Journal of Internal Medicine

Objectives: Patients with pediatric acute-onset neuropsychiatric syndrome (PANS) frequently report pain and fatigue. While some patients experience resolution of pain and fatigue following improvement in psychiatric symptoms, others develop persistent symptoms resembling fibromyalgia. Understanding these trajectories is critical for early identification and intervention in patients at risk for chronic pain or fatigue. In this study we characterize fibromyalgia symptoms in PANS and identify predictors of symptom progression following a PANS flare. Design: Prospective observational cohort study. Setting: Stanford University Immune Behavioral Health (IBH) Clinic in Menlo Park, California, USA. Participants: 204 consecutive patients with PANS evaluated by the IBH Clinic. The average (SD) age at first neuropsychiatric deterioration was 8.2 (3.3) years. Main outcome measures: We prospectively collected data on pain, fatigue, and other fibromyalgia symptoms using the 2016 American College of Rheumatology (ACR) Fibromyalgia Survey Questionnaire (FSQ), which includes the Widespread Pain Index (WPI) and Symptom Severity Scale (SSS). For the reference standard, clinician-documented diagnoses of pain syndromes were ascertained through a retrospective review of participants' electronic medical records. We report the prevalence of these symptoms in PANS patients and controls and evaluate factors associated with time to meeting ACR fibromyalgia criteria threshold scores following clinic presentation using a Cox proportional hazards model. Results: Among 204 patients with PANS (110 boys [54%]), eighty-five (42%) met ACR fibromyalgia criteria threshold scores at least once during follow-up (95% CI at 10 years follow-up time: 60.5 [46.7-74.5]). Twenty-eight of these 85 patients (13.7% of total cohort) progressed to meet full ACR fibromyalgia criteria (95% CI at 10 years follow-up time: 24.1 [15.6-36.2]). Compared with controls, patients with PANS reported substantially elevated rates of pain, daytime fatigue, waking unrefreshed, and cognitive symptoms (brain fog). Higher scores on the WPI and SSS at presentation were associated with a higher hazard of subsequently meeting ACR fibromyalgia criteria threshold scores. Conclusions: Fibromyalgia symptoms were common in this PANS cohort, with a notable subset developing symptoms meeting full ACR fibromyalgia criteria. These findings suggest that pain and fatigue may represent post-inflammatory sequelae of PANS and may overlap mechanistically with other post-infectious conditions. Recognizing these symptom patterns may inform clinical management, development of outcome measures, and future clinical trials in these patients, as well as support investigation into shared neuroimmune mechanisms underlying post-infectious pain and fatigue syndromes.

Background: Chronic musculoskeletal pain (CMP) is a common and debilitating symptom of Long COVID (LC), which shares several clinical features with Fibromyalgia Syndrome (FMS). Aims: This longitudinal study investigated whether the symptom overlap between LC-CMP and FMS persists over time, whether patterns differ according to pre-COVID CMP history, and the extent to which neuropathic pain features are present. Methods: Individuals with LC completed questionnaires assessing the symptom-based component of the 2010 American College of Rheumatology criteria for FMS and the presence of neuropathic pain features (PainDetect Questionnaire, PDQ) at baseline, 6- and 12-month follow-ups. Participants were grouped according to pre-COVID CMP history. Group differences were analysed using mixed-effects logistic regression. Results: 240 individuals completed the baseline assessment at a mean of 2.61 years after LC onset, including 131 (100 females) with new-onset CMP and 94 (87 females) with pre-existing CMP. The prevalence of participants meeting the symptom-based criteria for FMS remained high across follow-up (67.5-78.6%), with 50.0-61.0% of those with complete follow-up data fulfilling criteria at all timepoints. No significant subgroup differences were observed (OR = 0.43, 95% CI [0.14 1.39], p = 0.160). Across follow-up, 22.2-36.1% of participants reported likely neuropathic pain features, with significantly higher odds in the pre-existing CMP group (OR = 3.17, 95% CI [1.22 8.18], p = 0.017). Conclusions: FMS-like symptoms remain highly prevalent several years after acute COVID-19 and persist over a further 12 months, suggesting that LC-CMP frequently represents a persistent long-term condition with substantial overlap with FMS. These findings support closer integration of LC and chronic pain rehabilitation services and add to the wider literature linking post-infectious processes with FMS-like symptoms.

