Publications by Year: 2026

BACKGROUND: Intracranial arteriosclerosis (large- and small-vessel disease) is considered a risk factor for major neurological disorders, such as stroke, cognitive impairment, and dementia. While most studies investigating intracranial arteriosclerosis include individuals from industrialized populations, the prevalence and clinical meaning of intracranial vascular calcifications in populations with a subsistence lifestyle is unknown.

METHODS: In this population-based study evaluating data collected between 2017 and 2019 from Tsimane and Moseten people, 2 indigenous populations of forager-horticulturalists living in the Bolivian Amazon, we used computed tomography to determine the prevalence of vascular calcifications in the intracranial internal carotid arteries, vertebral arteries, and lenticulostriate arteries within the basal ganglia, and their association with demographic characteristics, brain atrophy, cognitive performance, and clinical factors.

RESULTS: Our analysis included 1232 individuals who underwent a head computed tomography scan. Intracranial vascular calcifications were found in most individuals (>90%) and their prevalence was higher than that reported for age-equivalent industrialized populations. These calcifications were significantly associated with higher age, brain atrophy, worse cognitive performance, and parkinsonian symptoms.

CONCLUSIONS: Despite the physically active subsistence lifestyle and the low rates of typical cardiovascular risk factors and coronary artery disease, intracranial vascular calcifications are common in these Bolivian Amerindian people, suggesting that alternative factors may contribute to intracranial arteriosclerosis and a novel dementia phenotype.

The epigenetic deregulation of CpG islands (CGIs) plays a crucial role in cancer initiation and progression. CGIs comprise 1%-2% of the human genome and are rich in differentially methylated regions (DMRs) that can serve as biomarkers in clinical samples and liquid biopsies. Focusing epigenetic sequencing on CpG-rich regions, including CGIs, while avoiding non-informative sequences, offers an efficient and sensitive approach for cancer detection and monitoring, especially in samples with excess normal DNA. To this end, we developed adaptor-anchored methylation amplification via proximity primers (aMAPPs), a versatile PCR-based enrichment method. Proximity primers (PPs) are specially designed primers that amplify either methylated or unmethylated proximal CpGs, depending on the selected methylation conversion method. aMAPP achieves high-coverage of genome-wide CGIs and detects numerous DMRs in tumor samples compared to adjacent normal tissue using ultra-low depth sequencing (∼300 000 reads). aMAPP enables detection of aberrant methylation down to 0.01% allelic frequency in tumor DNA dilutions and cell-free DNA, requires only picogram DNA input, and can be adapted to enrich either small panels of cancer-specific DMRs or large genomic-fractions including >90% of genomic CGIs. Overall, aMAPP provides a simple, cost-effective, and highly sensitive strategy for capturing the epigenetic footprint of genome-wide CpGs and identifying aberrant methylation events.

BACKGROUND: This study evaluated the long-term outcomes of asplenia syndrome with single ventricle palliation, hypothesizing that total anomalous pulmonary vein connection (TAPVC), pulmonary atresia (PA), and greater than or equal to moderate atrioventricular valve regurgitation increase mortality risk.

METHODS: This retrospective review analyzed 151 patients with asplenia syndrome who underwent single ventricle palliation between 1990 and 2024. The primary end point was mortality, with risk factors assessed by Cox regression analysis over a mean follow-up of 9.3 years.

RESULTS: The median age at initial operation was 35 days, including 70 neonates (46%). Overall, 62 (41%) patients died, whereas 66 (44%) patients are alive post-Fontan completion. Survival probabilities at 1 and 20 years were 75.7% (95% CI, 67.9-81.8) and 53.7% (95% CI, 44.5-62.0), respectively. TAPVC (P=0.014), PA (P=0.007), and greater than or equal to moderate atrioventricular valve regurgitation (P=0.040) emerged as independent risk factors for mortality in the overall cohort. In the TAPVC cohort, independent risk factors for mortality included PA (P=0.019), infracardiac TAPVC (P=0.045), and neonatal TAPVC repair (P=0.018). When stratified by the risk factors of TAPVC, PA, or greater than or equal to moderate atrioventricular valve regurgitation, survival probabilities did not differ between patients with none or 1 of these conditions (P=0.181) but were significantly lower in those with ≥2 risk factors (P<0.001, at 15 years: 0, 72.9%; 1, 59.1%; ≥2, 32.8%).

