The Journal of Pain

Background: Heatwrap is recommended for acute low back pain (ALBP), and previous research found heatwrap plus exercise more effective than each intervention alone. While recommended by clinical guidelines, their impact on mechanistic outcomes is unknown. This trial aimed to (i) assess immediate and short-term effects of heatwrap alone or combined with exercise, compared with a sham heatwrap, on pain sensitivity, lumbar muscle activity, current pain intensity, and trunk flexion range of motion, and (ii) explore whether changes in pain sensitivity and lumbar muscle activity are associated with changes in clinical symptoms from baseline to 1-week follow-up. Methods: A randomised controlled trial took place at a single research center. Of 315 individuals screened for eligibility, 99 adults with ALBP were recruited and assigned to one of three intervention groups: heatwrap plus exercise (n=34), heatwrap alone (n=33) or sham heatwrap (n=32). Interventions were applied for one hour at the first visit, and immediate effects were measured. Then, interventions were applied for 7 days, and short-term effects were measured at 1-week follow-up. Outcomes included pressure pain threshold, temporal summation of pain, flexion-relaxation ratio, trunk range of motion and current pain intensity. Results: Heatwrap and exercise did not produce greater effects over time than heatwrap alone or a sham heatwrap on all outcomes, and changes in sensorimotor outcomes at one week were not associated with changes in symptoms. Conclusions: Heatwrap and/or exercises did not influence specifically the potential sensorimotor mechanisms tested in individuals with ALBP. Trial registration: ClinicalTrials.gov; registration number: NCT03986047

Background: Fluctuations in pain intensity are intrinsic to non-specific chronic low back pain (nsCLBP). Nevertheless, pain fluctuations have rarely been considered when investigating pathophysiological mechanisms. Therefore, a novel study protocol was developed and implemented to systematically assess the impact of fluctuating pain states on pain-related measures. Methods: The final study cohort consisted of 45 nsCLBP patients and 47 age- and sex-matched healthy controls (HCs). Patients participated in three visits, conducted during different pain states (i.e. clinically relevant pain, low-intensity clinical pain / pain-free, clinically irrelevant pain induced using a Qutenza 8% capsaicin patch). Pain fluctuations were monitored through online assessments every four days and guided the pseudorandomized visit scheduling. HCs participated in a single visit. Each study visit comprised a multimodal battery of pain-related measures. Results: 93.33% of patients completed all three visit types in a pseudorandomized order (chi-squared=1.50, p=0.826). Visit scheduling was possible due to the high self-report adherence (median=93.48%), unrelated to self-report burden (rho=-0.097, p=0.53). Study visits were conducted during different pain states, as indicated by: i) the significantly higher low back pain intensity in the clinically relevant pain visit (mean[SD]: 3.98[0.90]), compared to the low-intensity clinical pain (1.03[0.86]) and clinically irrelevant pain (1.13[0.82]) visits (p-values<0.001), as well as by ii) the successful induction of a moderate-to-high clinically irrelevant pain across assessments. Conclusion: Despite scheduling complexity and pain state transition uncertainty, a pain state-dependent pseudorandomized study design is feasible and could improve the understanding of nsCLBP mechanisms.

Background and purpose: Patellofemoral pain syndrome (PFPS) is a multifaceted condition where proximal, local, and distal factors may contribute to symptoms and limitations. How these factors collectively contribute to PFPS remains poorly understood. Therefore, this study compared proximal, local, and distal mechanical characteristics between individuals with and without PFPS and investigated their association with pain intensity and functional disability. Methods: Eighty participants were included: 40 individuals with unilateral or bilateral PFPS, 40 healthy controls. Isometric muscle strength of hip, trunk, and ankle was assessed using a handheld dynamometer. Joint alignment (Q-angle, rearfoot angle, pelvic tilt) and muscle flexibility (iliotibial band, hamstrings, quadriceps, gastrocnemius, and soleus) were measured using standard clinical techniques. Pain severity was assessed using a visual analog scale (VAS), and functional disability was evaluated using the Kujala score. Results: Individuals with PFPS showed reduced iliotibial band flexibility, decreased hamstring and soleus length, lower hip abductor strength, and greater anterior and lateral pelvic tilt (all p < 0.02). Multivariate analysis identified reduced iliotibial band flexibility (OR = 7.48) and greater anterior pelvic tilt (OR = 11.75) as independent associates of PFPS. Anterior pelvic tilt predicted pain severity, while anterior trunk muscle strength and Q-angle predicted disability. Discussion: Reduced iliotibial band flexibility and increased anterior pelvic tilt were independently associated with PFPS, while anterior pelvic tilt predicted pain severity and anterior trunk muscle strength and Q-angle predicted functional disability. Clinical assessment and rehabilitation of PFPS should therefore extend beyond the knee to include iliotibial band flexibility, pelvic alignment, and trunk muscle strength.

