Pain

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: 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: 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

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: 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: The relative merits of infrainguinal bypass and primary major lower limb amputation (MLLA) for chronic limb-threatening ischaemia (CLTI) remain uncertain, and the baseline profiles of patients selected for each strategy are poorly described. Methods: A systematic review and meta-analysis were undertaken in accordance with PRISMA 2020 and prospectively registered (PROSPERO: CRD42022356094). MEDLINE, Embase, CENTRAL, and CINAHL were searched from inception to March 2025. Prospective studies of adults with CLTI undergoing primary infrainguinal bypass or primary MLLA were eligible. Mortality, major adverse cardiovascular events (MACE) and subsequent amputation outcomes were synthesised using random-effects meta-analysis of proportions. Baseline comorbidity profiles were also extracted. Results: Twenty-seven studies involving 6,576 patients were included: 5,779 underwent infrainguinal bypass and 797 underwent MLLA. After bypass, pooled mortality was 3.7% at 30 days (95% CI 2.8%-4.9%, I2 = 49.4%), 18.5% at 1 year (95% CI 15.6%-21.9%, I2 = 62.3%), and 54.3% at 5 years (95% CI 50.5%-58.0%, I2 = 0%). After MLLA, pooled mortality was 9.2% at 30 days (95% CI 4.1%-19.3%, I2 = 73.5%), 28.5% at 1 year (95% CI 13.3%-51.0, I2 = 70.8%), and 39.9% at 2 years (95% CI 0.3%-99.3, I2 = 90.5%), although longer-term estimates were limited by sparse data and marked heterogeneity. Thirty-day MACE was 6.5% (95% CI 4.3%-9.7, I2 = 63.5%) after bypass and 2.8% after MLLA (95% CI 0.1%-37.6%, I2 = 0%). Early subsequent major amputation after bypass occurred in 3.9% of patients (95% CI 2.0%-7.7%, I2 = 91.2%), rising to 16.2% at 1 year (95% CI 12.6%-20.5%, I2 = 82.0%) and 33.3% at 3 years (95% CI 20.1%-49.8%, I2 = 0%). Early re-amputation after MLLA occurred in 10.9% of patients (95% CI 4.5%-24.4%, I2 = 40.3%). Baseline comorbidity burden was high in both groups, with substantial heterogeneity across studies. Conclusions: CLTI carries a poor prognosis regardless of treatment strategy. Infrainguinal bypass is associated with lower early mortality and better early limb preservation than primary MLLA, but long-term survival remains poor and later limb failure is common. Primary MLLA is not a low-risk alternative. Better contemporary comparative evidence utilising modern causal inference approaches is needed to support individualised decision-making.

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 affects approximately 10% of reproductive-age women and is associated with substantial diagnostic delay and heterogeneous symptom presentation. Prior machine-learning prediction models have relied on comorbidity data alone or on small candidate-variant genetic scores, with inconsistent or incompletely reported performance. No study has combined a well-powered, multi-ancestry polygenic risk score (PRS) with environmental, reproductive, and symptom data in a single hybrid model. We developed and evaluated hybrid risk-prediction models integrating a genome-wide, multi-ancestry PRS with clinical and symptom data for endometriosis in the US-based All of Us Research Program. Methods: Among 69,376 participants (15,382 endometriosis cases, 53,994 controls) across six genetically inferred ancestry groups, we computed individual-level PRS values using PRS-CS weights derived from an independent, multi-ancestry GWAS. Five nested logistic regression, random forest, and XGBoost models progressively added age, ancestry, and within-ancestry genetic principal components (Model 1), environmental and reproductive factors (Model 2), symptom and comorbidity indicators (Model 3), all covariates combined (Model 4), and PRS x environment interactions (Model 5). Performance was assessed by AUROC in a held-out test set and 5-fold cross-validation, with class-weighted, Youden-optimized thresholds used for sensitivity, specificity, and predictive values; permutation importance identified top contributors. Pairwise AUROC differences were tested with a Holm-corrected DeLong-type test. Results: Discrimination improved from AUROC 0.63 (PRS, age, ancestry, principal components) to 0.72 for the full model, driven mainly by symptom and comorbidity data. XGBoost consistently outperformed logistic regression and random forest. The PRS ranked among the top individual predictors by permutation importance in nearly every model, alongside age, while genetic and demographic information alone gave only modest discrimination, and PRS x environment interactions did not improve on environmental factors alone. Threshold optimization yielded balanced sensitivity and specificity (~0.67/0.65) versus near-zero sensitivity at a default threshold. Conclusions: Combining the PRS with symptom and comorbidity data gave the best discrimination compared to solely a well-powered, multi-ancestry PRS as a predictor of endometriosis. This study clarifies both the promise and current limits of hybrid genetic-clinical prediction for endometriosis and points to symptom-based phenotyping, molecular subtyping, and external validation as priorities.

