Muscle & Nerve

Background: Hereditary transthyretin amyloidosis (hATTR) manifests as cardiomyopathy and/or polyneuropathy. The V142I variant predominantly causes cardiac disease in African Americans, though neurological involvement may be underrecognized. We characterized neuropathy documentation and treatment patterns in a predominantly V142I cohort. Methods: Retrospective review of 54 hATTR patients at a major academic medical center. Neuropathy was classified as: objective (abnormal EMG), possible polyneuropathy (documented symptoms suggestive of polyneuropathy), symptoms only (neuropathic symptoms without specialist evaluation), or unclear. Treatment with stabilizers (tafamidis, acoramidis, diflunisal) and gene silencers (patisiran, vutrisiran, eplontersen) was assessed. Results: Of 54 patients (88.9% African American, 85.2% V142I), 51 (94.4%) had confirmed cardiac involvement. Among cardiac patients, 40/42 eligible (95.2%) received stabilizers. Overall, 16 patients (29.6%) received gene silencers, with 13 (24.1%) receiving both a stabilizer and gene silencer concurrently. Possible neuropathy (objective, possible polyneuropathy, or symptoms) was documented in 30 patients (55.6%). Gene silencer use was highest among those with objective neuropathy (8/17, 47.1%) versus symptoms only (1/10, 10.0%). All three patients without confirmed cardiac disease received gene silencers. Conclusions: In this V142I-predominant cohort with 94.4% cardiac involvement, stabilizer use was high (95.2%) among eligible patients. Over half had possible neuropathy based on clinical documentation, though EMG completion was limited (57.4%). Gene silencer use was associated with objective neuropathy documentation and non-cardiac phenotype. These findings support systematic neurological assessment in hATTR, even when cardiac disease predominates.

Dysarthric speech severity assessment typically requires either trained clinicians or supervised machine learning models built from labelled pathological speech data, limiting scalability across languages and clinical settings. We present a training-free method (no supervised severity model is trained; feature directions are estimated from healthy control speech using a pretrained forced aligner) that quantifies dysarthria severity by measuring the degradation of phonological feature subspaces within frozen HuBERT representations. For each speaker, we extract phone-level embeddings via Montreal Forced Aligner, compute d scores along phonological contrast directions (nasality, voicing, stridency, sonorance, manner, and four vowel features) derived exclusively from healthy control speech, and construct a 12-dimensional phonological profile. Evaluating 890 speakers across10corpora, 5 languages for the full MFA pipeline (English, Spanish, Dutch, Mandarin, French) and 3 primary aetiologies (Parkinsons disease, cerebral palsy, amyotrophic lateral sclerosis), we find that all five consonant d features correlate significantly with clinical severity (random-effects meta-analysis rho = -0.50 to -0.56, p < 2 x 10^-4; pooled Spearman rho = -0.47 to -0.55 with bootstrap 95% CIs not crossing zero), with the effect replicating within individual corpora, surviving FDR correction, and remaining robust to leave-one-corpus-out removal and alignment quality controls. Nasality d decreases monotonically from control to severe in 6 of 7 severity-graded corpora. Mann-Whitney U tests confirm that all 12 features distinguish controls from severely dysarthric speakers (p < 0.001).The method requires no dysarthric training data and applies to any language with an existing MFA acoustic model (currently 29 languages) or a model trained from healthy speech alone. It produces clinically interpretable per-feature profiles. We release the full pipeline and phone feature configurations for six languages to support replication and clinical adoption. Author SummaryOne of the authors has lived with ALS for sixteen years. Bernard Muller, who built this entire analytical pipeline using only eye-tracking technology, has experienced the progression of the disease firsthand, including the dysarthric speech that comes with advancing ALS and the tracheostomy that followed. The problem this paper addresses is not abstract to him, and that shapes how the method was designed. We developed a method to measure how well a person with dysarthria can produce distinct speech sounds, without needing any recordings of disordered speech for training. Our approach works by analysing how a widely available AI speech model organises different sound categories -- such as nasal versus oral consonants, or voiced versus voiceless sounds -- and measuring whether those categories become harder to tell apart. We tested this on 890 speakers across 10 datasets in five languages, covering Parkinsons disease, cerebral palsy, and ALS. Because the method only needs healthy speech recordings to set up, it applies to any language with an existing acoustic model, currently covering 29 languages. The resulting profiles show clinicians which specific aspects of speech production are degrading, rather than providing a single opaque severity score. This could support remote monitoring of speech decline in neurodegenerative disease and enable screening in languages and settings where specialist assessment is unavailable.

Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited treatment options. Masitinib, a tyrosine kinase inhibitor targeting microglial and mast cell activity in ALS pathogenesis, offers potential neuroprotection. This study presents a post-hoc analysis of long-term survivors treated with masitinib at 4.5 mg/kg/day in study AB10015, comparing observed survival to predicted and historical benchmarks. Methods: Study AB10015 was a randomized, double-blind, placebo-controlled trial assessing masitinib with riluzole in ALS patients. Overall survival (OS) was measured from symptom onset to death, encompassing the double-blind period and post-study follow-up, including an optional open-label program. The ENCALS model predicted survival of long-term survivors ([&ge;]5 years). A delay in the need for mechanical assistance, such as permanent ventilation, gastrostomy, tracheostomy, or wheelchair dependence, was used as a surrogate measure for quality of life (QoL). Results: Among 130 patients receiving masitinib 4.5 mg/kg/day, the 5-year survival rate from onset was 42.3%, increasing to 50.0% in patients with an ALSFRS-R progression rate from disease onset of <1.1 points/month (AB10015 primary efficacy population), and 52.9% in a subgroup of patients without complete loss of functionality at baseline. Half of the long-term survivors had satisfactory QoL, defined as no mechanical assistance. The median OS for long-term survivors (n=55) was 121 months versus the ENCALS-predicted 42 months, yielding a 79-month residual median survival gain. Long-term survivors were prevalent across ALS baseline prognostic factors, including slow or moderate disease progression rate ({Delta}FS), severe or moderate functional severity, bulbar or spinal site of onset, respiratory function, and age. Long-term survival was less likely in patients with complete loss of function at baseline or fast progressing disease ({Delta}FS [&ge;]1.1 points/month) at baseline. Conclusions: Masitinib treatment in ALS patients showed substantial survival benefit. Long-term survivors were largely independent of ALS prognostic factors, suggesting a subpopulation driven by microglial/mast cell activity. A recently identified biomarker detecting masitinib effect on pro-inflammatory microglia may help identify responsive patients.

BackgroundGastroesophageal reflux disease (GERD) is highly prevalent in systemic sclerosis (SSc) and frequently persists despite proton pump inhibitor (PPI) therapy. However, the mechanisms underlying PPI-refractory GERD in SSc remain incompletely understood. MethodsWe conducted a singlel7lcentre, retrospective study of adults with SSc who underwent ambulatory pH-multichannel intraluminal impedance (pH/MII) monitoring while receiving twicel7ldaily PPI therapy (2021-2025). Esophageal motility (highl7lresolution manometry, HREM) and gastric emptying scintigraphy were integrated to examine associations between gastro-esophageal dysmotility and reflux phenotypes. ResultsThirty patients were included, of whom 67% had PPI-refractory reflux symptoms and 33% were undergoing pre-lung transplantation evaluation. Refractory GERD was present in 29/30 patients (97%) based on Lyon 2.0 classification, with conclusive evidence in 53% and borderline evidence in 43%. Esophageal dysmotility was identified in 80%, most commonly absent contractility (67%), and was associated with impaired reflux clearance, reflected by longer acid clearance times (2.20 [1.15-3.75] vs 1.15 [0.43-1.90] min) and prolonged reflux episode duration (16.60 [4.38-40.63] vs 1.95 [0.53-20.43] min). Gastric dysmotility was identified in 60.7% and was associated with an increased reflux episode burden (51.00 [30.00-81.50] vs 25.00 [21.00-54.00] episodes/24h). ConclusionsPPIl7lrefractory GERD is nearly universal in this SSc cohort and reflects heterogeneous, quantifiable abnormalities across the foregut, including impaired esophageal clearance and increased reflux burden related to gastric retention. These findings support integrated physiologic evaluation to define reflux mechanisms, inform risk stratification (including lung transplantation), and guide targeted, mechanism-based therapies beyond acid suppression.

