ERJ Open Research

Background Elexacaftor-tezacaftor-ivacaftor (ETI) has been demonstrated to improve lung function in clinical trials; however, evidence describing effects on trajectories and whether long-term improvements are sustained (>1-year) is lacking. We estimated within-person lung clearance index (LCI) trajectories before and after ETI initiation, assessing changes in level and rate of change, alongside acute LCI change, up to three years after ETI initiation. Methods Prospective observational study of children at a tertiary hospital. Children aged 3-17 years with [&ge;]2 LCI testing occasions (i) before and (ii) after starting ETI were used to describe lung function trajectories. Children with [&ge;]1 pre-ETI and [&ge;]1 post-ETI LCI occasion(s) were used to describe acute LCI change after ETI initiation. Age-adjusted LCI trajectories for time periods (i) before and (ii) after ETI initiation were estimated using linear mixed-effects models, and pre- and post-ETI LCIs were compared using paired Wilcoxon tests. Results Mean pre-ETI and post-ETI longitudinal changes in LCI were -0.007 (95% CI: -0.28, 0.27; n=35) and 0.12 (95% CI: -0.17, 0.41; n=20) turnovers per year, respectively. Before ETI initiation, 57% (30/53) of patients had an LCI[&ge;]7.1 turnovers (indicating impaired lung function), compared to 26% (14/53) post-ETI, with a median LCI difference of -0.70 (95% CI -0.84, -0.46; p<0.001) turnovers. Within-individual variability in LCI decreased post-ETI. Conclusions Our real-world data within a unique longitudinal study provide a comprehensive picture of ETI benefit by outlining not only acute improvement in LCI but maintained stability in LCI trajectories and improved LCI stability sustained up to three years post-initiation.

Rationale: Pulmonary hypertension is defined by pulmonary hemodynamics, but diagnostic and prognostic biomarkers remain limited. Nuclear magnetic resonance (NMR) spectroscopy provides detailed insights, particularly in the lipid metabolism. Objectives: To explore circulating NMR-derived metabolites and lipoprotein-related parameters for their association with pulmonary hemodynamics and to analyse their prognostic properties in pulmonary arterial hypertension (PAH). Methods: Retrospective analysis of a PAH cohort with complete diagnostic workup including right heart catheterization and baseline serum samples, from the prospective GRaz Pulmonary Hypertension-Metabolism (GRAPH-M) registry. Measurements: NMR-derived metabolites and lipoprotein-related parameters were analyzed for their association with clinically relevant parameters of PAH. We defined PHIHDL, a score derived from high-density lipoprotein (HDL) related measures based on their strong association with pulmonary hemodynamics, and evaluated its prognostic value. Results: We included 100 patients with PAH treated at the PH clinic of LKH University Hospital, Medical University of Graz, between 2011 and 2021. Age was 61{+/-}15 years, female/male ratio 2.5, BMI 26 {+/-}7 kg/m2, mPAP 41{+/-}16 mmHg, PAWP 8.8{+/-}3.2 mmHg, PVR 8.0{+/-}4.9 WU, and median survival was 8.0 years. During follow-up, 46 patients died. We identified a cluster of 12 HDL-related measures that showed significant inverse association to pulmonary hemodynamics and derived PHIHDL from the reversed scaled average of these particles. PHIHDL was associated with all-cause mortality after adjustment for age and sex (HR 2.96, 95% CI 1.52-5.70), independent of the clinical risk scores COMPERA 2.0 and REVEAL Lite2. Conclusion: PHIHDL, a pulmonary hemodynamics-based metabolomic score, provides independent prognostic information beyond established risk scores in PAH.

