Tag: nevin manimala

PLoS Genet. 2025 Oct 7;21(10):e1011848. doi: 10.1371/journal.pgen.1011848. Online ahead of print.

ABSTRACT

Investigation of the cellular and molecular mechanisms of disease progression from precursor plasma cell disorders to active disease increases our understanding of multiple myeloma (MM) pathogenesis and supports the development of novel therapeutic strategies. In this analysis, single-cell RNA sequencing, surface protein profiling, and B lymphocyte antigen receptor profiling of unsorted, whole bone marrow (BM) mononuclear cell samples was used to study molecular changes in tumor cells and the tumor microenvironment (TME). A cell atlas of the BM microenvironment was generated from 123 subjects including healthy volunteers and patients with monoclonal gammopathy of unknown significance (MGUS), smoldering MM (SMM), and MM. These analyses revealed commonalities in molecular pathways, including MYC signaling, E2F targets and interferon alpha response, that were altered during disease progression. Evidence of early dysregulation of the immune system in MGUS and SMM, which increases and impacts many cell types as the disease progresses, was found. In parallel with disease progression, population shifts in CD8 + T cells, macrophages, and classical dendritic cells were observed, and the resulting differences in CD8 + T cells and macrophages were associated with poor overall survival outcomes. Potential ligand-receptor interactions that may play a role during the transition from precursor stages to MM were identified, along with potential biomarkers of disease progression, some of which may represent novel therapeutic targets. MIF, IL15, CD320, HGF and FAM3C were detected as potential regulators of the TME by plasma cells, while SERPINA1 and BAFF (TNFSF13B) were found to have the highest potential to contribute to the downstream changes observed between precursor stage and MM cells. These findings demonstrate that myeloma tumorigenesis is associated with dysregulation of molecular pathways driven by gradually occurring immunophenotypic changes in the tumor and TME. Trial registration: This project has been registered at EudraCT (European Union Drug Regulating Authorities Clinical Trials Database) with protocol number NOPRODMMY0001 and EudraCT Number 2018-004443-23 on 12 December 2018.

PMID:41056512 | DOI:10.1371/journal.pgen.1011848

Hepatol Commun. 2025 Oct 7;9(11):e0824. doi: 10.1097/HC9.0000000000000824. eCollection 2025 Nov 1.

ABSTRACT

BACKGROUND: Large epidemiologic studies of autoimmune hepatitis (AIH) in the United States are limited. None have reported prevalence trends over time. This contemporary study examines AIH prevalence and demographic trends over 10 years in a community-based integrated healthcare system in Northern California. We further assessed whether prevalence trends differed by AIH ascertainment approach.

METHODS: This retrospective study used data from adults aged ≥18 years in Kaiser Permanente Northern California (2010-2019). AIH was identified by coded diagnosis and confirmed with diagnostic testing (laboratory and/or liver biopsy) and treatment response. Annual AIH prevalence was estimated and stratified by age, sex, and race/ethnicity.

RESULTS: Among 1129 patients with confirmed AIH, 80% were female, 44% non-Hispanic White, 26% Hispanic, 16% Asian/Pacific Islander, and 9% Black. In all, 76% of patients on AIH treatment demonstrated treatment response at 6 months. AIH prevalence (per 100,000 adults) increased from 9.1 in 2010 to 18.8 in 2019 (p<0.0001). Prevalence among older adults (≥75 years) quadrupled from 10.1 to 43.7 per 100,000. Prevalence rose among all ethnicities and in 2019 was highest for Black (28.9) and Hispanic populations (25.2) per 100,000.

CONCLUSIONS: AIH prevalence doubled over 10 years in a large healthcare system, with pronounced increases among older populations. Prevalence was highest among Black and Hispanic adults. Further studies should examine demographic differences in the clinical course of AIH, including response to therapy, adverse events, and outcomes.

PMID:41056496 | DOI:10.1097/HC9.0000000000000824

Mol Biol Evol. 2025 Oct 7:msaf253. doi: 10.1093/molbev/msaf253. Online ahead of print.