Objective Cerebral palsy (CP) affects approximately 1 million Americans and 18 million individuals worldwide, yet contemporary US epidemiologic data remains limited. We aimed to use Cerebral Palsy Research Network (CPRN) clinical registry to describe demographics and clinical characteristics of individuals with CP across the US and determine associations with gross motor function and genetic etiology. Methods Registry subjects were included if they had clinician-confirmed CP and prospectively entered data for Gross Motor Function Classification System (GMFCS) Level, gestational age, genetic etiology, CP distribution, and tone/movement types. Logistic regression was used to determine which of these variables plus race, sex, ethnicity, and age were associated with GMFCS level and genetic etiology. Results A total of 9,756 children and adults with CP from 22 CPRN sites met inclusion criteria. Participants were predominantly White (73.0%), male (57.3%), non-Hispanic (87.8%), and younger than 18 years (73.7%). Most were classified as GMFCS levels I-III (55.6%), born preterm (52.8%), had spasticity (83.8%), and had quadriplegia (41.9%); 12.2% were identified as having a genetic etiology. Tone/movement types, CP distribution, and gestational age were significantly associated with both GMFCS level and genetic etiology (p<0.001). Compared to White individuals, Black individuals were more likely to have greater gross motor impairment (p<0.001). Conclusion In this large US cohort, clinical and demographic factors, including race, were associated with gross motor function and genetic etiology in CP. These findings highlight persistent disparities and demonstrate the value of a national clinical registry for informing prognostication, quality improvement efforts, and targeted genetic testing strategies.

Background: Idiopathic pulmonary fibrosis (IPF) is a rare disease with a poor prognosis. Disease risk involves rare and common genetic variants. However, an inverse association have been described between them. Accordingly, IPF patients with a higher polygenic risk score (PRS) for IPF are less likely to carry rare deleterious variants and vice versa. Here, we evaluate weather PRS of IPF could serve as an additional criterion to patient prioritisation for rare variant discovery. Methods: We identified carriers based on the presence of rare qualifying variants (QVs) in genes linked to monogenic forms of pulmonary fibrosis in 888 IPF patients from the Pulmonary Fibrosis Foundation Patient Registry (PFF-PR). Genome-wide association study (GWAS) summary statistics from independent cohorts were used to construct a whole-genome PRS (WG-PRS) using a clumping and thresholding method (C+T) and a Bayesian method (SBayesRC). PRS were also derived from 19 known common sentinel IPF variants (Sentinel-PRS). Logistic regression models were used to evaluate associations between PRS and carrier status. Discriminatory performance was evaluated using area under the curve (AUC) analysis, and comparisons were made with DeLong test. Validation was performed in 472 IPF individuals from the UK PROFILE cohort. Results: IPF-PRS were strongly associated with the QVs carrier status: Odds Ratio [OR] 0.65 (95% Confidence Interval [CI] 0.53-0.79) for WG-PRSC+T, OR 0.71 (95% CI 0.59-0.86) for WG-PRSSBayesRC, and OR 0.77 (95% CI 0.63-0.94) for Sentinel-PRS. Adding WG-PRS to the patient personal clinical history improved the prediction of QVs carriers: AUC=0.62 for the clinical model, AUC=0.68 for WG-PRSC+T (DeLong test, p=9.54x10-4) and AUC=0.66 for WG-PRSSBayesRC (DeLong test, p=0.02). Adding of IPF-PRS to clinical variables correctly reclassified 22.8% of carriers when using WG-PRSC+T, 20.8% when using Sentinel-PRS, and 16.7% for WG-PRSSBayesRC. WG-PRSSBayesRC and the Sentinel-PRS also demonstrated improved prediction of QVs carriers in telomere-related genes in PROFILE. Conclusions: Incorporating IPF-PRS into a model based on the patient clinical history improves the identification of QVs carriers. Although the overall discriminatory power was moderate, these findings raise de the possibility of using WG-PRS as useful criterion for rare variant discovery in patients with IPF and enhance decision-making.