CONCLUSIONS: Survival after single ventricle palliation for asplenia syndrome remains suboptimal, particularly when TAPVC, PA, and greater than or equal to moderate atrioventricular valve regurgitation are present in combination rather than in isolation. Improved strategies or surgical techniques are required for this complex asplenia syndrome cohort.

INTRODUCTION: Globally, an estimated 56.8 million people require palliative care each year, with half in their final year of life. However, access appears to be scarce in the most impoverished settings, like rural sub-Saharan Africa. Africa is expected to experience a sharp rise in severe health-related suffering, underscoring the need to increase access to palliative care.

METHODS: A convergent parallel mixed-methods design was conducted to assess factors affecting palliative care access and utilisation in rural Malawi. Interviews using a question guide were conducted with patients, caregivers, and service providers to examine experiences in palliative care access and service utilisation, and the analysis used thematic content analysis. Electronic medical data were extracted, de-identified, and analysed using STATA software version 18.0 from nine palliative care implementing facilities using descriptive statistics.

RESULTS: Electronic medical records were analysed with 204 patients enrolled in the program. The mean age was 58.6 years, and 47% (n = 96) were aged 65+. Females predominated, comprising 65% (n = 132) of the enrollees. 72% (n = 139) of the patients lived more than five kilometres from the nearest clinic. Analysis of forty-four key informants’ interviews highlighted the importance of health system and facility management, structural and contextual determinants of healthcare access, and community-based care and household health determinants, which play a central role in program management and coordination, community health worker (CHW) engagement, and availability of essential supplies plays a central role in service accessibility and utilisation.

CONCLUSION: The findings from the study highlight the importance of addressing social determinants of health, supporting community-based health workers, and strengthening local leadership to improve palliative care access. Provider support and locally adapted strategies can facilitate the delivery of palliative care services in hard-to-reach settings. While these insights are drawn from a single district and may not be broadly generalizable, they provide context-specific guidance for program managers and policymakers aiming to enhance palliative care access and utilisation in similar low-resource settings.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12904-026-02003-5.

IMPORTANCE: International medical graduates (IMGs-physicians who graduated from a medical school outside the US) hold a significant role in the US healthcare system. Research suggests that clinicians' attitudes towards end-of-life (EOL) care may vary across countries.

OBJECTIVE: To compare EOL care processes and outcomes for older adults treated by IMGs vs. US medical graduates (USMGs).

DESIGN: Cross-sectional study.

PARTICIPANTS: A 20% random sample of Medicare fee-for-service beneficiaries aged 66 years or older who died in 2016-2019.

MAIN MEASURES: Seven EOL care-related measures: (i) palliative care counseling or hospice enrollment in the last 180 days of life; (ii) emergency department visits, (iii) hospital admissions, (iv) intensive care unit admissions, (v) use of mechanical ventilation or cardiopulmonary resuscitation, or (vi) feeding tube placement in the last 30 days of life; and (vii) death in an acute care hospital. We adjusted for beneficiary- and physician-level confounders; P-values were adjusted using the Bonferroni-Holm method for multiple comparisons.

RESULTS: Among 391,425 beneficiaries, 117,754 (30.1%) were attributed to IMGs and 273,671 (69.9%) to USMGs. We found no evidence that six of the seven measured EOL care processes and outcomes differ between IMGs and USMGs. Beneficiaries treated by IMGs were slightly less likely to have emergency department visits in the last 30 days of life (57.1% vs. 57.6%; adjusted difference, -0.5 pp; 95% CI, -0.9 to -0.2; P = 0.04) compared with those treated by USMGs. Subgroup analyses by beneficiaries with cancer or chronic heart failure showed no evidence that EOL care processes and outcomes differ by physician's country of medical school after adjustment for multiple comparisons.

CONCLUSIONS: EOL care processes and outcomes were similar for older adults treated by IMG and USMG physicians, despite potential differences in medical training during medical school.

BACKGROUND: Gestational diabetes mellitus is becoming increasingly prevalent and has been associated with adverse outcomes for both mothers and their children. Prenatal exposure to maternal obesity and hyperglycemia has been associated with higher risks of macrosomia, neonatal hypoglycemia and later metabolic disorders. However, because diagnostic fasting glucose thresholds vary internationally, it remains unclear how different cut-offs, as well as fasting glucose as a continuous measure, relate to offspring growth and metabolism. This study investigated whether maternal fasting glucose predicts offspring body composition, anthropometry and metabolic outcomes at birth and at 3 years.

