Frontiers in Aging

Introduction: Parkinson's disease (PD) and aging both disrupt hypothalamic-pituitary-adrenal (HPA) axis function and peripheral immune homeostasis. Whether aging or -synuclein (-syn) pathology alters glucocorticoid (GC) sensitivity of peripheral immune cells has not been investigated. Methods: Using an ex vivo GC sensitivity assay, we assessed the responsiveness of isolated and lipopolysaccharide (LPS)-stimulated splenocytes to the anti-inflammatory effects of increasing doses of corticosterone (CORT) in a wild-type (WT) aging cohort and in a PD -syn transgenic mouse model and respective age-matched controls. Results: Compared with splenocytes from 6-month-old WT mice, splenocytes from 20-month-old WT mice were less sensitive to 0.1 and 0.5 M CORT. Isolated splenocytes from PD vs. control mice were less sensitive to 0.05, 0.1, and 0.5 M CORT specifically at 16 months of age, but not at 6 or 20 months of age. As peripheral immune phenotyping revealed neither differences in HPA axis-related parameters nor in splenic GC receptor expression between PD and age-matched control mice at 6, 16, and 20 months, splenic GC resistance in PD mice at 16 months of age seems to be mediated by downstream GR signaling dysfunction. Conclusion: Together, our results support the hypothesis that -syn pathology accelerates an aging-associated decline in the peripheral sensitivity to anti-inflammatory GCs and may thereby sustain systemic and neuroinflammatory processes in PD.

Vaccine responses vary across individuals due to differences in ageing and health status. Using transcriptomic profiling, we analyzed early gene expression profiles after influenza (QIV) followed by pneumococcal (PCV13) vaccination in 148 participants spanning young, middle-aged, and older adults. The two vaccines induced distinct immune signatures: QIV elicited innate and interferon immune activation, while PCV13 triggered inflammation-based responses. Older adults showed weaker but similar transcriptomic profiles compared to young adults. Among older adults, frailty, in addition to age, was strongly associated with reduced innate responses. In addition, we identified associations between early-stage transcriptomic profiles and later-stage antibody responses for QIV; however, no such associations were observed for PCV13. Importantly, observed group differences arose not from altered immune modules but from differences in the magnitude of gene expression, paving the way for immune-boosting interventions to enhance early gene expression in at-risk populations.

Introduction Guatemala is the most populous country in Central America and a setting with unique opportunities for aging research. Approximately 40% of Guatemala's population is Indigenous Maya, who together speak 22 Mayan languages. Currently, there is no population-based aging study in Guatemala and few aging studies in Latin America among Indigenous populations. The Longitudinal Study of Aging in Guatemala (ELEGUA) aims to address these gaps by developing a nationally representative, population-based, longitudinal aging study modeled on the Health and Retirement Study and the Harmonized Cognitive Assessment Protocol, adapted to the cultural and linguistic context of Guatemala. The objective of this protocol is to describe the rationale and design of the ELEGUA pilot survey. Methods and analysis The ELEGUA pilot was a cross-sectional household survey of adults aged 40 years or older in Tecpan, Guatemala. Tecpan was chosen because its diverse population facilitated testing of study procedures in both Spanish and Kaqchikel, a common Mayan language. The survey included up to 600 households sampled using a multistage stratified cluster design. Within each household, one individual aged 40 years or older was selected, with oversampling of adults aged 55 years or older. This respondent completed a comprehensive questionnaire, including detailed cognitive tests, and provided physical measurements and a venous blood sample. Household respondents provided information on household economics and family structure, and an informant reported on the individual respondent's cognitive function. Data were collected using a computer-assisted personal interviewing system. Planned analyses include survey-weighted descriptive statistics and psychometric evaluation of the cognitive assessments. Ethics and dissemination Ethics approval was obtained from the ethics committees of the Institute of Nutrition of Central America and Panama, Maya Health Alliance, and the University of Michigan. Results will be disseminated through publications in peer-reviewed journals and presentations to local, national, and international audiences.