Background: Moderate- to high-intensity walking training (M-HIT) is an established intervention for improving walking capacity in chronic stroke. Musculoskeletal (MSK) adverse events commonly occur during M-HIT, yet tools to identify individuals at higher risk are limited. Baseline clinical characteristics may provide insight into susceptibility to training-related MSK adverse events during M-HIT. Thus, this study aimed to develop and internally validate a model for predicting MSK adverse events during a 12-week M-HIT program in chronic stroke using baseline clinical characteristics. Methods: Participants (n=100) from HIT-Stroke Trials 1 and 2 were included. Baseline clinical characteristics included measures of orthopedic history, pre-existing pain, motor function, recent exercise history, demographics and health characteristics, stroke chronicity, and psychological health. Logistic regression models evaluated all possible combinations of baseline characteristics with up to three predictors. Leave-one-out cross-validation was used for internal validation to mitigate overfitting. Predictive performance was quantified using the C-statistic, and the candidate model with the highest cross-validated C-statistic was selected as the final model. Results: MSK adverse events occurred in 32.0% of participants. The optimal three-variable model included prior orthopedic condition (Odds ratio [OR] 3.02 [95% CI 1.14-8.64]), Fugl-Meyer lower extremity motor score (OR 1.14 [95% CI 1.02-1.28]), and self-reported participation in regular walking exercise (OR 0.17 [95% CI 0.05-0.49]) at baseline. This model demonstrated moderate discrimination (cross-validated C-statistic = 0.74; apparent C-statistic = 0.78). Conclusions: Participants reporting at least one pre-existing lower extremity or lumbar spine orthopedic condition and those with better lower-extremity motor function exhibited greater odds of experiencing MSK adverse events during M-HIT, while participants reporting participation in regular walking exercise had lower odds. These findings suggest that baseline clinical characteristics may help identify individuals at elevated risk for MSK adverse events during M-HIT who may warrant closer monitoring or risk-reduction strategies. Future studies are needed for external validation. Clinical Trial Registration: https://ClinicalTrials.gov; Unique identifiers: NCT03760016, NCT06268041

Walking speed is widely used to assess gait recovery following stroke, yet it provides limited insight into how walking performance is mechanically organized. This study examined how center of mass (COM) work organization and propulsion-support coupling vary across walking speeds in individuals with post stroke hemiparesis to distinguish recovery of gait organization from recovery of limb level mechanical function. Eleven individuals with post stroke hemiparesis performed treadmill walking across speeds ranging from 0.2 to 0.7 m/s while ground reaction forces were recorded. Limb specific COM power and work were computed using an individual limbs framework, and interlimb asymmetry in net and positive work, along with the propulsion-support ratio (PSR), were quantified. A qualitative transition in gait organization was observed: at lower walking speeds, COM power exhibited a simplified two phase pattern, whereas at higher walking speeds (approximately >=0.5 m/s), a structured four phase COM power pattern emerged, including identifiable push off and preload phases. Despite this recovery of gait organization, interlimb work asymmetry remained elevated and paretic PSR remained reduced across all speeds, indicating persistent limb level mechanical deficits. These findings demonstrate that increases in walking speed and the emergence of typical COM power structure reflect recovery of gait organization rather than restoration of underlying limb level mechanical capacity. Consequently, walking speed alone is insufficient to characterize gait recovery after stroke, and biomechanically informed measures of COM work organization and propulsion-support coupling provide complementary insight by distinguishing organizational recovery from limb-level mechanical recovery.

Genetic counselling outcome measures are increasingly adapted for diverse clinical contexts. While the Genetic Counselling Outcome Scale (GCOS-24) is available in Swedish, no autism-specific version has been developed. Therefore, we adapted the Swedish GCOS-24 using the English version of the modified GCOS-24 (mGCSOS-24) to create a Swedish autism-specific mGCOS-24. Thereafter, we evaluated both the Swedish autism mGCOS-24 and the Swedish general GCOS-24 using Rasch analysis to assess their psychometric properties. Both instruments exhibited structural challenges, including multidimensionality, disordered thresholds, local item dependence, and invariance issues. For the Swedish autism mGCOS-24, we were able to identify subscales with acceptable measurement properties. However, applying the same structure to the Swedish general GCOS-24 did not resolve its broader limitations. This study introduces the first Swedish autism-specific mGCOS-24 and represents the first Rasch-based evaluation of any GCOS-24 or mGCOS-24 in Swedish. Our findings highlight important opportunities for measure refinement but also indicate that new or more substantially adapted tools may be needed to capture outcomes of genetic counselling in autistic populations.