METHODS: The analysis used data from the Lifestyle in Pregnancy (LiP) study and its 3-year follow-up, the LiPO study. Of 301 women in LiP, 157 participated in LiPO, and 75 children had DXA assessments. Maternal fasting plasma glucose at 28 weeks was analyzed continuously and across thresholds from 4.6 to 5.8 mmol/L using regression models adjusted for maternal age and pre-pregnancy BMI. Offspring outcomes included birth weight, birth weight z-score, BMI z-score, fat and fat-free mass, lipids and blood pressure.

RESULTS: Higher maternal fasting glucose was associated with a higher birth weight z-score. At 3 years, no significant associations were found for BMI z-score or metabolic markers, although small, non-significant trends toward higher fat and fat-free mass were observed. Threshold analyses showed that glucose ≥ 5.6 mmol/L predicted higher birth weight and increased large-for-gestational-age risk, and glucose ≥ 5.3 mmol/L predicted higher cord c-peptide. No threshold was linked to metabolic differences at 3 years.

CONCLUSION: Maternal hyperglycemia was associated with adverse neonatal outcomes but not with offspring adiposity at 3 years. Longer-term follow-up, including the ongoing 15-year LiP data, is needed to determine whether mild maternal hyperglycemia has later metabolic consequences.

TRIAL REGISTRATION: Both the LiP and LiPO studies received approval from the Regional Ethics Committee of Southern Denmark (S-20070058) and were registered with the Danish Data Protection Agency. The LiP study was registered at www.

CLINICALTRIALS: gov (NCT00530439) with a registration date of September 13, 2007. The LiPO follow-up, initiated in 2010 while the LiP study was still ongoing, was registered at www.

CLINICALTRIALS: gov (NCT01918319) to compare offspring of LiP participants.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHIs), characterized by tau tangles around small blood vessels at the depths of the sulci. Currently, CTE can be diagnosed only postmortem, but can present with an array of cognitive, behavioral, mood, and motor symptoms. However, traumatic brain injury is also associated with increased risk of Alzheimer's disease (AD) and may lead to comorbid neuropathology. Characterization of the in vivo biomarkers of CTE is a necessary next step to facilitate accurate diagnoses. We examined the profile of cerebrospinal fluid (CSF) biomarkers of amyloid-β, total tau (tTau), and phospho-tau (pTau) in a cohort of former professional (PRO, n = 100) and college (COL, n = 40) football players at high risk of CTE compared to asymptomatic unexposed controls (UE, n = 43). CSF was collected under controlled conditions using collection, processing, and cryostorage kits provided by the DIAGNOSE CTE Research Project Biomarker Core, and concentrations of Aβ40, Aβ42, tTau, and pTau (pTau181, pTau217, pTau231) were measured at the University of Gothenburg, Sweden, using immunoassays. Associations between CSF biomarker levels with football history, and diagnosis of traumatic encephalopathy syndrome (TES) were examined using linear regression, and corrected for age, education, APOE-ε4 allele status, race, and body mass index. Our analysis revealed that football exposure affected both CSF Aβ40 (p = 0.039) and Aβ42 (p = 0.038), particularly among those under 60 years of age in the PRO compared to the UE exposure group. Among former football players, estimates of RHI exposure were not generally associated with CSF Aβ, tTau, and pTau biomarker levels. CSF Aβ40 (p = 0.0041) and Aβ42 (p = 0.011) were lower in former football players with TES diagnosis compared to unexposed participants, although CSF Aβ, tTau, and pTau biomarker levels did not differ between former players with and without a TES diagnosis. Among former football players, reduced CSF Aβ40 (p = 0.011) and Aβ42 (p = 6e-04) were observed in those with cognitive impairment compared to those with neurobehavioral dysregulation. The findings of significant associations of reduced CSF Aβ levels with RHI in elite football players are in line with recent postmortem studies; however, the lack of relationship with CSF tTau and pTau species observed to be altered in the setting of AD suggests that the pathological features of CTE reflected in fluid biomarkers are complex and require further study. The overlapping comorbid age-dependent features of neurodegeneration that occur in those at risk for CTE suggest that tau pathology in CTE is not reliably reflected by currently available fluid biomarkers and that the use of multiple biomarkers related to the compound characteristics of CTE may be required for early detection.