Background Understanding the mechanisms underlying brain aging and age-related pathological changes is essential for advancing brain health research. Our group previously developed a mechanistic mathematical model of healthy brain, Chamberland et al. (2024) that integrates key biological processes involved in normal aging, from which Alzheimer's disease (AD) related changes may emerge naturally. Objectives To characterize and validate this brain model by evaluating its sensitivity, calibrating its parameters, and assessing generalizability in independent populations. Methods The model represents the evolution of key biological processes associated with brain aging, including amyloid beta (A{beta}), tau pathologies, neuroinflammation, and neuronal death. After identifying the 30 most influential parameters, we calibrated the model using cognitively normal (CN) participants from the AD Neuroimaging Initiative (ADNI) database (n = 211) by minimizing a loss function composed of three outcomes (AB) plaques, tau tangles, and neuronal density). The calibrated model was then applied to the UK Biobank cohort (n = 35,899) of normal controls (aged 44-82 years). The effects of sex and APOE were evaluated using stratified simulations. Results Parameter calibration significantly reduced the prediction errors for A{beta} and tau. Neuronal density predictions showed strong agreement in the UK Biobank cohort. The variance decomposition identified APOE status as a major contributor to variability in A{beta}. Conclusion Our validated brain health model links mechanistic pathways with population data and reproduces neuronal density patterns in an independent cohort. These findings support its use as a framework for studying brain aging and investigating how Alzheimer's disease related pathological changes may emerge with aging.

Hematopoietic stem cell (HSC) aging is associated with epigenetic remodeling, yet the molecular mechanisms driving these changes, their overlap with stress-induced alterations, and whether this course can be durably reset remain incompletely understood. Here, we show that transient induction of the Yamanaka factors OCT4, SOX2, KLF4, and MYC in young mice durably delays and partially reverses physiological and LPS-driven HSC aging in mice. Transient reprogramming improved hematopoietic reconstitution, reduced myeloid bias, and limited DNA damage. Multi-omic analyses revealed reduced chromatin accessibility at AP-1-enriched regulatory regions, attenuated age-associated AP-1 transcriptional programs, and repression of transposable elements (TEs). Pharmacological AP-1 inhibition prevented LPS-induced TE activation and loss of HSC clonogenicity. Reverse transcriptase inhibition in aged mice reduced DNA damage and improved HSC function, demonstrating a functional contribution of TE activity to HSC decline. Together, these findings identify AP-1-associated chromatin remodeling as a candidate mechanism linking inflammatory stress, TE activation and HSC aging.

Episodic memory decline is a common feature of cognitively normal aging, but its extent varies markedly across individuals. Although entorhinal tau pathology is thought to be a key contributor to episodic memory impairment, the neural mechanisms linking early tau accumulation to memory differences remain unclear. Grid-cell computations in the entorhinal cortex, which provide scaffolds for organizing experiences into episodic memories, offer one candidate mechanism. Here, we combined virtual-reality functional MRI, multivariate analysis, tau PET, and delayed word-list recall in cognitively normal older adults to test whether tau-related alterations in entorhinal coding are associated with worse episodic memory. Weaker left entorhinal grid-cell-like signal was associated with poorer memory performance, and individuals with higher left entorhinal tau burden showed weaker grid-cell-like signal. This association was specific to the canonical six-fold signal and was not explained by entorhinal volume, mean diffusivity, or intracortical myelination. A cross-sectional Bayesian mediation analysis further demonstrated that bilateral medial temporal tau burden is related to memory indirectly through left entorhinal grid-cell-like signal. Together, these findings provide evidence that entorhinal grid codes may constitute a functional pathway linking tau accumulation to memory variability in normal aging.

