The Journal of Pain

Chronic pelvic pain (CPP) affects up to 26% of women worldwide. While its pathophysiology is poorly understood, disturbances in body perception have been identified in various similar chronic musculoskeletal disorders. The Fremantle Perineal Awareness Questionnaire (FrePAQ) is a novel tool designed to specifically assess disturbed body perception in the pelvic region, but its structural validity and reliability require formal evaluation. Methods: Patient partners with lived experience contributed to study design. Participants with (n=417 and without (n=277) chronic pelvic pain completed the FrePAQ at baseline, as well as one week later. We assessed the validity and reliability of the FrePAQ following COSMIN guidelines for Classical Test Theory. Results: The validated FrePAQ comprises a two factor model, with a six item Distress & Disconnection (D&D) subscale and a two item Size & Shape (S&S) subscale. Confirmatory analysis showed excellent fit (CFI = .988; RMSEA = .048) and measurement invariance between diagnostic groups. Internal consistency was high (cronbach alpha = .838 CPP, .819 controls). Test retest reliability was high for D&D (ICC = .863) and acceptable for S&S (ICC = .695). FrePAQ scores showed a weak to moderate correlation with pain scores (r = .234 to .255), psychological distress (r = .226 to .443), and functional impact (r = .172 to .295), particularly for the D&D subscale. Conclusion: The FrePAQ is a reliable and valid instrument to measure perineal perceptual disturbances in CPP. Future research will evaluate the tools potential to support phenotyping and guide individualised interventions. Improved understanding of body perception disturbance in CPP can enhance diagnosis and treatment precision.

Introduction: Reduced or lost sensation and movement after a spinal cord injury (SCI) impairs the brain s ability to accurately localize paralyzed body parts, causing deficits in its internal body map, or mental body representations (MBR). These deficits hinder functional recovery and contribute to neuropathic pain. Medications for neuropathic pain are often ineffective and carry side effects. Our pilot trials found that in-person Cognitive Multisensory Rehabilitation (CMR), a physical therapy restoring MBR, led to prolonged pain reduction, improved sensorimotor function, and enhanced brain function, to greater extent than adaptive fitness. To explore more accessible interventions for those in rural areas or with transportation challenges, we examined whether 12 weeks of remotely delivered CMR or exercise would (1) improve function and reduce pain; (2) increase brain activity and connectivity related to sensorimotor function and MBR in adults with SCI. Methods: Of 19 adults with SCI who consented, 15 (51+/-15 years old, 8+/-10 years post-SCI) were randomized to 12 weeks of remotely delivered CMR or exercise (45min, 3x/week). Eight reported neuropathic pain equal or greater than 3/10. The Numeric Pain Rating Scale (NPRS), ASIA Impairment Scale (AIS), and Neuromuscular Recovery Scale (NRS) assessed pain and sensorimotor function at baseline, post-intervention, and 6-month follow-up. Functional MRI included resting-state and four tasks: imagining feeling the left leg, imagining moving the left leg, whole-body movement imagery, and a sensation task. Results: After CMR (n=8), participants improved on AIS (large effect sizes: touch: d=1.30; pinprick: d=1.21; lower limb motor function: d=1.83). Exercise (n=7) produced smaller improvements (touch: d=0.35; pinprick: d=0.36; lower limb motor function: d=0.80). CMR showed greater NRS effect sizes (core: d=1.48; upper limb: d=0.69; lower limb: d=1.25) than exercise (core: d=0.31; upper limb: d=0.74; lower limb: d=0.83). Benefits persisted at follow-up for both AIS and NRS, especially in the CMR group. Highest neuropathic pain intensity decreased in both groups post-intervention (CMR: d=-0.61; exercise: d=-0.73) and at 6-month follow-up (CMR: d=-0.55; exercise: d=-0.55). Unlike previous studies, group effects for CMR were not found due to high heterogeneity. Increased task-based activation, including in the lateral occipital cortex involved in visual body perception and spatial awareness, was seen for the exercise group (n=5). Discussion: These preliminary results support the potential of remotely delivered CMR and exercise to improve function and reduce neuropathic pain in adults with SCI, highlighting the need for larger trials. Clinicaltrial.gov: NCT05870189