Background: In Denmark, perioperative high-dose glucocorticoid treatment were step-wisely implemented for total hip arthroplasty (THA), total knee arthroplasty (TKA), and unicompartmental knee arthroplasty (UKA). We aimed to estimate the effect of a single high dose of glucocorticoids on opioid consumption following primary THA, TKA, and UKA. Methods: This was a prespecified analysis of a multicenter natural experiment using electronic health record data. We included elective THA, TKA, or UKA surgeries performed in Eastern Denmark from 2017-2025. At each center, surgeries before implementation of high-dose glucocorticoids served as controls, whereas surgeries after implementation comprised the intervention group. The primary outcome was the between-group difference in cumulative 0-24h opioid consumption, which included preemptive end-of-surgery doses. The predefined minimal important difference was set at 5 mg IV morphine equivalents. Secondary outcomes were maximum 0-10 numerical rating scale (NRS) pain score and incidence of opioid-related adverse events within 24 hours, hospital length of stay, and days alive and out of hospital at 30 days. Results: A total of 47,317 surgeries performed at nine centers were analyzed: 13,010 controls and 34,307 in the intervention group. During the study period, five centers implemented high-dose glucocorticoids for THA patients, two for TKA/UKA patients. High-dose glucocorticoids were administered to 6% of patients before implementation versus 92% after. High-dose glucocorticoids resulted in a mean reduction of 3.8 mg intravenous (IV) morphine equivalents (95% CI 3.3;4.3). The intervention also reduced the maximum 0-24h NRS pain score by 0.8 points (99% CI 0.7;0.9), but there was no difference in adverse events, length of stay, or days alive and out of hospital. Conclusions: Implementation of high-dose glucocorticoids reduced 0-24-hour opioid consumption by 3.8 mg IV morphine equivalents after elective hip and knee arthroplasty. This difference was below the prespecified minimal important difference threshold. Online registration: https://doi.org/10.1101/2025.11.11.25339982

Migraine is a leading cause of disability, yet preventive treatment remains largely empirical despite the availability of several mechanistically distinct therapies. Genetic data can clarify mechanisms and therapeutic hypotheses when association signals are integrated with molecular and clinical data. We meta-analyzed migraine GWAS data from 12 European ancestry cohorts (206,893 cases and 2,093,175 controls) and four African ancestry cohorts (22,115 cases and 178,626 controls). We identified 311 lead variants in European-ancestry analyses and 316 lead variants in trans-ancestry analysis. Fine-mapping and transcriptome-wide analyses prioritized variants and genes implicated in sensory neuronal signaling, vascular tone, and immune regulation, with convergent evidence at several established loci including TRPM8 and PHACTR1. Drug-repurposing analyses identified therapeutic targets and compounds, including established migraine treatments and candidates requiring experimental validation. Genetic correlations, Mendelian randomization, and a phenome-wide scan linked migraine liability to psychiatric, pain, and gastrointestinal phenotypes. Together, these findings expand the known genetic architecture of migraine across ancestries and provide a genetics-led map connecting association signals with biological pathways, multimorbidity and candidate therapeutic mechanisms, providing a foundation for future functional and translational studies.