The increasing incidence of H5N1 influenza virus transmission from animal species to humans has heightened concerns about an imminent H5N1 pandemic. Prior studies using recombinant hemagglutinin and neuraminidase proteins have reported age-dependent cross-reactivity to H5N1, attributed to immune imprinting from an individual's first influenza virus exposure. However, whether this pattern holds when using whole inactivated virus (WIV), capturing antibodies against diverse viral proteins, and is stable over time remains unknown. We therefore aimed to determine whether H5N1 cross-reactivity of pre-existing antibodies to whole virus follows an age-dependent or imprinting-specific pattern, and whether this pattern is stable over a five-year period. To this end, we measured serum antibody levels in adolescents, adults and seniors by ELISA using whole inactivated H5N1 virus as antigen rather than purified proteins. Detectable, albeit generally low, levels of H5N1-reactive antibodies were present in most individuals, irrespective of age. Comparison of antibody levels against H5N1 with those to five historical influenza virus strains revealed a consistent positive correlation between H5N1-reactive antibodies and responses to the H1N1pdm09 strain A/California/7/2009 (CA), across all age groups. Using unbiased clustering of antibody titers against H5N1, CA, and the H3N2 strain A/Perth/16/2009 (PE), we identified seven distinct age-transcending antibody profiles. These profiles covered individuals with varying titers to all three included viruses but also identified individuals with high anti-CA levels, yet low anti-H5N1 levels and vice versa. Moreover, despite stable antibody levels over a five-year interval in the study population, individual antibody levels and profiles fluctuated considerably over this period. Taken together, our results confirm the presence of H5N1-reactive antibodies in human sera and their association with previously circulating strains. However, they also caution against inferring antibody levels against a new strain based solely on responses to antigenically related strains and highlight the limitations of extrapolating immune status from single timepoint measurements.

Background: India has a rising incidence of chronic non-communicable diseases, making it a major healthcare burden today. Growing evidence suggests that chronic low-grade inflammation links ageing with cardiometabolic disorders, captured by the emerging concept of inflammaging. However, most evidence on biological ageing comes from Western populations, with no similar models developed for the Indian population. Given the country's distinctive genetic makeup, unique exposome, and heterogeneous NCD presentation, Western models may not capture inflammaging and its effects in the Indian population. Methods: We analysed baseline data from 4,240 adults in the Phenome India CSIR Health Cohort Knowledgebase (PI CheCK), a nationwide multi-centre cohort. Participants were stratified into eight cardiometabolic phenotype groups by BMI (Asian cut off), blood pressure and HbA1c status. We trained a Super Learner ensemble to predict chronological age in the lean normotensive-normoglycaemic reference group (n=615) using 44 plasma cytokines, sex, haemoglobin, and bioimpedance-derived visceral fat area, per cent body fat, and total body water. Performance was assessed by repeated five-fold cross-validation and in a held-out healthy test set. Calibrated biological age acceleration was then estimated in the remaining 3,625 participants. Results: Median age was 51.0 years (IQR 41.0 to 62.0) and 49.4% were female. The Super Learner outperformed elastic net and XGBoost comparators. Permutation importance identified visceral fat area, per cent body fat, CTACK, SDF1a, haemoglobin and sex as leading contributors, with body composition measures accounting for the largest share, indicating an immune-metabolic rather than cytokine-only signal. Biological age acceleration was concentrated in overweight/obese phenotypes. Lean phenotypes showed acceleration close to the reference (0.32 0.50 years). Conclusions: Cytokine and body composition measures capture a quantifiable immunometabolic ageing signal in a South Asian cohort, with acceleration driven predominantly by adiposity. External validation and longitudinal follow up are required.

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.

Biological aging occurs heterogeneously across individuals and organs. However, current measures of biological age incompletely capture organ-specific differences in health and disease risk. Because chest CT visualizes multiple thoracic organs, it offers an opportunity to quantify structural aging across organ systems. Here, we developed MOSAIC-Age, a framework characterizing eight organ-specific aging clocks on chest CT. The clocks were developed and validated using 9,971 CT scans from CT-RATE and MIDRC, and subsequently locked and applied to two independent prospective cohorts with 35,293 participants from the National Lung Screening Trial and Genetic Epidemiology of COPD study. CT-derived biological age gaps (BAGs) were examined in relation to lifestyle and socioeconomic factors, prevalent comorbidities, incident chronic diseases, and all-cause and cause-specific mortality. Higher BAGs, indicating organs that appeared older on CT than expected for their chronological age, were broadly associated with adverse health characteristics, chronic disease burden, and increased mortality risk. Multiple disease outcomes were associated with aging across several organs, whereas in multivariable analyses including all eight organ-specific BAGs, the remaining associations were more organ specific. A greater number of markedly older-appearing organs and a faster pace of aging were each associated with higher mortality. Together, these findings demonstrate that routine chest CT captures both shared and organ-specific patterns of biological aging and establish CT-derived organ aging as a quantitative imaging biomarker for assessing multi-organ health and long-term disease risk.