ABSTRACT

Bayesian phylogeographic inference is widely used in molecular epidemiological studies to reconstruct the dispersal history of pathogens. Discrete phylogeographic analysis treats geographic locations as discrete traits and infers lineage transition events among them, and is typically followed by a Bayes factor (BF) test to assess the statistical support. In the standard BF (BFstd) test, the relative abundance of the involved trait states is not considered, which can be problematic in the case of unbalanced sampling. Existing methods to correct sampling bias in discrete phylogeographic analyses using continuous-time Markov chain (CTMC) model, often require additional epidemiological information to balance the sampling effort among locations. As such data is not necessarily available, alternative approaches that rely solely on available genomic data are needed. In this perspective, we assess the performance of a modification of the BFstd, the adjusted Bayes factor (BFadj), which incorporates information on the relative abundance of samples by location when inferring support for transition events and root location inference without requiring additional data. Using a simulation framework, we assess the statistical performance of BFstd and BFadj under varying levels of sampling bias, estimating their type I and type II error rates. Our results show that BFadj complements the BFstd by reducing type I errors at the cost increasing type II errors for inferred transition events, while improving type I and type II errors in root location inference. Our findings provide guidelines for implementing the complementary BFadj to detect and mitigate sampling bias in discrete phylogeographic inference using CTMC modelling.

PMID:41056469 | DOI:10.1093/molbev/msaf253

J Orthop Trauma. 2025 Oct 7. doi: 10.1097/BOT.0000000000003092. Online ahead of print.

ABSTRACT

OBJECTIVES: To determine the rate at which abstracts accepted for the Orthopedic Trauma Association (OTA) Annual Meeting from 2019 to 2024 utilized the Fracture-related Infection (FRI) Consensus Group’s definition for infection.

METHODS: Data Sources: The data sources for this study included the Orthopedic Trauma Association (OTA) Annual Meeting Programs from 2019-2024 and the “abstract search” portion of OTA Website.

STUDY SELECTION: All podium and poster abstract presentations that utilized keywords for infection (“fracture-related infection,” “infection,” or “SSI”) in the title.

DATA EXTRACTION: All abstracts were reviewed, and grouped into one of the four following categories based on the methodologic descriptors used to define infection characteristics: 1) Utilized Consensus Group Definition, 2) Utilized CDC Definition [deep, superficial, organ/space, or SSI terminology], 3) Utilized an Author Specific Definition, 4) Did Not Utilize Any Definition.

DATA SYNTHESIS: Univariate statistics were conducted to determine yearly and overall percentages of abstracts that utilized the Consensus Group’s definition as compared to the other 3 definition categories. Bivariate analysis was performed to determine if the use of Consensus Group’s definition varied from 2019-2024.

RESULTS: 52 podium abstracts and 59 poster abstracts were included. Among the podium abstracts, 4 (7.7%) utilized the Consensus Group’s definition of FRI, 37 (71.2%) utilized language from the CDC definition, 4 (7.7%) used an author specific definition, and 7 (13.5%) abstracts did not utilize any definition of descriptors of infection. Poster abstracts demonstrated similar utilization of methodical infection descriptors, as 5 (8.5%) utilized the Consensus Group’s definition of FRI. The number of abstracts that utilized the Consensus Group’s Definition did not vary from 2019-2024 (p=0.952 for podiums, p=0.451 for posters).

CONCLUSIONS: Adoption of the FRI Consensus Group’s definition among accepted OTA 2019-2024 Annual Meeting abstracts was low.

LEVEL OF EVIDENCE: IV.

PMID:41056451 | DOI:10.1097/BOT.0000000000003092

Int J Audiol. 2025 Oct 7:1-11. doi: 10.1080/14992027.2025.2568647. Online ahead of print.

ABSTRACT

OBJECTIVE: To compare the long-term effects of two earplug fit-training methods on the ability of U.S. military personnel to self-fit a foam earplug and achieve sufficient attenuation of weapon noise during military training.

