Publications by Year: 2025

BACKGROUND: No randomized trial has compared, head-to-head, the effects of empagliflozin and dapagliflozin in patients with heart failure.

METHODS: This nationwide, prospective, new-user, active-comparator cohort study emulated a pragmatic target trial comparing heart failure rehospitalization and all-cause death risks in adults with heart failure who were initiating empagliflozin vs dapagliflozin. To study the effects of initiating and sustaining treatment analyses, we calculated 1- and 5-year risks and risk ratios (RRs) of outcomes. Follow-up began at treatment initiation (June 1, 2014-December 31, 2022) and continued until the first of an outcome, emigration, December 31, 2022, or 5 years of follow-up. Inverse probability of treatment and censoring weights were applied to balance baseline covariates and, in analyses of sustained treatment, to account for nonadherence.

RESULTS: Of our patients, 2860 initiated empagliflozin, and 6264 initiated dapagliflozin (median age, 70 [IQR, 61-78] years; 25% females). In the effect-of-initiating-treatment analyses, heart failure rehospitalization risks at 1 year were 16.1% in the empagliflozin group vs 19.8% in the dapagliflozin group (RR, 0.81 [95% CI 0.71-0.94]) and 30.5% vs 33.4% at 5 years (RR, 0.92 [95% CI 0.79-1.06]). The risks of all-cause death were 6.7% vs 6.9% at 1 year (RR, 0.97 [95% CI 0.74-1.27]) and 23.4% vs 23.8% at 5 years (RR, 0.98 [95% CI 0.77-1.25]). In the effect of sustained treatment analyses, the RRs for heart failure rehospitalization, comparing the empagliflozin with the dapagliflozin group, were 0.81 (95% CI 0.70-0.94) at 1 year and 0.82 (95% CI 0.67-1.00) at 5 years. The corresponding RRs for all-cause death were 1.12 (95% CI 0.84-1.49) at 1 year and 1.00 (95% CI 0.70-1.44) at 5 years.

CONCLUSIONS: Although this study cannot exclude lower short- and long-term risks of rehospitalization due to HF among patients with heart failure who initiate empagliflozin compared with dapagliflozin, no substantial difference was observed in the risks of all-cause death.

OBJECTIVES: To examine national trends and determinants of hypertension diagnosis, treatment and control in Indonesia, and to identify factors influencing the performance of hypertension care across three waves of national health surveys.

DESIGN: Repeated cross-sectional analysis of three nationally representative health surveys (2013, 2018 and 2023).

SETTING: Household-based, population-level surveys conducted across all provinces of Indonesia, representing primary healthcare settings.

PARTICIPANTS: Adults aged ≥18 years included in the 2013, 2018 and 2023 Indonesian National Health Research surveys (Riset Kesehatan Dasar and Survei Kesehatan Indonesia). Participants with complete blood pressure measurements and information on diagnosis and treatment were included; those with missing data were excluded. The weighted sample sizes were representative of Indonesia's adult population by sex, age group and urban-rural residence.

PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcomes were hypertension prevalence, diagnosis, treatment and control rates. Secondary analyses assessed sociodemographic, economic and health system factors associated with each stage of the hypertension care cascade using multivariate logistic regression. All estimates were adjusted for survey design and population weights.

RESULTS: Hypertension crude prevalence increased from 27.9% (95% CI 27.7% to 28.2%) in 2013 to 31.6% (95% CI 31.4% to 31.8%) in 2023. Diagnosis rates declined from 33.0% in 2013 to 24.1% in 2018, then slightly rose to 26.9% in 2023. Treatment rates doubled from 10.4% to 22.4% over the decade, corresponding to an estimated 10 million additional adults receiving antihypertensive therapy. However, control rates improved only modestly, from 2.3% to 4.2%, leaving over 95% of hypertensive adults with uncontrolled blood pressure. Women, urban residents and individuals in higher wealth quintiles had consistently better outcomes across all stages of care.

CONCLUSIONS: Indonesia faces a growing hypertension burden, with most cases being undiagnosed. Although treatment coverage has doubled over the past decade, control rates have remained stagnant, and disparities between wealth groups persist. Strengthening long-term management, follow-up and equitable care is essential to improve outcomes.