The olfactory and intranasal trigeminal systems interact closely, influencing chemosensory perception, yet the mechanisms underlying their interaction remain poorly understood and have been studied mainly in young adults. We aimed to characterize olfactory-trigeminal interactions in aging by comparing electrophysiological and behavioral responses under ipsilateral and contralateral olfactory-trigeminal co-stimulation, to determine the relative contributions of peripheral and central mechanisms. Using chemosensory event-related potentials and a localization task, 44 healthy older adults (66.3 {+/-} 4.6 years; 29 women) were tested under four conditions: pure trigeminal (carbon dioxide; CO2), pure olfactory (2-phenylethanol; PEA), ipsilateral co-stimulation (PEA+CO2 in the same nostril), and contralateral co-stimulation (PEA+CO2 in opposite nostrils). Ipsilateral, but not contralateral olfactory-trigeminal co-stimulation, improved trigeminal localization performance and induced larger late positive component amplitudes. Together, these findings suggest that olfactory-trigeminal interactions are driven primarily by peripheral rather than central mechanisms. This study also provides normative CSERP data for healthy older adults.

Background Limited heart rate rise contributes to reduced exercise tolerance for people who have heart failure with reduced ejection fraction (HFrEF), yet rate-adaptive pacing does not improve functional capacity due to an attenuated force-frequency relationship (FFR). How the FFR relates to total peripheral resistance and sympathetic tone in HFrEF is unknown. Methods In a prospective, observational study, participants with HFrEF and controls underwent an incremental pacing protocol, during which heart rate was increased from 50 to 140 beats per minute. At each heart rate increment LV contractility was measured by echocardiography to determine the FFR, as well as continuous beat-to-beat measurement of systolic and diastolic blood pressures with a plethysmography device to determine cardiac output, total peripheral resistance and blood pressure variability (BPV). A microneurography study was then conducted to measure muscle sympathetic nerve activity (MSNA) during incremental pacing. Results A total of 157 participants with HFrEF and 55 controls (mean age 71.1{+/-}1.4 years, 172 (81.1%) male) underwent the pacing protocol. We observed single units in seven of 11 participants who participated in the microneurography study. In both groups, LV contractility and cardiac output increased until the peak of the FFR, after which these declined. We observed a reduction in total peripheral resistance, blood pressure variability, MSNA frequency and incidence coinciding with the peak of the FFR, beyond which these increased. Whilst these relationships were present in both groups, they were more evident in participants with HFrEF. Conclusions For people with HFrEF there is a bidirectional relationship between heart rate and sympathetic activation, with a nadir of sympathetic tone occurring at the peak of the FFR. Both excessively low and high heart rates are accompanied by greater sympathetic activation. Taken together, these data suggest that optimal heart rate targets for HFrEF are likely to be individual.

Lysosomes make key contributions to the maintenance of cellular proteostasis, and their functional compromise has been linked to aging and neurodegenerative disease. A defining characteristic of lysosomes is their relative acidity compared to other subcellular compartments, a quality that enables the efficient breakdown of macromolecules. Evidence suggests that neuronal lysosomal pH becomes dysregulated with aging and neurodegenerative disease, yet the mechanisms by which lysosomal pH is maintained remain incompletely understood. To better understand neuronal lysosomal pH regulation, we conducted a genome-wide CRISPRi-based screen in iPSC-derived iNeurons for modifiers of lysosomal pH. We validated several previously known regulators of lysosomal pH and identified novel pathways capable of modifying lysosomal pH, including protein UFMylation and mitochondrial homeostasis. We demonstrate that loss of the lysosomal cationic amino acid exporter, PQLC2, prevents lysosomal acidification in a manner independent of amino acid transport. A novel, tauopathy-associated mutation in PQLC2 impairs lysosomal acidification and drives tau accumulation. Together, this study reveals novel genes that modify lysosomal pH and highlights potential new targets for ameliorating age-related lysosome dysfunction.