Introduction: Acute low back pain is a leading cause of disability worldwide. Clinical guidelines recommend non-pharmacological therapies as first-line treatment and advise caution with opioid prescribing. However pharmacological therapies, including opioids and gabapentinoids, remain commonly used. The comparative risks of subsequent opioid use disorder (OUD) and overdose diagnosis associated with initial treatment modality in large, real-world populations is not well characterized. We estimated the incidence of new-onset OUD and overdose diagnosis among opioid-naive, Medicaid-insured adults with newly diagnosed acute low back pain and estimated the association between initial treatment modalities and subsequent OUD and overdose diagnosis risk. Methods: We conducted a retrospective cohort study using Medicaid T-MSIS Analytic files from 25 states (2016-2019). We identified opioid-naive adults with a new diagnosis of acute low back pain who initiated pharmacologic or non-pharmacologic treatment within 1 month of diagnosis. The primary outcome was incident OUD and overdose diagnosis (based on diagnosis codes in claims) during follow-up. Associations between initial treatment modality and OUD and overdose diagnosis risk were estimated using a non-parametric, doubly robust estimator to adjust for measured confounding. Results: The cohort included 525,002 opioid-naive adults initiating treatment for low back pain. The cumulative incidence of OUD and overdose diagnosis was 1.5% and 2.4% at 7 and 13 months, respectively. Compared to non-use, use of gabapentinoids during the first month of treatment was associated with the highest relative risk (increasing risk) by 130.1%, 95% confidence interval (CI): 117.8%, 142.3%), the second-highest relative risk was estimated for higher-dose opioids, defined as > 50 daily Morphine Milligram Equivalents (MME) (118.1%, 95% CI: 99.2%, 137.0%). Lower-dose, short-duration opioids ([≤] 50 MME, [≤] 7 days) were also associated with elevated risk, though substantially smaller in magnitude (20.8%, 95% CI: 13.8%, 27.9%). In contrast, non-pharmacologic, non-interventional therapies were associated with reduced OUD and overdose diagnosis risk, with physical therapy demonstrating the largest relative reduction of 34.0% (95% CI: -40.9%, -27.1%). Discussion: In opioid-naive Medicaid patients with acute low back pain, initial non-pharmacologic treatment was associated with reduced OUD and overdose diagnosis risk. Gabapentinoids and opioids were each associated with increased risk; for opioids, the degree of risk increased with higher doses and durations. These results support guideline recommendations favoring non-pharmacologic treatment as first-line therapy and indicate the importance of cautious prescribing when pharmacologic treatment is considered.

Background Chronic pain is common in adults aged 85 years and older (85+) and is associated with detrimental outcomes. Chronic pain guidelines advise first line management with non-pharmacological measures; paracetamol and non-steroidal anti-inflammatory drugs are the preferred analgesics. Challenges in accessing non-pharmacological therapies for adults aged 85+, and the presence of multimorbidity and polypharmacy, mean that opioid medication is often prescribed for chronic pain despite the potential for opioid-related adverse effects and guidance identifying long-term opioids for chronic pain as a potentially inappropriate prescription. Aim This study aims to explore patient, caregiver, and healthcare professional perspectives on the prescription of opioid medications for pain management for chronic pain in adults aged 85+ to support development of resources for optimising opioid prescribing. Design and Setting In this qualitative study, participants were recruited through primary care, in the community or in care home settings. Method 36 semi-structured interviews were conducted with care home residents and community dwellers aged 85+ (n=12), caregivers (informal and care home staff) (n=12), and healthcare professionals (n=12). Interviews were transcribed and analysed using reflexive thematic analysis. Results Four themes were developed: contextual complexity, satellite influences, balancing act, and pragmatic prescribing. Using opioids in adults aged 85+ is a balancing act to support patients best possible quality of life within their unique circumstances whilst using the pain management tools available. Conclusion Opioids continue to have an important role in pain management in adults aged 85+ largely due to paucity of alternatives and the drive to support quality of life.

Background: Olfactory dysfunction (OD) in children remains underdiagnosed and poorly characterised. Despite its known impacts on nutrition, quality of life, safety awareness, and psychosocial development, no standardised diagnostic or management pathway currently exists for paediatric OD. This study aimed to characterise global practice patterns and identify diagnostic and therapeutic challenges unique to paediatric care. Methodology/Principal: A 44-item cross-sectional online survey was distributed to a verified international network of paediatric otolaryngologists across 36 countries via a closed professional platform. The survey assessed five domains: diagnostic practices, management protocols, technology and innovation, education and training, and barriers to effective care. Regional grouping was used to facilitate meaningful statistical comparisons. Categorical variables were evaluated using chi-square tests, with odds ratios and 95% confidence intervals reported for significant findings. Results: Of 351 potential participants, 167 responded (47.6% response rate). Most respondents (83%) reported seeing children with OD, yet 95% saw fewer than ten such patients annually. Psychophysical testing was never performed by 54.8% of respondents, while 88.4% routinely ordered cross-sectional imaging. Testing frequency increased significantly with patient age (Cochran's Q p<0.001). The most common barriers to objective testing were insufficient training (44.3%), time constraints (29.9%), and funding limitations (28.1%). Multidisciplinary collaboration was negligible. Significant regional variation was observed across most practice domains. Conclusions: Paediatric OD care is characterised by functional underinvestigation, fragmented multidisciplinary collaboration, and systemic educational gaps. These findings support urgent development of standardised clinical guidelines, age-appropriate validated assessment tools, and formal interdisciplinary care pathways.

