Publications by Year: 2026

Conventional hydrogel-based bioprinting methods often suffer from insufficient cell densities, which may limit crucial cell-cell interactions and impair overall tissue functions. Here, we present an approach that modifies cell membranes with acrylate bonds, allowing living cells at physiological densities (up to ∼109 cells mL-1) to serve directly as bioinks, demonstrating photoactivated bioprinting through digital light processing using purely cellular bioinks. Our cell-dense bioinks (CLINKs) rapidly produce tissue constructs that closely mimic native tissues, characterized by strong structural relevancy and robust functionality. The high cellularity and living nature of CLINKs enable the creation of advanced biological models such as connected neural circuits and rhythmically contracting mini-hearts derived entirely from stem cells, effectively capturing essential native-like behaviors. Implants created through this method showcase the capacity to integrate with the host, thereby promoting regeneration. Our CLINK technology holds substantial promise in tissue biofabrication, opening alternative avenues for biomedical applications.

OBJECTIVES: H syndrome is a rare autosomal recessive disorder caused by mutations in SLC29A3, encoding the nucleoside transporter hENT3. Its heterogeneous clinical presentation often includes skin hyperpigmentation, systemic inflammation, endocrinopathies and sensorineural hearing loss. However, typical cutaneous signs may be absent, leading to diagnostic challenges. The objective was to describe a patient with H syndrome misdiagnosed until adulthood as having cryopyrin-associated periodic syndrome (CAPS), due to overlapping clinical and functional features.

METHODS: We conducted clinical, immunological, genetic and functional assessments in a 24-year-old male with a complex history of early-onset urticarial rash, fever, hearing loss, oral ulcers, colitis and episodic inflammation. Genetic analyses included whole-exome sequencing (WES) and segregation study by quantitative PCR (qPCR). Functional assays evaluated IL-1β secretion, ASC speck formation, reactive oxygen species (ROS) production and type I interferon signature.

RESULTS: The patient showed enhanced and accelerated IL-1β secretion and increased ASC speck formation in CD14+ cells after lipopolysaccharide (LPS) stimulation, indicating NLRP3 inflammasome hyperactivation, hallmark features of CAPS. ROS production was significantly elevated in both granulocytes and monocytes, even at baseline. A type I interferon signature was intermittently positive. Genetic testing ultimately revealed a homozygous deletion of exon 2 in the SLC29A3 gene, confirming H syndrome.

CONCLUSION: This case highlights the phenotypic overlap between H syndrome and CAPS, including shared inflammasome dysregulation. Absence of typical skin hyperpigmentation delayed diagnosis despite early-onset systemic inflammation and partial response to IL-1 blockade. Functional assays may support diagnostic refinement in autoinflammatory syndromes with atypical features or inconclusive genetics.

OBJECTIVES: Interleukin-6 (IL-6) and neurofilament light chain (NFL) are predictive biomarkers of postoperative delirium in patients undergoing cardiac surgery. This study was designed to compare postoperative changes in IL-6 and NFL between patients receiving multimodal general anesthesia (MMGA) guided by electroencephalography (EEG) versus standard-of-care anesthesia.

DESIGN: Randomized, controlled, investigator-blinded clinical trial.

SETTING: A single-center, tertiary referral hospital.

PARTICIPANTS: Adults ≥60 years old undergoing coronary artery bypass grafting, valve, or combined procedures.

INTERVENTIONS: MMGA included intraoperative EEG monitoring, total intravenous anesthesia with propofol, remifentanil, ketamine, dexmedetomidine, pecto-intercostal fascial block, and postoperative pecto-intercostal fascial block. Controls received inhaled anesthetics and intravenous fentanyl, without EEG guidance.

MEASUREMENTS AND MAIN RESULTS: IL-6 and NFL were measured at baseline, postoperative day 1, and postoperative day 2. EEG was recorded intraoperatively and postoperatively. Cognition was assessed using the Confusion Assessment Method and Montreal Cognitive Assessment up to 6 months. No significant differences were observed in IL-6 or NFL levels at any time point. Delirium incidence and long-term cognitive dysfunction were also similar. However, burst suppression duration was significantly longer in the MMGA group (mean = 4.83 minutes, standard deviation = 3.47) versus controls (mean = 1.68 minutes, standard deviation = 2.2), particularly during and after cardiopulmonary bypass in male patients.

CONCLUSIONS: MMGA did not reduce postoperative IL-6 or NFL levels, nor did it improve neurocognitive outcomes, compared with standard of care. The higher burst suppression in the MMGA group underscores the need for structured EEG education among cardiac anesthesiologists. Future studies should explore other EEG metrics and multimodal strategies for perioperative brain protection.

OBJECTIVE: To evaluate how availability of pediatric-capable hospitals has changed over 2 decades.

