Journal of Internal Medicine

Nociplastic pain features are common in systemic lupus erythematosus (SLE), yet its longitudinal trajectory remain poorly characterized. SLE patients in the FORWARD Databank were classified as Minimal, Type 1, Type 2, or Mixed using the Polysymptomatic Distress Scale (PSD[&ge;]8) and the Systemic Lupus Activity Questionnaire (SLAQ) inflammatory domain score ([&ge;]2). Cross-sectional analyses (N=372) compared clinical outcomes and medication use. Longitudinal analyses (n=301; median 3.7 years) characterized phenotype transitions using continuous-time Markov models and identified latent trajectories using joint group-based trajectory modeling (GBTM). At baseline, 29% were Minimal, 12% Type 1, 13% Type 2, and 47% Mixed. Functional impairment increased stepwise: from Minimal to Mixed, SF-36 physical component scores decreased from 49.7 to 30.0 and PROMIS Pain Interference scores increased from 46.2 to 63.6 (both p<0.001). Organ damage, depression, and opioid use were highest in Mixed. Longitudinally, Minimal and Mixed were persistent (mean duration 2.0 and 1.8 years; one-year retention 70%), while Type 1 and Type 2 were transient (~0.5 years; retention 18% and 28%). Exit trajectories were asymmetric: Type 1 moved preferentially to Minimal (49% of exits), whereas Type 2 moved to Mixed (65%; p<0.001). Population-average PSD was nearly flat (+0.014 SD/year, p=0.07); while opioid use declined to near zero in Minimal and Type 1 but remained high in Type 2 and Mixed. Joint GBTM identified four severity classes along a Minimal-to-Mixed diagonal. Nociplastic phenotypes in SLE are persistent, severity-stratified, with substantial functional, psychological, organ-damage, and opioid burdens. Transient Type 1 and Type 2 states have divergent longitudinal transitions.

ABSTRACT Importance: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in patients with Systemic Lupus Erythematosus (SLE), due to both traditional CVD risk factors and SLE specific factors. Although statins are first-line therapy for primary prevention of CVD in the general population, it is unclear whether statins protect against first time cardiovascular events (CVEs) in patients with SLE. Objective: Determine whether statins are protective in primary prevention of CVEs among patients with SLE. Design, setting, and participants: This cohort study is a retrospective analysis of a well-characterized, prospective cohort of patients with SLE with patient follow-up beginning in 2013. Main outcome and measures: CVEs were defined as the occurrence of myocardial infarction, thrombotic stroke, onset of angina, or coronary bypass procedure. Statin use in the prior year was quantified based on standardized defined daily doses (DDD). Rates of occurrence were compared using pooled logistic regression. A multivariable model was performed to adjust for possible confounders. Results: The analysis was based on 8708 person-years of follow-up from 1396 cohort participants: 1283 (92%) were women, 567 (41%) Black, and 665 (48%) White. Patients were stratified by use of statin within the last year: none, < standard DDD, or [&ge;] standard DDD. The rate of events per 1000 person-years was respectively 5.3, 8.5, and 8.0 (p=0.31) within these 3 groups, suggesting potential lack of protective effect of statin treatment. The rates of CVEs among statin versus non-statin users remained the same after adjusting for and stratifying by total cholesterol level (p=0.18). Significantly higher rates of CVEs occurred among those with body mass index (BMI) 25-30 kg/m^2 (p=0.0066) and those prescribed [&ge;] 10 mg/day of prednisone (p=0.0003). Multivariable analysis also suggested a potential lack of protective effect of statins against CVEs (OR 1.48; 95% CI, 0.79-2.75; p=0.21883) and diabetes mellitus was found to be independently associated with an increased risk for development of CVEs (OR 4.48; 95% CI 1.99-10.08; p=0.00029). Conclusion and Relevance: Among patients with SLE, statin use may not be protective in primary prevention of CVEs, regardless of statin exposure. Prednisone use, history of diabetes mellitus, and elevated BMI were drivers of increased cardiovascular risk in univariate analysis. Diabetes mellitus persisted as an independent risk factor for CVEs in a multivariable model. Our work reinforces findings from clinical trials which have shown no reduction in subclinical measures of atherosclerosis with statin use among patients with SLE, as well as a mechanistic substudy which demonstrated that statins are ineffective in normalizing the pro-atherogenic changes induced by SLE.

