Publications by Year: 2026

This 11-minute video aims at improving skills for the structural assessment of sinus venosus defects using 2-dimensional transthoracic echocardiography (TTE) to increase the ability to diagnose-or rule out-the different types of interatrial communications. Of the five types of lesions, this video focuses on superior and inferior sinus venosus defects. This is the second video in our MicroLearning Video Series, designed to help a target audience of sonographers, general cardiologists, general practitioners who want to gain knowledge on fundamental cardiology, and technicians. View the video at https://vimeo.com/1153585209.

INTRODUCTION: Diabetic kidney disease (DKD) is a major complication of diabetes, with genetic factors contributing to its progression. Although genome-wide association studies (GWAS) have identified common variants, the role of low-frequency and rare coding variants remains underexplored.

METHODS: We performed exome-wide meta-analysis of up to 10,312 individuals with type 1 diabetes (T1D) genotyped using genome arrays with focused exome content. We included 10 DKD definitions based on albuminuria, estimated glomerular filtration rate (eGFR), or both. We analyzed nonsynonymous variants individually and used gene-level analyses for low-frequency (minor allele frequency [MAF] < 5%) and rare (< 1%) variants. Replication was performed in 10,066 participants with T1D and in UK Biobank participants with type 2 diabetes (T2D). Gene expression was assessed in cultured human podocytes.

RESULTS: In addition to the known COL4A3 variant, a novel rare missense variant in EXD3 (p.Asp555Asn, rs200080727, minor allele frequency [MAF] = 0.4%) was associated with DKD (odds ratio [OR] = 8.7, P = 4.5 × 10-9). The variant was predicted to be deleterious and EXD3 was downregulated in DKD in kidney expression datasets. EXD3 knock-down in a cultured human podocyte cell line reduced nephrin gene expression, suggesting a functional role in podocyte biology. Gene-level analyses identified 7 DKD-associated genes (P < 3.4 × 10-6), including MUC5B, which harbored multiple low-frequency missense variants and with evidence of replication. Replication in UK Biobank supported the association of EXD3 rs200080727 with albuminuria (P = 0.014).

CONCLUSION: This study identified a rare EXD3 variant with a strong effect on DKD risk in T1D. Functional data support a role for EXD3 in podocyte integrity and DKD pathogenesis. However, further functional investigations are necessary to understand the underlying molecular mechanisms.

The blood-brain barrier (BBB) plays a vital role in regulating the passage of biomolecules between the bloodstream and the central nervous system (CNS) while also protecting the CNS from pathogens. Pericytes reside at the interface between endothelial cells and the brain parenchyma. These cells are critical for maintaining BBB integrity and regulating vessel permeability, blood flow, and immune cell migration. In this study, we developed a serum-free protocol to generate neural crest cell-derived pericytes (NCC-PCs) from human pluripotent stem cells (hPSCs). These NCC-PCs can be co-cultured with hPSC-derived brain microvascular endothelial cells (BMECs) in a co-culture BBB model that recapitulates the in vivo cellular interactions at the BBB. We used this model to evaluate the pathological consequences of BBB exposure to highly neuroinvasive flaviviruses. Our results identify a previously undescribed role for NCC-PCs in maintaining BMEC barrier integrity during infection and reducing the spread of viral infection to the CNS.

Peripheral nerve injuries lead to diminished function and pain via nociplastic phenomena. We propose a new strategy called directed functional reinnervation, in which nerves are reassigned to new peripheral targets with the intention of altering circuit function. Here, we redirect the saphenous sensory nerve into a skeletal muscle graft to curb nociplasticity and provide benign sensations or useful inputs for prosthetic applications. Electrophysiological functional characterization demonstrated robust afferent responses to mechanical stimulation of the muscle. Immunofluorescence staining indicated widespread innervation of various synapses within the muscle graft. With immediate graft placement, the injured nerve's dorsal root ganglia revealed comparable levels of nociceptive markers to uninjured nerves, suggesting a molecular basis for the prevention of pain sensitization. These findings contribute to the mechanism by which skeletal muscle grafts alleviate neuropathic pain and can be used as a sensory transmitter in conjunction with neural interfaces.