Background: Endometriosis is a chronic pain condition in which hormonal therapies form the cornerstone of long-term management. Treatment tolerability is critical for adherence and therapeutic success, but most comparative studies and reviews have focused on their ability to reduce menstrual pain, while their impact on non-menstrual pelvic pain (NMPP), bleeding patterns, adverse events (AEs), treatment discontinuation and quality of life (QoL) remain poorly characterised. This systematic review and meta-analysis evaluate these outcomes across currently available hormonal therapies, providing practical evidence for clinical decision-making. Methods: PubMed/MEDLINE, Scopus, and Embase were searched up to November 2025 for randomised controlled trials comparing at least two active first- or second-line hormonal treatments for endometriosis. Studies without confirmed endometriosis, treatment duration less than three months and comparing therapies to placebo only were excluded. Data were extracted by two reviewers from reports. Pain outcomes were pooled as mean differences (MD, 95% CI), with bleeding patterns, AEs, and discontinuations as proportions. Analyses were performed in R. PROSPERO: CRD420251137785. Findings: Of 1892 records screened, 48 trials (5583 women) met our inclusion criteria. Overall pelvic pain (0-10 scale) was significantly reduced across all treatment categories (p<0.001): combined oral contraceptives (COCs) (MD 3.17), oral and long-acting progestogens (MD 3.83; MD 4.29), and GnRH-analogues (MD 3.81). Sensitivity analyses restricted to studies reporting NMPP yielded comparable results. GnRH-agonists showed the most favourable bleeding profile, followed by continuous COCs. However, all regimens reported class-specific AEs, including mood changes, nausea, headache, weight gain, and decreased libido (pooled proportions >10%). Overall discontinuation due to AEs was 7.7%, and vaginal bleeding was the leading cause. Heterogeneity across meta-analyses was high. Risk of bias (RoB2) was moderate to high. Interpretation: Given similar reductions in overall pelvic pain across hormonal therapies, treatment decisions should prioritise differences in bleeding profiles, therapy-specific AEs, and QoL. Funding: None.

Background: Lumbar disc herniation, with or without concomitant disc degeneration, is a major cause of lumbar radiculopathy and low back pain, which also a key public musculoskeletal disorder without an exact pathophysiology. Studies have suggested that inflammatory cells and biochemical markers of inflammation also play an important role in lumbar radiculopathy in addition to nerve compression. The aim of the present study was to assess the association of selected circulatory inflammatory markers (CRP, hs-CRP and E-selectin) in patients with lumbar disc herniation without radiological degeneration (LDH) and lumbar disc herniation with radiological degeneration (LDHD). Materials & methods: This case-control study included 208 participants, comprising 104 patients with lumbar disc pathology and 104 controls. Patients were further stratified into LDH (n=67) and LDHD (n=37). Serum CRP, hs-CRP and E-selectin concentrations were measured. Results: Among the patients, 35.6 % presented with LDHD while 64.4 % had only LDH. Significantly increased median hs-CRP (p<0.001) and CRP (p<0.001) were observed in patients groups compared to controls, while CRP showing a consistent independent association across the combined disease (OR=1.68, 95% CI=1.33-2.14, p<0.001), LDHD (OR=1.62, 95% CI=1.16-2.20, p=0.005) and LDH (OR=1.69, 95% CI=1.30-2.20, p<0.001) multivariable models. No significant difference was observed in serum E-selectin between the study groups. Multivariable models incorporating inflammatory and clinical variables demonstrated substantially greater discriminatory performance than individual biomarkers alone. Conclusion: Elevated circulating CRP and hs-CRP concentrations were associated with lumbar disc pathology, with CRP showing a consistent independent association across the combined disease, LDH and LDHD multivariable models, whereas E-selectin showed no significant association. Multivariable models incorporating inflammatory and clinical variables demonstrated greater discriminatory performance than individual biomarkers. These findings support a potential systemic inflammatory component in lumbar disc pathology, although the cross-sectional nature of the measurements does not establish causality or a local inflammatory response within the disc.

Background: Higher Body Mass Index (BMI) is an established risk factor of sleep disturbance. It is not known if the effect is homogeneous across the lifecourse or if there is a particular time point in life that might be best to target. Methods: Two-sample Mendelian randomization (MR) was used to investigated the effect of childhood adiposity (adjusting on adulthood adiposity and obstructive sleep apnea (OSA)) on insomnia, morning chronotype, sleep duration, daytime sleepiness and daytime napping. Similarly, total, and direct effect of adulthood adiposity on these outcomes was explored. We used summary statistics from a genome-wide association study (GWAS) of UK Biobank for childhood and adulthood adiposity (n=453,169) and large-scale consortia of OSA (Million Veteran Program) (n=410,268), insomnia, and chronotype (23andMe) (n=1,978,022 and n=248,1000, respectively). Results: Two-sample univariable MR analysis provided no evidence of an effect of genetically predicted childhood adiposity on later life insomnia (Odds ratio (OR)= 0.94, 95% Confidence interval (CI)= 0.87, 1.03). Whereas, multivariable MR (adjusted for adulthood adiposity) analysis provide strong evidence of direct protective effect of genetically predicted childhood adiposity on later life insomnia (OR= 0.70, CI= 0.64, 0.77). Further, both in univariable and multivariable MR, a strong positive effect of increased childhood body size on morning chronotype was observed (OR= 1.16, CI= 1.01, 1.33 and OR= 1.36, CI= 1.15, 1.62, respectively) after accounting for adulthood body size. In both analysis the estimate did not change considerably after aditionally adjusting for OSA. However, childhood and adulthood adiposity found to be associated with OSA and OSA with insomnia. In both univariable and multivariable analysis, increased body size in adulthood increased the risk of having insomnia and a morning chronotype. Conclusions: The findings suggest that higher body size in childhood is not a risk factor for later life insomnia, whereas higher body size in adulthood was. Further, if healthy body size is maintained in adulthood, high childhood adiposity may decrease the risk of insomnia and increase the risk of being a morning person in later life. Keywords: childhood, adulthood, obesity, insomnia, morning chronotype, medelian randomization