Background: Crohn's disease is a chronic relapsing inflammatory bowel disease with an unpredictable clinical course that may lead to recurrent hospitalizations and surgery, making early identification of patients at risk a key challenge in longitudinal monitoring. Objective: To evaluate the prognostic value of blood biomarkers for anticipating hospitalizations in patients with Crohn's disease by moving beyond exclusive reliance on conventional reference intervals toward the analysis of personalized biological drift. The underlying premise is that fluctuations that remain within standard reference ranges (and are therefore invisible to conventional thresholds) may still carry a risk signal when interpreted relative to an individual's optimal baseline. Design: We conducted a retrospective study of 993 patients with Crohn's disease followed at the University Hospital of Liege between 2005 and 2023. Longitudinal laboratory measurements were linked to Crohn's disease-related hospitalizations. Biomarkers were transformed into z-scores relative to optimized and personalized reference populations and classified into drift categories. Time to first hospitalization was analyzed using the Kaplan-Meier method, and recurrent hospitalizations were modeled using Cox models. Results: Hospitalization-free survival differed significantly across drift categories, including for deviations within conventional reference ranges (e.g., albumin, global log-rank p<0.0001). Among 57 biomarkers screened, 32 were significant in the global log-rank analysis, including 5 that were significant for intra-reference drift classes: low lymphocytes (%), low monocytes (%), low albumin, high potassium, and low aspartate aminotransferase. Conclusion: Personalized biomarker drift detects clinically meaningful risk signals that are missed by conventional reference-interval thresholds and may enable earlier risk stratification in Crohn's disease.

Introduction Hospitalised community-acquired pneumonia (CAP) is heterogeneous in aetiology, severity, and outcome. Phenotyping and endotyping approaches offer potential to stratify patients biologically and guide targeted therapy, but require well-characterised cohorts with linked biosamples. We describe the PARIS (Pneumonia: Acute Respiratory Infection +/- Sepsis) study: a prospective observational cohort of hospitalised patients with pneumonia, designed to characterise functional outcomes and to provide a biobank for translational immunological research. Methods Adults admitted with CAP to a single NHS district general hospital were enrolled within 24 hours of admission between December 2020 and March 2022. Clinical, functional, and physiological data were collected at enrolment, hospital discharge, and 6-8 week follow-up. Serial blood samples were collected for flow cytometry, transcriptomics, pathogen DNA detection, and plasma biobanking. Results Forty-seven patients were enrolled (15 without and 32 with sepsis [SOFA >=2] at enrolment); 87% met sepsis criteria by 24 hours post enrolment. Most patients (30/47, 64%) were managed as COVID-19, microbiologically confirmed in 27. Mean age was 57 years (SD 16), 70% were male, and baseline comorbidity burden was low. Severity was moderate (median NEWS2 4 at enrolment, rising to 6 by 24 hours post enrolment; p<0.001). Mortality was 4/47 (8.5%), with 44/47 (94%) alive at hospital discharge. Median length of stay was 8 days (IQR 5.5-11). Translational samples were collected from the majority: fresh flow cytometry (44/47, 94%), transcriptomics from the sepsis subgroup (31/32, 97%), pathogen DNA sampling (35 samples received across study timepoints; see Table 5), and stored plasma (29/47, 62%). The primary outcome of functional decline (Barthel score decrease >=1.85) occurred in only 1/29 patients with paired assessments (3.4%). Persistent CRP elevation (>3 mg/L) at 6-8 week follow-up was present in 16/31 (52%) survivors with available data. Conclusions The PARIS cohort provides a well-characterised clinical platform and linked biobank to support translational studies of pneumonia and sepsis. The low rate of functional decline reflects the younger, lower-comorbidity, COVID-predominant population recruited. Primary protocol endpoints were not achieved owing to pandemic-related disruption. Data and samples underpin a programme of linked translational studies.

Background: Anti-synthetase syndrome (ASyS) is a subgroup of idiopathic inflammatory myopathies that is increasingly recognized as a distinct entity with features of myositis, interstitial lung disease, inflammatory arthritis, and Raynaud phenomenon. Co-reactivity with anti-Ro-52, an antibody directed against the Ro-52 E3 ubiquitin ligase, has been shown to be associated with progressive interstitial lung disease within this patient population. However, less is known regarding the association of anti-Ro-52 positivity with cardiovascular outcomes. Methods: A sub-cohort of patients with anti-synthetase antibodies at a large single institution center was retrospectively analyzed to define presence of anti-Ro-52 positivity (defined as anti-Ro-52 titer greater than or equal to 11 utilizing the line immunoblot platform, Euroline Autoimmune Inflammatory Myopathies, EuroImmun Diagnostics, Lubeck, Germany). Patients who did not meet 2017 ACR/EULAR classification criteria for idiopathic inflammatory myopathies were excluded from the final analysis. Cardiovascular outcomes ascertained via retrospective chart review included atrial fibrillation, left bundle branch block, right bundle branch block, pulmonary hypertension (confirmed via right heart catheterization), heart failure with reduced ejection fraction (HFrEF, defined as ejection fraction less than or equal to 40 percent), acute coronary syndrome (based on clinical diagnosis and angiography if available), and myocarditis (based on clinician diagnosis and either cardiac MRI or troponin elevation). When a pre-specified cardiac outcome was identified, the date of onset was recorded. Differences in proportions were analyzed via Chi-squared and Fishers exact tests, and time-to-event analyses were performed via Cox Proportional Hazards Models, incorporating a false discovery rate correction for multiple outcomes. All analyses were performed using SAS v9.4. Results: 88 patients were included in the final analysis, of whom 69 (78.4 percent) were categorized as anti-Ro-52 positive. Patients with anti-Ro-52 positivity had a higher maximum recorded serum creatine kinase (median 1297 vs 395 units per liter, p = 0.042). No significant associations between anti-Ro-52 positivity and the pre-defined cardiovascular outcomes were found over median follow up time of 12.5 years. Conclusions: In a large, single-center cohort of patients with ASyS, anti-Ro-52 positivity was not associated with an increased burden of negative cardiovascular outcomes, including the onset of pulmonary hypertension. Future studies may seek to further elucidate the mechanisms underlying the pleiotropic effects of anti-Ro-52 antibodies on the cardiopulmonary system.