Inadequate autophagy promotes smoking-induced cellular senescence involved in chronic obstructive pulmonary disease (COPD) pathogenesis. Transcription factor EB (TFEB) is a master regulator of the autophagy-lysosome axis. For the first time, we investigated the therapeutic potential of pemafibrate, a putative TFEB inducer. COPD lung epithelial cells showed reduced TFEB expression. Pemafibrate enhanced autophagy/mitophagy flux and restored lysosomal acidification observed during cigarette smoke (CS) extract exposure in human bronchial epithelial cells, resulting in reduced cellular senescence. TFEB knockdown demonstrated involvement of pemafibrate-induced TFEB in these effects. Pemafibrate induced TFEB expression, mitigated alveolar enlargement and airflow obstruction, and attenuated the CS-induced increase in static lung compliance in a long-term CS-exposed mouse model. It reduced the CS exposure-induced cellular senescence, possibly through autophagy/mitophagy, as suggested by bulk RNA sequencing of mouse lungs. A retrospective cohort study showed that patients given pemafibrate displayed attenuated FEV1.0 decline compared with those given bezafibrate or fenofibrate. In conclusion, pemafibrate is a promising therapeutic agent for COPD, potentially exerting its effects through the regulation of the TFEB-autophagy/mitophagy-lysosome axis.

Background: Higher Body Mass Index (BMI) is an established risk factor of sleep disturbance. It is not known if the effect is homogeneous across the lifecourse or if there is a particular time point in life that might be best to target. Methods: Two-sample Mendelian randomization (MR) was used to investigated the effect of childhood adiposity (adjusting on adulthood adiposity and obstructive sleep apnea (OSA)) on insomnia, morning chronotype, sleep duration, daytime sleepiness and daytime napping. Similarly, total, and direct effect of adulthood adiposity on these outcomes was explored. We used summary statistics from a genome-wide association study (GWAS) of UK Biobank for childhood and adulthood adiposity (n=453,169) and large-scale consortia of OSA (Million Veteran Program) (n=410,268), insomnia, and chronotype (23andMe) (n=1,978,022 and n=248,1000, respectively). Results: Two-sample univariable MR analysis provided no evidence of an effect of genetically predicted childhood adiposity on later life insomnia (Odds ratio (OR)= 0.94, 95% Confidence interval (CI)= 0.87, 1.03). Whereas, multivariable MR (adjusted for adulthood adiposity) analysis provide strong evidence of direct protective effect of genetically predicted childhood adiposity on later life insomnia (OR= 0.70, CI= 0.64, 0.77). Further, both in univariable and multivariable MR, a strong positive effect of increased childhood body size on morning chronotype was observed (OR= 1.16, CI= 1.01, 1.33 and OR= 1.36, CI= 1.15, 1.62, respectively) after accounting for adulthood body size. In both analysis the estimate did not change considerably after aditionally adjusting for OSA. However, childhood and adulthood adiposity found to be associated with OSA and OSA with insomnia. In both univariable and multivariable analysis, increased body size in adulthood increased the risk of having insomnia and a morning chronotype. Conclusions: The findings suggest that higher body size in childhood is not a risk factor for later life insomnia, whereas higher body size in adulthood was. Further, if healthy body size is maintained in adulthood, high childhood adiposity may decrease the risk of insomnia and increase the risk of being a morning person in later life. Keywords: childhood, adulthood, obesity, insomnia, morning chronotype, medelian randomization

Background: Low-dose computed tomography (LDCT) screening reduces lung cancer mortality but is limited by low uptake and associated with high rates of false-positives and indeterminate-nodules. Breath volatile organic compound (VOC) analysis is a non-invasive candidate biomarker approach that could complement LDCT, but prior work has relied on laboratory-based high-resolution mass spectrometry (HRMS), limiting point-of-care deployment. Methods: In this pilot study, breath samples were collected from 40 patients with treatment-naive, pathologically confirmed non-small cell lung cancer (NSCLC) and 25 lung-cancer-screening-eligible healthy controls. Paired samples were analyzed via a compact point-of-care GC-MS platform (CLARION) and a laboratory HRMS reference. Diagnostic classification models were built independently for each platform using elastic net logistic regression with leave-one-out cross-validation, and performance was evaluated by area under the receiver operating characteristic curve (AUC). Results: CLARION identified 103 VOCs across breath specimens, compared to over 900 identified by HRMS. Despite this difference in panel size, CLARION achieved diagnostic performance nearly identical to HRMS for distinguishing NSCLC cases from controls (AUC 0.864 vs. 0.863). Compared to controls, performance statistics were similar for early-stage NSCLC (AUC 0.854 vs. 0.841) and adenocarcinoma (AUC 0.770 vs. 0.787). VOCs of interest include p-cymene, phenol, propylbenzene, tetradecane, {beta}-ocimene, 2,3-dihydro-indole, and 1-methylthio-(Z)-1-propene. Conclusion: A compact, point-of-care breath GC-MS platform achieved diagnostic performance for NSCLC detection comparable to a laboratory HRMS reference despite a substantially smaller detected VOC panel. These findings support continued development of point-of-care breath VOC testing as a non-invasive, field-deployable complement to LDCT-based lung cancer screening.