METHODS: We studied US acute care hospitals from 2003 to 2022 using the Healthcare Cost and Utilization Project Kids' Inpatient Database. We determined the annual proportion of hospitals by pediatric capability level from 1 to 4, defined by which of 24 services were provided (level 1: broadest range; level 4: minimal services). We used Poisson models adjusting for hospital characteristics to evaluate changes from 2003 to 2022. We also measured changes in provision of each specific service.

RESULTS: We analyzed a mean 3927 hospitals per year, which in 2022 were 67.3% nonprofit, 39.7% urban teaching, 47.0% small, and 37.4% in the South. The number of high-capability hospitals decreased over time. Adjusting for hospital characteristics, level 1 hospitals decreased 38% (95% CI, 27-48), level 2 hospitals decreased 54% (95% CI, 47-60), level 3 hospitals decreased 48% (95% CI, 43-53), and level 4 hospitals increased 137% (95% CI, 119-156). For 17/24 (71%) capabilities, fewer hospitals were capable in 2022 than 2003. The steepest declines of hospital-level specific services were for moderate-intensity services including appendectomy (-50.5%), pneumonia hospitalization (-42.3%), and asthma hospitalization (-41.1%). The smallest changes were for extracorporeal membrane oxygenation (+0.8%), organ transplant (0.0%), and Fontan surgery (-0.1%).

CONCLUSIONS: Low-capability hospitals more than doubled over 2 decades, corresponding to substantial losses in hospitals at all higher levels of pediatric capability. This would be expected to limit child access to care across a range of conditions and complexity.

Westernization of diet, partly characterized by long-chain fatty acid excess, perturbs intestinal immune responses in Crohn's disease (CD). The cellular and molecular framework of lipid sensing in intestinal inflammation remains enigmatic. By small intestinal transcriptional profiling of CD, we identified increased transcriptional activity of retinoid X receptor alpha (RXRα) specifically in intestinal epithelial cells (IECs). Transcriptional RXRα activity was induced in IECs of mice by ω-3 and ω-6 polyunsaturated fatty acid (PUFA) excess in a Western diet. PUFA-induced RXRα activity in Paneth cells governed chronic transmural enteritis by enabling the expression of CXCL1. Oral exposure to isotretinoin ameliorated PUFA-induced metabolic enteritis in two mouse models, and isotretinoin therapy reduced the odds of developing CD in an analysis of electronic health care records from 170,597 patients. Collectively, we identify RXRα in Paneth cells as a metabolic stress sensor that enables enteritis, providing novel perspectives for the prevention and treatment of CD.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used for type 2 diabetes mellitus (T2DM) and overweight or obesity, but their association with cancer is unclear.

PURPOSE: To investigate the risk for obesity-related cancer associated with GLP-1RAs.

DATA SOURCES: PubMed, Embase, Web of Science, Scopus, and the Cochrane Central Register of Controlled Trials from inception to August 2025.

STUDY SELECTION: Randomized placebo-controlled trials reporting any of the following cancer outcomes: thyroid, pancreatic, colorectal, gastric, esophageal, liver, gallbladder, breast, ovarian, endometrial, or kidney cancer; multiple myeloma; or meningioma.

DATA EXTRACTION: Risk of bias was evaluated using the Cochrane Risk of Bias 2 tool, and certainty of evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Odds ratios (ORs) were pooled using random-effects meta-analysis.

DATA SYNTHESIS: The review included 48 trials involving 94 245 participants. GLP-1RAs probably have little or no effect on risk for thyroid cancer (OR, 1.37 [95% CI, 0.82 to 2.31]; 1 fewer to 9 more cases per 10 000 patients treated), pancreatic cancer (OR, 0.84 [CI, 0.53 to 1.35]; 9 fewer to 6 more per 10 000), breast cancer (OR, 0.95 [CI, 0.60 to 1.49]; 10 fewer to 12 more per 10 000), or kidney cancer (OR, 1.12 [CI, 0.78 to 1.60]; 5 fewer to 13 more per 10 000) (moderate certainty). GLP-1RAs may have little or no effect on colorectal, esophageal, liver, gallbladder, ovarian, or endometrial cancer; multiple myeloma; or meningioma (low certainty). The effect on gastric cancer is very uncertain. Results were consistent in sensitivity analyses of trials with low risk of bias and studies of semaglutide or tirzepatide and across subgroups stratified by follow-up duration, population, GLP-1RA class, weight loss profile, dose, and duration of action.

LIMITATION: The included trials were not designed to evaluate cancer outcomes and had short follow-up.

CONCLUSION: GLP-1RAs may have little or no effect on risk for obesity-related cancers. Longer-term studies are needed to clarify potential risks or benefits.

PRIMARY FUNDING SOURCE: None. (PROSPERO: CRD42024608365).