Background: Temporary 60-day percutaneous peripheral nerve stimulation (PNS) can relieve pain in refractory occipital neuralgia (ON), but whether it alters acute healthcare utilization relative to the natural trajectory of the disease is unknown, because prior studies have lacked a concurrent comparator. Methods: We performed a secondary analysis of prospectively collected data from a tertiary interventional pain center. Adults with medically refractory ON (primary diagnosis occipital neuralgia, ICD-10-CM M54.81) who underwent 60-day occipital PNS (n = 42) were compared with concurrent patients who were clinically eligible for PNS but were denied insurance authorization and continued optimized non-PNS management (usual care; n = 63). Headache-related emergency department (ED) encounters - index (occipital neuralgia) and non-index (other headache/facial-pain diagnoses) - were ascertained over the 12 months before and after the treatment window via the electronic record and the statewide health information exchange. Patients were 1:1 propensity-matched on a priori confounders (age, sex, baseline total headache-related ED utilization, HIT-6, and baseline headache-medication use). The primary analysis was a difference-in-differences (DiD) comparison of the change in headache-related ED utilization, reported as the additive difference (Hodges-Lehmann estimate, distribution-free 95% CI) and, alongside, as a multiplicative rate ratio (RR). Results: Thirty-six matched pairs were well balanced. Baseline headache-related ED utilization was nearly identical between matched groups (6.3 vs. 6.2 visits/year). Over the following year, PNS patients' utilization fell to 2.5 while usual-care patients' rose to 6.9. The DiD was 5.0 fewer headache-related ED visits per patient (95% CI 3.0-6.0; p < 0.001), corresponding to a rate ratio of 0.36 (95% CI 0.27-0.48; p < 0.001). Results were consistent in the full sample, in covariate-adjusted models, and after excluding controls denied for incomplete conservative-therapy trials. The effect was driven by non-index headache visits. Conclusions: Relative to a concurrent, matched usual-care cohort whose headache related ED utilization rose over time, 60-day occipital PNS was associated with a substantial reduction in acute-care use, strengthening the case for a role of PNS on healthcare utilization in refractory ON.

Background: Dysfunction of the KCND3-encoded Kv4.3 channel, which carries the transient outward potassium current (Ito), has long been suspected to contribute to the pathophysiology of Brugada Syndrome (BrS). Although recent genome-wide association studies (GWAS) have implicated KCND3, the role of rare variation in this gene remains uncertain and clinically unactionable. Methods: Genome sequencing was performed in 983 BrS probands from Europe and Thailand. Putative gain-of-function (GoF) rare variants in KCND3 identified in patients were functionally characterized by patch-clamp analysis of Kv4.3 current properties using a HEK293 cell heterozygous model. Biobank datasets were utilized to evaluate rare-common variant interaction at the KCND3 locus. Results: Eight BrS cases carried six different rare KCND3 variants which clustered at the Kv4.3 C-terminus, with terminal exon rare variants significantly enriched in cases versus study (p=0.004) and population (p=2.0e-6) controls. Four of the five KCND3 case variants studied demonstrated significant GoF effects versus wild-type and putative benign variants, including increased Ito amplitude (p.Leu586Val, p.Ala634Thr) and slower inactivation (p.Gly600Arg, p.Ala654Thr, p.Ala634Thr). Analysis of p.Gly600Arg carriers in the UK Biobank and All of Us revealed a significant enrichment of the protective KCND3 expression-reducing allele of the GWAS lead single-nucleotide polymorphism rs12090194, suggesting a possible epistatic common-rare variant interaction modifies penetrance in carriers. Conclusions: GoF rare variants at the C-terminus of KCND3 are associated with BrS in a small proportion of cases. Determination of the rare and common variant status in BrS patients and their relatives may provide information about disease risk.

Background Cardiac amyloidosis is an increasingly recognized cause of heart failure in older adults, yet Colombian data, and data from the southwest of the country in particular, remain scarce. We describe the clinical, diagnostic, imaging and outcome profile of patients with cardiac amyloidosis at two high-complexity institutions in Cali. Methods Observational, descriptive, retrospective, two-center study. Patients were identified in the institutional registries of both centers using ICD-10 codes for amyloidosis, and clinical data were abstracted manually from medical records. Continuous variables are reported as median (interquartile range) and categorical variables as counts and percentages over the number of patients with available data. Results Thirty-two patients were analyzed (median age 77 years; 68.8% men). Heart failure (90.6%), atrial fibrillation (46.9%) and carpal tunnel syndrome (31.2%) were frequent. The etiological classification depended on the test considered: bone scintigraphy was positive (Perugini 2-3) in 23 of 26 patients studied (88.5%), but a monoclonal protein was screened for in only 22, and the full non-invasive criteria for ATTR were met in 16 of 32 (50.0%). Genetic testing was positive in 9 of 18 tested, and the variant was Val142Ile in all 8 patients in whom it was characterized. The working diagnosis was ATTR in 26 patients (81.2%) and AL in 6 (18.8%). Tafamidis was used in 37.5%. Eleven of the 31 patients with known vital status died (35.5%), and NT-proBNP was markedly higher among those who died (6640 vs 1186 pg/mL; p=0.003). Conclusions In this southwestern Colombian cohort, cardiac amyloidosis presented as the classic transthyretin phenotype, with the Val142Ile variant in all 8 patients in whom it was characterized. Bone scintigraphy was frequently positive, but screening for a monoclonal protein was often omitted, so only half the cohort met the full non-invasive criteria for ATTR. Mortality was high and closely associated with NT-proBNP.