BACKGROUND: Muscle atrophy is a common complication of ageing, and many chronic conditions, lacks defined therapeutic interventions. It is still mostly unknown how circular RNAs contribute to muscle atrophy.

METHODS: circRNA sequencing and quantitative real-time PCR were performed to detect the changed circRNAs in muscle atrophy models and aged muscle. Then the gain-of-function and loss-of-function experiments were used to investigate the function of circSnd1 in muscle atrophy and muscle ageing. Furthermore, we used RIP-MS and RIP assay to determine the downstream and upstream mechanism of circSnd1 in muscle atrophy.

RESULTS: Here, we characterized the function and mechanism of highly species-conserved circRNA derived from staphylococcal nuclease and Tudor domain containing 1 gene (named circSnd1) in muscle atrophy. CircSnd1 is upregulated in many types of muscle atrophy models in both in vivo and in vitro (all p < 0.01). Meanwhile, circSnd1 is also higher expressed in aged muscle in humans (+2.2-fold, n = 5, p < 0.05), mice (+43.96%, n = 6, p < 0.05) and myotubes (+42.21%, n = 6, p < 0.05). Functional analyses show that circSnd1 promotes muscle atrophy and muscle ageing at the cellular level and mouse level while repressing it ameliorates multiple types of muscle atrophy (all p < 0.05). Mechanistically, the RNA binding protein eukaryotic translation initiation factor 4A3 (EIF4A3) can bind to the intron flanking sequence of circSnd1 to induce circSnd1 cyclization and increase circSnd1 expression in muscle atrophy. In addition, circSnd1 promotes the binding between human HLA-F adjacent transcript 10 (FAT10) and eukaryotic translation elongation factor 1 alpha 1 (EEF1A1). FAT10 competes with ubiquitin for binding with EEF1A1, which decreases the ubiquitination of EEF1A1 and stabilizes the protein level of EEF1A1 in muscle cells to promote atrophy.

CONCLUSIONS: We have identified circSnd1 as a novel circRNA that promotes muscle atrophy and highlighted its potential as a novel therapeutic target.

BACKGROUND: Racial inequities in hospital-based care for Black adults are well-documented, yet the mechanisms by which interpersonal and institutional racism contribute to these inequities remain poorly understood. Non-clinician hospital staff, such as patient care assistants, spend significant time with patients and are often members of minoritized communities, yet their perspectives on racism in the hospital are rarely studied.

OBJECTIVE: To investigate non-clinician staff members' perspectives on how interpersonal and institutional racism affect hospital-based care for Black adult patients.

DESIGN: Qualitative study using in-depth, semi-structured interviews and community-based participatory research principles.

PARTICIPANTS: Fifteen hospital staff members (patient care assistants, custodians, transporters, and ward clerks) from a large, urban, academic medical center on the West Coast. Participants self-identified as Black (27%), Hispanic (20%), and/or Asian (53%).

APPROACH: Semi-structured interviews explored respondents' perspectives on racism in the hospital. Interviews were analyzed using thematic analysis. A Community Advisory Board of eight Black individuals provided feedback and member checking.

KEY RESULTS: Five themes emerged from the data: (1) staff members experienced workplace racism; (2) racial stereotypes appeared to contribute to inequitable care for Black patients; (3) institutional factors, such as inadequate staffing, were felt to contribute to inequitable care; (4) individual factors, such as going "above-and-beyond" job responsibilities, helped mitigate inequitable care; and (5) institutional diversity, equity, and inclusion (DEI) interventions received mixed appraisals, with staff often excluded from initiatives.

CONCLUSIONS: Inequities in hospital-based care for Black patients may have roots in complex interactions between individual biases, workplace discrimination, institutional factors, and systemic underinvestment in non-clinician staff. Respondents perceived that institutional factors, such as inadequate staffing and demanding workloads, amplified racist beliefs, resulting in inequitable care for Black patients. Hospitals should invest in non-clinician hospital staff and address structural factors impeding staff members' ability to provide equitable care to all patients.