Background: Aerobic exercise is recommended during stroke rehabilitation to improve cardiorespiratory fitness and support recovery; however, participation rates remain low. While institutional and system-level barriers have been widely examined, less is known about how individual patient factors influence engagement in aerobic exercise during rehabilitation. Objectives: We aimed to determine whether depressive symptoms, apathy, self-efficacy and outcome expectations for exercise, perceived barriers, or past exercise history were associated with aerobic exercise participation in stroke rehabilitation. Methods: In this prospective cohort sub-study, adults admitted to in- or out-patient stroke rehabilitation at three urban hospitals completed validated questionnaires assessing depressive symptoms, apathy, exercise self-efficacy, outcome expectations for exercise, perceived barriers to being active, and premorbid exercise history. Participants were separated into two groups for analysis: those who completed aerobic exercise during rehabilitation and those who did not. Equivalence testing and between-group comparisons were performed. Results: Sixty-two participants were enrolled; 16 participated in aerobic exercise and 46 did not. Groups were not equivalent on any individual-level factors. Compared to non-participants, those who performed aerobic exercise had significantly higher depressive symptom scores (p=0.0025) and lower self-efficacy for exercise (p=0.0087). Non-participants demonstrated significantly higher apathy (p=0.0007). No significant differences were found for outcome expectations, perceived barriers, or exercise history. Conclusion: Depressive symptoms and lower self-efficacy did not impede aerobic exercise participation during rehabilitation. Increased apathy, however, was associated with non-participation. Findings highlight the need for individually tailored aerobic exercise prescriptions that consider motivational and affective factors to optimize engagement during stroke rehabilitation.

Background and Objectives: Recurrence following burr-hole drainage of chronic subdural haematoma (cSDH) occurs in 10-25% of cases, sustained by neovascularisation of the subdural neomembrane supplied by the middle meningeal artery (MMA). MMA embolisation reduces recurrence; whether incidental burr-hole intersection of MMA branches during drainage confers similar benefit is unknown. Methods: We performed a multicentre retrospective cohort study of consecutive adults undergoing burr-hole drainage for cSDH at two UK tertiary neurosurgical centres. Postoperative thin-slice CT was used to classify burr-hole intersection of the underlying MMA groove (no hit, distal-branch hit or main-branch hit) and measure perpendicular burr-hole-to-MMA-groove distance. Co-primary outcomes were radiological recurrence and recurrence requiring intervention. Patient-clustered multivariable logistic regression adjusted for prespecified clinical covariates and treating site. Results: 227 patients (284 operated hemispheres) were included. Radiological recurrence decreased from 34.4% with no branch hit to 22.9% with main-branch intersection, with the gradient confined predominantly to unilateral cSDH. Main-branch intersection was associated with lower adjusted odds of radiological recurrence in unilateral cSDH (adjusted OR 0.30, 95% CI 0.11- 0.81; P = .018), with a similar but non-significant association in the overall cohort (adjusted OR 0.53, 95% CI 0.26-1.07; P = .075). Burr-hole-to-MMA-groove distance demonstrated a more consistent association: in the overall cohort, each 5-mm increase independently increased the odds of radiological recurrence (adjusted OR 1.38, 95% CI 1.04-1.82; P = .025). In unilateral cSDH, each 5-mm increase was independently associated with both radiological recurrence (adjusted OR 1.45, 95% CI 1.03-2.04; P = .034) and recurrence requiring intervention (adjusted OR 1.52, 95% CI 1.05-2.20; P = .027). Conclusion: Main-branch intersection of the middle meningeal artery during routine burr-hole surgery is associated with lower recurrence of unilateral cSDH, while the accompanying burr-hole-to-MMA-groove distance gradient provides biologically plausible support for a dose-response relationship. Together, these findings provide mechanistic rationale for prospective evaluation of intentional neuronavigation-guided MMA targeting (BURR-MMA; NCT07549893).

