation of deep and rapid eye movement (REM) sleep were associated with increased risk in certain conditions. Our study supports the development of real-time, automated tools to assess disease risk alongside clinical care.

ObjectivesWe determined the frequency of sexually transmitted infection (STI) testing among people accessing sexual health services (SHS) in England. MethodsWe assessed STI testing frequency in face-to-face and online SHSs in England using data from the GUMCAD STI surveillance system. We quantified different combinations of tests (e.g. single chlamydia test or full STI screen), number of tests completed in 2024 and test positivity by sociodemographic and behavioural characteristics, as well as clinical setting and outcomes. ResultsOverall, there were 2,222,028 attendances at SHS in England in 2024 that involved tests for chlamydia, gonorrhoea, syphilis and/or HIV. Most of these attendances involved tests for all four of these STIs. Most people accessing SHS in England tested once (80.1%), and a small minority (1.9%) tested at least quarterly (4+ times). Some groups had a comparably larger proportion of quarterly testers; these included gay, bisexual, and other men who have sex with men (GBMSM) (6.7%), London residents (3.6%), online testers (2.5%), people using HIV-PrEP (13%), and people with 5+ partners in the previous 3 months (10.6%). Only 10.5% of GBMSM reporting higher-risk sexual behaviours tested quarterly despite recommendations for quarterly testing in this group. ConclusionsThe majority of those who tested for STIs in England in 2024 only tested once. The minority who tested at least quarterly had a higher proportion of GBMSM, people using HIV-PrEP, London residents and people reporting higher risk behaviours. Quarterly testing often appears to be aligned with current testing recommendations in England; however, we also observed that only a low proportion of behaviourally high-risk GBMSM and HIV-PrEP users are meeting these recommendations. It is important to acknowledge groups with lower or higher testing frequency when developing interventions and updating guidelines related to STI testing. WHAT IS ALREADY KNOWN ON THIS TOPICThe effectiveness of asymptomatic testing for chlamydia and gonorrhoea in gay, bisexual and other men who have sex with men (GBMSM), and the potential impact of the consequent increased antibiotic use on rising antimicrobial resistance and individual harm has recently been questioned. Testing and treatment remains a key pillar of STI prevention and management; despite this, there is limited evidence of STI testing frequency within sexual services (SHS) on a national level. WHAT THIS STUDY ADDSThis analysis shows that the majority of people attending SHSs in England in 2024 tested once, and only a small proportion of behaviourally high-risk people tested frequently. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYAwareness of groups that are behaviourally high risk but testing infrequently is important to guide interventions and messaging regarding STI testing. The low levels of frequent testing, even among those who would be recommended quarterly testing under UK guidelines, provides important context for wider discussion around asymptomatic STI screening.

BackgroundTimely cancer diagnosis in children and adolescents is critical to improving outcomes, yet substantial variation in diagnostic intervals persists across cancer types and care settings. We aimed to quantify time to diagnosis and assess variations by patient, demographic, and system-level factors. MethodsWe conducted a retrospective population-based study of children and adolescents aged 0-19 years diagnosed with one of 12 common cancers between 2010 and 2022 in Quebec, Canada. The diagnostic interval was defined as the time from first cancer-related healthcare encounter to diagnosis. We calculated medians and interquartile ranges (IQR) overall and by cancer type and used multivariable quantile regression to identify factors associated with time to diagnosis at the 25th, 50th, and 75th percentiles. ResultsAmong 2,927 individuals with cancer, diagnostic intervals varied by cancer type and age. Median intervals were longest for carcinomas (100 days; IQR 33-192) and shortest for leukemias (8 days; IQR 3-44). Compared with children living in Montreal, living in regional areas and other large urban centres was associated with longer 50th and 75th percentiles of time to diagnosis for hepatic and central nervous system (CNS) tumours. Diagnostic intervals were shorter in the post-pandemic period (2020-2022) across several cancer sites, with CNS tumours showing reductions across all quantiles. InterpretationDiagnostic timeliness differed by cancer type, age, and rurality, but not by sex, material, or social deprivation. The shorter diagnostic intervals observed in the post-pandemic period suggest that pandemic-related changes in care pathways may have expedited diagnosis for some cancers.

We used 2492 whole genome sequences from Laos to investigate the molecular epidemiology of SARS-CoV-2 from 2021 through 2024, covering the major waves of COVID-19 disease in Laos including time periods of travel restrictions and after relaxation of travel across international borders. We identify successive waves of COVID-19 caused by shifts in the dominant lineage, beginning with the Alpha variant in April 2021 and continuing through the Delta and Omicron variants. We quantify a shift from a small number of viral introductions responsible for widespread transmission in early waves to a larger number of introductions for each variant after travel restrictions were lifted, and identify potential routes of introduction into the country. Our study underscores the importance of genomic surveillance to public health responses to characterize viral transmission dynamics during pandemics.

BackgroundThe World Health Organization has developed several global template protocols for epidemiological investigations, including for household transmission investigations (HHTIs). These investigations facilitate rapid characterisation of novel or re-emerging respiratory pathogens and support evidence-based public health actions. Beyond technical readiness, community buy-in is central to the feasibility and acceptability of HHTIs. Research is needed to determine the perceived legitimacy among the community to inform local protocol adaptation and development of implementation plans that consider community attitudes and needs. MethodsIn 2025, we conducted a convenience survey of community members living in Victoria, Australia to explore: their understanding of emerging respiratory diseases; their willingness to take part in public health surveillance activities such as HHTIs; the acceptability of clinical and epidemiological data collection and respiratory/blood sample collection as main components of HHTIs, and; participant comfort towards including their companion animals in HHTIs. ResultsWe received 282 survey responses, of which 235 were included in the analysis dataset. Compared to the general Victorian population, our participants included a higher proportion of participants who reported being female, tertiary-educated, of Aboriginal and/or Torres Strait Islander heritage, born in Australia and speaking only English at home. Participants indicated overall high levels of comfort and acceptability towards participation in HHTIs, particularly in relation to clinical and epidemiological data collection, with lesser but still high levels of comfort with providing multiple respiratory specimens in a 14-day period. Participants were least comfortable with other specimens such as urine and blood. Involving companion animals in HHTIs was similarly acceptable as human-focused components. ConclusionsDespite our survey population being non-representative of the general Victorian population, our findings provide valuable descriptive insights into the acceptability of HHTIs in Victoria, Australia from which to benchmark future local and international surveys and community engagement activities.