Introduction Dysmenorrhoea is highly prevalent globally and interferes with engagement in education, work, social participation, and quality of life. Although evidence suggests that sociocultural beliefs influence how menstrual pain is understood and managed, relatively little research has explored dysmenorrhoea-related knowledge and beliefs within South Africa. This study aimed to (1) determine the frequency of dysmenorrhoea, (2) assess dysmenorrhoea-related knowledge and compare knowledge between menstruating and non-menstruating individuals, and (3) explore commonly held generational, cultural, and religious beliefs related to dysmenorrhoea in a South African university cohort. Methods We analysed data collected as part of a cross-sectional survey conducted among staff and students at a South African university. Participants completed demographic questions, items assessing dysmenorrhoea-related knowledge, and an adapted Working Ability, Location, Intensity, Days of Pain, Dysmenorrhoea (WaLIDD) questionnaire. Participants were also invited to provide free-text responses describing generational, cultural, and religious beliefs about dysmenorrhoea. Quantitative data were analysed descriptively and compared between menstruating and non-menstruating participants. Free-text responses were analysed using reflexive thematic analysis. Results A total of 863 participants completed the survey, including 578 current or past menstruators. The frequency (95%CI) of dysmenorrhoea was 75.4% (71.7-78.9). Most participants were classified as having moderate (53%) or severe (31%) dysmenorrhoea on the WaLIDD scale. Awareness of dysmenorrhoea was higher among participants who had menstruated than among those who had never menstruated (80.4% vs 55.3%, p<0.001). Most participants (85.1%) reported wanting more education about dysmenorrhoea and its impact. Reflexive thematic analysis of 246 free-text responses identified five themes: (1) menstrual pain is normalised, dismissed, and expected to endure, (2) reproductive meanings attached to menstrual pain, (3) moral, spiritual, and cultural interpretations of menstrual pain, (4) negotiating competing explanations for menstrual pain, and (5) managing and controlling menstrual pain symptoms. Across themes, dysmenorrhoea was interpreted through social, cultural, reproductive, spiritual, and biomedical frameworks that shaped how pain was understood, communicated, and managed. Conclusion Dysmenorrhoea is common in this South African university cohort, and is rarely understood as a purely biological symptom. Instead, menstrual pain is understood and managed through broader social, cultural, reproductive, moral, and biomedical narratives, which shape how pain is recognised, disclosed, legitimised, and treated. These findings highlight the importance of considering sociocultural beliefs alongside clinical factors when developing menstrual health education, support strategies, and healthcare services.

Background: Low-intensity focused ultrasound (LIFU) is an emerging noninvasive neuromodulation technique capable of targeting deep cortical and subcortical structures with high spatial precision. In healthy human volunteers, LIFU has demonstrated a favorable safety and tolerability profile across multiple studies. However, its safety and tolerability in clinical populations remains poorly characterized, representing a critical barrier to clinical translation. Here, we prospectively evaluate the safety and tolerability of LIFU targeting the left dorsal anterior insula (dAI) in patients with fibromyalgia (FM). Methods: In a single-blind, sham-controlled, within-subjects crossover design, 13 individuals with FM (43.1 +/- 13.2 years; 12 female) received 10 minutes of active LIFU (500 kHz, 1 kHz PRF, 36% duty cycle, 4.2 W/cm2 Isppa; 100 x 1-second pulse trains with a 5-second inter-train interval) targeting the left dorsal anterior insula (dAI) or sham on separate visits. Safety was evaluated through neuroradiological review of post vs. pre LIFU FLAIR MRI, quantitative voxel-wise FLAIR analysis, and patient report of symptoms (ROS). Tolerability was assessed using an experience assessment. Efficacy of the LIFU intervention was assessed using quantitative sensory testing (QST) including temporal summation of pain (TSP) and conditioned pain modulation (CPM). Results: Neuroradiological review identified no new evidence of edema, microhemorrhage, acute ischemia, or white matter injury on post-LIFU structural imaging. Quantitative FLAIR analysis using contralateral-mirror-referenced relative FLAIR (rFLAIR) showed no significant within-subject change in the stimulated beam volume (delta rFLAIR = 0.002 +/- 0.025, t(12) = 0.30, P = 0.769, Cohen's dz = 0.08). No serious adverse events were documented and ROS indicated no change due to LIFU sonication. Participants rated the procedure as comfortable and could not distinguish active from sham LIFU. LIFU did not result in statistically significant changes for TSP (p = 0.797) or CPM (p = 0.465). Conclusions: Ten minutes of LIFU targeting the left dAI was safe and well tolerated in individuals with FM, with no neuroradiological or quantitative MRI evidence of tissue effects and no serious adverse events. Blinding was preserved, and participants rated the procedure as comfortable. Although no significant changes were observed in experimental pain measures, these findings support the feasibility of targeting deep salience and pain amplification circuitry with LIFU in patients with FM and provide a foundation for adequately powered efficacy trials.