Disseminating study results to participants is an ethical responsibility for researchers but remains uncommon in low- and middle-income countries, and participants preferences for receiving study results are poorly understood. This study examined study result dissemination preferences among pregnant women in a phase III malaria prevention trial in Papua New Guinea (PNG). Participants completed an interviewer-administered questionnaire (survey) assessing their interest in and motivation for receiving trial results and preferences for dissemination methods and content. Associations between participants characteristics and dissemination preferences were explored using multivariable logistic regression analysis. Of 1172 trial participants, 96.0% (1125/1172) completed the survey, and of these 99.6% (1121/1125) wanted to learn about the trial results. The main motivation factors driving participants interest were an acknowledgment of their contribution to research (51.7%; n=579) and a better understanding of the study (45.0%; n=505). Most participants (78.9%; n=884) wanted to learn about the trial findings through written summary and a group meeting with other participants at the nearest clinic (31.1%, n=349). Multivariable regression analysis indicated that participants from rural/peri-urban clinics were more likely to choose non-electronic media dissemination approaches such as a group meeting as compared to urban-dwelling participants. Frequently selected items (>50% of participants) for content included information regarding good results of the study, purpose of the study, medical treatment advances, results specific to me, and how study was conducted. There was heterogenicity in the preference for dissemination content: compared to urban clinics rural clinics are less likely to want to learn about how and why study was conducted and medical and scientific advances. Overall, the majority wanted to learn about trial results, highlighting the importance of integrating dissemination into research activities in PNG. Variation in preferences for mode and content of dissemination between study clinics suggests that dissemination activities could be tailored to local context and preferences.

Background: Fibrosis, characterised by excessive accumulation of collagen type I (COL1), is a common feature of chronic diseases, including liver diseases (LDs), chronic kidney disease (CKD) and heart failure (HF). COL1 degradation products can be detected in urine by proteomics/ peptidomics analyses and may serve as non-invasive biomarkers of fibrosis. We aimed to identify a common molecular signature of fibrosis across these diseases that may ultimately guide interventions to slow disease progression and prevent organ damage. Methods: Using capillary electrophoresis coupled to mass spectrometry (CE-MS), naturally occurring COL1 degradation products (peptides) in the urine of patients with fibrotic disease, LDs (n=127), CKD (n=263) or HF (n=187), were investigated and compared with the same number of matched controls. Disease-associated COL1 peptides were identified separately for each condition, and peptides showing consistent associations across the three diseases were selected to define a common fibrosis signature. A support vector machine model based on the selected peptides was developed and validated in independent cohorts of patients with LDs (n=110), CKD (n=93), HF (n=32) and controls (n=643). Results: We identified a common fibrotic signature consisting of 50 COL1 degradation products, mainly downregulated in fibrosis. A model based on these peptides achieved a strong performance, with an area under the receiver operating characteristic curve (AUC) of 0.935 (95% confidence interval (CI) 0.917-0.953, p<0.0001) in an external validation cohort comprising pooled disease groups (LDs, CKD, and HF) and controls. Performance was maintained in LDs, CKD and HF, with AUCs of 0.917 (95% CI 0.890-0.944, p<0.0001), 0.951 (95% CI 0.931-0.971, p<0.0001) and 0.950 (95% CI 0.903-0.997, p<0.0001), respectively. The model scores were significantly associated with fibrosis stage in LDs (p=0.0097) and with interstitial fibrosis and tubular atrophy in CKD (p=0.045). Conclusion: A model of urinary COL1 peptides captures a shared collagen degradation signature across organs and diseases, enabling the non-invasive assessment of fibrosis irrespective of its origin. As these peptides exclusively reflect collagen degradation, the findings suggest impaired collagen degradation as a driver in fibrosis. Future clinical studies are warranted to evaluate the utility of this model for early fibrosis detection and earlier implementation of anti-fibrotic interventions.