Background: Hereditary spastic paraplegia (HSP) comprises a heterogeneous group of neurodegenerative disorders characterized by progressive lower-extremity weakness and spasticity, with or without additional neurological symptoms. Objectives: To characterize the molecular genetic spectrum, inheritance patterns, molecular finding rate, and clinical characteristics of HSP within a multicenter Canadian cohort. Methods: We investigated 671 patients from 423 families who met clinical criteria for HSP identified through the Canadian HSP (CanHSP) registry from 7 medical centers across Canada. Patients were evaluated using known HSP and HSP mimic gene panels, whereas unsolved and more recent patients underwent whole-exome sequencing (WES). 435 individuals underwent gene-panel testing and 485 underwent WES. Copy-number variants (CNVs) were assessed using ExomeDepth, and candidate CNVs using multiplex ligation-dependent probe amplification (MLPA). Results: Molecular findings were identified in 426 of 671 individuals (63.5%): 351 (52.3%) had HSP-associated findings, 70 (10.4%) HSP-mimicking disorders, and five (0.7%) other molecular findings; 245 (36.5%) remained unresolved. Candidate variants were found in 80 relevant genes, 36 of which were HSP-associated genes. The most frequently implicated genes were SPAST (22.5%), SPG7 (5.7%), ATL1 (5.2%), SPG11 (3.6%), and SPG8 (3.3%). Phenotypically, SPAST, ATL1, and SPG8 w[zg1.1]ere predominantly associated with pure HSP, whereas SPG7 and SPG11 more often showed complicated phenotypes, with prominent cerebellar involvement in SPG7 and cognitive and developmental features in SPG11. Conclusion: Patients in CanHSP present with genetic and phenotypic heterogeneity. Reanalysis and complementary approaches, including whole-genome, RNA, and long-read sequencing, may increase diagnostic yield.

Background Several disease-modifying agents for transthyretin amyloid cardiomyopathy (ATTR-CM) have been investigated, but differences in trial design and background stabilizer use complicate interpretation of their efficacy. This meta-analysis assessed their efficacy overall and by background stabilizer use. Methods PubMed, Embase, and the Cochrane Library were searched through September 2026 for phase III randomized, placebo-controlled trials of disease-modifying therapy in ATTR-CM. Primary endpoints were all-cause mortality, 6-minute walk distance (6MWD), Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score, and N-terminal pro-B-type natriuretic peptide (NT-proBNP), pooled with a random-effects model. Treatment effects were compared between the monotherapy and baseline stabilizer strata using a mixed-effects model. Results Five trials (ATTR-ACT, APOLLO-B, ATTRibute-CM, HELIOS-B, CARDIO-TTRansform; N=3497) were included. Disease-modifying therapy reduced all-cause mortality (risk ratio, 0.76; 95% confidence interval [CI], 0.66-0.87; I2=0%) and improved 6MWD (pooled standardized mean difference [SMD], 0.43; 95% CI, 0.20-0.67), KCCQ-OS score (SMD, 0.37; 95% CI, 0.19-0.55), and NT-proBNP (SMD, -0.53; 95% CI, -0.89 to -0.18). The mortality benefit was similar whether therapy was given alone or added to a background stabilizer (pooled risk ratio, 0.77 vs. 0.71; P for interaction = 0.59), but treatment effects on 6MWD (pooled SMD, 0.49 vs. 0.14), KCCQ-OS score (0.44 vs. 0.07), and NT-proBNP (-0.65 vs. -0.13) were smaller among patients receiving a background stabilizer (P for interaction = 0.012, <0.001, and 0.029, respectively). Conclusion Disease-modifying treatments reduced all-cause mortality and favored functional capacity, health status, and NT-proBNP outcomes in patients with ATTR-CM. Exploratory subgroup analyses showed smaller treatment effects on 6MWD, KCCQ-OS score, and NT-proBNP among patients receiving a background stabilizer, with no statistically significant difference in the mortality effect according to baseline stabilizer use.