Importance Non-inferiority trials are becoming increasingly popular in abdominal surgery. The non- inferiority margin is critical in the interpretation and conclusion of these trials. Objective This systematic review aims to assess the methodological and reporting quality of non- inferiority randomized controlled trials in abdominal surgery. Evidence Review Non-inferiority trials were systematically identified by searching Ovid Medline, Embase and the CENTRAL databases from 2006 until December 2025. Randomized controlled trials in adult patients with any type of abdominal surgical intervention in at least one trial arm and a sample size greater than or equal to 100 were eligible for inclusion. The primary outcome was the definition of the non- inferiority margin. Secondary outcomes were the reporting of the non-inferiority margin, the robustness of its estimation, the uncertainty of the point estimate and the adequacy of conclusions. Findings A total of 11 045 trials were identified, of which 101 were eligible, enrolling 44 370 patients. Most trials provided a rationale for the non-inferiority design, while six (5.9%) trials did not. Previous literature was commonly used (n=56; 55.4%), but the non-inferiority margin was most often based on a clinical fixed margin or on historical comparison of the treatment and the active comparator. Based on the margin, investigators tolerated substantially worse outcomes of the treatment compared to the comparator. Conclusions were appropriate based on the confidence interval and the predefined non- inferiority margin in 88 (87.1%) of trials. The clinical judgement of the conclusion was overall adequate. Confidence interval estimations were reported in 16 (15.8%) of trials. Simulation studies were limited by the reporting quality. Conclusions and Relevance Clinical fixed margins are commonly used in abdominal surgery non-inferiority randomized controlled trials, however, substantial shortcomings in reporting limit the interpretability and reproduction of study findings. Based on the findings of this study, guidance on surgical- specific non-inferiority margin definitions is needed.

Importance: Chronic stress may contribute to adverse health outcomes through cumulative physiologic dysregulation. Allostatic load (AL), a composite measure of multisystem physiologic burden, may capture biologic effects of structural, social, and psychosocial stress not reflected by self-reported measures. Objective: To evaluate racial and ethnic differences in AL among women with familial cancer risk and examine how socioeconomic status, psychosocial factors, clinical characteristics, and health behaviors contribute to variations in AL. Design: Cross-sectional study of underrepresented minority participants enrolled in the HERSTORY cohort from October 2023 through September 2025, with comparison participants from the UCLA ATLAS biobank. Setting: UCLA academic health system. Participants: The study included 303 racially and ethnically diverse female HERSTORY participants aged [&ge;]35 years with a family history of cancer and matched non-Hispanic White female ATLAS participants (n=709). Exposures: Race and ethnicity, age, neighborhood deprivation, cancer history and stage, depression, perceived stress, cancer worry, and physical activity. Main Outcomes and Measures: The primary outcome was AL, calculated from cardiometabolic and organ-function measures. A secondary index incorporated race- and ethnicity-specific neutrophil-to-lymphocyte ratio (NLR) derived from 326,826 women in the UCLA Health population. Multivariable regression models evaluated factors associated with elevated AL. Results: Compared with matched non-Hispanic White participants, Black and Asian/Pacific Islander HERSTORY participants had significantly higher AL after adjustment. Hispanic/Latina participants did not have significantly elevated AL. Older age, greater area-level socioeconomic deprivation, and depression were independently associated with higher AL. Prior cancer diagnosis, cancer worry and perceived stress were not significantly associated with AL, whereas regular physical activity was associated with lower AL. Among cancer patients, advanced stage was associated with greater AL. Conclusions and Relevance: This study demonstrates elevated AL among understudied racial/ethnic minority groups with familial cancer risk and identifies associations with neighborhood deprivation, depression, and physical activity. The association between cancer stage and AL suggests that physiologic stress may reflect variation in cancer burden. The lack of association with perceived stress and cancer worry further indicates that physiologic and self-reported psychosocial measures capture distinct dimensions of stress. The development of race/ethnicity-specific NLR thresholds derived from large population samples provide a benchmark for future studies.