DESIGN: Participants were randomly assigned to one of two earplug fit-training methods (control [typical; n = 239], experimental [experiential hearing protection device (eHPD); n = 151]), and one of two hearing protector fit-testing (HPFT) schedules (quarterly, annually).

STUDY SAMPLE: 390 U.S. Marine Corps Infantry training recruits.

RESULTS: Passing had no association with participants tested quarterly or annually and were merged to two groups for analysis. Immediately post-training, 57% of the control and 78% of the experimental training groups achieved a passing personal attenuation rating (PAR) of at least 25.0 A-weighted decibels. Approximately 12 months post-training, the passing PAR proportion reduced to 19% (control) and 37% (experimental). The differences in pass rates between groups at both time points were statistically significant (p < 0.05).

CONCLUSIONS: The individualised eHPD fit-training resulted in a greater proportion of participants able to achieve adequate noise protection (both immediately and one year later) with issued foam earplugs. Based on our study results, the ability to adequately self-fit in-ear hearing protection is a perishable skill and annual training is justified.

PMID:41056447 | DOI:10.1080/14992027.2025.2568647

J Orthop Trauma. 2025 Oct 6. doi: 10.1097/BOT.0000000000003094. Online ahead of print.

ABSTRACT

OBJECTIVES: To compare the effectiveness and safety of aspirin versus low-molecular-weight heparin (LMWH) for thromboprophylaxis in 11 high-risk or fracture location subpopulations.

METHODS: Design: A post-hoc secondary analysis of the published PREVENT CLOT trial.

SETTING: 21 trauma centers.

PATIENT SELECTION CRITERIA: Adult patients with an operatively treated extremity fracture or any pelvic or acetabular fracture were enrolled from April 2017 through August 2021. Patients with only hand or foot fractures, presenting >48 hours after injury, or with a history of VTE within 6 months of injury were excluded. The 11 subpopulations included i) a head injury, ii) an abdominal injury, iii) a spinal injury, iv) a thoracic injury, v) multiply injured patients, vi) obesity, vii) previous VTE ≥ 6 months, viii) isolated upper extremity fracture, ix) isolated lower extremity fracture, x) isolated pelvic or acetabular fracture, and xi) geriatric femur fracture.

OUTCOME MEASURES AND COMPARISONS: The primary outcome was 90-day all-cause mortality. Secondary outcomes included non-fatal pulmonary embolism, proximal deep vein thrombosis (DVT), distal DVT, and bleeding events. Outcomes were assessed using Kaplan-Meier estimators and Cox proportional hazards models comparing 81 mg of aspirin versus 30 mg of LMWH twice daily. The threshold for statistical significance was a Bonferroni-corrected alpha of 0.001 to account for multiple comparisons.

RESULTS: The largest subpopulations were isolated lower extremity fractures (n=6,289), obesity (n=4,234), and polytrauma with Injury Severity Score (ISS) >16 (n=1,596). No comparison of aspirin vs LMWH within the 11 subpopulations for the 5 outcomes reached the corrected threshold for statistical significance of P < 0.001. However, 5 comparisons of aspirin vs LMWH were less than the conventional P-value of 0.05. Specifically, the aspirin group demonstrated lower mortality in patients with a head injury (difference, -3.2%; 95% CI -6.1% to -0.3%; P = 0.03) or a spine injury (difference, -6.0%; 95% CI -11.7% to -0.3%; P = 0.04) than the LMWH group. The LMWH group demonstrated a lower rate of distal DVTs for patients with a head injury (difference, 4.4%; 95% CI, 0.8% to 8.1%; P = 0.03), thoracic injury (difference, 1.5%; 95% CI, 0.0% to 2.9%; P=0.034) or with ISS >16 (difference, 1.7%; 95% CI, 0.2% to 3.3; P = 0.03) than the aspirin group.

CONCLUSIONS: Within 11 high-risk or fracture location-specific subpopulations, there were no statistically significant differences between aspirin or LMWH in the 90-day rates of all-cause mortality, non-fatal PE, proximal DVT, distal DVT, or bleeding complications at a threshold corrected for multiple comparisons (P < 0.001).