Pernicious anemia is a chronic autoimmune disease characterized by impaired of vitamin B12 absorption and deficiency. Current diagnostic approaches rely on laboratory biomarkers with limitations in sensitivity and specificity, leading to diagnostic uncertainty and potentially delayed and/or suboptimal treatment. The 2024 NICE guidelines acknowledge that treatment frequency should be guided by individual symptom response rather than current one-size-fits-all schedules; however, the symptom heterogeneity underpinning this recommendation remains poorly characterized. We conducted secondary analysis of symptom survey data from 1,117 members of the Pernicious Anaemia Society (PAS) collected between August 2010 and November 2012. We applied latent class analysis (LCA) to 46 self-reported indicators comprising demographic characteristics, symptoms, and comorbid conditions, to identify distinct symptom-based subtypes and assess whether such subgroups can inform more tailored management of PA. Associations between symptom subtypes and diagnostic test results, age when symptoms first started, symptom duration, and treatment satisfaction were examined using chi-square and Fisher's exact tests. The best model included three distinct symptom subtypes: High Burden (n=334, 29.9%), Moderate Burden (n=613, 54.9%), and Low Burden (n=170, 15.2%). The High Burden subtype exhibited fatigue (99.4%), cognitive dysfunction (97.9% memory loss), neurological manifestations (95.5% clumsiness), and suicidal thoughts (41.6%). Intrinsic factor antibody (IFA) status did not differ significantly across subtypes ({chi}2=1.04, df=2, p=0.593). Age at symptom onset differed significantly across subtypes (p=0.002), with the Low Burden subtype overrepresented in older age groups. The High Burden subtype had the longest diagnostic delays (56.9% >2 years). Standard three-monthly injections showed low satisfaction across all classes (High Burden: 8.5%, Moderate Burden: 23.7%, Low Burden: 30.7%). Symptom-based stratification identifies clinically meaningful subgroups independent of IFA status, supporting tailored, symptom-guided treatment rather than the current piecemeal approach. The inverse association between high symptom burden and age of onset warrants clinical attention. The co-occurrence of markedly elevated rates of depression and suicidal thoughts in the High Burden subtype suggest that integrated mental health assessments should form part of routine clinical management.

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating, often infection-triggered illness with no cure and no effective treatment. Marked symptom heterogeneity hampers diagnosis, disease management, and trial design. Using phenotype data from the world's largest ME/CFS cohort, this study aimed to identify groups of patients with similar symptom profiles using cluster analysis, to assess the association between cluster membership and onset type, and to explore genetic associations with cluster membership. Methods: This study included 19,019 DecodeME participants, ages 16 and over, with ME/CFS in the UK, from 2022-2024. We performed a k-modes cluster analysis of individuals based on similar symptoms. Cluster metrics identified the optimal number of clusters, which were characterised and compared. A sex-stratified subgroup analysis explored differences between clusters among males and females. The association between ME/CFS onset type (infectious, non-infectious, or unknown) and cluster membership was assessed with logistic regression models, adjusting for sex, age, deprivation, and ethnicity. Genetic associations with cluster membership were assessed using a genome-wide association study. Results: We identified two clusters in our study population: a high symptom burden cluster (HSBC; 57% of participants) and a lower symptom burden cluster (LSBC; 43%). The HSBC was characterised by higher prevalence of symptoms across all domains, more comorbidities, and greater illness severity. Individuals with infectious and unknown onset had 1.24 times (95% CI: 1.15-1.35) and 1.30 times (95% CI: 1.18-1.43) higher adjusted odds of HSBC membership relative to non-infectious onset, respectively. A similar pattern was observed in the sex-stratified analyses, although it showed an overall higher symptom prevalence for females and a higher proportion of females in the HSBC compared to males. No genetic variant was significantly associated with cluster membership. Conclusions: This large-scale cluster analysis of DecodeME symptom data reinforces that ME/CFS is a heterogeneous condition with clinical subtypes. The identification of symptom-based phenotypes, along with sex-based differences in symptom burden and cluster characteristics, highlights the importance of incorporating symptom burden and sex in future research, clinical decision-making, and public health strategies. Tailoring future interventions to these subgroups could enhance patient management and improve outcomes.