Objective: To determine whether paradoxical relief, feeling unusually better after a seizure compared to before it, is more common after functional/dissociative seizures (FDS) than epileptic seizures (ES), quantify its diagnostic accuracy, and explore its relationship with preictal symptoms. Methods: Consecutive patients admitted to a tertiary epilepsy unit for prolonged inpatient EEG monitoring underwent a structured clinical interview on admission, before final multidisciplinary diagnostic classification. Preictal dissociative and autonomic/somatic symptom burden was assessed using items adapted from established questionnaires. Diagnostic classification incorporated clinical history, seizure semiology, video electroencephalography findings, and collateral information. Patients with dual or indeterminate diagnoses were excluded. Associations with paradoxical relief were examined using logistic regression, followed by an exploratory mediation analysis. Results: Of 176 patients assessed, 66 with FDS and 65 with ES were included. Paradoxical relief was reported by 46/66 patients with FDS (69.7%) and 10/65 with ES (15.4%; unadjusted odds ratio [OR] 12.65, 95% confidence interval [CI] 5.57 to 31.09). As a diagnostic signal for FDS, paradoxical relief had 69.7% sensitivity (95% CI 57.1 to 80.4), 84.6% specificity (95% CI 73.5 to 92.4), a positive likelihood ratio of 4.53 (2.51 to 8.19), and a negative likelihood ratio of 0.36 (0.24 to 0.52). FDS diagnosis remained independently associated with paradoxical relief after adjustment (OR 10.59, 95% CI 3.42 to 38.06). In a parallel mediation analysis, dissociative symptom burden showed a significant indirect effect, accounting for 19.5% of the association between diagnostic group and relief, whereas the indirect effect through somatic/autonomic symptom burden was not significant. Significance: Paradoxical relief is substantially more common after FDS than ES and may provide a simple, clinically useful diagnostic signal. Its absence does not exclude FDS, and the finding requires external validation. The association with dissociative symptoms is exploratory and supports prospective investigation of whether relief reflects transient resolution of a disturbed, disembodied preictal state.

Objective: Whether a scheduled antiseizure medication (ASM) continues on schedule across the ICU-to-floor transfer has not been characterized. We quantified ASM administration-gap frequency across this transfer and compared it with gap frequency during matched non-transfer intervals in the same patient and drug. Methods: In this retrospective MIMIC-IV (version 3.1) cohort study, we identified epilepsy and status-epilepticus admissions with an ICU stay followed by floor transfer and a scheduled ASM order active at ICU departure. A gap was defined as an interval exceeding 1.5 times the expected dosing interval between the last ICU dose and first floor dose, or no further dose before discharge, and compared with a matched non-transfer control interval in the same patient and drug (paired McNemar test). A multivariable model evaluated six prespecified clinical predictors; sociodemographic variables were summarized descriptively. Results: Among 2,469 ASM transition-by-drug observations (1,583 admissions, 1,335 patients), an administration gap occurred in 251 (10.2%; 95% CI, 8.7%-11.7%). Gap frequency across the transfer exceeded frequency during matched non-transfer control intervals in the same patient and drug: a paired rate difference of 5.8 percentage points (95% CI, 4.4-7.1; 7.5% vs 1.7%; P = 7.3 x 10^-22) before the transfer and 6.4 percentage points (95% CI, 4.9-7.9; 8.9% vs 2.5%; P = 1.9 x 10^-23) after. Gap rates were similar for intravenous-available (9.9%) and oral-only (11.4%) drugs (rate difference, 1.5 percentage points; 95% CI, -1.6 to 4.5; P = .34). None of six prespecified predictors reached significance after correction. Significance: An antiseizure medication administration gap occurred in approximately 1 of every 10 drug-transition observations at the ICU-to-floor transfer, exceeding matched non-transfer gap rates by 5.8 to 6.4 percentage points. This transfer-associated excess, rather than any single medication or patient characteristic, supports a structured medication-continuity check.