Background. Videolaryngoscopy still requires adjuncts or hyperangulated rescue in a clinically important minority, and bedside screening discriminates modestly. Point-of-care ultrasound (POCUS) of the anterior airway is a promising alternative, but existing prediction models are opaque or assume a pre-specified functional form. We developed and internally validated a parsimonious, fully disclosed POCUS risk equation whose form is recovered from data and whose structural properties are machine-checked by formal proof - to our knowledge the first formally verified clinical risk predictor - following TRIPOD+AI 2024. Methods. In a prospective single-centre, single-operator cohort of 259 adults undergoing elective videolaryngoscopy (no-Easy airway 68/259, 26.3%), Sequentially Thresholded Least Squares with bootstrap stability selection (B=300) screened a 71-term library of nine POCUS features and retained a seven-term logistic equation; a two-term bootstrap-stable model was pre-specified as robustness analysis. Internal validation used 5x10 repeated cross-validation plus temporal and device hold-outs, with pre-specified overfitting and optimism assessments. Five behavioural properties of the deployed equation were machine-checked in Lean 4. Results. Two interactions met the |c|/sigma_c>2 stability criterion: skin-to-epiglottis x skin-to-hyoid-bone distance and tongue volume x sagittal tongue area. The seven-term equation reached a 5x10 cross-validated C-statistic of 0.966 (optimism-corrected 0.968) and held across temporal and device hold-outs (0.94-0.97). Calibration-in-the-large matched prevalence, with cross-validated slope 0.90 attenuating to 0.625 out-of-time; standard recalibration restored 0.92 without loss of discrimination. The pre-specified two-term robustness model reproduced this performance (C-statistic 0.964-0.968; events-per-parameter 34; shrinkage 0.99), confirming the result is not an artefact of the screening stage. Net benefit over a clinical baseline was positive across 10-50% thresholds. All five Lean 4 theorems compiled without sorry. Conclusions. A sparse, formally verified POCUS equation predicts difficult videolaryngoscopy with high internally validated discrimination and quantified, modest overfitting. Because the equation was developed in a single-operator cohort and its inputs are operator-dependent, external validation requires prior harmonisation of the measurement protocol and operator credentialing.

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.

Obesity is a significant public health concern. Early-onset obesity in the context of rare disease can reflect genetically-mediated pathology or elevated susceptibility through indirect mechanisms. Mapping the diverse characteristics and needs of young people with obesity in the rare disease population is a first step toward mechanistic and translational research. We carried out a retrospective comparative analysis of demographic, genotypic, phenotypic and health service utilisation data for young people with obesity (cases: n=500) and without obesity (controls: n=11,444) from the UK 100,000 Genomes Project rare disease cohort. Cases and controls were recruited prior to genomic diagnosis, across clinical disorder categories. We observed significant association between socioeconomic deprivation and obesity risk. Young people with obesity had significantly higher utilisations of acute care and mental health services, indicating an overall higher health burden. A curated panel of 519 candidate obesity-associated genes demonstrated aggregate association with obesity, although no single gene reached significance. Phenotypic comparison between cases and controls highlighted increased multi-organ and neurological system involvement, highlighting the overlap between neurodevelopmental and obesity risks. Within the case group, we conducted cluster analysis to identify early-onset obesity groups with different phenotypic profiles, potentially arising from different causal pathways - this identified six obesity subgroups of interest, with differing involvement of neurodevelopmental and other systems. Our study confirms that obesity co-occurs with a wide range of factors within the rare disease population, and is associated with significant physical and mental health needs, requiring holistic lifelong care.