Objective: To evaluate the clinical efficacy of non-invasive electrical pulsed radiofrequency (PRF) stimulation on diagnostic thresholds and subjective pain in chronic, pedal diabetic peripheral neuropathy (DPN). Methods: A randomized, single-blind, placebo-controlled trial (ClinicalTrials.gov: NCT07725419) enrolled 92 patients with pedal DPN naive to PRF and scoring [&ge;] 4/10 on the Douleur Neuropathique 4 (DN4) test. Participants received either active PRF stimulation (n = 46) or a non-stimulating placebo (n = 46) applied bilaterally to the sciatic nerve in the popliteal fossa for 10 minutes per limb, once weekly for three weeks. The primary outcome was clinical neuropathic resolution (DN4 < 4). Secondary outcomes included subjective pain tracking via the Brief Pain Inventory-Short Form (BPI-SF) Worst Pain scale over a 6-month follow-up window. Missing data were handled via Non-Responder Imputation (NRI). Longitudinal continuous trajectories were modeled using Linear Mixed-Effects Models (LMMs) adjusted for age, gender, and baseline medication use. Results: In the Intention-to-Treat population (N = 92), a significant diagnostic responder effect occurred at 3 months, with 39.1% of active patients dropping below the diagnostic threshold for neuropathy (DN4 < 4) versus 19.6% of placebo controls (p = 0.039). For subjective pain, 47.7% of active patients achieved a Minimally Clinically Important Difference ([&ge;] 3-point reduction) in BPI Worst Pain at 1 month compared to 19.4% of placebo controls (p = 0.008). Multivariable logistic regression identified active treatment as a significant independent predictor of clinical response (Adjusted OR = 4.86; 95% CI: 1.56 to 17.53; p = 0.010). Continuous LMM tracking confirmed a statistically significant treatment-by-timepoint interaction for BPI Worst Pain at 1 month (p = 0.046). Conclusion: A brief, three-week course of non-invasive PRF stimulation serves as a safe, effective, non-pharmacological adjunct that aids in managing the diagnostic presentation of neuropathic pain and mitigates worst pain experiences in patients suffering from pedal DPN.

Background. Chronic pelvic pain with involuntary pelvic-floor hypertonicity is common, disabling, and inconsistently measured, and no validated condition-specific severity instrument exists. A refractory subset has been proposed to represent a focal dystonia of the pelvic musculature, termed pelvic dystonia. Purpose. To develop the Pelvic Dystonia Severity Scale (PDSS) and evaluate its measurement properties as a patient-reported measure of pelvic-pain symptom severity and burden, following the COSMIN guidelines. Methods. Cross-sectional study with a test-retest component in 102 adults from an outpatient multidisciplinary pain practice. We assessed data quality, structural validity, internal consistency, test-retest reliability, measurement error, and construct validity against the Global Dystonia Severity Rating Scale (GDS) and Brief Pain Inventory (BPI). Because no validated diagnostic criteria exist, a clinician blinded to PDSS responses rated each participant for clinical signs of pelvic dystonia (present/possible/absent) as a provisional reference standard. Results. 100 of 102 participants (98%) returned complete data, with 0% item-level missing data. Factor analysis supported a unidimensional structure (single factor, 68.6% of variance; loadings 0.56-0.93), with high subscale intercorrelations (r = 0.81-0.97). Internal consistency (Cronbach's 0.810-0.924) and test-retest reliability (ICC 0.857-0.953) were strong. Convergent validity was supported by correlations with GDS pelvic-region items (r = 0.56-0.68) and BPI severity (r = 0.44-0.55), and discriminant validity by weak correlations with anatomically remote regions (shoulder/arm r = 0.03-0.16). PDSS scores rose monotonically across blinded clinical-signs categories (absent 14.9, possible 32.7, present 52.0; Kruskal-Wallis p < 0.001), discriminating signs-present from signs-absent participants with a very large effect (Hedges g = 2.19; ROC AUC = 0.92). Conclusion. The PDSS is a psychometrically robust, unidimensional measure of pelvic-pain symptom severity and burden with strong data quality, reliability, and construct validity. It is suitable for characterizing symptom severity and, pending responsiveness testing, for monitoring treatment. The dystonia interpretation of the underlying phenotype is discussed as a hypothesis for future neurophysiologic and longitudinal study.

