Publications by Year: 2026

Myocardial ischemia-reperfusion (I/R) injury remains a significant challenge in cardiovascular medicine, with its molecular mechanisms still not fully understood. Screening the GEO and Comparative Toxicogenomics Database as well as spatial multi-omics data, we identify Cdkn2a, encoding p16INK4a, as a determinant in I/R injury. Cdkn2a expression is elevated in the myocardium of ischemic cardiomyopathy patients and p16INK4a protein is enriched in cardiomyocytes within ischemic zones of myocardial infarction tissues. We find that p16INK4a is consistently upregulated in both in vivo and in vitro I/R models, promoting apoptosis in neonatal rat cardiomyocytes (NRCMs) and human embryonic stem cell-derived cardiomyocytes (hESC-CMs) exposed to oxygen-glucose deprivation/reperfusion (OGD/R). p16INK4a inhibition confers cellular protection, an effect also observed in in vivo I/R injury models. Mechanistically, p16INK4a promotes binding of the RNA-binding protein CUGBP1 to the GRE sequence of Npas2 mRNA reducing its stability and translation, likely by inhibiting CDK4. This regulation impairs transcription of the Nasp2 target Slco1a4 and consequently bile acid transport, resulting in accumulation of intracellular bile acids and apoptosis. These findings identify p16INK4a-regulated bile acid transport as a driver of cardiac I/R injury.

BACKGROUND: Prenatal metal exposure and genetics may affect birth size, and genetic factors could modify metal toxicity. However, few studies examined gene-metal interactions on birth size.

METHODS: We used data from 324 mother-infant pairs in the Taiwan Birth Panel Study. Cord blood levels of 16 metals were measured with inductively coupled plasma mass spectrometry, and we selected 13 SNPs related to birth size, folate and metal metabolism. Birth weight, birth length and head circumference were abstracted from medical records. Multivariable generalized linear regression was applied to assess single metal-birth size associations and interactions, and quantile g-computation and Bayesian kernel machine regression were applied for metal mixture analyses.

RESULTS: Prenatal barium exposure was negatively associated with birth size, whereas prenatal zinc exposure was positively associated with birth size. We observed several metal-SNP interactions on birth size, particularly between cobalt and multiple genetic variants. Genetic variants also modified the effects of metal mixtures on birth size.

CONCLUSIONS: Genetic factors may influence the impact of prenatal metal exposure on birth size. Identifying these gene-environment interactions may help guide precision strategies to reduce metal-related risks in early life.

IMPACT: Elevated prenatal Ba and Zn levels were associated with birth size in opposite directions. Genetic variants in folate and metal metabolism modified prenatal metal effects, with the strongest interactions seen for cobalt and folate-pathway variants. Metal mixture-birth size associations were most pronounced for the rs10830963 genotype and several other variants. Gene-metal interactions can inform precision prenatal risk reduction strategies for metal exposure.

OBJECTIVE: Optimize use of rapid genomic sequencing (rGS) in a level IV NICU.

STUDY DESIGN: We designed interventions to improve patient identification, ordering processes, and provider education for rGS in our level IV NICU. We measured the percentage of infants eligible for rGS by internal criteria who had rGS sent, diagnostic yield of rGS (balancing measure), and days from genetics consult to rGS result (balancing measure).

RESULT: Our study included 560 infants undergoing genetics evaluation. The percentage of eligible infants who had rGS sent significantly increased from 37% pre-intervention (January 2019-March 2021) to 54% post-intervention (April 2021-September 2024) (p < 0.001). Diagnostic yield of rGS remained stable (32% vs 34%). Time from genetics consult to rGS result significantly decreased from median 32 to 27 days (p = 0.04).

CONCLUSION: Our quality improvement initiative increased rGS use with stable diagnostic yield and decreased time to rGS result for critically ill infants with suspected genetic disorders.

Inflammation is a biological phenomenon beneficial for homeostasis, but it is unfavorable if dysregulated. Although major progress has been made in characterizing inflammation in specific diseases, a global, holistic understanding is still elusive. This is particularly intriguing, considering its function for human health and the potential for modern medicine if fully deciphered. In this study, we leveraged advances in single-cell transcriptomics to delineate inflammatory processes of circulating immune cells during infection, immune-mediated inflammatory diseases and cancer. Our single-cell atlas of more than 6.5 million peripheral blood mononuclear cells from 1,047 patients (56% female, 43% male) and 19 diseases allowed us to learn a comprehensive model of inflammation in circulating immune cells. The atlas expands current knowledge of the biology of inflammation of immune-mediated diseases, acute and chronic inflammatory diseases, infections and solid tumors and lays the foundation to develop a disease classification framework using unsupervised as well as explainable machine learning. Beyond a disease-centered analysis, we charted altered activity of inflammatory molecules in peripheral blood cells, depicting discriminative inflammation-related genes to further understand mechanisms of inflammation. We present a rich resource for the community and lay the groundwork for learning a classifier for inflammatory diseases, presenting cells in circulation as living biomarkers.