Routine childhood growth surveillance is a cornerstone of pediatric care. Growth pattern abnormalities are often early manifestations of chronic disease. Yet subtle abnormalities are frequently underrecognized, leading to diagnostic delays and avoidable morbidity. We introduce SPROUT (System for Pediatric Recognition Of Undiagnosed Trajectories), a generalized, multi-agent large language model (LLM) reasoning system designed to identify a broad spectrum of pediatric growth-related conditions from longitudinal electronic health records (EHRs) earlier than standard clinical practice. Using a large pediatric primary care EHR dataset, we developed and validated SPROUT as a two-stage system. First, a highly specific LLM screener flags concerning longitudinal growth patterns. Second, an Orchestrator module coordinates a multidisciplinary panel of LLM agents to generate a ranked differential diagnosis. To correct systemic reasoning errors, a Trainer module injects meta-knowledge into the panel via a dedicated "Learner" agent. Diagnostic capability was evaluated using a walk-forward, visit-by-visit simulation leading up to the diagnosis date. The SPROUT screener model achieved 98% (83/85) specificity and 28% (9/32) sensitivity on a gold-standard dataset of pediatric primary care patients when evaluated one year before the index date, and 100% specificity and 47% sensitivity when evaluated using longitudinal data up to the day of diagnosis. When applied to 300 control patients (i.e., healthy or undiagnosed), the screener flagged 15. Subsequent expert panel review confirmed high suspicion for undiagnosed pathology in 33% (5/15) of these cases. In chronological walk-forward validation on disease cases, the diagnostic engine identified conditions well before standard-of-care documentation. One year prior to clinical diagnosis, the system achieved sensitivities of 81% for type 1 diabetes mellitus, 56% for pituitary disorders, and 44% for celiac disease. The SPROUT multi-agent system demonstrates the ability to detect a significant portion of latent growth-related pediatric conditions months to years before current clinical standards while minimizing false positives. These results support its potential as a decision support tool for reducing diagnostic delays in pediatric care.

To evaluate the cost-utility and 5-year budget impact of first-line olaparib plus abiraterone versus abiraterone alone for metastatic castration-resistant prostate cancer (mCRPC) in China after the eleventh round of volume-based procurement (VBP). The intention-to-treat (ITT) population was assigned primary decision-analytic weight; the prespecified BRCA1/2-mutated (BRCAm) subgroup was a supporting analysis.

Biological aging occurs heterogeneously across individuals and organs. However, current measures of biological age incompletely capture organ-specific differences in health and disease risk. Because chest CT visualizes multiple thoracic organs, it offers an opportunity to quantify structural aging across organ systems. Here, we developed MOSAIC-Age, a framework characterizing eight organ-specific aging clocks on chest CT. The clocks were developed and validated using 9,971 CT scans from CT-RATE and MIDRC, and subsequently locked and applied to two independent prospective cohorts with 35,293 participants from the National Lung Screening Trial and Genetic Epidemiology of COPD study. CT-derived biological age gaps (BAGs) were examined in relation to lifestyle and socioeconomic factors, prevalent comorbidities, incident chronic diseases, and all-cause and cause-specific mortality. Higher BAGs, indicating organs that appeared older on CT than expected for their chronological age, were broadly associated with adverse health characteristics, chronic disease burden, and increased mortality risk. Multiple disease outcomes were associated with aging across several organs, whereas in multivariable analyses including all eight organ-specific BAGs, the remaining associations were more organ specific. A greater number of markedly older-appearing organs and a faster pace of aging were each associated with higher mortality. Together, these findings demonstrate that routine chest CT captures both shared and organ-specific patterns of biological aging and establish CT-derived organ aging as a quantitative imaging biomarker for assessing multi-organ health and long-term disease risk.

Background: Cancer is a growing public health challenge in Ghana, with 27,385 new cases and 17,944 deaths recorded in 2022. Ghana developed a National Cancer Control Strategy (NCCS) in 2011 to guide prevention, early detection, treatment, and palliative care. The strategy expired in 2016 and has not been formally evaluated or renewed, leaving cancer control efforts without a guiding policy framework for nearly a decade. This study examined how the strategy was implemented, what barriers were encountered and what stakeholders recommend for a strengthened national cancer response. Methods: We conducted a qualitative descriptive study using semi-structured key informant interviews. Fifteen participants were recruited through purposive sampling, supplemented by snowball referrals, representing three groups: Ministry of Health policymakers, frontline healthcare providers and representatives of cancer-focused non-governmental organisations. Data were collected between June and September 2025 and analysed using Braun and Clarke's six-phase thematic analysis framework, guided deductively by the WHO Health Systems Building Blocks framework Results: Three themes emerged: NCCS interventions and systems implemented, capturing progress in cancer awareness, HPV vaccination and pilot screening programmes alongside persistent geographic and financial inequities in access; barriers to implementation, including inadequate financing, infrastructure and workforce shortages, the absence of a national cancer registry and governance failures, among them the finding that no frontline healthcare provider interviewed had any awareness of the NCCS; and recommended implementation strategies, including co-production of a renewed strategy, establishment of a dedicated National Cancer Control Programme, expanded health insurance coverage and decentralisation of oncology services. Conclusion: The NCCS was not operationally embedded in the health system. The evidence points to failures in policy dissemination as a constraint that precedes resource constraints. Addressing Ghana's rising cancer burden requires renewed political commitment, co-produced governance structures and accountability mechanisms. These findings have relevance for other low- and middle-income country settings facing similar challenges.