LEVEL OF EVIDENCE: Therapeutic Level I.

PMID:41056444 | DOI:10.1097/BOT.0000000000003094

J Orthop Trauma. 2025 Oct 6. doi: 10.1097/BOT.0000000000003093. Online ahead of print.

ABSTRACT

OBJECTIVES: To investigate the occurrence and risk factors for breakage of 2.7 mm variable angle (VA) locking screws from Depuy – Synthes during removal.

METHODS: Design: Retrospective cohort study.

SETTING: Two urban tertiary care hospitals in India.

PATIENT SELECTION CRITERIA: Patients from 2018 to 2024, undergoing removal of VA locked implants after healing of distal humerus (AO/OTA 13 – A2,3 and 13 – C1,2,3) and distal tibia fractures (AO/ OTA 43 – A1,2,3 and C2,3).Outcome measures and comparisons: The primary outcome measure was breakage of 2.7 mm VA locked screws. Difference in breakage between titanium and stainless-steel screws were examined. Age, gender, bone quality (measured in Hounsfield units using preoperative computerised tomography), body mass index, screw length, and time between surgery and implant removal were analysed for association with screw breakage.

RESULTS: Of 28 patients included, 16 patients underwent removal of titanium implants from the distal humerus and 12 patients underwent removal of stainless-steel implants from the distal tibia. There were 16 males and 12 females with mean age of 41years (range 20-20, SD 15). 95 out of 254 VA locking screws were reported broken during removal. 46 out of 105 (43.8%) stainless steel screws broke compared to 49 out of 149 (32.8%) titanium screws. This difference was not statistically significant (p = 0.234). Younger age (β = -0.48, SE = 0.2, p = 0.022), longer screw length (β = 0.21, SE = 0.23, p = 0.038) and a longer interval between surgery and removal (β = 0.43, SE = 0.42, p = 0.002) were associated with a higher incidence of screw breakage.

CONCLUSIONS: A high incidence of breakage was observed during removal of 2.7 mm VA titanium and stainless-steel locking screws. Younger patients, longer screws and late removal were associated with more risk for breakage. It is important for patients undergoing removal of these implants to be adequately informed and surgeons should be prepared to address this challenge intraoperatively.

LEVEL OF EVIDENCE: IV Retrospective cohort study.

PMID:41056442 | DOI:10.1097/BOT.0000000000003093

Rheumatology (Oxford). 2025 Oct 7:keaf481. doi: 10.1093/rheumatology/keaf481. Online ahead of print.

ABSTRACT

OBJECTIVE: To report a VEXAS syndrome patient presenting with muscular manifestations, at diagnosis and to review the literature on this rare involvement.

METHODS: We conducted a narrative review through 3 databases (Cochran, PubMed and Google Scholar) to identify all reports of muscle involvement associated with VEXAS syndrome. No statistical analysis was performed.

RESULTS: We reported a 73-year-old male VEXAS syndrome patient presenting with muscular manifestations with ptosis, trismus, lower limb myalgia and identified 15 other patients in the literature. All were male with a median age of 71. The most common UBA1 mutations in exon 3, codon 41 involved methionine 41. Muscle inflammation at the onset of VEXAS syndrome was diagnosed by MRI or CT scan. It mostly involved orbital and facial muscles (n = 7), causing diplopia, proptosis, periorbital oedema or chemosis, and the muscles of the lower limbs, causing myalgia, weakness or oedema (n = 7). Muscle histological analysis was also performed in a few cases (n = 5) and revealed an inflammatory infiltrate with macrophages. Other symptoms were quite common: fever, skin and lung involvement, chondritis, arthralgia and thromboembolic events. Corticosteroid therapy was a routine, and the use of corticosteroid-sparing agents was almost systematic.

CONCLUSION: Taken together, these new data describe the specific muscle involvement of VEXAS syndrome and extend its phenotypic spectrum. It enables us to identify three very distinct manifestations of muscle involvement: orbital, facial, and lower limb inflammation. A case series study would provide a better description of these symptoms.