Background: Sleeve gastrectomy is the most frequently performed bariatric procedure worldwide but is associated with the development of de novo gastroesophageal reflux disease (GERD). Hiatal hernia has been identified as a relevant anatomical factor in postoperative reflux, although most studies evaluate it dichotomously without analyzing whether its size influences GERD risk. The aim was to evaluate the association between preoperative hiatal hernia size and de novo GERD after sleeve gastrectomy. Methods: Retrospective, single - center, observational study of patients undergoing sleeve gastrectomy at Hospital Central Norte de Petroleos Mexicanos (2018 - 2025). Demographic and clinical characteristics, endoscopic classification of hiatal hernia size (small <2 cm, medium 2.1 - 4 cm, large >4 cm), and evidence of de novo GERD were analyzed using descriptive statistics, Fisher's exact test, odds ratio (=R) estimation with 95% confidence intervals (CI), and binary logistic regression. Statistical significance was set at p<0.05. Results: Fiftysix patients were included (mean age 48.3 {+/-} 8.1 years; 67.9% male). Hiatal hernia classification was conclusive in 46 patients (82.1%): 63.0% no hernia, 4.3% small, 30.4% medium, and 2.2% large. De novo GERD occurred in 14.0% of patients without preexisting GERD (6/43). No significant association was found between hiatal hernia size and de novo GERD (Fisher p=0.515). In the reduced logistic model, neither hiatal hernia (medium/large vs. absent/small; OR 3.47; 95% CI 0.50 - 29.43; p=0.207) nor age (OR 1.02; 95% CI 0.90 - 1.13; p=0.754) was significantly associated. No evaluated factor (sex, smoking, alcohol, age) reached significance. Conclusions: In this cohort, no statistically significant association was demonstrated between preoperative hiatal hernia size and de novo GERD after sleeve gastrectomy; however, the low number of events limits the ability to exclude a clinically relevant association. These findings are compatible with a multifactorial mechanism rather than with the isolated presence of this finding. Prospective studies with larger sample sizes and standardized reflux assessment instruments are required to confirm these results.

Background: Pressure ulcers often develop complex three-dimensional morphologies that extend beyond the visible wound surface. Subsurface extensions such as tunneling and undermining create hidden cavities that complicate clinical assessment and wound management. Despite their clinical relevance, the prevalence and spatial characteristics of these subsurface wound morphologies have not been well characterized at scale. Methods: We performed a registry-based analysis using data from the LIFT-OFF Pressure Ulcer Registry, which captures longitudinal clinical documentation of pressure ulcers treated in routine care. The registry included approximately 18,000 patients with 32,000 documented pressure ulcers. Spatial characteristics of tunneling and undermining were analyzed using measurements recorded during routine wound assessments, including tract length, direction, and circumferential extent. Directional and circumferential distributions of subsurface defects were examined to characterize wound geometry. Results: Tunneling was present in 764 of 14,700 full-thickness pressure ulcers (5.2%), whereas undermining occurred in 2,293 wounds (15.6%). Tunneling tracts were typically short and exhibited directional clustering relative to the wound bed. In contrast, undermining demonstrated broader circumferential distributions and frequently involved larger subsurface separations beneath the wound margin. Both morphologies demonstrated distinct spatial patterns across anatomical locations and wound stages. Conclusion: Tunneling and undermining are common subsurface features of pressure ulcers and exhibit distinct spatial geometries. Whereas tunneling manifests as directional tract-like extensions, undermining more frequently produces circumferential tissue separation beneath wound margins. Improved characterization of subsurface wound architecture may enhance assessment of wound complexity and provide information not captured by surface measurements alone. Future studies should evaluate whether these features contribute to wound severity assessment, prognosis, and risk stratification.

Background: Inequalities exist for many health outcomes, but there is limited evidence regarding menstrual symptoms despite their importance for health and wellbeing. We aimed to investigate inequalities in menstrual symptoms according to socioeconomic position and childhood adversity. Methods: In two generations (G0 mothers and G1 offspring) from the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK prospective cohort study, we examined associations of multiple indicators of socioeconomic position (SEP) and adverse childhood experiences (ACEs) with menstrual symptoms (pain, abnormal uterine bleeding, and premenstrual syndrome (PMS) measured 3-8-years post-birth in G0 and 17-21-years-old in G1), using multivariable logistic regression. Samples ranged from 4,828 to 9,335 G0 participants and 1,288 to 2,757 G1 participants depending on the exposure-outcome association. Missing data were addressed using multiple imputation and inverse probability weighting. Results: Financial difficulties were associated with greater odds of menstrual pain (G1 OR 1.41; 95% CI 1.07, 1.86: G0 OR 1.55; 95% CI 1.36, 1.76) and irregular cycles (G1 OR 1.60; 95% CI 1.12, 2.29: G0 OR 1.48; 95% CI 1.27, 1.72) in both generations, as well as with short/long cycle lengths in G0 only. Lower education and manual social class were also associated with these three menstrual symptoms in at least one generation. Conversely, higher SEP was associated with PMS in both generations. Higher cumulative ACEs were consistently associated with menstrual pain (4+ compared to none: G1 OR 2.15; 95% CI 1.48, 3.11: G0 OR 1.52; 95% CI 1.29, 1.80) and irregular cycles (G1 OR 1.92; 95% CI 1.20, 3.09: G0 OR 1.54; 95% CI 1.26, 1.87) but not cycle length. Lower parental education, financial difficulties, and cumulative ACEs were associated with heavy bleeding in G1 offspring only, whereas financial difficulties, own manual social class, and cumulative ACEs were associated with prolonged bleeding in G0 mothers only. Higher cumulative ACEs were also associated with PMS in G1 offspring only. Conclusions: We found evidence of inequalities according to socioeconomic disadvantage and childhood adversity for multiple menstrual symptoms, although some associations were only observed in one generation. Findings suggest that menstrual symptoms are disproportionately experienced by socially and socioeconomically disadvantaged women.