Saccadic eye movements are established biomarkers in neuroscience and clinical neurology, where video-oculography (VOG) remains the gold standard. However, VOG's high cost, bulky equipment, and poor portability restrict its clinical utility. Electrooculography (EOG) offers a promising alternative by detecting cornea-retinal potential changes during eye movements. To enable quantitative saccadic analysis using EOG as a VOG alternative, this study develops and validates a mathematical transformation model converting EOG data into VOG-equivalent values. A prospective observational study was conducted on 4 healthy adults without neurological or sleep disorders. Horizontal saccades were recorded simultaneously using EOG and VOG during controlled gaze shifts. EOG peak saccadic velocity was derived from voltage change rate, whereas VOG was calculated from angular displacement over time. A derivation dataset of fixed horizontal saccades ({+/-}20{degrees}) formulated the transformation model, achieving a strong correlation coefficient (r = 0.95 rightward, r = 0.93 leftward, p < 0.0001). Multiple filter settings were evaluated, and 0.3 Hz high-pass and 35 Hz low-pass filtering were identified as optimal. The fixed horizontal saccades derived model was applied to a validation dataset of random horizontal saccades, confirming robustness across saccades without significant differences from VOG measurements. These findings establish EOG's feasibility for quantitative analysis of horizontal saccades and provide a validated transformation model. By systematically optimizing filtering parameters, this approach enables EOG as a cost-effective VOG alternative while maintaining high-precision measurement accuracy.

Markerless motion capture has emerged as a potential substitute for traditional marker-based systems, offering scalable, non-invasive acquisition of human movement. Despite increasing adoption in research and sports applications, its clinical utility for children with complex gait patterns remains an open question. To address this gap, simultaneous marker-based and markerless data were collected in 202 pediatric children (12.1 {+/-} 3.9 years). Marker-based kinematics were processed using the Shriners Children's Gait Model (SCGM), while markerless outputs were computed using Theia3D with identical Cardan sequences. Agreement between systems was evaluated using statistical parametric mapping (SPM), root-mean-square error (RMSE), and a gait pattern classification based on the plantarflexor-knee extension index. Markerless output systematically underestimated pelvic tilt, hip rotation, and knee rotation and demonstrated reduced between-subject variance in the transverse plane. SPM revealed widespread waveform differences, although most were of negligible effect, especially in the sagittal plane. Mean sagittal-plane RMSEs were < 5{degrees} for the knee and ankle and < 8{degrees} for the pelvis and hip. Coronal-plane deviations were < 7{degrees}, whereas transverse-plane errors exceeded 10{degrees}. RMSE increased significantly with body mass index and use of a walker (p < 0.001). Agreement in sagittal-plane gait classification was moderate between systems ({kappa} = 0.60; 67% overall concordance). These results indicate that markerless motion capture is suitable for analyses emphasizing sagittal deviations but remains limited for applications requiring precise axial or frontal-plane estimation. Future work should address algorithmic underestimation of transverse motion and evaluate markerless performance across increasing severity of gait deviation.

Objectives. The association between skeletal muscle gene expression and knee osteoarthritis (OA) was examined among older adult participants of the Study of Muscle, Mobility and Aging (SOMMA). Methods. Inclusion criteria included knee radiographs and bulk RNA sequencing (RNAseq) in vastus lateralis muscle, resulting in 523 participants (56% female). Radiographic knee OA was determined by Kellgren-Lawrence (KL) grades. Differential gene expression was analyzed using a control group (KL [&le;] 1, n = 326) and two nested case groups: (a) KL [&ge;] 2 (n = 197), (b) KL [&ge;] 3 (n = 112). Results. Compared with controls, there were 27 and 41 genes associated (FDR [&le;] 0.05) with KL [&ge;] 2 and KL [&ge;] 3, respectively, and 16 genes significantly associated in both contrasts. For 15 of the 16 genes, the association magnitude was larger with more severe OA (KL [&ge;] 3). Genes associated in both contrasts included brain-derived neurotrophic factor (BDNF) and interferon regulatory factor-2 (IRF2). Gene sets enriched in KL [&ge;] 2 and KL [&ge;] 3 contrasts included DNA repair and branched chain amino acid (BCAA) catabolism. Conclusions. Our results in older adult SOMMA participants indicate that knee OA is associated with genes and pathways expressed in skeletal muscle that are involved in pain sensitization, BCAA catabolism, muscle function preservation, calcium transport and storage, inflammation, and extracellular matrix remodeling. Additional longitudinal studies will be needed to determine how these genes could affect the progression of knee OA.