Introduction: Nicotine Pouches are increasingly used as a smokeless alternative to cigarettes and other nicotine products, yet their acute cardiovascular effects remain poorly documented. While nicotine's impact on heart rate and electrocardiogram (ECG) parameters is well-documented in smoking, no trials have evaluated these effects specifically for nicotine pouches. Methods: This study is a single-center, double-blind, placebo-controlled, crossover trial which will include 20 healthy adult nicotine users. Participants will undergo three sessions, receiving either a placebo, 6 mg, or 14 mg nicotine pouch in random order. Heart rate obtained by an ECG and various other ECG parameters, vital signs, and subjective symptoms will be measured at baseline, and multiple time points over 30 minutes. Conclusions: This study aims to determine whether nicotine pouches cause acute changes in heart rate, ECG parameters, vital signs, and self-reported symptoms. We hypothesize that higher nicotine pouch does will lead to measurable increases in heart rate and other autonomic effects compared to placebo.

The availability of hearing aids that can connect wirelessly to smartphone technologies via Bluetooth has grown exponentially in recent years. However, there is limited evidence assessing the benefits of user-adjustability afforded by these devices. This study aimed to assess the benefits of smartphone-connected hearing aids and an accompanying application (or app) in new and existing hearing aid users. In this single-centre, prospective, observational study, 44 adult hearing aid users (14 new and 30 existing) were recruited. Participants were fitted bilaterally with smartphone-connected hearing aids that could be adjusted by the user via an app. Self-reported outcome measures were collected at fitting and after seven-weeks of using the device in everyday life. For both new and existing hearing aid users, significant improvements in social participation, hearing-related fatigue, and hearing aid benefit and satisfaction were found. For existing hearing aid users, all outcomes were significantly better for the smartphone-connected hearing aids plus app in comparison to their existing hearing aids that did not connect to a smartphone, all with moderate-to-large clinical effect sizes (d> .6). User-controllability via the app was identified as the key benefit, and most participants (68%) reported that the app met their needs 'extremely' or 'very well'. These results suggest that, when used in conjunction with an app, smartphone-connected hearing aids can improve hearing outcomes due to greater user-controllability to improve listening. Thus, smartphone-connected hearing aids have the potential to facilitate patient-centred care, empowering the individual to successfully manage their hearing loss.

Background: Adult congenital heart disease (ACHD) patients are prone to HLA-antibody formation from multiple surgeries, transfusions, and prosthetic surgical material. Females with ACHD may accrue additional, non-surgical alloantigen exposure. Whether sex modifies the impact of allosensitization on heart transplant (HT) access and outcomes in ACHD remains unknown. Methods: We retrospectively analyzed the OPTN/UNOS registry of adults with ACHD listed for first-time HT (2018-2025). Sensitization was defined by calculated panel reactive antibodies (cPRA) at listing. We tested the sex x sensitization (highly sensitized, cPRA >50%) interaction on transplant access using Fine-Gray competing-risks regression, treating transplantation as the event of interest and death or removal from the waitlist as competing events, and on post-transplant survival using multivariable Cox proportional-hazards regression, both adjusted for age at listing, mechanical support at listing, and the number of distinct prior cardiac surgery categories. Results: Among 856 candidates (38% female), females were more often highly sensitized than males (23% vs 14%; age-adjusted OR 1.81, 95% CI 1.26-2.61), even after adjusting for surgical burden. Sensitization reduced transplant access in females (84% to 71%; median wait 60 to 110 days, p < 0.001) but not males (79% vs 79%, median wait 88 vs 98 days). In adjusted Fine-Gray models, the subdistribution hazard for transplant was reduced in sensitized females (sHR 0.54, 95% CI 0.41-0.72) with no effect in males (sHR 0.96, 95% CI 0.73-1.26), and the sex x sensitization interaction was significant (interaction sHR 0.64, 95% CI 0.44-0.94, p = 0.02). Post-transplant mortality was numerically higher in sensitized than non-sensitized candidates in both sexes and the sex x sensitization interaction on 1-year mortality was not significant. The sex-asymmetric effect persisted and was more pronounced in the multiorgan candidates. Conclusions: Allosensitization is not a sex-neutral barrier to transplant in HT candidates with ACHD. Females are more sensitized and have reduced transplant access without differences in 1-year mortality. The female excess in sensitization is not accounted for by surgical burden, and the exposures responsible remain to be defined. These findings warrant a sex-aware listing strategy and further studies.

