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.

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.

Fibromyalgia syndrome (FMS) is characterized by chronic widespread pain, fatigue and cognitive difficulties, but its underlying mechanisms remain incompletely understood. The uncertainty of the origins of FMS has hampered the development of treatments and diagnostic methods, and the available therapeutic options offer limited relief to patients, an estimated 2-4% of the population. The severe burden of FMS thus represents an urgent unmet clinical need. MicroRNAs (miRNAs), non-coding short RNAs that have vital inhibitory roles in gene expression, have been explored in FMS pathophysiology. MicroRNA signatures associated with FMS may facilitate diagnosis and reveal new insights into the cellular and molecular mechanisms of FMS. We compiled and analyzed publicly available data of dysregulated miRNAs in FMS. MiRNAs were categorized according to the direction of dysregulation (levels up or down in FMS vs health) and compared across studies. Only miRNAs identified as dysregulated in the same direction in at least two studies were included. RNA targets of at least two microRNAs were inferred using TargetScan and subjected to pathway enrichment analysis using Reactome , ShinyGo v.8, miRNA Tissue Atlas 2025 and EnrichR. This analysis revealed enrichment in pathways central to cell signaling and immune function, such as regulation of PTEN, circadian rhythm and RNA metabolic processes. Additionally, the dysregulated miRNAs in FMS were over-represented in immune-related tissues such as lymph node and spleen. Collectively, these findings support a role for immune dysregulation in FMS. By using an integrative approach, we identified candidate pathways and molecular targets that warrant further experimental validation.

Background Trimethylaminuria (TMAU) is a rare metabolic disorder characterized by malodor resulting from impaired metabolism of trimethylamine, but its broader impact on patients lives remains insufficiently characterized. This study aimed to assess the diagnostic, psychosocial, educational, occupational, and treatment-related burden of TMAU across a multinational patient population and to explore cognitive manifestations identified during the study. Methods We conducted a multinational, cross-sectional, patient-reported survey using an anonymous online questionnaire. Of 450 submissions, 401 participants provided valid authorization for analysis. The survey assessed demographic characteristics, symptom and diagnostic experiences, educational and occupational consequences, psychosocial burden, and perceptions of current management. Cognitive complaints emerging during the initial study prompted a follow-up survey focused on cognitive symptoms and their functional impact, completed by 306 participants from the original cohort. The association between cognitive symptom frequency and severity was assessed using Spearman rank correlation. Results Participants represented more than 40 countries, and 61.1% were female. A substantial diagnostic gap was observed, with 65.8% reporting no official diagnosis or clear medical explanation of probable TMAU. Social and psychological consequences were prominent, including physical rejection or social exclusion (78.8%), bullying or derogatory treatment (61.1%), and substantial disruption of educational and occupational participation. Most participants (84.3%) considered currently available treatment options insufficient. In the cognitive follow-up survey, 68.0% reported cognitive difficulties at least several times per week, 58.8% reported moderate or severe symptoms, and 66.7% reported at least moderate interference with daily activities, work, or studies. Greater cognitive symptom frequency was significantly associated with greater severity (Spearman coefficient = 0.451, p < 0.001). Conclusions TMAU is associated with a multidimensional patient-reported burden extending beyond malodor to psychosocial, educational, occupational, and previously underrecognized cognitive manifestations. These findings support earlier recognition, multidisciplinary care, and development of mechanism-based therapies evaluated using patient-centered outcomes that include daily functioning, cognitive symptoms, and quality of life.

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: Delayed diagnosis of immunoglobulin light-chain cardiac amyloidosis (AL-CA) worsens prognosis, partly because AL-CA and wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) are difficult to distinguish at the initial cardiology visit. We developed and validated a practical score to triage AL-CA from ATTRwt-CA. Methods: We retrospectively analyzed 541 consecutive patients with cardiac amyloidosis (91 AL-CA, 450 ATTRwt-CA) at our institution's amyloidosis center, randomly divided into derivation (n=378) and validation (n=163) cohorts. Candidate first-visit variables underwent LASSO selection after multiple imputation, with estimates pooled by Rubin's rules. Performance was assessed by bootstrap validation, calibration, and decision curve analysis. The model was converted into a simplified point-based score. Results: Seven variables were retained: age, absence of atrial fibrillation, absence of carpal tunnel syndrome, low serum albumin, proteinuria ([&ge;]1+), low voltage, and thinner left ventricular posterior wall thickness. Areas under the curve (AUC) were 0.97 in the derivation cohort and 0.99 in the validation cohort; the bootstrap optimism-corrected AUC was 0.96. The model provided net benefit across threshold probabilities of 0.01-0.50. Risk tiering categorized the validation cohort into low (0-5 points; AL-CA 0%), intermediate (6?9 points; 26%), and high (10-13 points; 95%) probability groups. Discrimination remained high for AL-CA versus monoclonal protein-positive ATTRwt-CA at a cutoff of [&ge;]8 points (AUC 0.90). Adding this score to monoclonal protein testing significantly improved diagnostic performance compared with monoclonal protein testing alone. Conclusions: This simple first-visit score may help cardiologists rapidly triage suspected AL-CA and prioritize urgent hematology referral and subtype-specific confirmatory testing.