Hirschsprung disease (HSCR) is a congenital neurodevelopmental disorder characterized by segmental aganglionosis due to impaired developmental processes of enteric neural crest cells (NCCs). Despite being the leading genetic cause of functional intestinal obstruction in early childhood, HSCR represents a paradigmatic challenge in precision medicine: its multifactorial etiology, complex gene-environment interactions and limited resolution of single-modality analyses have long hindered mechanistic understanding and therapeutic translation. Here, we applied an integrative multi-omics approach combining genetic, phenotypic, epigenomic and transcriptomic analyses of matched ganglionic and aganglionic formalin-fixed paraffin-embedded (FFPE) patient tissues, complemented by patient-specific in vitro models. Beyond established genetic contributors, our integrative approach reveals novel regulatory pathways predominantly affecting enteric NCC differentiation, with convergent evidence pointing to epigenetic dysregulation as a primary disease mechanism. Notably, we identified over 1,300 differentially methylated positions between ganglionic and aganglionic FFPE samples, with HAND2 emerging as a key candidate due to multiple hypermethylated sites and consistently reduced expression levels in aganglionic tissues and in vitro models, suggesting a potential role in HSCR pathophysiology. We propose that our multi-omics approach offers a powerful and comprehensive framework for dissecting disease mechanisms. Beyond advancing biological understanding, this strategy holds promise for paving the way for molecularly informed patient stratification and supporting the development of personalized treatment and postoperative management strategies.

Importance: Autistic people have increased risks of cardiometabolic conditions and premature mortality; however, no studies specifically assess risks of major ischaemic events in the autistic population. Objective: To determine whether autistic people are at increased risk of major ischaemic events after accounting for known risk factors. Design: A retrospective matched cohort study from 1/1/1990 to 31/12/2019. Cox regression models accounting for matching factors, sociodemographic characteristics, intellectual disability, and cardiovascular risk factors were employed. Setting: This population-based study leveraged lifetime primary and secondary care electronic health records from the Clinical Practice Research Datalink and Hospital Episode Statistics, as well as sociodemographic, ethnicity, and death registration data from the Office of National Statistics. Participants: 23,612 autistic people were matched 1:5 on birth year (+/-2 years), general practitioner practice ID, and gender to 118,060 non-autistic people. Autistic people were defined as those with a clinical autism diagnosis recorded during the study period. Patients missing Indices of Multiple Deprivation and ethnicity data, and an end date prior to their CPRD start date were excluded along with their matched set. Exposure: Clinical diagnosis of autism. Secondary exposures included health conditions associated with cardiovascular disease with some additional conditions relevant to autism. Main Outcome and Measures: Time to first major ischaemic event (any of myocardial infarction, angina, other ischaemic heart disease, ischaemic stroke, and transient ischaemic attacks). Results: Autistic people had a greater risk of a major ischaemic event in the study period in the minimally adjusted Model 1 (HR 1.19; 95% CI: 1.00, 1.42) as well as for autistic females even after accounting for risk factors (adjusted HR 1.71; 95% CI: 1.10, 2.67). There was also evidence that several cardiometabolic risk factors had a higher prevalence among the autistic group such as severe mental illness, dyslipidaemia, and obesity (all P<0.001). Conclusions and Relevance: Autistic people have an increased risk of major ischaemic events and need improved cardiometabolic risk management. This risk remained in autistic women after adjusting for cardiometabolic and sociodemographic factors. As cardiovascular disease is a primary cause of death globally, research is needed to better understand the mechanism that drives this association.

Background and aims: Longitudinal data and tracking of serum lipoprotein(a) (Lp(a)) concentrations through childhood?s development from infancy to adolescence are lacking. We aimed to establish the strength of the tracking phenomenon from early infancy to adolescence and to examine whether a heart-healthy dietary intervention and individual dietary components influence serum concentrations of Lp(a). Methods: 1062 healthy children aged 7 months were recruited and randomized into control (N=522) and intervention (N=540) groups in the Special Turku Coronary Risk Factor Intervention Project (STRIP). Serum Lp(a) concentration was measured at 10 age points (0.7, 1.3, 2, 3, 4, 5, 9, 11, 13, and 15 years) and median serum Lp(a) levels were studied longitudinally. Tracking across age points was studied using Spearman's rank-order correlation. Sex differences and the effects of the dietary intervention and individual dietary components were analyzed with linear mixed-effects models for repeated measures. Results: A total of 7018 Lp(a) measurements were analyzed. Median serum Lp(a) concentrations increased from infancy until approximately age 13 years. After age 13, median Lp(a) declined in boys (-15.1%) but was largely unchanged in girls. Girls had higher Lp(a) concentrations at all age points (P=0.01). Spearman's correlation analysis indicated a strong tracking between age points in both sexes (r=0.854-0.956). Achievement of at least one dietary fat quality goal of the intervention corresponded to a 2.5% increase in serum Lp(a) concentration (P=0.0004). Higher sucrose intake was associated with modestly higher Lp(a), whereas fiber intake showed no association. At age 15 years, 16.2% of all participants with available measurements had elevated Lp(a) ([&ge;] 30mg/dL). Conclusions: A rising trend was observed in median serum Lp(a) concentrations from infancy to adolescence. Due to strong tracking, these findings suggest that early-life measurements may provide valuable insight for longitudinal cardiovascular risk assessment. Heart-healthy diet does not meaningfully influence serum Lp(a).