Background: Many at-risk patients lack access to genetic services due to a genetic counselor (GC) workforce shortage. Little is known about how digital alternatives impact patients with and without cancer who meet criteria for genetic testing. Methods: eREACH2 is a randomized 4-arm non-inferiority trial where pre-test (visit 1) and/or return of results (visit 2) GC counseling was replaced with a patient-centered digital intervention. Arms include: A (GC/GC), B (GC/digital), C (digital/GC) and D (digital/digital). Primary outcomes were non-inferiority in uptake of genetic services and change in genetic knowledge and general anxiety from baseline to post-disclosure of results (T0-T2). Secondary cognitive and affective outcomes were assessed using non-inferiority ANOVAs and equivalency chi-squared tests in intention-to-treat and per-protocol analyses. Findings: 773 participants were recruited nationwide; 46.6% from rural areas. Mean age was 51 years (range 20-87), 13% male, 12% non-white, 29% had less than a college education, and 33% had a personal history of cancer. 584 (76%) patients completed testing (14% had a positive result, 16% had a VUS). In the primary ITT analyses, we met the non-inferiority for uptake of genetic services and anxiety, but results were inconclusive for knowledge. Secondary outcomes were heterogeneous across arms. Arm C demonstrated consistently favorable effects, while Arms B and D showed less favorable outcomes in select domains (e.g. satisfaction and MICRA). Patients who received positive or VUS results via digital disclosure had significantly higher MICRA scores - indicating greater negative response to testing. Interpretation: In this large, randomized trial of patients with and without cancer, the eREACH intervention was effective for pre-test counseling, but inconclusive for digital disclosure of results. Exploratory analyses suggest that digital delivery could be a reasonable alternative for individuals receiving negative results, while those receiving positive or VUS results may derive some short-term psychosocial benefit from GC disclosure.

Background: Immunochemotherapy (ICT) is considered standard in regards to care for small-cell lung cancer (SCLC) in extensive stages, yet reliable biomarkers for treatment response remain elusive. While previous univariate analyses suggest specific peripheral lymphocyte subsets correlate with survival, the systemic immune response involves complex, multivariate interactions that require advanced analytical approaches. Methods: This paper analysed high-dimensional flow cytometry data from 32 patients with stage IV SCLC treated with carboplatin, etoposide, and atezolizumab. Peripheral blood was analysed at baseline (V0) and longitudinally during treatment. To identify potential early predictive biomarkers and mitigate sample attrition in later cycles, we focused on baseline and measurements after two cycles of ICT (V1). We employed a rigorous machine learning framework utilising nested cross-validation, bootstrapping, and permutation-based statistical testing to evaluate eleven different regression and survival models. Results: Under model-appropriate metrics, regressors did not generalise (R2 <0); conversely, censoring-aware Random Survival Forests (RSF) successfully extracted robust prognostic signatures. Baseline immune profiles (V0) achieved a concordance index (C-index) of 0.66 (p= 0.015), while dynamic changes from V0 to V1 ({triangleup}V) achieved a C-index of 0.65 (p= 0.022). Crucially, absolute values measured after two cycles of ICT (V1) yielded no significant signal (p= 0.445). Feature importance analysis confirmed the prognostic value of Th17 normalisation and identified Naive Regulatory T cells and Memory B cells as candidate components. Conclusion: Machine learning validation confirms a predictive signal in the peripheral immune profile of SCLC patients. Early dynamic shifts in the balance between regulatory and effector immune arms are associated with prognosis, contrasting with the lack of signal in absolute counts after two cycles of ICT. These findings establish a proof of concept for multivariate liquid biopsy immune profiling, warranting confirmation in larger cohorts and highlighting the necessity of integrating systemic and tumour-intrinsic data.