Background and Aims: Fatigue is a prevalent and disabling symptom in inflammatory bowel disease (IBD), yet its underlying biological mechanisms remain poorly understood. We aimed to characterize fatigue-associated molecular signatures in IBD patients by integrating DNA methylation and mRNA expression analyses. Methods: Peripheral blood was collected from 40 patients with Crohn's disease (CD), 29 with ulcerative colitis (UC), and 10 healthy controls. Fatigue severity was assessed continuously using the Multidimensional Fatigue Inventory (MFI). Epigenome-wide DNA methylation profiling and mRNA sequencing were performed, identifying differentially methylated regions (DMRs) and differentially expressed genes (DEGs) for active and quiescent CD and UC, adjusting for age, sex, and smoking status. Pathway enrichment analysis was performed on genes with differential methylation and expression. Results: In active CD, more severe fatigue was associated with transcriptional suppression of immune and metabolic pathways (246 DMRs; 1,090 DEGs), versus upregulation of mitochondrial and metabolic processes in quiescent CD (200 DMRs; 1,619 DEGs). In active UC, fatigue was associated with anabolic pathway upregulation and epigenetic silencing of neuroactive pathways (6,927 DMRs; 343 DEGs; 56 concordant genes). Quiescent UC showed transcriptional changes without significant epigenetic pathway enrichment (1,710 DMRs; 3,224 DEGs). Healthy controls exhibited a distinct profile spanning metabolic, immune, and neuronal pathways (8,621 DMRs; 395 DEGs). Fatigue-associated signatures were largely non-overlapping across all five groups. Conclusions: Fatigue-associated molecular profiles differed substantially by disease subtype and activity state, highlighting the biological heterogeneity of IBD-related fatigue and laying the foundation for multi-omics approaches to identify biomarkers and potential therapeutic targets.

Background Evidence on factors associated with cannabis for medical purposes (CMP) authorizations among Veterans Affairs Canada (VAC) clients remains limited and inconsistent, particularly concerning mental health and posttraumatic stress disorder (PTSD), a leading indication for use. We investigated demographic, clinical and service characteristics associated with VAC authorizations for CMP reimbursement. Method We linked VAC administrative CMP program data with responses from the 2019 Life After Services Studies cross-sectional survey of Regular Force veterans released between 1998 and 2018. Multivariable logistic regressions examined associations between CMP reimbursement (yes/no) and demographic, clinical and well-being factors, with analyses stratified by PTSD status. Results Among 1,289 respondents (weighted n=33,131), 18.4% were authorized for CMP reimbursement. Younger age (<40 vs. [&ge;]60 years: OR 4.78, 95% CI: 2.24-10.21), unemployment with inability to work vs. employed (OR 3.10, 95% CI: 1.78-5.40), land service vs. air (OR 2.07, 95% CI: 1.22-3.50), PTSD (OR 2.81, 95% CI: 1.69-4.66), anxiety (OR 2.32, 95% CI: 1.45-3.70), and severe pain vs. no pain (OR 3.61, 95% CI: 1.97-6.60) were independently associated with authorization. Unemployment and severe pain were consistent correlates across PTSD strata. Among those without PTSD, younger age, multiple physical conditions, and frequent mental health visits were significant; among those with PTSD, shorter service, witnessing destruction, and suicidal ideation were additional factors. Conclusions CMP authorization patterns among Canadian veterans reflect the intersection of mental health, pain, and functional impairment, with variation by PTSD status. These findings underscore the need for longitudinal research on CMP mechanisms, effectiveness and safety.