Background: Localized or segmental overgrowth is a rare condition that may co-occur with vascular malformations. These diseases generally are caused by somatic mutations in the PI3K/AKT/mTOR pathway. Most lesions are progressive and may cause symptoms including pain, functional impairment, and disfigurement. Treatment options are limited, especially for the overgrowth component. Objective: To evaluate the efficacy and safety of the mTOR inhibitor sirolimus in patients with overgrowth with or without a vascular malformation over a 6-months treatment period. Methods: We conducted a single-arm, open-label, phase II study including 18 patients (12 pediatric, six adult) with overgrowth, all of whom initiated oral sirolimus. 16/18 (88.9%) participants received oral sirolimus for 6 months, with dosing adjusted to achieve target blood trough levels of 3-8 ng/mL. Primary outcome was radiological response at six months assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Secondary outcome parameters were evaluated at three, six and nine months and included size and visual appearance of the overgrowth, quality of life (QoL), pain intensity, performance status, and safety. Results: No patient achieved complete or partial radiological response. 17 of 18 patients (94.4%) maintained stable disease at month six; one was not evaluable. QoL measured with WHOQOL-BREF improved modestly in patients aged >= 18 years (n=5, mean difference to baseline +9.3 (95%-CI: -0.9 to 19.5) in physical and +9.2 (95%-CI: 0.7 to 17.7) in psychological domains at month 6). In pediatric participants, no relevant improvement in KINDL total scores was observed over the study period. No significant changes occurred in pain scores. Performance status measured by the Lansky/Karnofsky scales showed minor improvement (mean +3.5 points (95%-CI: 1.0 to 6.1)). All patients experienced at least one adverse event, but no serious adverse events or CTCAE v5.0 grade [&ge;]3 toxicities occurred. Sirolimus was well tolerated. Six patients decided to resume sirolimus after study completion. Conclusions: Sirolimus induced minor lesion shrinkage in a subset of patients, although this did not meet the predefined radiological RECIST endpoint. However, sirolimus can lead to functional improvement in some adults, which may indicate that the primary radiological outcome did not capture patient-perceived benefit.

Background: The practice of hospitalizing emergency department (ED) patients with chest pain after ruling out acute myocardial infarction (AMI) varies widely. The long-term outcome and cost implications of this variation are uncertain. Methods: Analyzing 2007-2021 claims from a national commercial insurer, we identified 223,569 adults (18 years or older) ED visits with a principal diagnosis of chest pain without major secondary cardiopulmonary diagnoses, seen by 19,001 clinicians in 2,273 EDs. Within each ED, clinicians with the highest and lowest terciles of risk-adjusted hospitalization rates were classified as high- versus low-admitting. Primary outcomes were 30- and 180-day subsequent AMI hospitalizations. Secondary outcomes included 7-day cardiac testing, 30-day coronary intervention, and 30-day total and out-of-pocket costs. We estimated adjusted rate ratios (aRRs) and relative cost differences using generalized estimating equations, adjusting for patient and visit characteristics. Results: Patients had a mean age of 48.6 years, and 53.9% were female; measured characteristics were similar between groups. Compared with low-admitting clinicians, visits to high-admitting clinicians had higher 7-day cardiac testing (13.1% vs 10.8%; aRR 1.22, 95% CI 1.17-1.27) and 30-day coronary interventions (4.3% vs 3.8%; aRR 1.16, 95% CI 1.09-1.23). AMI hospitalization did not differ at 30 days (0.60% vs 0.60%; aRR 1.00, 95% CI 0.84-1.15) or 180 days (0.85% vs 0.87%; aRR 0.97, 95% CI 0.85-1.10). Thirty-day total costs were higher after visits to high-admitting clinicians (relative change 11.3%, 95% CI 8.8-13.8), and out-of-pocket costs $1,000 or more were more common (32.0% vs 29.6%; relative change 8.2%, 95% CI 6.1-10.3). Conclusions: Higher clinician hospitalizing tendency for ED chest pain is associated with greater downstream testing, more coronary interventions, and higher costs without lower short- or intermediate-term AMI risk. Reducing marginal admissions among high-admitting clinicians may decrease spending and practice variation with minimal impact on AMI outcomes.