Objectives To evaluate whether access to a certified large language model (LLM)-based clinical decision support system improves physician diagnostic performance in rheumatology compared with conventional diagnostic resources alone. Methods In this multicentre, open-label, randomised controlled trial, 82 physicians from seven hospitals in two countries were randomised 1:1 to conventional diagnostic resources plus Prof. Valmed or conventional resources alone. Participants assessed three rheumatology vignettes before and after assistance. The primary outcome was top-1 diagnostic accuracy. Secondary outcomes included top-3 accuracy, diagnostic reasoning, confidence, case-processing time and perceived support quality. Results Top-1 accuracy increased from 22.2% to 33.3% in the intervention group and from 23.3% to 35.0% in the control group, with no between-group difference in improvement (adjusted OR 0.99, 95% CI 0.45 to 2.19; p=0.979). Differences in top-3 accuracy, diagnostic reasoning and confidence were also not significant. Assisted case-processing time was substantially shorter with LLM support (94 vs 206 s; adjusted mean difference -112 s, 95% CI -141 to -83; p<0.001). Information timeliness and perceived diagnostic support quality were rated significantly higher in the intervention group. Exploratory analyses showed persistent overconfidence and substantial AI over-reliance. Conclusions Certified LLM-based diagnostic support did not improve diagnostic accuracy compared with conventional resources, but substantially reduced case-processing time and improved perceived support quality. These findings suggest potential workflow benefits while highlighting overconfidence and over-reliance as important safety considerations.

Background. The imprecision of current metrics to capture the complex genetic admixture and racial identity among Hispanic/Latino individuals in the United States [US] is a concern. We examined the relationship of self-reported race and genetic ancestry with hypertension [HTN] among Hispanics/Latinos. Methods. Cross-sectional study of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), including 10,586 Hispanic/Latino unrelated adults. Genetic ancestry: West African [AA], Amerindian [AI], and European [EA]. Self-reported race: White, Black, Native American, or Multiple/Missing (More than one race or Unknown/Not reported/Refused). HTN: systolic (SBP) [&ge;]130 mmHg, diastolic blood pressure (DBP) [&ge;]80 mmHg, and/or use of HTN medications. Age- and sex adjusted models were used. Results. Self-reported race was White (38{middle dot}6%), Black (3{middle dot}6%), Native American (4{middle dot}1%), and Multiple/Missing (53{middle dot}7%), with Unknown/Not reported/Refused representing 32{middle dot}7%. Black and White Hispanics/Latinos had the greatest AA (55{middle dot}7%) and EA (69{middle dot}3%) ancestries, respectively. Each 10% AA increase was associated with OR 1{middle dot}15, SBP beta +0{middle dot}9 mmHg, and DBP beta +0{middle dot}7 mmHg. Conversely, each 10% AI increase was associated with OR 0{middle dot}83, SBP beta -0{middle dot}4 mmHg, and DBP beta -0{middle dot}6 mmHg. HTN prevalence was highest among those with Black race or in the highest AA quantile (45{middle dot}6% and 48{middle dot}0%, respectively), and lowest among those with Native American race or in the highest AI quantile (37{middle dot}6% and 26{middle dot}7%, respectively). Conclusion. One-third of Hispanics/Latinos did not self-report race. Black or White self-reporting race did somewhat relate to AA or EA ancestry, respectively. HTN profiles were related to self-reported race and genetic ancestry in this admixed population.

Background: Inequalities exist for many health outcomes, but there is limited evidence regarding menstrual symptoms despite their importance for health and wellbeing. We aimed to investigate inequalities in menstrual symptoms according to socioeconomic position and childhood adversity. Methods: In two generations (G0 mothers and G1 offspring) from the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK prospective cohort study, we examined associations of multiple indicators of socioeconomic position (SEP) and adverse childhood experiences (ACEs) with menstrual symptoms (pain, abnormal uterine bleeding, and premenstrual syndrome (PMS) measured 3-8-years post-birth in G0 and 17-21-years-old in G1), using multivariable logistic regression. Samples ranged from 4,828 to 9,335 G0 participants and 1,288 to 2,757 G1 participants depending on the exposure-outcome association. Missing data were addressed using multiple imputation and inverse probability weighting. Results: Financial difficulties were associated with greater odds of menstrual pain (G1 OR 1.41; 95% CI 1.07, 1.86: G0 OR 1.55; 95% CI 1.36, 1.76) and irregular cycles (G1 OR 1.60; 95% CI 1.12, 2.29: G0 OR 1.48; 95% CI 1.27, 1.72) in both generations, as well as with short/long cycle lengths in G0 only. Lower education and manual social class were also associated with these three menstrual symptoms in at least one generation. Conversely, higher SEP was associated with PMS in both generations. Higher cumulative ACEs were consistently associated with menstrual pain (4+ compared to none: G1 OR 2.15; 95% CI 1.48, 3.11: G0 OR 1.52; 95% CI 1.29, 1.80) and irregular cycles (G1 OR 1.92; 95% CI 1.20, 3.09: G0 OR 1.54; 95% CI 1.26, 1.87) but not cycle length. Lower parental education, financial difficulties, and cumulative ACEs were associated with heavy bleeding in G1 offspring only, whereas financial difficulties, own manual social class, and cumulative ACEs were associated with prolonged bleeding in G0 mothers only. Higher cumulative ACEs were also associated with PMS in G1 offspring only. Conclusions: We found evidence of inequalities according to socioeconomic disadvantage and childhood adversity for multiple menstrual symptoms, although some associations were only observed in one generation. Findings suggest that menstrual symptoms are disproportionately experienced by socially and socioeconomically disadvantaged women.