Introduction: Auditory brainstem response (ABR) is a standard objective method for estimating hearing threshold, especially in patients who cannot reliably participate in behavioral audiometry. However, ABR interpretation is usually performed by an expert. This study evaluated whether two general-purpose artificial intelligence (AI) multimodal large language model (LLM) chatbots, ChatGPT and Qwen, can accurately estimate ABR hearing thresholds from ABR waveform images. The accuracy was measured by comparisons with the judgements of 3 expert audiologists. Methods: A total of 500 images each containing several ABR waveforms recorded at different stimulus intensities were analyzed. Three expert audiologists established the reference auditory thresholds based on visual identification of wave V at the lowest stimulus intensity, with the most frequent judgment among the three used as the reference. Each waveform image was independently submitted to ChatGPT (version 5.1) and Qwen (version 3Max) using the same standardized prompt and without additional clinical context. Agreement with the expert thresholds was assessed as mean errors and correlations. Sensitivity and specificity for detecting hearing loss (>20 dB nHL) were also calculated. In cases where the AI and expert thresholds nominally matched, corresponding latency measures were also compared. Results: Auditory thresholds derived from both LLMs correlated strongly with expert opinion, with Pearson r = 0.954 for ChatGPT and r = 0.958 for Qwen. ChatGPT showed a mean error of +5.5 dB and Qwen showed a mean error of -2.7 dB. Exact nominal agreement with expert values was achieved in 34.6% of ChatGPT estimates and 35.6% of Qwen estimates; agreement within +/-10 dB was observed in 75.6% and 80.0% of cases, respectively. For hearing-loss classification, ChatGPT achieved 100% sensitivity but low specificity (20.4%), whereas Qwen showed a more balanced profile with 91.6% sensitivity and 67.5% specificity. Curiously, estimates of wave V latency were markedly poor for both LLMs, with systematic underestimation and weak correlations with the expert judgements. Conclusion: ChatGPT and Qwen demonstrated a moderate ability to estimate ABR thresholds from waveform images, although their performance was not good enough for independent clinical use. Both models captured general patterns of hearing loss severity, but there was systematic bias, limited specificity and sensitivity balance, and poor latency estimation. General-purpose multimodal LLMs may have potential as assistive or preliminary tools, but clinically reliable ABR interpretation will likely require specialized, domain-trained AI systems with expert oversight.

Stroke is the third leading cause of death and disability combined worldwide and often results in hemiparesis. Functional magnetic resonance imaging (fMRI) is a non-invasive technique used to investigate changes in brain activations during tasks aimed at restoring the lost motor function. Participants with chronic stroke and residual hemiparesis in the upper extremity were recruited for a clinical intervention that included neurofeedback training and fMRI sessions with motor-execution and motor-imagery tasks. The present study provides a baseline characterization of brain activations prior to neurofeedback training. Since lesion site and volume varied across participants, two fMRI preprocessing pipelines were applied. The first one was used for twelve participants with lesions restricted to a single hemisphere and for one participant with small secondary lesions in the contralesional hemisphere, whereas the second one was used for two participants with large bilateral lesions. These were followed by quality control measures and statistical analysis. First-level (i.e., single-participant) analysis returned the strongest and most extensive activation across participants during motor-execution tasks, with clusters identified in the ipsilesional parietal lobe, bilateral occipital lobes, and cerebellum after Family-Wise Error correction. Second-level (i.e., group-level) analysis involving participants who underwent the first fMRI preprocessing pipeline revealed a significant cluster in the cerebellum after False Discovery Rate correction. These results are consistent with previous studies involving participants with chronic stroke performing motor-tasks. Cerebellar recruitment observed consistently across participants could reflect compensatory mechanisms supporting motor control after stroke.

In humans, germline mutation rates are three- to four-fold higher in males than females, for largely unknown reasons. We investigated whether transcription, a well-documented source of both DNA damage and repair in somatic tissues, is associated with sex differences in germline mutations. To this end, we used expression data from male and female germline cells and phased de novo germline mutations from pedigrees. Focusing on protein-coding genes, we found no relationship between the male mutation rate and gene expression levels in the fetal germline or in adult testis tissue, despite evidence for transcriptional asymmetry. Individual stages of spermatogenesis differ in their contribution to mutation, however: expression levels in spermatogonial stem cells are significantly positively associated with paternal mutation rates, while those in primary spermatocytes are significantly negatively associated. Thus, transcription may have varying effects over male gametogenesis that are not readily detected from its cumulative effect on the total germline mutation rate. In females, by contrast, mutation rates increase significantly with transcription levels in the fetal germline, adult oocytes and adult ovary tissues, consistent with widespread transcription asymmetry. We confirm the difference between the sexes by analyzing phased mutations from three-generation pedigrees and the lack of an association in males by analyzing paternal mutations from seminiferous tubules and sperm. Thus, transcription has distinct effects on the mutation rate in the two sexes, leading to an increase in mutations in females but not males, in contrast to what one might expect from the overall paternal bias in germline mutations.