OBJECTIVES: Tuberculosis (TB) remains a global health challenge, with current antibiotic therapies being limited by long treatments, side effects and multidrug-resistant mycobacterial strains. In addition, Mycobacterium tuberculosis (Mtb), the main causative agent of TB, employs evasion mechanisms particularly within alveolar macrophages being the primary host cells. Conventional therapies fail to modulate macrophage function or effectively target host immunity, which is crucial in TB pathogenesis. Emerging evidence points to induced pluripotent stem cell-derived macrophages (iMacs) with enhanced bactericidal activity as a promising cell-based approach for TB treatment. Therefore, this study aimed to compare iMacs with blood monocyte-derived macrophages (MDMs) in response to Bacillus Calmette-Guérin (BCG), the live attenuated TB vaccine and heat-killed Mtb (HKMT).

METHODS: iMacs and MDMs were challenged with BCG and HKMT to assess their functional responses. Key parameters evaluated included cell migration, phagocytosis kinetics, levels of autophagy- and apoptosis-related proteins, and cytokine production profiles following infection.

RESULTS: iMacs displayed enhanced migration, faster phagocytosis and increased expression of autophagy- and apoptosis-related proteins compared with MDMs. Moreover, iMacs showed a stronger pro-inflammatory cytokine response and rapid return to baseline cytokine levels post-infection.

CONCLUSION: These findings support the potential of iMacs as an immunocompetent model for studying mycobacterial infections and as a tool for cell-based TB immunotherapies.

BACKGROUND: Geriatric patients awaiting medical admission frequently experience extended emergency department (ED) stays and receive care in ED hallways. While prolonged ED stays are associated with increased delirium and mortality, the effect of placement in hallways remains unknown. This study's objective was to assess whether prolonged ED hallway exposure is associated with incident delirium and severe agitation in older adults and older persons living with dementia (PLWD).

METHODS: We conducted a multi-site retrospective cohort database study between January 1, 2022 and December 31, 2023 of older adults (age 65+) without prevalent delirium admitted to a general medicine service with an ED stay > 8 h. Patients were dichotomized into two groups: > 8 or < 8 h of care in ED hallways. Our primary outcome was incident delirium and severe agitation (a composite outcome of ICD-10 code for delirium, positive nursing screen, use of parenteral antipsychotics, and/or physical restraints) after admission request. Secondary outcomes included hospital length of stay, inpatient and 30-day mortality, and 30-day ED revisit and readmission. We employed mixed-effect logistic regression models, independent of and mediated by history of dementia and adjusted for additional confounders.

RESULTS: Our sample included 11,105 patients (median age 77, 51% female), with 2299 in the hallway group and 8806 in the non-hallway group. Prolonged ED hallway exposure was not associated with delirium and severe agitation for our general geriatric cohort (OR 0.87 [0.53-1.42]) but was for PLWD (OR 1.48 [1.03-2.13]). We observed no association between hallway care and our secondary outcomes except that the hallway group was associated with lower 30-day readmission (OR 0.69 [0.52-0.92]).

CONCLUSIONS: Prolonged ED hallway care was not associated with delirium and severe agitation in a general geriatric cohort but was for older PLWD. Prospective research is needed to determine if hospitals should consider prioritizing PLWD for rooms.

BACKGROUND: Disturbances in sleep-wake homeostasis (Process S) and circadian rhythm (Process C) are common precipitants of delirium, especially among older hospitalized adults. We conducted a systematic review and meta-analysis to test whether four sleep-modulation agents-melatonin, ramelteon, suvorexant, and lemborexant-lower delirium incidence or shorten its duration in hospitalized patients, with stratified analyses by drug class, age, and surgical status.

METHODS: We systematically searched PubMed, Embase, and CENTRAL through March 2025. We included randomized controlled trials (RCTs) and observational studies assessing delirium prevention with melatonin, ramelteon, suvorexant, and lemborexant in hospitalized adults (≥ 18 years), compared to placebo or standard care. Data synthesis was performed separately for RCTs and observational studies using random-effects models. Meta-regression was used to explore effect modifiers. Risk of bias was assessed using RoB2/ROBINS-I tools. Certainty of evidence was graded using the GRADE assessment.

RESULTS: Thirty-seven studies (27 RCTs, 10 observational) comprising 7845 patients were included. Among RCTs, melatonin (RR 0.94; 95% CI 0.72-1.22) and ramelteon (RR 0.63; 95% CI 0.39-1.03) showed no significant effect on delirium incidence, whereas orexin receptor antagonists were associated with a lower risk (RR 0.55; 95% CI 0.35-0.87). Evidence for a class difference was inconsistent across analytic approaches: a subgroup heterogeneity test suggested differential effects (interaction-p = 0.09), but the meta-regression found no between-class difference (p = 0.14). No other specific test for subgroup differences was statistically significant in RCTs. Meta-regression confirmed patient setting as a significant modifier in observational studies, but not in RCTs.