Background: Circadian syndrome (CircS) comprises metabolic abnormalities, short sleep, and depressive symptoms, and is associated with cardiovascular, liver, and lung diseases and mortality; evidence on digestive disease is scarce. We assessed its association with incident non-neoplastic digestive disease in Chinese adults. Methods: In this prospective analysis of the China Health and Retirement Longitudinal Study (CHARLS), we included 2011 baseline participants aged >=45 years free of digestive disease, with follow-up to 2018. CircS (>=4 of 7 components) was analysed as a continuous score and as a binary exposure. Cox models estimated hazard ratios (HRs) adjusting for demographic factors, BMI, smoking, and alcohol use. We did dose-response, component, subgroup, and sensitivity analyses; hs-CRP mediation was explored. Findings: 907 (19.0%) of 4 771 participants developed digestive disease over a median 84 months. Each additional CircS component raised the risk by 9.1% (HR 1.091, 95% CI 1.041-1.144, P<0.001); CircS positivity (36.1%) was associated with a 25.7% higher risk (HR 1.257, 1.084-1.456, P=0.002). Risk rose approximately linearly to about 70% higher at 5-7 components. Short sleep (HR 1.178, 1.017-1.365) and depressive symptoms (HR 1.570, 1.367-1.803) were the only independently associated components; no metabolic component was associated. Results were robust across sensitivity analyses; hs-CRP did not mediate the association. Interpretation: CircS is associated with incident non-neoplastic digestive disease, driven by its circadian-emotional rather than metabolic components. Sleep and mood may be targets for prevention. Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Keywords: circadian syndrome; digestive diseases; cohort study; sleep; depression; brain-gut axis

Background Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-COVID condition are complex, debilitating illnesses characterized by persistent fatigue and post-exertional malaise. Recovery is uncommon without targeted intervention; however, emerging clinical reports suggest that a subset of patients experience full resolution of symptoms after engaging in mind-body approaches. Patient perspectives on these interventions are divided, and qualitative evidence exploring successful recovery pathways is rare. This protocol outlines a study to investigate the contextual factors and patient-constructed explanations surrounding full recovery from ME/CFS or post-COVID condition using mind-body approaches. Methods and analysis We will employ a qualitative descriptive design rooted in a constructivist paradigm. Purposive and snowball sampling will be used to recruit approximately 20 adults from established infection-associated fatigue networks who self-report full recovery (lasting three months or more) from ME/CFS or post-COVID condition following a mind-body approach. Data will be collected through semi-structured interviews conducted via Zoom, and investigator reflexivity will be reported. Demographic information, including comorbidities, will be documented to contextualize the sample. Data will be analyzed inductively using reflexive thematic analysis. To ensure research rigor and reporting transparency, the study will adhere to the 15-point checklist of criteria for good thematic analysis proposed by Braun and Clarke. Dissemination We will publish our findings in a peer-reviewed, open-access journal and present at relevant academic conferences. A lay summary of the results will also be shared directly with participating patient recovery networks.

ABSTRACT Background: The esophageal String Test (EST) is emerging as a minimally invasive alternative for assessing disease activity in eosinophilic esophagitis (EoE), yet the molecular composition of its protein content remains unknown. Objective: To comprehensively characterize the esophageal EST proteome, define an EoE-associated luminal protein signature, and evaluate its biological and clinical relevance. Methods: EST samples were obtained from patients with active EoE, healthy controls (C) and patients with gastroesophageal reflux disease (GERD). Label-free proteomic profiling was performed by liquid chromatography-tandem mass spectrometry. Differential protein accumulation, principal component analysis (PCA), pathway annotation, comparison with published esophageal tissue and salivary proteomes, receiver operating characteristic (ROC) analyses and correlations with clinical disease activity were performed. Results: More than 3,000 proteins were identified in esophageal EST samples. Global proteomic profiling clearly separated patients with EoE from both C and GERD, whereas only limited differences were observed between the latter two groups. This enabled the identification of an EoE-associated luminal protein signature comprising inflammatory, epithelial, and tissue remodeling proteins. Comparison with published proteomic datasets indicated that the EST samples a complex esophageal luminal protein microenvironment containing proteins represented in esophageal mucosa and saliva, together with inflammatory and extracellular components. Several individual proteins showed high discriminatory performance in this exploratory cohort for distinguishing EoE from non-EoE subjects, and multiple proteins correlated with eosinophil counts and endoscopic measures of disease activity. Conclusions: This study demonstrates that the EST provides access to a complex esophageal luminal protein microenvironment and establishes a molecular framework for its minimally invasive characterization in EoE. KEYWORDS: eosinophilic esophagitis, esophageal string test, esophageal luminal protein signature