Increasing knowledge about the common widespread, distal-predominant polyneuropathies is shifting the standard of care beyond merely palliating symptom toward intervention. This is less advanced for the more prevalent but harder-to-ascertain distal sensory polyneuropathies (DSP) than for motor and demyelinating neuropathies. DSP comprises the sensory-predominant large-fiber axonal/demyelinating neuropathies plus the small-fiber sensory/autonomic axonopathies. Small-fiber disturbances can cause premature fatigue, neuropathic pain and itch, postural orthostasis tachycardia, and gastrointestinal distress. Diagnosis is difficult - screening for classic causes is mandatory but unproductive in a third to a half of patients (initially idiopathic DSP/iiDSP). Multiple large case series and two small passive-transfer studies suggest that autoimmunity may be a prevalent cause of iiDSP, particularly for small-fiber neuropathy. So, despite the knowledge gaps, immunotherapies effective for other neuropathies are increasingly considered for dysimmune iiDSP; particularly in otherwise healthy young patients with impaired life trajectories. To inform these difficult treatment decisions, this chapter summarizes diagnostic requirements for large- and small-fiber iiDSP and evaluates the type and strength of the evidence suggesting autoimmune causality in some. Concomitant rheumatologic conditions including often undiagnosed Sjögren's syndrome, predispose. Youth, abrupt onset, other organ dysimmunity, immune seromarkers, and prior responses to immunotherapy can provide additional evidence, but autoantibody panels are almost never useful. Uncontrolled studies suggest that apparently autoimmune DSP sometimes responds to corticosteroids, intravenous immunoglobulins, and plasmapheresis. However, these cannot be prescribed indiscriminately due to risk, cost/availability, and lack of controlled trials and guidelines. Enough preliminary data may have accrued to permit formulating initial consensus recommendations for selecting the subsets of patients in whom immunotherapy should or should not be considered. Patients, clinicians, and payors would benefit immediately, and highlighting priorities for research could promote long-term advances.

Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are rare autoimmune neuroinflammatory disorders of the central nervous system (CNS) characterized by recurrent attacks of optic neuritis, transverse myelitis, brainstem, and brain syndromes. In contrast with multiple sclerosis (MS), the accumulation of disability in NMOSD and MOGAD is primarily related to relapses, while accumulation of disability between attacks is less common. Therefore, treatment strategies should mainly focus on effective treatment of acute relapses and relapse prevention. Over the past decade, a better understanding of the underlying pathophysiology of NMOSD and MOGAD has led to newer, more specific treatment approaches, culminating in the first FDA-approved treatments for relapse prevention in NMOSD, while randomized clinical trials in MOGAD are underway. In this review, the current treatment options for NMOSD and MOGAD will be discussed, as well as potential treatments that are expected to become available in the near future.

Onset of multiple sclerosis (MS) in childhood and adolescence has now been well-recognized over the past 10-15 years. There have been significant advances in the understanding of the disease course of pediatric MS, which is highly inflammatory, with a higher relapse rate than adult MS. High-efficacy, disease-modifying treatments are recommended for the management of pediatric MS, and these treatments have been studied in open-label and retrospective studies, several of which are outlined here. Fingolimod (Gilenya) is approved for pediatric MS in the United States and many world regions. Several treatments used for adult MS are now being trialed in pediatric MS.

BACKGROUND: The Veterans Affairs Frailty Index (VA-FI) has been implemented in subgroups of U.S. Veterans. The objectives were to operationalize the VA-FI in long-term care residents and examine its associations with mortality, falls, and fractures.

METHODS: This retrospective cohort study included Veterans ≥65 years who stayed ≥90 days in Community Living Centers (CLCs). We calculated the VA-FI by dividing the count of health deficits by 31. We categorized the residents in 4 groups: non/pre-frail, mildly, moderately and severely frail. Mortality, the first events of falls and fractures were examined with a 1-year follow-up. Cox regression and Fine-Gray competing-risk models were fit to assess associations between frailty and outcomes.

RESULTS: Among 45 183 CLC residents, 12.2% were non/pre-frail, 24.2%, 28.8%, and 34.8% were mildly, moderately and severely frail. With increasing frailty severity, rates of mortality, falls and fractures ranged respectively from 65.3 to 59.0, 13.1 to 18.8, and 1.9 to 2.2 per 100 person-years. Relative to the non/pre-frail, residents with mild, moderate and severe frailty had lower rates of death (HRs [95% CIs]: 0.88 [0.84-0.92], 0.87 [0.83-0.91], 0.90 [0.85-0.94]), higher rates of falls (SHRs [95% CI]: 1.26 [1.10-1.43], 1.32 [1.17-1.50], 1.29 [1.14-1.46]) and fractures (1.29 [0.92-1.81], 1.47 [1.06-2.04], 1.45 [1.04-2.02]).

CONCLUSIONS: Frailty was highly prevalent in Veterans receiving long-term care in CLCs and was associated with higher rates of falls and fractures. Frail residents had a lower rate of mortality compared with their non/pre-frail counterparts. Length of stay, confounded by unobserved factors, and collider bias could potentially serve as explanations for this counterintuitive finding.