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.

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.

Background. Small fibre pathology has been proposed as a peripheral substrate for a subset of patients with fibromyalgia. A 2019 meta-analysis of 8 studies (222 patients) reported a pooled prevalence of 49% with moderate heterogeneity, and concluded that this supported a distinct fibromyalgia phenotype. The evidence base has since expanded substantially. Methods. We systematically searched PubMed for original human studies reporting the proportion of adults with fibromyalgia showing abnormal small fibre findings on an objective structural or functional test (skin biopsy with intraepidermal nerve fibre density, corneal confocal microscopy, sudomotor testing, microneurography, or laser-evoked potentials). Proportions were pooled with a random-effects model on the logit scale (REML). We pre-specified subgroup analyses by diagnostic method and assessment site, meta-regression on publication year and sample size, leave-one-out sensitivity analysis, and risk-of-bias appraisal with the JBI prevalence checklist. Where cohorts overlapped, the most complete report was retained. Search and initial screening were AI-assisted; eligibility, extraction and appraisal were performed independently by two reviewers with consensus. Results. Of 83 records, 34 studies met eligibility and 21 (1,268 patients) provided extractable proportions. Applying a uniform rule of abnormality at any assessed site, the pooled prevalence was 46.5% (95% CI 34.3-59.1), with I2=92.7% and a 95% prediction interval of 8.6% to 89.0%. Individual estimates ranged from 0% to 85.2%. Contrary to our pre-specified hypothesis, diagnostic method did not explain heterogeneity (QM p=0.89, R2=0). Assessment site was the dominant moderator: using each study's site-specific data, distal-leg assessment yielded 30.5% (22.4-40.1; 15 studies) and proximal-thigh assessment 73.9% (53.5-87.4; 4 studies). Three studies assessed both sites in the same patients and all three found more abnormality proximally (31.6% vs 46.2%; 12.3% vs 85.2%; 9.7% vs 83.9%). Publication year (p=0.50) and sample size (p=0.24) were not associated with prevalence. Leave-one-out estimates remained between 44.4% and 49.6%. Conclusions. More than tripling the evidence base did not stabilise the pooled prevalence estimate and more than doubled heterogeneity (I2 68% to 93%). The prediction interval now spans almost the entire possible range, and the method difference reported in 2019 is no longer detectable. Studies do not share a common definition of abnormality, and several do not report one at all. A pooled prevalence figure for small fibre pathology in fibromyalgia is therefore not currently interpretable; a standardised case definition is a prerequisite for meaningful synthesis. The anatomical site of assessment, not the technique, emerges as the dominant source of variation and should be treated as a primary moderator in future work.

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.

Irritable bowel syndrome (IBS) is a common disorder of brain-gut interaction characterized by recurrent abdominal pain and altered bowel habits. Although music-based interventions (MBIs) have shown benefits on pain and stress, the mechanisms associated with MBI-related changes in IBS pain remain poorly understood, and the feasibility of capturing these responses using multimodal wearable monitoring in everyday settings has not been established. This protocol describes a single-arm pilot mechanistic trial examining clinical and multimodal mechanistic responses to an MBI in adults with IBS and the feasibility of extending physiological monitoring from the laboratory to home settings. Thirty-six adults aged 18-50 years with provider-confirmed IBS will be enrolled, with approximately 30 expected to complete the post-intervention laboratory visit. Participants will receive board-certified music therapist-guided laboratory sessions and complete four weeks of self-administered home practice using a standardized 20-minute MBI protocol at least five days per week. Guided by a brain-gut mechanistic framework, assessments will include patient-reported pain, stress, and IBS symptoms; quantitative sensory testing; gut microbiome profiling using 16S rRNA gene sequencing; and multimodal physiological recordings of neural, autonomic, and muscular activity. Analyses will characterize within-session and longitudinal changes in clinical and mechanistic measures and assess recruitment, retention, MBI adherence, wearable data completeness, and participant acceptability. Findings will inform the selection of candidate mechanisms and wearable monitoring approaches for evaluation in a future adequately powered randomized controlled trial.

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.

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: 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.

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.