Abstract Objective: Glaucoma is a chronic disorder that impairs ocular health and may exacerbate ocular surface disease leading to tear film instability, dry eye symptoms and decreased quality of life. This study compared changes in tear quantity among glaucoma subjects living with and without diabetes mellitus, attending an eye clinic in Nigeria. Methods: A comparative cross sectional research design was used. 157 subjects which comprised 74 glaucoma subjects living with diabetes mellitus and 83 glaucoma subjects living without diabetes mellitus participated in the study. Tear quantity assessment included the Schirmer I test and tear meniscus height (TMH) measurement. Descriptive statistics, independent samples t-test and Chi-square test were used to examine the data at 0.05 level of significance. Results: Glaucoma subjects living with diabetes mellitus showed substantially decreased tear production (11.4 +/- 6.8 mm) compared with glaucoma subjects living without diabetes mellitus (19.6 +/- 9.6 mm; p < 0.001). Tear meniscus height in glaucoma subjects living with diabetes mellitus (0.8 +/- 0.3 mm) was significantly greater than in subjects living without diabetes mellitus (0.7 +/- 0.3 mm; p = 0.034). Conclusion: Diabetes mellitus dramatically deteriorates the ocular surface function in glaucoma subjects by decreasing tear production, altering the tear meniscus height and increasing the severity of ocular surface symptoms. Routine glaucoma care, especially in patients with diabetes mellitus, should include a full ocular surface evaluation including Schirmer I test, TBUT, TMH, and OSDI assessment to allow early detection and management of ocular surface disease, better treatment adherence, and improved visual outcomes. Keywords: Glaucoma, Diabetes Mellitus, Tear production, Tear Meniscus Height, Ocular Surface Disease.

Purpose: To evaluate the safety, procedural performance, sample recovery, and surgeon preference of an ophthalmic needle designed specifically for anterior chamber (AC) paracentesis. Methods: In this multicenter study, AC paracentesis was performed in clinic and operating-room settings using a 32-gauge x 4-mm needle with low dead space. The procedure was evaluated using a standardized physician survey. Prespecified outcomes included procedure-related adverse events (primary outcome), needle entry and handling, aspiration and sample recovery, comparative performance versus a 30-gauge needle, and physician preference for future use. Results: A total of 110 needle uses by eight surgeons were included. No ocular complications occurred, including lens or iris injury, hyphema, AC collapse, wound leak, hypotony, infection, or retinal complication, and no procedure required needle exchange or conversion to another device. Two technical events without ocular sequelae were noted, in which needle entry was partial thickness and did not reach the AC (1.8%; exact 95% CI, 0.2%-6.4%). Physicians rated needle entry, handling and sample recovery as good or excellent. Compared with a 30-gauge needle, the study needle was rated as at least comparable across all assessed domains. All surgeons rated it better or much better for intra-procedural safety and preferred it for future AC taps. Conclusions and Relevance: This short, 32-gauge low-dead-space ophthalmic needle demonstrated a favorable safety profile and was preferred over a 30-gauge needle by all surgeons. As aqueous humor liquid biopsy expands in clinical diagnostics and trials, an ophthalmic-specific needle design may help improve the consistency and safety of aqueous humor collection for molecular analysis and broader clinical use. Keywords: Anterior chamber paracentesis; Aqueous humor; Liquid biopsy; Low dead space; Ophthalmic needle