PMID:41056436 | DOI:10.1093/rheumatology/keaf481

J Appl Physiol (1985). 2025 Oct 7. doi: 10.1152/japplphysiol.00393.2025. Online ahead of print.

ABSTRACT

Understanding the dynamic interaction between cardiovascular and cerebrovascular systems during exercise is essential to evaluate the mechanisms supporting brain perfusion. This study examined age- and sex-specific differences in cardiovascular and cerebrovascular dynamic response and used systems modeling to assess physiological coupling during moderate intensity exercise. We recruited adults to complete a single session of moderate intensity exercise on a recumbent stepper. Middle cerebral artery blood velocity (MCAv), mean arterial pressure (MAP), heart rate (HR), and end-tidal CO₂ (P_ETCO₂) were continuously recorded. In 164 participants, we analyzed the dynamic responses to exercise using mono-exponential modeling and functional data analysis. Granger causality within a subject-specific vector autoregression framework evaluated directional influence among physiological signals. Advancing age was associated with an attenuated dynamic response for MCAv, P_ETCO₂, and HR while MAP was elevated. Older adults exhibited significantly smaller MCAv amplitude and slower time constants than young and middle-aged groups. While sex did not influence overall MCAv, MAP, or HR kinetics, men had significantly higher P_ETCO₂ throughout exercise. Granger causality analysis revealed bidirectional coupling among MCAv, HR, MAP, and P_ETCO₂. Prior P_ETCO₂ levels significantly predicted MCAv while MAP had both short- and long-lag predictive effects on MCAv. MCAv also influenced subsequent changes in MAP and P_ETCO₂, indicating feedback regulation. P_ETCO₂ emerged as a dominant driver of MCAv, though systemic interactions reflect an integrated physiological network with multi-component feedback loops. This study advances understanding of cerebrovascular regulation and highlights the utility of systems modeling during exercise.

PMID:41056428 | DOI:10.1152/japplphysiol.00393.2025

Br J Radiol. 2025 Oct 7:tqaf246. doi: 10.1093/bjr/tqaf246. Online ahead of print.

ABSTRACT

OBJECTIVES: To validate the diagnostic accuracy of pelvic floor ultrasound (PFUS) for pelvic organ prolapse (POP) and its correlation with the Pelvic Organ Prolapse Quantification (POP-Q) staging system by performing a rigorous quantitative comparison of anatomical measurements between women with POP and asymptomatic controls.

METHODS: In this prospective observational study, 80 women with clinically confirmed POP and 60 asymptomatic controls underwent standardized PFUS and POP-Q examinations. PFUS was utilized to measure bladder, uterine, and rectal positions during maximal Valsalva maneuver. POP-Q staging was conducted by two blinded urogynecologists (inter-rater reliability κ = 0.87). Statistical analyses included Spearman’s correlation (ρ), diagnostic performance metrics (sensitivity, specificity, accuracy), and group comparisons using t-tests or chi-square tests.

RESULTS: The POP group exhibited significant organ descent versus controls, including mean bladder descent (4.5 ± 1.2 cm vs. 1.8 ± 0.3 cm; P = 0.004) and uterine descent (5.2 ± 1.4 cm vs. 2.05 ± 0.40 cm; P = 0.012). PFUS measurements demonstrated strong correlation with POP-Q stages (compartment-specific ρ = 0.87-0.91). Overall agreement was 90.0% (ρ = 0.92, P < 0.001), with high diagnostic accuracy (93.5%), sensitivity (>90%), and specificity (>96%).

CONCLUSIONS: PFUS is a reliable, non-invasive method to quantify pelvic organ displacement, showing excellent agreement with the clinical standard POP-Q system. Its high diagnostic performance supports its integration into clinical practice for objective diagnosis, severity grading, and comprehensive anatomical characterization of POP.

ADVANCES IN KNOWLEDGE: This study provides robust evidence validating PFUS as a reproducible objective tool for POP assessment.

PMID:41056418 | DOI:10.1093/bjr/tqaf246