The practice of neurology requires an understanding of clinical ethics for decision-making. In multiple sclerosis (MS) care, there are a wide range of ethical considerations that may arise. These involve shared decision-making around selection of a disease-modifying therapy (DMT), risks and benefits of well-studied medications in comparison to supplements with limited information, allocation of resources and accessibility to MS care, and disparities in healthcare. We share a series of cases that illustrate ethical issues that may arise in the care of patients with MS. This narrative review articulates relevant ethical theories and frameworks that can be applied to common clinical scenarios in the current practice of MS.

For the MHC, MR1 and CD1 systems, antigen recognition involves contact of the membrane distal surfaces of both the αβ T cell receptor (TCR) and the antigen-presenting molecule. Whether other antigen display mechanisms by antigen-presenting molecules operate remains unknown. Here, we report mass spectrometry analyses of endogenous lipids captured by CD1c when bound to an autoreactive αβ TCR. CD1c binds twenty-six lipid species with bulky headgroups that cannot fit within the tight TCR-CD1c interface. We determined the crystal structures of CD1c presenting several gangliosides, revealing a general mechanism whereby two lipids, rather than one, are bound in the CD1c cleft. Bulky lipids are oriented sideways so that their polar headgroups protrude laterally through a side portal of the CD1c molecule - an evolutionarily conserved structural feature. The sideways-presented ganglioside headgroups do not hinder TCR binding and so represent a mechanism that allows autoreactive TCR recognition of CD1c. In addition, ex vivo studies showed that the sideways-presented gangliosides can also represent TCR recognition determinants. These findings reveal that CD1c simultaneously presents two lipid antigens from the top and side of its cleft, a general mechanism that differs markedly from other antigen-presenting molecules.

Understanding the architectural principles that shape human brain networks is a major challenge for systems neuroscience. We hypothesize that the centrality of the different brain circuits in the human connectome is a product of their embryogenic age, such that early-born nodes should become stronger hubs than those born later. Using a human brain segmentation based on embryogenic age, we observed that nodes' structural centrality correlated with their embryogenic age, supporting our hypothesis. An opposite trend was found at functional level. The difference in embryonic age between nodes inversely correlated with the probability of existence of links and their weights. Brain transcriptomic analysis revealed strong associations between embryonic age, structure-function centrality, and the expression of genes related to nervous system development, synapse regulation and human neurological diseases. Our results highlight two key principles regarding the wiring of the human brain: older-get-richer rule, whereby earlier-born regions become network hubs, and a preferential-age-attachment rule, whereby regions preferentially connect to others with similar neurogenic timing.

In this study, we present the results of archaeogenetic investigations of Early Bronze Age individuals from Lower Austria, specifically associated with the Únětice and Unterwölbling cultural groups. Through analysing newly generated genome-wide data of 129 individuals, we explore the social structure and genetic relationships within and between these communities. Our results reveal a predominantly patrilocal society with non-strict female exogamic practices. Additionally, Identity-by-Descent analysis detects long-distance genetic connections, emphasizing the complex network of interactions in Central Europe during this period. Despite shared social dynamics, notable genetic distinctions emerge between the Únětice and Unterwölbling groups. These insights contribute to our understanding of Bronze Age population interconnections and call for a nuanced interpretation of social dynamics in this historical context.

BACKGROUND: Antiretroviral therapy (ART) in human immunodeficiency virus (HIV) markedly improved life expectancy in persons living with HIV (PLWH), but cardiac disease has emerged as the leading cause of death in this population. The prevalence of impaired diastolic function and heart failure with preserved ejection fraction (HFpEF) is higher among PLWH on ART. However, the specific role that HIV itself, and/or ART may have on the cardiomyocyte phenotype is unknown. We investigated modified molecular pathways in cardiomyocytes after exposure to serum from the same patients who were initially ART-naïve and then subsequently ART-treated.