Background: Ebola virus disease is a life-threatening illness caused by the Ebolavirus, with symptoms manifesting two to twenty-one days after infection. Although Uganda has faced multiple Ebola outbreaks, many patients survive only to encounter persistent challenges. Therefore, this study explored the post-discharge experiences of survivors following the 2022 Ebola Virus Disease outbreak in Uganda. Methods: An exploratory qualitative study comprising of in-depth participant interviews was conducted at Mubende Regional Referral Hospital in central Uganda. Interviews were face-to-face and data were analyzed manually by inductive content analysis. Ten male and female participants were Ebola Virus Disease survivors in Mubende district who had lived in the community for at least six months post-discharge from the Ebola Treatment Unit. Results: Four themes emerged: (i) Psychosocial Burdens and Social Exclusion, (ii) Economic Hardship and Loss of Financial Stability, (iii) Chronic Physical and Health Burdens Post-Recovery and (iv) Rebuilding Lives: Psychological, Social, and Medical Pathways to Recovery. Survivors faced significant emotional burdens such as survivor guilt, grief, trauma from loss, and anxiety about transmission risks. They experienced social isolation, stigma, and discrimination, which often led to their exclusion from community activities. Financially, they struggled with debt and the loss of livelihoods, compounded by ongoing health issues. Additionally, survivors endured chronic physical complications, including pain and fatigue, which hindered their recovery. Despite these challenges, survivors sought psychological, social, and medical pathways to recovery, including confirmation of their recovery, support from family and organizations, and health maintenance practices. Supportive medical care and community assistance were crucial in their physical and emotional rehabilitation. Conclusion: Ebola Virus Disease survivors in Uganda face significant psychosocial, health, social, and economic challenges post-discharge. The findings highlight the critical need for comprehensive medical and community-based support systems to aid survivors' recovery and well-being. Further research on long-term neurological effects and community reintegration programmes is needed to inform targeted interventions that support Ebola survivors and reduce stigma and discrimination.

Introduction: Polyendocrine metabolic ovarian syndrome (PMOS), formerly known as polycystic ovary syndrome (PCOS), is a common endocrine disorder affecting women of reproductive age. Besides reproductive and metabolic disturbances, PMOS negatively impacts psychological well-being and quality of life. Despite available treatment options, there remains a need for safe and effective therapies that improve both clinical symptoms and fertility outcomes. Aim: To compare the efficacy of VAMHA and MYRHA tablet combination therapy with standard non-hormonal therapy in restoring regular menstruation. Secondary objectives included assessment of ovulation, menstrual symptoms, polycystic ovarian morphology, hormonal and metabolic parameters, anthropometric measures, and skin manifestations. Study Design: Open-label, randomized, multicentre, prospective comparative clinical study. Methods: Seventy-one women with PMOS were randomized to Group A (n=37) or Group B (n=34). Group A received VAMHA and MYRHA tablets (2 tablets each), while Group B received Metformin 500 mg plus Myoinositol 600 mg (1 tablet), twice daily for 180 days. Data were recorded in Case Report Forms. Statistical Analysis: Continuous variables were summarized using mean and standard deviation, while categorical variables were expressed as frequencies and percentages. Appropriate statistical tests, including Chi-square, were used. A p-value [&le;]0.05 was considered significant. Results: Significantly more participants in Group A achieved regular menstrual cycles than Group B (31 vs. 22; p<0.05). Ovulation occurred in 16 participants in Group A compared with 6 in Group B (p<0.05). Both groups showed significant improvement in menstrual irregularity and related symptoms. Significant reductions in Anti-Mullerian Hormone (AMH), fasting insulin, and body mass index (BMI) were observed in both groups (p<0.05). Resolution of polycystic ovarian morphology occurred in 13 participants (38.23%) in Group A and 10 (33.33%) in Group B. Both treatments were well tolerated with no major safety concerns. Conclusions: VAMHA and MYRHA combination therapy was superior to standard non-hormonal therapy in improving menstrual regularity and ovulation. It also produced favourable metabolic, hormonal, and ultrasonographic outcomes, suggesting its potential as a safe and effective option for comprehensive PMOS management and fertility enhancement.