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).

Objectives: To estimate the prevalence of Post-Exertional Malaise (PEM) among adults with prior COVID-19 and associated mental health and disability outcomes. Methods: We conducted a cross-sectional analysis of data from a survey of 9,620 adults with prior COVID-19 in New York City, collected May - June 2024. PEM was measured with the DePaul Symptom Questionnaire - Post Exertional Malaise, categorized by symptom duration (< 14 vs. [&ge;]14 hours). Weighted prevalence estimates were stratified by socio-demographic and clinical characteristics. Modified Poisson regression was used to assess the association of PEM with depression, anxiety, and disability. Results: The prevalence of PEM symptoms was 20.9% overall and 4.0% with symptom duration [&ge;]14 hours, representing over 800,000 New Yorkers affected and over 150,000 who meet a diagnostic criterion for ME/CFS. PEM prevalence was higher among women, transgender and non-binary adults, people of color, and lower educational attainment, chronic comorbidities, or disabilities. PEM was associated with 3 - 4 times higher prevalence of mental health outcomes and 4 - 5 times higher disability scores. Conclusions: PEM symptoms were common and strongly associated with disability and adverse mental health. Screening, pathways to care, and supportive policies are needed to mitigate long-term consequences, particularly among marginalized populations.

Objective: To examine how medial plantar nerve shear wave speed (Cs) and viscosity coefficient (Vi) are associated with the severity of diabetic peripheral neuropathy (DPN), and to assess their ability to differentiate adjacent severity categories. Materials and Methods: Based on TCSS, the 113 patients with type 2 diabetes mellitus were assigned to the non-DPN (n = 33), mild DPN (n = 46), and moderate DPN (n = 34) groups. Medial plantar nerve Cs and Vi were measured using shear wave elastography and viscosity imaging. Receiver operating characteristic analysis evaluated Cs, Vi, and their logistic regression-based combination; areas under the curves (AUCs) were compared using DeLong tests. Results: Cs and Vi increased progressively across the three groups (both P < 0.001). For non-DPN versus mild DPN, the AUCs of Cs, Vi, and the combined model were 0.688 (95% CI, 0.604-0.772), 0.741 (0.660-0.822), and 0.745 (0.665-0.826), respectively, without significant pairwise differences. For mild versus moderate DPN, the corresponding AUCs were 0.707 (0.625-0.789), 0.794 (0.724-0.865), and 0.799 (0.731-0.867). The combined model outperformed Cs (P = 0.045), whereas Cs versus Vi and Vi versus the combined model did not differ significantly (P = 0.162 and 1.000, respectively). Conclusion: Medial plantar nerve Cs and Vi increased with DPN severity. Their combination improved discrimination between mild and moderate DPN compared with Cs alone but not with Vi alone. Quantitative medial plantar nerve viscoelastic assessment may complement clinical severity grading.