IntroductionCirculating proteins may augment prognostic scores and provide mechanistic insights for cardiovascular disease. Their role for adding precision to predicting response to therapeutic exercise training is less certain. Older adults with HF frequently experience geriatric syndromes, which may influence response to a rehabilitation intervention (RI). We sought to determine if the functional benefits of a 12-week tailored, structured, and progressive multidomain physical RI program in older adults, following a HF admission, could be estimated by pre-intervention levels of proteins. MethodsHospitalized adults age [&ge;] 60 years with HF were randomized to 12-week multidimensional (aerobic, strength, balance, flexibility) physical therapist-led RI versus attention control (AC). Outcomes included change in the short physical performance battery (SPPB) and 6-minute walk distance (6MWD). At pre-intervention and 12-weeks, 92 circulating proteins associated with CVD and inflammation were measured. Using linear regression, LASSO and ensemble tree-based approaches for flexible feature selection, proteins were selected for stratification of treatment response. Decision trees were developed to incorporate a multi-protein approach to optimize stratification of treatment response (effect measure modifiers [EMM]) for both functional outcomes. Differences in 12-week temporal changes based on RI vs AC and mediation analysis were used to assess possible causal roles for these proteins. ResultsBaseline proteomic data was available in 243/349 participants (69.6%). For SPPB, 2 proteins (GP6, ST2), and for 6MWD, 3 proteins (ALCAM, Gal-4, PECAM-1) were selected as EMMs. For SPPB, a decision tree with ST2 followed by GP6 level identified a differential 12-week improvement in score for RI vs AC from -0.8 (95%CI -1.9, 0.2) to 2.1 (95%CI 1.5, 2.7). For 6MWD, the optimized decision tree was based only on ALCAM with a differential 12-week improvement in score for RI vs AC from 10m (95%CI -17m, 36m) to 85m (95%CI 56m, 113m). However, none of the EMM proteins were mediators of change for the functional outcomes. ConclusionsCirculating proteins related to CVD and inflammation (GP6, ST2, ALCAM) stratify a successful functional response to the REHAB-HF rehabilitation program in older adults following HF hospitalization. Further investigation is needed to identify proteins associated with a causal role for rehabilitation benefits.

Background: Although opioids are frequently prescribed for refractory chronic neuropathic pain, few data are available on baseline factors that may identify individuals more likely to respond and inform individually tailored practice. Methods: This was a post hoc, exploratory analysis of individual-level data from a placebo-controlled trial of methadone for chronic neuropathic pain (NCT05235191). Baseline clinical, psychological, psychophysical and radiological variables were tested for association with 30% or more pain reduction in the methadone group. The correlation between expectation of improvement and pain reduction was examined in both groups. Results: Of the 81 participants completing the 8-week follow-up, 28 (70%) on methadone and 14 (34.1%) on placebo achieved 30% or more pain reduction. In the methadone group, responders had higher baseline expectation of improvement (median 100 [80-100] vs. 55 [50-81]; p=0.004), which correlated moderately with percentage pain reduction (rs=0.508; p<0.001). Neither finding was observed in the placebo group (p=0.211 and p=0.161, respectively), although the correlation did not differ significantly between groups (p for interaction=0.728). Other clinical, sociodemographic, psychological and psychophysical variables were not associated with response. In the subsample with peripheral neuropathic pain and structural MRI (n=37), lower left precentral cortex volume was associated with response to methadone (p=0.041), and lower right paracentral volume with response to placebo (p=0.003). Conclusions: Baseline expectation may influence treatment outcomes, supporting its inclusion as a covariate to improve the precision of treatment effect estimates in trials, and its use in clinical practice to help tailor treatment to individual patients. These exploratory findings require confirmation in larger studies.

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSIntroductionC_ST_ABSPolyunsaturated fatty acid (PUFA) status is an important marker of metabolic health across the lifespan, and omega-3 (n-3) PUFA were shown to have anti-inflammatory and cardioprotective effects. The omega-3 index, a composite of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), is widely used to assess n-3 PUFA supplementation status, and product-to-precursor fatty acid ratios are used as proxy indices of desaturation and elongation. Previous data indicate a higher proportion of n-3 PUFA with age. Whether the same pattern can be found in an NHANES cohort, and whether long-chain n-3 status relates to phenotypic age (PhenoAge), a composite measure of biological age, has not been established. MethodsWe analyzed erythrocyte fatty acid profiles measured by electron capture negative-ion mass spectrometry in erythrocytes of participants of the National Health and Nutrition Examination Survey (NHANES) 2021-2023. Adults aged 20-79 years with a complete 21-fatty-acid panel were included (n = 4,863) and stratified into five age groups (20-34, 35-44, 45-54, 55-64, 65-79 years). In the fasting subsample with a measured fasting glucose (n = 2,822) we additionally computed PhenoAge according to Levine and assessed PhenoAge acceleration (PhenoAge regressed on chronological age) in relation to EPA and DHA. ResultsPercentage of summarized PUFA and n-6 PUFA decreased with age while percentage of n-3 PUFA and EPA + DHA increased. In contrast, total saturated fatty acids did not differ across age groups. EPA and DHA rose with age, whereas linoleic acid (LA), dihomo-{gamma}-linolenic acid (DGLA) and -linolenic acid (ALA) declined. The delta-5-desaturase (D5D) index (AA/DGLA) and the AA/LA ratio were positively associated with age, while elongation-related proxies ELOVL2 (DTA/AA, DPA/EPA) and ELOVL5 (DGLA/GLA) were inversely associated. Higher EPA + DHA was associated with lower PhenoAge acceleration with the most pronounced effect of - 4,7 years in the group with highest ([&ge;]8%) EPA+DHA content. DiscussionAge-related shifts in erythrocyte PUFA composition and in desaturase and elongase proxy indices reported previously in a clinical cohort from Germany are reproduced in a large US population. In addition, long-chain n-3 status was inversely associated with PhenoAge acceleration.