Importance: Chronic stress may contribute to adverse health outcomes through cumulative physiologic dysregulation. Allostatic load (AL), a composite measure of multisystem physiologic burden, may capture biologic effects of structural, social, and psychosocial stress not reflected by self-reported measures. Objective: To evaluate racial and ethnic differences in AL among women with familial cancer risk and examine how socioeconomic status, psychosocial factors, clinical characteristics, and health behaviors contribute to variations in AL. Design: Cross-sectional study of underrepresented minority participants enrolled in the HERSTORY cohort from October 2023 through September 2025, with comparison participants from the UCLA ATLAS biobank. Setting: UCLA academic health system. Participants: The study included 303 racially and ethnically diverse female HERSTORY participants aged [&ge;]35 years with a family history of cancer and matched non-Hispanic White female ATLAS participants (n=709). Exposures: Race and ethnicity, age, neighborhood deprivation, cancer history and stage, depression, perceived stress, cancer worry, and physical activity. Main Outcomes and Measures: The primary outcome was AL, calculated from cardiometabolic and organ-function measures. A secondary index incorporated race- and ethnicity-specific neutrophil-to-lymphocyte ratio (NLR) derived from 326,826 women in the UCLA Health population. Multivariable regression models evaluated factors associated with elevated AL. Results: Compared with matched non-Hispanic White participants, Black and Asian/Pacific Islander HERSTORY participants had significantly higher AL after adjustment. Hispanic/Latina participants did not have significantly elevated AL. Older age, greater area-level socioeconomic deprivation, and depression were independently associated with higher AL. Prior cancer diagnosis, cancer worry and perceived stress were not significantly associated with AL, whereas regular physical activity was associated with lower AL. Among cancer patients, advanced stage was associated with greater AL. Conclusions and Relevance: This study demonstrates elevated AL among understudied racial/ethnic minority groups with familial cancer risk and identifies associations with neighborhood deprivation, depression, and physical activity. The association between cancer stage and AL suggests that physiologic stress may reflect variation in cancer burden. The lack of association with perceived stress and cancer worry further indicates that physiologic and self-reported psychosocial measures capture distinct dimensions of stress. The development of race/ethnicity-specific NLR thresholds derived from large population samples provide a benchmark for future studies.

This study aimed to quantify the longitudinal tracking and cross-sectional construct validity of a single-item questionnaire measuring recreational physical activity frequency (RPAF) in the Womens Healthy Ageing Project. At baseline, 474 participants aged 45-55 reported RPAF from 1993 to 2014. Longitudinal tracking of the RPAF item was assessed as a consecutive-wave and baseline-referenced measure using linear weighted kappa (LWK), Spearman correlations, exact agreement and within-one-category agreement. Construct validity in the form of convergent and known-group validity was assessed using the International Physical Activity Questionnaire (IPAQ) leisure activity domains, Short Form 36 physical function (SF-36-PF) subscale, Timed Up and Go (TUG), hand grip strength (HGS) and waist-to-height ratio (WHtR). 474 participants provided baseline RPAF data. Pairwise longitudinal samples ranged from 176 to 459 across the study. Consecutive-wave LWK ranged from 0.38 to 0.49, and Spearman correlations ranged from 0.44 to 0.57. Exact and within-category agreement ranged from 41.4%-50.8% and 72.0%-79.0%. Baseline-referenced LWK ranged from 0.22 to 0.47, with Spearman correlations of 0.29 to 0.56. RPAF correlated with total IPAQ leisure score (rs = 0.60), IPAQ walking score (rs = 0.58), SF-36-PF (rs = 0.33) and TUG score (rs = -0.25). No significant correlation was identified between RPAF, HGS or WhTR. RPAF discriminated known groups for WHO guideline-sufficient activity, SF-36-PF, and TUG fall risk. The RPAF item demonstrated fair-to-moderate agreement in consecutive waves, with weaker baseline-referenced tracking. Cross-sectional validity was highest with total IPAQ leisure activity. The item may provide a pragmatic measure for RPAF in womens cohort studies.