Objectives To analyse the long-term effects of a cruciate ligament (CL) injury on health and socioeconomic outcomes. Methods We used a comprehensive national injury insurance database to identify CL injuries occurring in New Zealand between 2009 and 2022, and employed a doubly robust staggered difference-in-differences research design to identify the effects of these injuries on outcomes up to 10 years after injury. The outcomes of interest were healthcare use (hospitalisations, emergency department visits, medications, knee replacement surgery for osteoarthritis), associated healthcare costs, and labour market outcomes (employment rates, income, and government benefit payments). Results We identified 61 344 CL injuries for inclusion in the analysis. Over 10-year follow-up, a CL injury resulted in increased healthcare use (0.6 more hospitalizations [95%CI 0.4 to 0.7], 1.7 more days spent in hospital [95%CI 1.3 to 2.1], 0.4 more emergency department visits [95%CI 0.3 to 0.6], 2.5 more outpatient visits [95%CI 1.8 to 3.2], and 4.7 more medications dispensed [95%CI -1.8 to 11.2]) and public healthcare costs ($7 537; 95%CI 5 888 to 9 186), reduced income (-$6 060; 95%CI -11 644 to -475), and increased benefit payments ($1 152; 95%CI 542 to 1 761). Conclusion CL injuries have long-term impacts on healthcare use and socioeconomic outcomes. Strategies to reduce the incidence of CL injuries have the potential to realise large health and economic benefits.

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.

This study aimed to quantify the longitudinal tracking and cross-sectional construct validity of a single-item questionnaire measuring recreational physical activity frequency (RPAF) in the Womens Healthy Ageing Project. At baseline, 474 participants aged 45-55 reported RPAF from 1993 to 2014. Longitudinal tracking of the RPAF item was assessed as a consecutive-wave and baseline-referenced measure using linear weighted kappa (LWK), Spearman correlations, exact agreement and within-one-category agreement. Construct validity in the form of convergent and known-group validity was assessed using the International Physical Activity Questionnaire (IPAQ) leisure activity domains, Short Form 36 physical function (SF-36-PF) subscale, Timed Up and Go (TUG), hand grip strength (HGS) and waist-to-height ratio (WHtR). 474 participants provided baseline RPAF data. Pairwise longitudinal samples ranged from 176 to 459 across the study. Consecutive-wave LWK ranged from 0.38 to 0.49, and Spearman correlations ranged from 0.44 to 0.57. Exact and within-category agreement ranged from 41.4%-50.8% and 72.0%-79.0%. Baseline-referenced LWK ranged from 0.22 to 0.47, with Spearman correlations of 0.29 to 0.56. RPAF correlated with total IPAQ leisure score (rs = 0.60), IPAQ walking score (rs = 0.58), SF-36-PF (rs = 0.33) and TUG score (rs = -0.25). No significant correlation was identified between RPAF, HGS or WhTR. RPAF discriminated known groups for WHO guideline-sufficient activity, SF-36-PF, and TUG fall risk. The RPAF item demonstrated fair-to-moderate agreement in consecutive waves, with weaker baseline-referenced tracking. Cross-sectional validity was highest with total IPAQ leisure activity. The item may provide a pragmatic measure for RPAF in womens cohort studies.

Purpose: The primary objective of the Stanford Knee Osteoarthritis PET/MRI Evaluation (SKOPE) study is to develop and evaluate a multimodal, dynamic [18F]NaF PET-MRI framework for characterizing whole-joint physiology and its relationship to osteoarthritis (OA) risk, pain, and disease progression. Specifically, we aim to integrate dynamic PET with quantitative and anatomical MRI, to characterize structural, compositional, and metabolic features across the knee and surrounding musculoskeletal system, evaluate acute tissue responses to exercise, and identify imaging biomarkers associated with OA risk, pain, and disease progression. Methods: The SKOPE study includes multimodal PET-MRI of the knee and surrounding musculoskeletal tissues, with imaging of the knee, tibia, ankle, thigh, hip, pelvis, and lumbosacral spine. Dynamic [18F]NaF PET is combined with conventional anatomical MRI and quantitative MRI techniques, including quantitative double-echo steady-state (qDESS) T2 mapping of cartilage, Dixon fat-fraction imaging, ultrashort echo time (UTE) T2* mapping of short-T2 tissues, UTE imaging of tibial bone, and zero echo time (ZTE) imaging for bone morphology and pseudo-CT generation. Additional MRI sequences characterize muscle composition, bone and joint anatomy, intervertebral discs, and regional vascular anatomy. Selected scans are acquired before and after a standardized exercise protocol to assess the acute physiological response of the joint. Automated segmentation is used to generate subject-specific masks of muscles, bones, vertebrae, and intervertebral discs. A subset of the MRI protocol is repeated at 1- and 2-year follow-up to assess longitudinal changes. Expected Impact: By combining dynamic bone metabolic imaging with quantitative measures of cartilage, menisci, muscle, bone, fat, vascular structures, and the spine and hip, the SKOPE protocol provides a whole-joint and multijoint framework for studying the structural, metabolic, and physiological processes associated with OA and pain. Exercise and longitudinal imaging further enable assessment of acute tissue responses and changes over time, supporting the development of quantitative imaging biomarkers for OA risk, pain, and disease progression.