Background & Aims: Fatigue is a central symptom of chronic liver disease (CLD), substantially impacting health-related quality of life (HRQoL). This study aimed to further understand CLD symptomatology, including fatigue, and its impact on HRQoL from a patient perspective. Methods: Abbott Global Assessment of Patients unmet needs (aGAP) was a multinational, cross-sectional survey in adults with compensated CLD in China, India and Mexico, conducted between July and November 2024. Adult participants who self-reported that they had physician-diagnosed CLD and were experiencing fatigue completed a quantitative survey to assess symptom burden and included three HRQoL patient-reported outcome (PRO) questionnaires (Patient-Reported Outcomes Measurement Information System [PROMIS]-29+2, Work Productivity and Activity Impairment - Specific Health Problem version 2.0 [WPAI: SHP], Multidimensional Fatigue Inventory [MFI]). Results: Overall, 505 participants (China: 200; Mexico: 105; India: 200) completed the study. Participants reported that their CLD-related fatigue sometimes, often or always affected their self-esteem/confidence (45.1%) and ability to maintain or acquire new employment (38.6%). Most participants reported moderate (51.3%) or serious (26.9%) fatigue, with 33.5% experiencing fatigue every day or almost every day. Many participants felt their social life was negatively impacted by their fatigue (47.3%) and that there were related financial difficulties (53.9%). Use of validated PRO tools demonstrated severe fatigue (MFI: overall mean [SD] 13.9 [3.4] general fatigue and 13.4 [3.6] physical fatigue) as well as substantial levels of work and activity impairment (WPAI: SHP overall mean [SD] 53.0 [26.4]) and high levels of anxiety, pain interference, depression and sleep interference (PROMIS T-scores [&ge;]54). Conclusions: Fatigue has a substantial impact on HRQoL among adults with CLD across several countries, highlighting a global unmet need for targeted interventions to effectively identify and manage the condition.

Importance: Evidence on GLP-1/GIP therapies is largely derived from trials enrolling selected populations or medical records that miss utilization outside healthcare channels. No nationally representative cohort has characterized real-world uptake, indications, and access. Objective: To characterize GLP-1/GIP prevalence, indication, clinical profile, and access. Design: Prospective cohort study with three GLP-1/GIP surveillance waves (March 2024, December 2024, October 2025). Setting: The Understanding America Study, an address-based, nationally representative panel of approximately 15,000 US adults aged 18+ years initiated in 2014. Participants: UAS participants responding to at least one surveillance wave (n=9150). Exposures: GLP-1/GIP use status (never vs any use, comprising current and former use), self-reported primary indication (diabetes, weight loss, or other), and access pathway (traditional vs non-traditional). Main Outcomes and Measures: Survey-weighted prevalence of GLP-1/GIP use, overall and by indication and access pathway; sociodemographic, cardiometabolic, treatment, and access characteristics; and smartwatch-derived resting heart rate, heart rate variability, maximum activity heart rate, step count, and sleep duration and variability. Results: Among n=9150 adults (1274 with any use; 60.9% female; median age 53 years), weighted prevalence increased 46%, from 8.2% (March 2024) to 12.0% (October 2025) representing 32 million. Weight-loss indications grew, reaching nearly half of use (4.1% to 5.6%); diabetes-indicated use was stable (5.3% to 5.4%). Users carried high cardiometabolic burden (obesity, 68.2%; diabetes, 53.6%) but diverged by indication: diabetes-indicated users were older (median, 59 vs 49 years), whereas weight-loss-indicated users were more often female (69.9% vs 51.3%) and healthier. One in three users (~9 million) had non-traditional access, especially in weight-loss-indicated users, of whom 33% had no conventional prescription; 41% used compounding, online, or foreign pharmacies; and, 43% lacked coverage. Non-traditional users were five times as likely to report an unlisted, likely compounded formulation (19.8% vs 4.1%). All p<0.05. Conclusions and Relevance: Real-world GLP-1/GIP use has grown rapidly and diversified substantially in indication, access, and population profile. One in 3 users obtained treatment through nontraditional channels largely invisible to claims data, raising long-term safety, efficacy, and coverage questions. GLIMMER provides a public, nationally representative longitudinal evidence base for future payer and provider decisions.

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.