Ecological momentary assessment (EMA) enables real-time, longitudinal measurement of symptoms and behavior via smartphones, yet nearly all feasibility evidence comes from protocols lasting one to two weeks, far shorter than the timescales over which chronic diseases fluctuate and clinical decisions unfold. Whether daily compliance can be sustained over months, or whether it decays as short-protocol trends predict, is unknown. Here, 214 participants (173 with pain, 41 healthy controls) completed a 4-month (122-day) EMA protocol via the Soma smartphone app, generating 26,907 check-ins. Half the sample completed the full protocol without a two-week lapse. Aggregate compliance appeared moderate (50%), but this conflated two distinct phenomena: when recomputed over each participant's active period, compliance rose to 71%, with 91% achieving moderate-to-high adherence, and remained stable across all 17 study weeks. Pain status predicted earlier disengagement but not lower compliance among those who remained; after adjustment for differential retention, group differences disappeared. To our knowledge, this is the longest continuous daily EMA evaluation in a clinical population. It suggests the primary barrier to long-duration EMA is not declining motivation among active participants but concentrated early disengagement, with direct implications for the design of digital health protocols, decentralized trials, and remote symptom monitoring.

Postoperative resilience varies widely among older adults, yet the biological drivers of recovery remain unclear. We evaluated whether preoperative immune profiles, measured in plasma and through ex vivo whole blood stimulation, predict resilience to the acute stress of total knee arthroplasty. A total of 152 adults (greater or equal to 60 years) in the PRIME KNEE cohort underwent elective total knee arthroplasty and had available blood samples for measurement of 45 immune biomarkers, quantified in plasma and in whole blood stimulated ex vivo for 24 hours with lipopolysaccharide (LPS) or influenza antigen (FLU). Resilience was assessed using Expected Recovery Differential (ERD) and Resilience Trajectory (RT) across pain severity, pain interference, lower extremity physical activities of daily living (LE PADLs), and step counts. An exploratory stability selection framework using LASSO identified biomarker predictors of postoperative outcomes. Plasma and stimulated biomarkers showed broadly similar predictive performance. A shared set of biomarkers, including LBP, leptin, TNFR1, CD30, and LIF, was consistently selected across models. Immune predictors explained ~12-24% of the variance in resilience outcomes. Distinct immune signatures emerged for pain versus functional recovery: pain related predictors mapped to local inflammatory and neuroimmune pathways, whereas function related predictors reflected systemic inflammatory load and cytokine signaling. Preoperative immune biomarkers, whether measured in plasma or after ex vivo stimulation, capture meaningful variance in postoperative resilience. The divergence between pain related and function related immune signatures highlights biologically distinct pathways underlying different dimensions of recovery and supports further development of immune based perioperative risk assessment.

Abstract Background Rheumatoid arthritis (RA) is an autoimmune inflammatory disease with complex and incompletely understood molecular mechanisms. Understanding circulating proteins associated with RA may improve understanding of disease biology and clarify its pathological links with cardiometabolic comorbidities. Methods A proteome-wide two-sample Mendelian randomisation (MR) drug target analysis was conducted using plasma proteins measured in 54,219 participants from the UK Biobank Pharma Proteomics Project as exposures and RA and cardiometabolic diseases as the outcomes. Summary statistics for RA included 53,663 cases and 1,070,200 controls. Colocalisation analysis was performed to confirm shared single causal variants and prioritise RA proteins supported by both MR and colocalisation. The prioritised proteins were then evaluated in the Accelerating Medicines Partnership RA Phase II synovial single-cell dataset for cell-type expression patterns. Druggability was then assessed followed by analysis of genetic overlap between RA-associated proteins and cardiometabolic diseases. Results 37 plasma proteins had a causal effect on RA risk, supported by combined evidence from MR and conditional colocalisation. In synovial tissue, TPPP3, RARRES2, AKAP12, and GGT5 were predominantly expressed in stromal and endothelial cell clusters. Druggability assessment identified IFNGR2, IL6R, CD40, and FCGR2B as Tier 1 targets. However, several biologically relevant proteins, including RARRES2, AKAP12, TPPP3, and SNX2, had limited available druggability data. Genetic overlap analysis demonstrated shared protein signals between RA and cardiovascular diseases, including overlap of RARRES2 and TPPP3 with coronary artery disease (CAD) and FCGR2B with atrial fibrillation (AF). To approximate the therapeutic effect of target inhibition, the direction of effect estimates for proteins showing overlap between RA-CAD and RA-AF was reversed. Conclusion This study identified circulating proteins involved in RA pathogenesis and reveals shared mechanisms between RA and cardiovascular diseases. While some proteins showed clear translational potential targets, several prioritised proteins had limited available druggability information and could not be confidently classified. Addressing these gaps may help identify new targets relevant to RA management. Future work should also use phenome-wide MR studies to evaluate potential on-target adverse effects of protein inhibition across RA-CAD and RA-AF.