Background: Refractory and macrolide-resistant Mycoplasma pneumoniae pneumonia (MPP) has emerged as a major challenge in pediatric respiratory medicine, amplified by the post-2023 resurgence. However, a systematic overview of the research landscape specific to treatment-refractory and drugresistant disease in children remains lacking. Methods: Research articles and reviews on pediatric refractory or macrolide-resistant MPP published between 2000 and 2025 were retrieved from OpenAlex using Boolean searches. After screening, 2,286 records were quantitatively analyzed for annual output, contributing countries/institutions, thematic clusters, and citation-burst dynamics using Python. Results: Annual publications grew exponentially, with a pronounced surge after 2023 (n=378 in 2025). China produced the highest volume (45.1%) but recorded fewer citations per publication than the US, Japan, and Canada. The literature resolved into four clusters: macrolide resistance/molecular basis, epidemiology, etiology/co-infection, and refractory disease management. Burst analysis showed an evolution from earlier fronts like 23S rRNA mutations and azithromycin to recent emerging trends like pandemic-related co-circulation, genotype surveillance, and co-infection. Conclusions: Research on pediatric refractory and resistant MPP is expanding rapidly, shifting in emphasis from etiologic descriptions toward resistance mechanisms and clinical management. Standardizing the treatment of macrolide-unresponsive disease and post-pandemic epidemiological surveillance represent the principal directions for future work. Keywords: Mycoplasma pneumoniae; children; macrolide resistance; refractory pneumonia; bibliometric analysis; research trends

Background: Lumbar disc herniation, with or without concomitant disc degeneration, is a major cause of lumbar radiculopathy and low back pain, which also a key public musculoskeletal disorder without an exact pathophysiology. Studies have suggested that inflammatory cells and biochemical markers of inflammation also play an important role in lumbar radiculopathy in addition to nerve compression. The aim of the present study was to assess the association of selected circulatory inflammatory markers (CRP, hs-CRP and E-selectin) in patients with lumbar disc herniation without radiological degeneration (LDH) and lumbar disc herniation with radiological degeneration (LDHD). Materials & methods: This case-control study included 208 participants, comprising 104 patients with lumbar disc pathology and 104 controls. Patients were further stratified into LDH (n=67) and LDHD (n=37). Serum CRP, hs-CRP and E-selectin concentrations were measured. Results: Among the patients, 35.6 % presented with LDHD while 64.4 % had only LDH. Significantly increased median hs-CRP (p<0.001) and CRP (p<0.001) were observed in patients groups compared to controls, while CRP showing a consistent independent association across the combined disease (OR=1.68, 95% CI=1.33-2.14, p<0.001), LDHD (OR=1.62, 95% CI=1.16-2.20, p=0.005) and LDH (OR=1.69, 95% CI=1.30-2.20, p<0.001) multivariable models. No significant difference was observed in serum E-selectin between the study groups. Multivariable models incorporating inflammatory and clinical variables demonstrated substantially greater discriminatory performance than individual biomarkers alone. Conclusion: Elevated circulating CRP and hs-CRP concentrations were associated with lumbar disc pathology, with CRP showing a consistent independent association across the combined disease, LDH and LDHD multivariable models, whereas E-selectin showed no significant association. Multivariable models incorporating inflammatory and clinical variables demonstrated greater discriminatory performance than individual biomarkers. These findings support a potential systemic inflammatory component in lumbar disc pathology, although the cross-sectional nature of the measurements does not establish causality or a local inflammatory response within the disc.