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 ([&le;] 50 MME, [&le;] 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: Risk stratification in pericarditis relies mainly on clinical presentation, suspected etiology, imaging findings, and conventional inflammatory biomarkers. Whether complete blood count-derived inflammatory indices are associated with mortality in pericarditis and whether these associations are directionally consistent across independent real-world datasets remain unclear. Methods: We conducted a retrospective dual-cohort study of hospitalized adults with pericarditis using a Hong Kong cohort from the Clinical Data Analysis and Reporting System (CDARS) as the primary analysis cohort and the Medical Information Mart for Intensive Care IV (MIMIC-IV) cohort as an independent reproducibility cohort. Baseline neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) were analyzed as continuous variables and cohort-specific tertiles. The primary outcome was long-term all-cause mortality in the Hong Kong cohort. Secondary and reproducibility outcomes included 90-day mortality in the Hong Kong cohort and 30-day, 90-day, and observable follow-up mortality in MIMIC-IV. Cox models were adjusted for age, sex, renal disease, diabetes mellitus, hypertension, ischemic heart disease, and malignancy. Results: Among 504 patients in the Hong Kong cohort and 464 patients in MIMIC-IV, all-cause mortality occurred in 241 and 113 patients during cohort-specific follow-up, respectively. In the Hong Kong cohort, higher NLR was associated with long-term all-cause mortality after full adjustment. Compared with NLR tertile 1, the adjusted hazard ratio was 1.60 for tertile 3. Higher SII was also associated with long-term mortality, with an adjusted hazard ratio of 1.55 for tertile 3 versus tertile 1. NLR and SII showed directionally consistent associations with 90-day mortality in the Hong Kong cohort and with 30-day, 90-day, and observable follow-up mortality in MIMIC-IV. Sensitivity analyses yielded broadly consistent findings. Conclusions: In two independent real-world cohorts of hospitalized patients with pericarditis, higher baseline NLR and SII were associated with increased all-cause mortality, with NLR showing the more consistent prognostic signal. These complete blood count-derived indices may provide simple adjunctive information for mortality risk stratification, although prospective validation is needed before incorporation into formal management algorithms.

Introduction Acute lower respiratory tract disease (aLRTD) is a leading cause of hospitalisation and death, particularly in older adults and adults with comorbidities, with acute lower respiratory tract infection (aLRTI; pneumonia and non-pneumonic LRTI) being a major component. Non-pulmonary complications and functional decline after aLRTI are recognised, but their pathogen-specific burden is poorly described. We aimed to quantify renal, hepatic, thromboembolic and functional complications, and mortality, after aLRTI hospitalisation, by clinical phenotype and pathogen. Methods We conducted a cohort study of adults (>18 years) admitted with aLRTD to two hospitals in Bristol, UK (01 August 2022-31 July 2024). aLRTD was classified as pneumonia, non-pneumonic LRTI (NP-LRTI) or no diagnosis of aLRTI. Pathogens were identified from standard-of-care and research microbiology. Outcomes were acute kidney injury (AKI), acute liver dysfunction, venous thromboembolism (VTE), in-hospital falls, reduced mobility at discharge, increased care requirements, and 30-day and 1-year mortality. Analyses were descriptive. Results Among 246,797 adult admissions, 21,456 aLRTD hospitalisations were included: 10,239 (47.7%) pneumonia, 7,742 (36.1%) NP-LRTI and 3,475 (16.2%) with no evidence of aLRTI. Of 19,152 tested aLRTD admissions, 8,503 (44.4%) had a positive microbiological/virological test, yielding 9,204 pathogen detections; 1,194 (6.2%) had co-infections, and SARS-CoV-2 was most frequent, with influenza the second most common in pneumonia and NP-LRTI. Pneumonia had greater severity than NP-LRTI and no diagnosis of aLRTI (median length of stay 6 vs 4 vs 4 days; ICU admission 3.4% vs 0.7% vs 0.5%, respectively). Overall, 22.2% developed AKI, 6.1% acute liver dysfunction, 0.6% DVT and 2.4% PE; 1.8% had a fall, 11.5% reduced mobility, and 16.6% required increased care at discharge. 30-day and 1-year mortality were highest for pneumonia (14.0% and 32.0%, respectively). Pathogen-specific analyses showed longer stays and higher complications and mortality rates for SARS-CoV-2 and Streptococcus pneumoniae, and shorter stays with lower complication and mortality rates for influenza and Haemophilus influenzae. Conclusions Non-cardiovascular complications and functional decline after aLRTI were common, particularly in pneumonic and SARS-CoV-2 or pneumococcal disease. These findings support routine surveillance for renal, hepatic, thromboembolic events, early mobilisation and rehabilitation, and consideration of multi-system outcomes when evaluating public health and economic value of vaccines and therapies.