Immune checkpoint inhibitor-associated immune thrombocytopenia (ICI-ITP) has been described in case reports and small case series, but comprehensive data on its incidence, risk factors, clinical features, treatment, and outcomes are lacking. We reviewed medical records of all adults initiating ICI therapy between 2016 and 2023 at 29 US hospitals across 7 major cancer centers to identify patients with ICI-ITP. Multivariable logistic regression was used to identify risk factors, and Cox modeling was performed to assess the association between ICI-ITP, its severity, and mortality. Among 86 467 patients, ICI-ITP occurred in 214 (0.25%). Independent risk factors included lower baseline platelet count, combination ICI therapy, stage IV cancer, and additional immune-related adverse events. ICI-ITP occurred at a median of 8 weeks (interquartile range [IQR], 4-18) after ICI initiation, with a median nadir platelet count of 41 × 109/L (IQR, 17 × 109/L to 64 × 109/L). Patients were treated with glucocorticoids (n = 106 [49.5%]), immune globulin (n = 39 [18.2%]), and thrombopoietin receptor agonists (n = 29 [13.6%]). Recovery occurred in 161 patients (75.2%) at a median of 2.3 weeks (IQR, 1.0-5.3). Of 76 patients rechallenged with ICIs, 23 (30.3%) developed recurrent ICI-ITP. ICI-ITP and its severity were associated with higher all-cause mortality, with a nearly threefold increase in risk among patients with severe ICI-ITP than those without ICI-ITP (adjusted hazard ratio, 2.96 [95% confidence interval, 2.14-4.08]). These findings establish ICI-ITP as a rare but clinically significant complication of ICI therapy, provide, to our knowledge, the first large-scale description of its risk factors and clinical course, and underscore the importance of timely recognition and management.

IMPORTANCE: Cognitive symptoms negatively impact people with narcolepsy type 1 (NT1). While the effects of orexin receptor 2 (OX2R) agonists have been explored on diagnostic features of the disorder (excessive daytime sleepiness and cataplexy), effects on cognitive symptoms are not characterized.

OBJECTIVE: To explore the effects of oveporexton, an oral OX2R-selective agonist, on cognition in people with NT1.

DESIGN, SETTING, AND PARTICIPANTS: This is a secondary analysis of the TAK-861-2001 phase 2, 8-week, parallel-group, double-blind, placebo-controlled randomized clinical trial, conducted from January 2023 to December 2023, with a 4-week follow-up period. TAK-861-2001 was a multicenter study conducted in clinical settings. Eligible participants were 18 to 70 years of age, with an International Classification of Sleep Disorders, Third Edition diagnosis of NT1. Data analysis was performed from July 2024 to July 2025.

INTERVENTIONS: Participants were randomized 1:1:1:1:1 to twice-daily oral oveporexton or matching placebo, dosed 3 hours apart, in dose groups of 0.5/0.5 mg, 2/2 mg, 2/5 mg, 7 mg/placebo, or placebo/placebo, for 8 weeks.

MAIN OUTCOMES AND MEASURES: Cognitive symptoms were assessed using the Psychomotor Vigilance Task (PVT) for attention, the Continuous Paired Associate Learning (CPAL) test for memory, and the One Back (ONB) test and International Digit Symbol Substitution Test-symbols (IDSST-s) for executive function.

RESULTS: Of 161 eligible individuals screened, 48 did not meet study inclusion criteria, 1 withdrew, and 112 were included in the study. Of 112 participants, mean (SD) age was 34.0 (11.5) years, and 58 participants (51.8%) were female. A total of 112 participants were randomized and received 1 or more doses of oveporexton (0.5/0.5 mg, n = 23; 2/2 mg, n = 21; 2/5 mg, n = 23; 7 mg, n = 23) or placebo (n = 22). Oveporexton improved attention, memory, and executive function over 8 weeks. Least-squares (LS) mean placebo-adjusted changes from baseline were -10.77 (95% CI, -16.74 to -4.79), -9.45 (95% CI, -15.66 to -3.24), -8.60 (95% CI, -14.84 to -2.36), and -8.69 (95% CI, -14.90 to -2.47) PVT lapses with 0.5/0.5 mg, 2/2 mg, 2/5 mg, and 7 mg/placebo doses, respectively. LS mean placebo-adjusted changes were -22.52 (95% CI, -34.95 to -10.10), -16.92 (95% CI, -30.12 to -3.71), -15.51 (95% CI, -28.82 to -2.21), and -17.59 (95% CI, -30.50 to -4.68) for CPAL errors; -0.05 (95% CI, -0.10 to -0.01), -0.07 (95% CI, -0.12 to -0.02), -0.07 (95% CI, -0.12 to -0.02), and -0.05 (95% CI, -0.10 to 0.00) units for ONB log10-transformed performance speed; and 4.72 (95% CI, -1.38 to 10.83), 7.33 (95% CI, 1.06-13.61), 7.85 (95% CI, 1.75-13.95), and 11.82 (95% CI, 5.75-17.89) for IDSST-s correct responses.

CONCLUSIONS AND RELEVANCE: In this secondary analysis of the TAK-861-2001 randomized clinial trial, the OX2R agonist oveporexton improved NT1-associated cognitive symptoms in adults.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05687903.