Importance: Pain varies in its intensity and course, yet much of our understanding of pain is based on cross-sectional assessments or longitudinal studies of selected clinical populations. Routinely collected electronic health record data may enable characterization of longitudinal pain patterns at scale. Objective: To identify longitudinal pain profiles among U.S. Veterans and characterize their clinical and polygenic correlates. Design: Cohort study using electronic health record and genomic data from the Million Veteran Program, with up to 16 years of pain assessments collected between 2000 to 2025. Setting: U.S. Department of Veterans Affairs health care system. Participants: Million Veteran Program participants assigned to African-like, Admixed American-like, East Asian-like, European-like, or South Asian-like genetically inferred ancestry groups who have at least three years of outpatient numeric rating scale pain records. Exposures: Outpatient pain ratings and polygenic scores for psychiatric, sleep, and substance use traits. Main Outcomes and Measures: Pain profiles were identified using Gaussian finite mixture modeling of pain intensity, directional change, and within-person variability. Profiles were characterized by pain, psychiatric and substance use diagnoses, opioid exposure, body mass index, and polygenic scores. Results: Among 624,996 participants (Mean [SD] age at first pain rating=53.4 [13.5] years; 568,833 [91.0%] male), 51,731,567 outpatient pain ratings were analyzed. Three profiles were identified: stable no pain, stable mild pain, and mild-to-moderate increasing pain. Compared with the stable no pain profile, the increasing pain profile had higher odds of chronic pain (OR=21.14 [95% CI: 18.96-23.57]), opioid use disorder (OR=9.32 [95% CI: 8.31-10.45]), opioid exposure (OR=8.61 [95% CI: 8.41-8.83]), major depressive disorder (OR=3.77 [95% CI: 3.67-3.87]), and posttraumatic stress disorder (OR=3.72 [95% CI: 3.61-3.84]). Associations were attenuated but remained after adjustment for mean pain severity. Polygenic scores for depression, insomnia, attention-deficit/hyperactivity disorder, and tobacco use disorder were the most consistent predictors of increasing pain across the three largest genetically inferred ancestry groups. Conclusions and Relevance: Longitudinal modeling of routinely collected pain scores identified pain profiles associated with clinical burden and polygenic liability. These profiles captured clinically meaningful information beyond mean pain severity alone, highlighting the value of longitudinal pain phenotyping in electronic health record data.

Background: Metabolic perturbations associated with cardiovascular disease (CVD) risk factors prior to clinical disease manifestation may inform novel preventative measures. Here we characterize metabolome-wide associations with various cardiometabolic risk factors in an asymptomatic population to develop a mechanistic metabolic framework of preemergent metabolic shifts. Methods: Plasma was collected from a clinically healthy cross-sectional cohort (n = 361; Clinical Trials.gov ID: NCT02367287). Cohort mass spectrometry-based metabolomics (biocrates MxP(R) Quant 500 kits) were complemented with expanded lipidomic coverage for a sex/age-matched subset with LDLc difference > 60 mg/dL (n = 38). LDLc-focused partial least square regressions and discriminate analyses were performed, after false discovery rate corrections. Results: As LDLc levels increased, plasma sphingolipids and cholesteryl esters, and transulfuration products were higher, while ether-linked phosphatidylcholines serine, glycine, alanine, methionine were lower. The subset analysis further highlighted elevations in triglycerides and deoxyceramides with elevated LDLc. When adjusted for alanine concentrations, deoxyceramide concentrations increased as serine declined (p = 0.0012), and the deoxyceramide:ceramide ratios were higher in the high LDLc group (p = 0.039). Lower serine levels were also accompanied by parallel changes in glycine (p= 0.0004), and anti-parallel changes in transsulfuration pathway metabolites particularly when adjusted for ceramide levels. Notably, the alanine:serine ratio was more strongly associated with fasting triglycerides (r = 0.38; p <0.0001) than LDLc. Conclusions: Serine depletion by increased demands of sphingolipid, and possibly transsulfuration pathway, metabolism is associated with elevations in cytotoxic deoxyceramides and reductions in glycine and methionine availability for one-carbon metabolism. These changes were strongly associated with fasting triglycerides and insulin resistance, a key marker of residual CVD risk.