BACKGROUND Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, life-threatening disease. Sociodemographic factors may influence time to treatment initiation and resulting clinical outcomes, yet these relationships are poorly characterized. OBJECTIVE Assess the effects of sex and race on tafamidis initiation and subsequent outcomes and their interaction with factors such as ATTR-CM type and social deprivation measures. METHODS A retrospective cohort analysis was conducted using the US Komodo Healthcare Map (01/2016-06/2024) among patients with amyloidosis, identified by ICD-10-CM diagnosis codes. Cumulative incidence of treatment initiation and survival probabilities for cardiovascular-related hospitalization (CVH) or death were estimated by Kaplan-Meier, stratified by sex and race. Cox proportional hazards models were fitted for both endpoints to estimate hazard ratios, adjusting for demographics and clinical characteristics. RESULTS Of 11,311 patients identified, White and Black patients (n=9,223) were included in subsequent analyses. Within 12 months of diagnosis, White women had the lowest cumulative incidence of tafamidis initiation (11.4%), followed by Black women (22.0%), Black men (26.7%), and White men (31.0%). Event-free survival at 12 months was lowest in Black women (42.9%), followed by Black men (46.8%), White women (48.6%), and White men (54.4%). Median (95% CI) time to CVH or death was shortest for Black women (8.0 months [6.8-10.0]) followed by Black men (9.9 months [8.8-12.0]), White women (11.0 months [9.6-13.0]), and White men (15.0 months [14.0-16.0]). CONCLUSIONS In this large, real-world cohort of US patients with ATTR-CM, sex and race contributed to disparities in tafamidis initiation and survival, underscoring compounded disparities in both access and outcomes.

Background: Psoriatic arthritis (PsA) is an inflammatory condition involving joints, tendon-bone entheses and synovium that can develop in individuals with psoriasis. Early, accurate clinical diagnosis remains difficult. Extracellular vesicles (EVs) carry proteins and miRNAs that Methods: PubMed and Embase were searched from inception through May 21st, 2026, and human studies examining EV-associated protein or miRNA biomarkers in PsA and related psoriatic or inflammatory diseases were included, with risk of bias assessed using a modified Newcastle-Ottawa Scale and diagnostic accuracy summarized using HSROC/BRMA models when data were sufficient. Results: Seven studies met the inclusion criteria, including 119 individuals with PsA (weighted mean age: 49.8 years; 43.7% female), 205 individuals with non-PsA psoriasis (weighted mean age: 46.4 years; female %: NA), 55 controls (weighted mean age: 44.5 years; 38.2% female), and 50 individuals with other inflammatory joint disorders (weighted mean age: 58.0 years; 58.0% female). EV-associated protein markers demonstrated heterogeneous findings related to immune, vascular, inflammatory, and osteoimmunological signaling. Only 4.2% (4/95) of miRNAs were consistently identified across studies comparing PsA with non-PsA psoriasis, with lower overlap (1.5%, 1/67) in studies comparing PsA with controls. ROC meta-analysis suggested preliminary diagnostic potential, particularly for distinguishing PsA from non-PsA psoriasis, although evidence was constrained by small study numbers. Conclusions: EV-associated proteins and miRNAs are potential biomarker candidates for PsA, reflecting inflammatory, vascular, and osteoimmunological processes underlying disease pathophysiology. However, current evidence remains preliminary and limited by small cohorts, methodological heterogeneity, and inconsistent reporting across studies.

Mitochondrial diseases (MDs) are caused by variants in the mitochondrial (mtDNA) or nuclear (nDNA) genome and encompass a diverse disease spectrum, whilst mitochondrial dysfunction more broadly is implicated in aging and neurodegeneration, with distinct and overlapping phenotypic features. Recent population genomic studies reveal pathogenic MD variation to be common in the population and somatic mtDNA variants accumulate from the seventh decade. Cumulative burden of mtDNA variation, quantified using mitochondrial genome constraint measures, may mediate mitochondrial dysfunction generally. However, the clinical relevance of incidentally identified variation for MDs, and of mitochondrial constraint measures for aging and neurodegeneration, is unclear. We have quantified pathogenic mtDNA and nDNA variation, as well as measures of mitochondrial genome constraint in the Medical Genome Reference Bank (MGRB), a cohort of healthy older individuals. We evaluated association of identified pathogenic MD variants with clinical features relevant to MD across four domains including physical function, cognitive function, endocrine-metabolic function and mood. Associations of mitochondrial genome constraint with clinical measures of aging and neurodegeneration were also explored. No significant associations between MD variants and phenotypes were identified, although surprisingly, mood measures appeared healthier for variant carriers compared to non-carriers. Summed mtDNA constraint showed significant inverse association with blood pressure and a trend toward inverse association with physical function. Measures of cognitive function did not demonstrate association with summed or mean mitochondrial genome constraint. Pathogenic MD variants are relatively common in the population and may be carried through to old age in good health, emphasising the importance of clinical context for counselling. Mitochondrial genome constraint measures warrant further evaluation as a surrogate biomarker for mitochondrial genome quality and mitochondrial dysfunction.