Introduction: Continuous glucose monitoring (CGM) offers an advancement over traditional self-monitoring of blood glucose (SMBG) for people living with type 1 diabetes (T1D). However, evidence on the acceptability and feasibility of different CGM use cases in African populations remains limited. Methods: This was a pragmatic three-arm, randomised controlled trial on CGM conducted among people living with T1D in three public healthcare clinics in South Africa. Participants were assigned to Arm 1 (continuous CGM), Arm 2 (periodic CGM), or Arm 3 (SMBG). Diabetes education was provided at all study visits. Feasibility was assessed by adherence to CGM use and through the Glucose Monitoring Satisfaction Survey (GMSS). Diabetes distress was measured by the Diabetes Distress Scale (DDS), health-related quality of life (HRQoL) by the EQ-5D scales, and acceptability using the Theoretical Framework of Acceptability (TFA). Surveys were collected on paper and transferred to OpenClinica. Analyses were performed in R. The trial was registered in the Clinical Trials Registry (NCT05944718) on July 13, 2023. Results: A total of 83 participants were included in Arm 1, 85 in Arm 2, and 80 in Arm 3. CGM mean active time was 55% in Arm 1 versus 69% in Arm 2. The proportion of participants meeting the [&ge;]70% active time threshold was higher in Arm 2 (52%) than in Arm 1 (34%). Diabetes' distress declined across arms during the intervention period, with no significant difference between arms; distress increased slightly six months post-intervention but remained below baseline. At 6 months, glucose monitoring satisfaction was significantly higher in both CGM arms than in the SMBG arm, and satisfaction increased over time in CGM arms. Health-related quality of life remained stable across arms during the intervention period with no significant difference between arms. High acceptability was observed in both CGM arms, with higher ratings in the periodic arm. Conclusions: CGM was acceptable to people living with type 1 diabetes and feasible to use in public-sector clinics in South Africa, with high acceptability under continuous and periodic use. Health-related quality of life remained stable across arms, and diabetes-related distress declined, during the intervention period, across arms. Glucose monitoring satisfaction rose significantly in both CGM arms compared to SMBG. Periodic CGM might be a promising and potentially more scalable option than continuous use for public-sector care.

Background: In Tanzania, over 10,000 women aged 15-44 are diagnosed with cervical cancer annually, and more than 6525 die. The majority are diagnosed at an advanced stage, which contributes to delays in treatment enrollment and illness complications. Multiple factors can affect womens willingness and ability to access cervical pre-cancer screening. Purpose: To explore the barriers and facilitators to attending cervical pre-cancer screening among women living in a resource-constrained area of Southern Tanzania Methods: A qualitative study of 17 focus group discussions and 12 in-depth interviews was conducted from December 2023 to July 2024. Data collection took place in the community and health centers of a town and the surrounding rural areas in Kilombero district. The study used purposive sampling to recruit 112 women and 23 men aged 18- 50+ years. Results: Fear of death emerged as a central theme in the data, acting as both a barrier to and a facilitator of womens screening behavior. Women linked death with the screening procedure, receiving results and undergoing treatment. Participants mistrusted the speculum itself and linked it to pain, vaginal infection, and infertility. Conversely, fear of physical and social death motivated other women to attend the screening to learn about their health and prevent the consequences of a positive diagnosis. Public trust in the healthcare system and the role of health information sources were also identified as influencing women's decisions to undergo or not undergo screening. Conclusion: Our findings showed that cervical cancer screening uptake is influenced by fear of death and other co-factors. To improve early cervical cancer screening, programs and policy interventions are needed to raise awareness of the disease while also addressing womens specific concerns. Also, strengthening structural dimensions such as the availability of the healthcare workforce, healthcare facilities, and ensuring equitable service availability are essential to reducing cervical cancer complications and avoidable mortality.