METHODS: Rat cardiomyocytes were treated for 24 hours with serum obtained longitudinally from PLWH (N = 10) before and after being on ART for 6 months. Transcriptomic changes were determined by RNA sequencing. Measures of apoptosis, calcium handling, and extracellular matrix remodeling were analyzed using TUNEL assay and western blot.

RESULTS: Here we show that exposure to serum from ART-naïve PLWH increases cardiomyocyte cell death. In contrast, exposure to serum obtained from the same PLWH after six months on ART results in altered expression of calcium-handling proteins and upregulation of profibrotic and extracellular matrix-related markers, indicating altered contraction and relaxation, and adverse cardiac remodeling.

CONCLUSIONS: These findings demonstrate dysregulated molecular pathways in cardiomyocytes following exposure to untreated HIV serum versus ART-treated HIV serum from patients followed longitudinally. Altogether, these data suggest that HIV infection and ART contribute to changes seen in the cardiomyocyte phenotype and play complementary roles in the pathogenesis of diastolic dysfunction and HFpEF in PLWH.

Periprosthetic joint infections (PJIs), particularly those caused by multidrug-resistant organisms (MDROs), remain a major therapeutic challenge. Antimicrobial blue light (ABL) offers a promising non-antibiotic approach, inducing bacterial killing through photoexcitation of endogenous chromophores and subsequent reactive oxygen species generation. However, conventional single-point illumination systems are limited by uneven light distribution and poor penetration, restricting their use to superficial infections. We evaluated a novel isotropic optical fiber designed to overcome these geometric and optical constraints. The fiber was tested against vancomycin-resistant Enterococcus faecium (VR-Ef) and carbapenemase-producing Klebsiella pneumoniae (CP-Kp) in time-to-kill assays under low-power (20.1 mW mm-1) and high-power (40.3 mW mm-1) conditions over 60 min. Bacterial counts (CFU per mL) were determined at 0, 10, 20, 30, and 60 min. A one-way analysis of variance (ANOVA) with Tukey's post hoc test assessed time-dependent reductions; a two-way ANOVA evaluated the combined effects of illumination power and exposure time. ABL exposure resulted in time- and intensity-dependent bacterial reduction in both strains. Significant CFU reductions occurred from 30 min onward under high-power ABL (HP-ABL) and after 60 min under low-power ABL (LP-ABL) for both VR-Ef and CP-Kp ( p < 0.001 ). The two-way ANOVA revealed significant main and interaction effects of illumination power and exposure time (all p < 0.001 ). Although bactericidal thresholds ( ≥ 3 log⁡ 10  reduction) were not reached, bacterial killing increased markedly with higher power and longer exposure. This novel isotropic optical fiber enables uniform intraluminal ABL delivery, potentially extending blue-light therapy from superficial to deep surgical infections such as PJIs. Further optimization of illumination parameters and potential integration with photosensitizers may enhance its antimicrobial efficacy and clinical applicability.

Vocal fold leukoplakia (VFL) is a descriptive term for a white plaque in the true vocal folds (TVF). It is estimated at 10.2 cases per 100,000 males and 2.1 per 100,000 females. The most critical aspect of managing a VLF is achieving an accurate pathological diagnosis, since a white plaque in the TVF can have numerous differential diagnoses. Patients with VFL usually complain of hoarseness and vocal strain. The common cause of VFL is premalignant lesions with primary risk factors of tobacco and alcohol consumption. Inflammatory aggressors such as laryngopharyngeal reflux disease are proven to affect directly the incidence of VFL. Infectious agents such as human papilloma virus and Helicobacter pylori may also play a role in the development of VFL. Frequent differential diagnosis includes laryngeal candidiasis, prolonged ulcerative laryngitis, previous head and neck radiotherapy, and, more rarely, lichen planus. The clinical investigation for a VLF includes laryngeal exam through a rigid or a flexible laryngoscope; videochromoendoscopy is a useful tool. Biopsy is mandatory so a pathological diagnosis is made. The most accepted classification for VFL and premalignant lesions is the fifth edition of the World Health Organization, and it uses a two-tiered system. The treatment for VFL and premalignant lesions can be done by cold knife surgery, KTP laser, or CO2 laser.