Objective: Improved diet quality is increasingly important for comorbidities management and healthy aging in people with HIV (PWH). Yet, limited data exist on dietary patterns and their correlates in this population. This study aimed to (1) characterize dietary patterns among adult PWH and (2) identify demographic, clinical, and HIV related factors associated with diet quality. Methods: We conducted a cross sectional analysis of PWH enrolled in the PROSPER HIV study across four U.S. academic medical centers. Dietary intake was assessed using three 24 hour dietary recalls and scored using the Healthy Eating Index 2015 (HEI2015). Participants were categorized into tertiles based on total HEI2015 scores. Between group comparisons were performed using Kruskal Wallis and chi square tests. Factors independently associated with HEI2015 scores were identified using multivariable linear regression. Results: A total of 491 PWH were included with a median age of 54 years; 76.4% were male. Overall diet quality was low with inadequate intake of dietary protein, fiber, and micronutrients. When classified by tertiles of HEI 2015 score, higher diet quality was characterized by greater intake of fiber, protein, and key micronutrients. Older age was independently associated with higher HEI 2015 scores, while Black race was associated with lower scores. Full time employment and absence of current pain were marginally associated with better diet quality. Conclusions: Diet quality among PWH varies substantially and is influenced by age, race, and social determinants. Tailored nutritional strategies are needed to support healthy aging and reduce disparities in this population.

Previous studies have linked opioid use to altered metabolic profiles, but findings have been inconsistent and mechanisms remain unclear. One potential mechanism involves increased adiposity, leading to chronic low-grade inflammation that elevates metabolic risk. Here, we examined metabolic profiles in individuals with opioid use disorder (OUD) and matched non-OUD controls, focusing on the sequential mediating roles of BMI and inflammation. Data from individuals with OUD (n=281) and non-OUD (n=246) were drawn from a natural history screening protocol from the National Institute on Alcohol Abuse and Alcoholism intramural program. Groups were matched on age, sex, race, ethnicity, socioeconomic status, and education via propensity score matching. Metabolic measures included BMI, blood glucose, hemoglobin A1c (HbA1c), and lipid profiles, with lipid imbalance indexed by the atherogenic index of plasma (AIP). Inflammatory markers included C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Individuals with OUD had significantly higher BMI (F1,481=12.9, p<0.001), HbA1c (F1,481=10.5, p=0.001), lower high-density lipoprotein cholesterol (HDL-C; F1,481= 46.2, p< 0.001), higher low-density lipoprotein cholesterol (LDL-C; F1, 481=11.9, p< 0.001), and higher AIP (F1,481=20.7, p< 0.001) compared to non-OUD. Inflammatory markers were also elevated in individuals with OUD, including CRP (F1,481=9.4, p=0.002) and ESR (F1,481=7.4, p= 0.007), and statistically mediated group differences in AIP and HbA1c, respectively. Our results are consistent with prior evidence of metabolic dysfunctions in individuals with OUD and suggest inflammation as a contributing mechanism. Targeting metabolic health and inflammation may offer new avenues for improving long-term health outcomes in OUD.