Background: Histological examination of mucosal tissue in inflammatory bowel diseases (IBD) is a sensitive tool to measure disease activity, and histological remission is emerging as a potentially important treatment target. There are several existing histopathological indices, but they often encompass caveats such as not primarily having been designed to measure the degree of inflammation, encompassing subjective components with poor intra- and interindividual reproducibility, and requiring expert pathologists who are scarce, thus resulting in extended response times. Aim: To construct a new computerized, automated index to objectively measure histological disease activity in the ileal and colonic mucosa, applicable to both Crohn's disease (CD) and ulcerative colitis (UC). Materials and methods: Ileocolonic biopsies were collected from control subjects and patients with CD or UC. A group of CD patients was sampled before and after 12 weeks of anti-TNF therapy. Another group of CD and UC patients functioned as a small validation cohort. Epithelial cells, neutrophils, macrophages, and T cells were immunohistochemically stained, followed by digitalization of the color signal and computerized delineation of the epithelial and lamina propria compartments. The various immune cell types within the epithelium and the lamina propria, respectively, were enumerated, and the numbers were compared between control subjects and patients with CD or UC. Results: The numbers of neutrophils and macrophages in the epithelium, and neutrophils in the lamina propria, showed the highest sensitivity and specificity for distinguishing control-subject tissues from CD and UC tissues. These three parameters were thus chosen to construct a new index, named QiC3 1.0, that could separate tissues from control subjects and patients with CD or UC with high precision. It performed equally well in a small validation cohort of patients. The QiC3 index correlated well with previously described histopathological indices, fecal calprotectin, and endoscopic scores in UC, but showed worse correlation with endoscopic scores in CD and symptomatic scores. When applying the new index to tissues from CD patients before and after therapy, it showed good responsiveness, demonstrating a distinct amelioration in the microscopic inflammatory status that corresponded well to improvements in histopathological scores. Conclusion: We describe a new quantitative, computerized, automated, non-subjective, and response-sensitive immunohistological index (QiC3) for measuring disease activity in ileal and colonic mucosal biopsies, suitable for both CD and UC.

Background: Mass gathering events (MGEs) are associated with several public health challenges and may cause a strain on healthcare services. Literature findings on the impact of MGEs on emergency departments (EDs) are heterogeneous. Objectives: To examine shifts in ED attendance characteristics during a major sporting tournament, namely the UEFA European Football Championship 2024 held in Germany. Methods: We conducted a retrospective observational study using ED data from the Emergency Department Data Registry. We compared baseline ED attendance characteristics between the tournament and the reference period, defined as two weeks before and two weeks after the tournament, and between Germany game days and non-Germany game days. Hourly attendance patterns were analysed for all Germany games using a reference range. Results: We included data from 41 EDs, totalling 253,493 attendances during the study period. A 1.57% increase in attendance was observed during the tournament compared to the reference period, with baseline characteristics remaining similar. The median daily attendance within all EDs was slightly lower on Germany game days (4066) compared to non-Germany game days (4128). Modest changes were observed in the hourly attendance on Germany game days, most notable during the last Germany game where a decrease in attendance below the reference range extended over three hours. Conclusions: The observed shifts in ED attendance were minimal, suggesting that no major changes of public health relevance occurred in ED attendance during the tournament. We highlight the utility of using ED data for monitoring and for enhancing the understanding of the public health risks and challenges associated with MGEs.