Many pathological conditions, including chronic pain (CP), can impair cognitive functions. These functions are essential for adapting and evolving in concordance with the environment, which are key processes for coping with CP. However, in CP centers, cognitive assessment is rarely included in CP patient follow-up due to a lack of time, appropriate tools, or trained health professionals. To fill this gap, our team developed EasyCog, a digital tool that enables rapid self-assessment of cognitive functions. It enables cognitive evaluation without an experimenter's help, thanks to speech recognition powered by an artificial neural network. In the initial validation steps, we established normative values for 7 cognitive functions on a cohort of 76 healthy subjects. Because EasyCog includes tests comparable to the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE), we assessed its reliability against available normative values. To assess its specificity, we compared data from healthy subjects with 15 subjects with mild cognitive impairment (MCI) and 15 age-matched CP patients selected from a medical center. Finally, we tested EasyCog's test-retest reliability by repeating sessions at different time intervals. EasyCog showed excellent sensitivity to age-related decline, similar to MoCA normative values. Several cognitive functions were significantly and differentially impaired in MCI subjects and CP patients compared to normative values in healthy subjects, confirming good specificity. Finally, test-retest analysis showed no effect at a 4-month interval. In conclusion, EasyCog appears to be a convenient and reliable numeric tool for rapidly assessing and monitoring cognitive functions in patients.

FBXO31 encodes the substrate receptor of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase that recognizes C-terminal amide-bearing proteins (CTAPs) and targets them for proteasomal degradation, a function of particular importance in neurons. A recurrent de novo missense variant, c.1000G>A p.(Asp334Asn), reprograms FBXO31 substrate specificity and causes an autosomal-dominant neurodevelopmental disorder with spastic cerebral palsy through a neomorphic gain-of-function mechanism. By contrast, biallelic loss of function has tentatively been linked to a recessive disorder. Here we report a female patient, born to consanguineous parents, with moderate intellectual disability, developmental delay and dysmorphic features, who carries a homozygous 54.3 kb deletion removing exons 2-8 and the coding part of exon 9 of FBXO31. The deletion retains only the exon 1-encoded F-box domain, while removing the coding sequence for the entire C-terminal substrate-recognition region. It is predicted to result in loss of function. Segregation is consistent with autosomal-recessive inheritance, with both parents and three of five unaffected siblings being heterozygous carriers. Together with two previously reported recessive families and the experimentally established neomorphic action of p.(Asp334Asn), the homozygous deletion supports an FBXO31 allelic series comprising dominant gain of function and recessive biallelic loss of function.

Introduction: Across major phases of the COVID-19 pandemic (March 2020-April 2023), we compared the burden of severe COVID-19 among individuals with systemic autoimmune rheumatic diseases (SARDs) versus immunocompetent individuals with and without comorbidities. Methods: This population-based cohort study used administrative datasets to estimate crude and age- and sex-standardized SARS-CoV-2 and severe COVID-19 incidences among adults >18 years with SARDs, chronic comorbidities, or no comorbidities. Relative to the latter, we used Cox models to derive adjusted hazard ratios (aHRs) for infection, hospitalization, and intensive care unit admission or death (ICU/death) during the pre-vaccination (March-December 2020), vaccination pre-Omicron (December 2020-December 2021), and Omicron (December 2021-April 2023) periods. Results: We included 81,434 adults with SARDs, and 2,020,356 with comorbidities versus 3,144,700 without comorbidities. Despite similar adjusted infection rates, the SARDS cohort had higher risks of hospitalization and ICU/death during the pre-vaccination period (aHRs: 3.4, 95%CI:2.8-4.1; and 4.0, 95%CI:2.8-5.7, respectively), persisting through the Omicron period (aHRs: 4.5, 95%CI:4.0-4.9; and 4.4, 95%CI:3.6-5.4, respectively). Among SARDS, rheumatoid arthritis, psoriatic arthritis and systemic lupus erythematosus contributed highest burden, with comparable hospitalization and mortality rates among younger rheumatoid arthritis versus healthy older adults. Highly immunosuppressive rituximab- or mycophenolate-treated patients had highest hospitalization and ICU/death risks, particularly during the Omicron period (aHRs: 11.9, 95%CI:9.9-14.3; and 17.6, 95%CI:13.0-23.9, respectively). Conclusion: Individuals with SARDs, especially receiving highly immunosuppressive therapies, experienced elevated COVID-19 burden and severe outcome risks throughout the pandemic, warranting their prioritized consideration during future public health emergencies.