Background Poor physical function has been associated with higher cardiovascular disease (CVD) risk. However, the association between physical function and atrial fibrillation (AF) remains understudied. The comprehensive investigation of the association between physical function and incident AF risk could highlight a novel target for AF prevention. Methods A total of 4,803 participants without diagnosed AF from the Atherosclerosis Risk in Communities (ARIC) Study cohort with physical function assessed in 2011-2013 were studied. Physical function was measured using Short Physical Performance Battery (SPPB), 4-meter walk time, and grip strength. Hospital discharge codes and death certificates were used to ascertain incident AF through 2022, and through 2020 for participants from Jackson. Cox regression was used to assess the association between physical function and incident AF risk, adjusting for multiple covariates. Z-score transformations were performed to identify the physical function measure most strongly associated with incident AF risk, and SPPB component analysis was performed to identify the most influential SPPB component. Results Mean age of the study participants was 75.1 {+/-} 5.0 years, with 41.2% being male participants and 22.2% being black participants. During a median follow-up of 9.2 years, there were 809 incident AF events. SPPB (HR: 0.93, 95% CI: 0.90-0.96, per 1-point increase) and grip strength (HR: 0.87, 95% CI: 0.78-0.96, per 10kg increase) were inversely associated with incident AF risk, while 4-meter walk time (HR: 1.08, 95% CI: 1.03-1.13, per 1-second increase) was positively associated with incident AF risk. SPPB had the strongest association with incident AF risk. Within SPPB, only the chair stand component was significantly associated with incident AF risk. Conclusions The findings suggest that better physical function is associated with reduced incident AF risk, with higher SPPB having the strongest association. Given the modifiable nature of physical function, these findings highlight a potential novel target for AF prevention in aging populations.

Background: The COVID-19 pandemic disrupted childhood immunization programmes in many countries worldwide. However, evidence on its impact in low and middle-income countries remains limited. This study examined the impact of the COVID-19 pandemic on childhood immunization coverage across 514 districts in Indonesia and identified district-level associated factors. Methods: We conducted a nationwide longitudinal analysis of the Expanded Programme on Immunization to compare immunization coverage before and after the pandemic. The outcome variable was the annual childhood immunization coverage (proportion of children aged 0-12 months who have received all recommended doses of childhood immunization as per the national immunization schedule). The explanatory variables include COVID-19 burden and vaccination rates, health system and human development indicators. Mixed-effect logistic regression was done to assess association between the explanatory and outcome variables. Results: At the national level, the coverage was 83.2% in pre-pandemic, 75.0% in the first year of pandemic, and 88.6%, in the second. In the first year, 69.3% of districts experienced significant decline, with a lower national coverage ratio of 0.92 (95% confidence interval 0.89-0.94). In the second year, 36.2% districts were still affected. The multivariable analysis showed that a significant decline in coverage during the first pandemic year was associated with high COVID-19 incidence (adjusted odds ratio 2.19, 95%CI 1.01-4.73 for the highest vs. lowest group), low midwife adequacy (5.84, 2.40-14.16 for the lowest vs. the highest group, 2.61, 1.26-5.40 for low-middle vs. the highest group), and a high proportion of health facility-based births (2.98, 1.49-5.98 for middle-high vs. the lowest group). Conclusions: The COVID-19 pandemic negatively and unevenly impacted childhood immunization in Indonesia, with greatest impacts in districts facing a higher COVID-19 burden and weaker health system capacity. These findings underscore the need for targeted efforts to strengthen the local health system for future health crises. Keywords: COVID-19, pandemic, immunization, vaccine preventable diseases

Background: Kidney transplantation is the preferred treatment strategy for end-stage kidney disease. Deceased donor kidneys usually undergo cold storage until kidney transplantation, leading to cold ischemia injury that may contribute to poor graft outcomes. However, the molecular characterization of potential mechanisms of cold ischemia injury remains incomplete. Results: To bridge this knowledge gap, we leveraged the 10x Visium spatial transcriptomic technology to perform full transcriptome profiling of murine kidneys subject to varying durations of cold ischemia typical in a deceased donor kidney transplant setting. We developed a computational workflow to identify and compare spatiotemporal transcriptomic changes that accompany the injury pathophysiology in a tissue compartment-specific manner. We identified proportional enrichment of oxidative phosphorylation (OXPHOS) genes with increasing duration of cold ischemia injury within the oxygen-lean inner medulla region, suggestive of atypical metabolic presentation. This was distinct in cold ischemia injury tissue compared to warm ischemia-reperfusion kidney injury tissue. Spatiotemporal trends were validated by qPCR and immunofluorescence in a larger cohort of mice. We provide an interactive online browser at https://jef.works/CellCarto-ColdIschemia/ to facilitate exploration of our results by the broader scientific and clinical community. Conclusions: Altogether, our spatiotemporal transcriptomic analysis identified coordinated molecular changes within metabolic pathways such as OXPHOS deep within the cold ischemic kidney, highlighting the need for increased attention to the inner medulla and potential opportunities for new insights beyond those available from superficial biopsy-focused tissue examinations.