PURPOSE: As the armamentarium of BPH therapies continues to expand, it remains imperative to maximize patient satisfaction and minimize decisional regret. We sought to determine the impact of time from BPH diagnosis to index treatment on symptom improvement and subsequent procedural events. MATERIALS AND METHODS: We queried the American Urological Association Quality Registry for men [&ge;] 40 years old with BPH, available IPSS data, and no receipt of prior BPH treatment. Index treatment included medication, surgery, or minimally invasive surgical therapy (MIST). Outcomes included IPSS over 3 years of follow-up, change in percentage of mild lower urinary tract symptoms (LUTS) by 3 months, and time to procedural event. Patients were stratified by time from index diagnosis to treatment by <12 months, 1-3 years, and >3 years. Outcomes were compared across time-to-treatment cohorts with appropriate statistical tests with p < 0.05 as significant. RESULTS: 43,919 patients met criteria with 19,642 pursuing treatments. Patients pursued treatment at comparably lower baseline IPSS compared to prior prospective series. Patients undergoing surgery and MIST had significantly higher baseline IPSS, while medical comorbidities were significantly more common among men initiating pharmacotherapy. Early surgery and MIST were associated with significant improvement in IPSS within 6-12 months and an increase in mild LUTS by 3 months. All forms of early treatment were associated with delayed time to procedural events, including catheterization and fulguration. CONCLUSIONS: Early procedural intervention for BPH is associated with early symptom improvement and delayed time to procedural events among real-world, contemporary practice.

Background. Obesity is a modifiable risk factor for osteoarthritis and may contribute to pain, functional impairment, inflammation, and cartilage degradation. Resveratrol has potential anti-inflammatory and chondroprotective effects, but its efficacy as an adjunct to dietary intervention remains unclear. Objective. This study evaluated whether resveratrol supplementation provides additional benefits when combined with a low-calorie diet in postmenopausal women with obesity and knee osteoarthritis. Methods. A total of 97 postmenopausal women with obesity and knee osteoarthritis were included in this randomized controlled clinical study. Participants received either a 10-day low-calorie diet alone or the same diet combined with 150 mg/day trans-resveratrol. Anthropometric parameters, body composition, biochemical markers, pain intensity, functional status, and urinary CTX-II were assessed at baseline and follow-up. Results. Both interventions were associated with reductions in body weight, BMI, waist and hip circumferences, fat mass, glucose, HOMA-IR, lipid parameters, hsCRP, VAS, WOMAC, LAI, and urinary CTX-II. Compared with diet alone, resveratrol supplementation did not provide additional benefits for anthropometric parameters, glucose metabolism, lipid profile, or WOMAC score. However, the resveratrol group showed a greater reduction in hsCRP and urinary CTX-II. The obesity class did not modify the treatment effect. Conclusion. A short-term low-calorie diet improved metabolic, inflammatory, and osteoarthritis-related parameters in postmenopausal women with obesity and knee osteoarthritis. The addition of resveratrol did not enhance weight loss or improve most metabolic outcomes but was associated with greater reductions in hsCRP and urinary CTX-II. These findings suggest a potential anti-inflammatory and cartilage-related effect of resveratrol, which requires confirmation in longer randomized trials.

Mosquito-borne diseases continue to pose significant public health challenges worldwide, particularly in densely populated regions of South Asia and parts of North America experiencing increasing vector prevalence due to climate and environmental changes. Commercial mosquito repellents are widely used as a primary preventive measure; however, their efficacy, safety, and public health impacts vary depending on formulation, active ingredients, environmental conditions, and user practices. This study presents a comparative evaluation of commonly used mosquito repellent products in South Asia and North America, including coils, vaporizers, sprays, creams, and Natural repellents. The research aims to assess repellent efficacy against major mosquito vectors, evaluate potential health and respiratory effects associated with prolonged exposure, and analyze consumer awareness and usage patterns across different regions. Laboratory-based efficacy testing and field observations were conducted to compare protection duration, repellency rate, and environmental performance under varying climatic conditions. Safety assessments included analysis of chemical composition, indoor air quality impact, and reported adverse health symptoms among users. The findings indicate significant differences in effectiveness and safety profiles among product categories and geographical regions. Synthetic repellents generally demonstrated higher repellency duration, while herbal formulations showed improved safety and environmental compatibility. The study highlights the importance of standardized evaluation protocols, regulatory oversight, and public awareness in promoting safe and effective mosquito control strategies. These findings may support policymakers, healthcare professionals, and manufacturers in improving mosquito repellent technologies and reducing the burden of mosquito-borne diseases globally.