PURPOSE: To assess the predictive performance of panel protein biomarkers as well as an established algorithm that considers repeat biomarker testing for risk prediction of PDAC among a prospective cohort of patients with New-onset diabetes. PATIENTS AND METHODS: A panel of protein biomarkers (CA19-9, CA125, CEA, LRG1, REG3A and TIMP1) were assayed in 6,516 serially collected pre-diagnostic plasma samples from 2,121 NOD patients from the Consortium of Chronic Pancreatitis Diabetes and Pancreatic Cancer (CPDPC)-initiated NOD study who completed the 3-year study follow-up period. The specimen set included 25 pre-diagnostic samples from the 12 PDAC cases diagnosed during study follow-up. We applied a single threshold (ST) method, which considers biomarker levels at a single time point, as well as a previously established parametrical empirical Bayes (PEB) algorithm, which considers prior biomarker measurements, with case calls made based on pre-specified cutoffs corresponding to 1% 1-year risk. Resultant biomarker data as well as case calls were provided to the EDRN Data Management and Coordinating Center as part of a Prospective-sample-collection-Retrospective-Blinded-Evaluation (ProBE)-compliant Phase 3 biomarker validation study. Area under the Receiver Operating Characteristic Curves (AUC), sensitivity, specificity, population-level positive predictive value (PPV), and negative predictive value (NPV) are reported. RESULTS: The 3-year incidence of PDAC in the NOD cohort was 0.57%. When considering PDAC vs non-cancer controls, respective AUCs of individual protein biomarkers ranged from 0.52-0.94, with CA19-9 achieving the highest overall performance of 0.94 (95% CI: 0.86-1.00). At the pre-defined 1% 1-year risk threshold, CA19-9 yielded sensitivity of 83.3% at 97.2% specificity. Additional markers CEA, CA125, and TIMP1 demonstrated sensitivity of 33.3%, 41.7%, and 8.3%, respectively. In a subset of patients, CA19-9 first tested positive at a median (interquartile range [IQR]) of 7 months (4 to 14 months) prior to clinical PDAC diagnosis. Of the two PDAC cases missed by CA19-9 using the ST method, one (diagnosed with stage III PDAC) was detected using the PEBCA19-9 algorithm. CONCLUSION: In the setting of adult new onset diabetes, CA19-9 is a readily available and promising biomarker that can be leveraged for earlier detection of an underlying pancreatic cancer. Additional protein biomarkers may improve sensitivity for earlier detection of PDAC among cases with low CA19-9.

Background Falls are increasingly recognized as adverse events in coronary heart disease (CHD) patients, yet their prognostic implications remain incompletely understood. This study examined the independent associations of falls with mortality and major adverse cardiovascular events, and the roles of functional status and frailty in these relationships. Methods This retrospective cohort study enrolled 2,139 CHD patients with median follow-up of 36 months. Falls were ascertained via telephone interviews every 3 months. Primary outcomes included major adverse cardiovascular events (MACE) and major adverse cardiovascular and cerebrovascular events (MACCE). Secondary outcomes comprised all-cause and cardiac mortality. Multivariable Cox models with stepwise adjustment for functional status indicators were constructed, with subgroup analyses stratified by frailty status. Results During follow-up, 171 patients (8.0%) experienced falls. Falls were associated with mortality in univariate analysis but not after adjusting for functional status, indicating mediation by functional decline. In contrast, falls remained independently associated with MACE (HR=1.73, 95%CI: 1.17-2.57, P=0.006) and MACCE (HR=1.67, 95%CI: 1.14-2.46, P=0.009) in fully adjusted models. Frailty significantly modified this association (P for interaction <0.001). Among robust patients, falls conferred substantially elevated risk (MACE: HR=4.08, 95%CI: 2.37-7.01; MACCE: HR=3.94, 95%CI: 2.30-6.76), whereas no significant association was observed in pre-frail or frail patients. Conclusions Falls independently predict long-term MACE and MACCE in CHD patients, with mortality effects mediated by functional status. Frailty significantly modifies the fall-cardiovascular event relationship--robust patients experiencing falls face substantially elevated cardiovascular risk and warrant comprehensive evaluation. These findings support integrating fall history into cardiovascular risk assessment and implementing frailty-stratified management.