CONCLUSION: Sleep-wake pharmacotherapies may reduce incident delirium in hospitalized adults. In randomized trials, melatonin and ramelteon did not significantly reduce delirium incidence, whereas dual orexin receptor antagonists showed a possible benefit, but the meta-regression did not demonstrate a reliable between-class difference, and the evidence remains limited. Adequately powered randomized trials across inpatient settings are needed to clarify any true differences and define clinical relevance.

Affective experiences are inevitably accompanied by physiological changes. However, it is still a matter of intense debate whether events evoking similar affective experiences produce comparable physiological responses (fingerprint hypothesis) or variation is the norm within individuals (populations hypothesis). We reanalyzed data from two independent samples (N = 695; N = 64), using representational similarity analysis (RSA) to examine the trial-by-trial similarity patterns of subjective experience of valence and arousal and affect-related physiological measures (skin conductance [SCR] and startle blink responses) and their modulation by physiological intraindividual variability. Across physiological measures and tasks (passive picture viewing, passive sound listening, and imagery tasks), we observed that disregarding versus considering intraindividual variability when constructing psychophysiological response patterns yielded different associations with affective models, aligning with the fingerprint hypothesis and the populations hypotheses of affect, respectively. More importantly, follow-up analysis revealed that considering intraindividual variability yields a better representation of the SCR and startle patterns across individuals and tasks. Our results demonstrated that similar affective experiences are rather reflected by distinct physiological responses and emphasized the importance of considering intraindividual variability in future studies to better understand how physiological changes contribute to conscious affective experiences in humans.

OBJECTIVES: Given that hyperuricemia is a metabolic condition with a prolonged asymptomatic period and strong associations with gout and various metabolic disorders, we investigated the role of lymphocyte subsets in asymptomatic hyperuricemia (aHUA) and explored their potential implications for immune regulation.

METHOD: The study enrolled 59 male patients with aHUA, 29 with acute gout (AG), and 28 healthy male controls (HCs). Laboratory data, including blood cell counts, inflammatory markers, blood lipids, liver and renal function, and the percentage and absolute counts of lymphocytes and CD4 + T cell subpopulations in peripheral blood, were collected. We used flow cytometry to assess the peripheral blood lymphocyte subsets in these participants.

RESULTS: There were significant differences in GGT levels among all three groups, with the aHUA group showing the lowest value (AG vs. aHUA vs. HC, 69.00 vs. 23.00 vs. 35.50; P < 0.001). The lymphocyte subset data revealed a significant increase in the counts of helper T2 (Th2) (AG vs. aHUA vs. HC, 10.73 vs. 10.63 vs. 5.78; P < 0.001), Th17 (AG vs. aHUA vs. HC, 16.86 vs. 10.23 vs. 7.78; P < 0.001), and T suppressor (Ts) cells (AG vs. aHUA vs. HC, 669.32 vs. 655.00 vs. 488.84; P = 0.023), as well as the Th17/Treg ratio (AG vs. aHUA vs. HC, 0.44 vs. 0.37 vs. 0.26; P < 0.001) in both aHUA and AG groups. Furthermore, the increase in Th17 cells and the Th17/Treg ratio was more pronounced in the AG group. Total T cell levels were higher in both the aHUA and AG groups than in HCs, with the aHUA group showing the highest levels (statistically significant versus HCs) (AG vs. aHUA vs. HC, 1517.00 vs. 1620.00 vs. 1316.10; P < 0.001). Furthermore, the univariate regression analysis suggests that GGT [OR (95% CI) = 1.132 (1.069, 1.198), P < 0.001], Th17 [OR (95% CI) = 1.228 (1.104, 1.366), P < 0.001], and the Th17/Treg ratio [OR (95% CI) = 18.900 (1.892, 188.833), P = 0.012] are positively associated with acute gout flare. Multivariate regression analysis indicated that GGT [OR (95% CI) = 1.113 (1.049, 1.181), P < 0.001] and Th17 [OR (95% CI) = 1.235 (1.033, 1.476), P = 0.020] are positively correlated with acute gout flare.

CONCLUSIONS: Our study highlights significant alterations in lymphocyte subsets in aHUA, emphasizing their potential role in the immune response and providing insights for future therapeutic strategies. Key Points • Th17 elevation and Th17/Treg imbalance in asymptomatic hyperuricemia (aHUA) suggest early immune dysregulation. • Th17 cell levels and GGT are positively associated with acute gout flares, serving as biomarkers of disease activity. • Both aHUA and gout patients show immune activation, while there were immunological differences across groups.