Cultural engagement is associated longitudinally with better mental health and reduced depression incidence, but evidence has largely relied on self-reported symptoms and diagnoses, leaving uncertainty about clinically recorded disorders, and residual confounding remains a concern. Here, we examined whether cultural engagement (including going to cinemas, museums, galleries, exhibitions, theatre, concerts, or opera) predicts hospital-treated mental disorders in 8,274 adults aged 50 years or older from the English Longitudinal Study of Ageing. Participant records were linked to ICD-10 diagnoses in Hospital Episode Statistics and mortality records with follow-up of up to 20 years. In fully adjusted Cox models accounting for sociodemographic, lifestyle, and social factors and multiple testing, frequent cultural engagement was associated with lower risk of any mental disorders (HR 0.71, 95% CI 0.62-0.82, FDR adjusted P value<0.001), dementia (0.71, 0.56-0.89, FDR adjusted P value=0.010), substance misuse (0.75, 0.59-0.95,FDR adjusted P value=0.040), and mood disorders (0.73, 0.56-0.95, FDR adjusted P value=0.044), but not neurotic disorders. Associations persisted after excluding early incident cases and adjusting for baseline depressive symptoms and cognition, and showed robustness to unmeasured confounders. To further probe causality, eye disease, ear disease, and traumatic brain injury, which share similar socio-demographic profiles to mental disorders, were prespecified as negative control outcomes. Cultural engagement was not associated with any negative control outcomes. These findings provide triangulated statistical data to suggest that cultural engagement is associated with reduced risk of several clinically recorded mental disorders and support further testing of cultural engagement as a population mental health strategy.

Metabolic diseases such as type 2 diabetes (T2D) arise through complex interactions between physiological, molecular, and environmental processes. Clinical traits including age, sex, adiposity, and glycaemic status are strongly associated with disease risk and progression, yet most molecular studies examine these factors independently and assume relatively static molecular regulation. Consequently, how physiological state dynamically reshapes molecular organisation across omics layers remains poorly understood. Here, we integrated transcriptomic, proteomic, metabolomic, and genetic data from 3,027 individuals in the IMI DIRECT cohort to characterise the joint molecular effects of age, sex, body mass index (BMI), and glycated haemoglobin (HbA1c). We identified widespread associations between these traits and molecular phenotypes. However, interaction analyses revealed a more complex context-dependent regulation, showing that the molecular effect of one trait frequently depends on the state of another, with sex-specific effects of age being more prominent. We also investigated relationships between different types of molecular phenotypes and how these relationships are modulated by metabolic disease relevant traits, demonstrating that cross-omic molecular coordination is itself dynamically remodelled by physiological and metabolic state. Probabilistic causal inference identified a directionally structured network of age-associated molecules, revealing pathways through which age effects propagate across omics layers, showcased in the example of the mTOR signalling pathway. Integration of this directed network with genetic colocalisation analyses also identified a sub-network relevant for T2D. Collectively, our findings demonstrate that metabolic disease relevant traits not only independently influence molecular phenotype abundance but also jointly reshape the directional organisation of cross-omic molecular networks. These results support a model in which metabolic disease susceptibility emerges through dynamic rewiring of interconnected molecular systems and provide a framework for context-dependent biomarker discovery, disease stratification, and precision metabolic medicine.

Medical discrimination may alter how patients relate to health information sources following adverse care encounters. We examined whether discrimination experience is associated with selective erosion of institutional health trust and with compensatory digital health engagement, using nationally representative data from the Health Information National Trends Survey (HINTS) 6 (2022; n=6,252) and HINTS 7 (2024; n=7,278). Survey-weighted modified Poisson regression estimated prevalence ratios (PRs) for binary high-trust outcomes, and survey-weighted ordinary least squares estimated coefficients for continuous outcomes; jackknife replicate weights (50 replicates) provided variance estimates. Discrimination was associated with substantially lower probability of high trust in the healthcare system (PR=0.39; 95% CI 0.30-0.52) and physicians (PR=0.85; 95% CI 0.77-0.94), with no significant association for trust in scientists, government, family, or religious organisations. The clinical-institutional pattern replicated in HINTS 6, which additionally showed reduced trust in scientists for race/ethnicity-based discrimination. Contrary to a disengagement hypothesis, discrimination-exposed adults showed higher probability of online health information seeking (PR=1.06), health app use (PR=1.11), and online provider messaging (PR=1.13); these associations persisted after adjustment for trust in physicians. Discrimination was independently associated with lower health self-efficacy (b=-0.271). Medical discrimination selectively erodes trust in clinical institutions while leaving broader epistemic trust largely intact. Despite this, discrimination-exposed patients engage more actively with digital health channels, consistent with compensatory reorientation toward non-clinical information sources. These findings describe engaged but institutionally alienated patients, with implications for restoring clinical trust and for equity-centred digital health design.