Publications by Year: 2026

Sepsis is associated with hypotension, vascular leakage, vasoplegia and microvascular dysfunction. Therefore, the endothelium is a target for sepsis therapies. Since truncated procalcitonin exerts vascular activity, we here evaluated the efficacy of targeting procalcitonin for vascular integrity and sepsis outcomes. Sepsis up-regulated >2000 genes involved in pro-inflammatory responses while similar numbers of genes involving cell growth and maintenance were down-regulated. Transcriptomic changes in endothelial cells diminished by >50% by anti-procalcitonin antibodies and this was functionally associated with preserved vascular barrier integrity in lungs and intestines, reduced sepsis-induced vasoplegia, preserved endothelial nitric oxide bioavailability, improved organ integrity and reduced sepsis severity in mice. Mechanistically, procalcitonin neutralization was associated with reduced signaling of the interleukin-17 pathway. We here show sepsis induces substantial changes to the endothelial transcriptome and vascular integrity and neutralizing procalcitonin is a suitable means to preserve endothelial homeostasis at a transcriptomic and functional level that could translate into organ protection during sepsis.

Image-guided volumetric bioprinting allows for the adaptive fabrication of complex structures for tissue engineering. Seminal work by Florczak et al. introduces Generative, Adaptive, Context-Aware 3D Printing, a workflow that uses computer vision to automatically generate functional, vascular-like networks that conform to living cells within hydrogels, improving their functionality.

BACKGROUND: Antidepressants are among the most prescribed medications in the USA, yet challenges in access to mental health treatment persist.

OBJECTIVE: To assess current and lifetime antidepressant and psychotherapy use among American adults, and examine attitudes towards potential federal restrictions on antidepressant prescribing.

METHODS: We conducted a cross-sectional survey study using data from a national non-probability internet-based panel weighted to approximate national demographics (age, gender, race and ethnicity, education, US census region, and urbanicity) based on 2020 US Census data. Data were collected between 10 April and 27 May 2025 from 30 810 adults residing in the USA. The primary outcomes were self-reported current and past antidepressant and psychotherapy use, and support for or opposition to potential federal restrictions on antidepressant prescribing. Logistic regression models estimated demographic and treatment-related features associated with these outcomes.

FINDINGS: Among 30 115 respondents with complete antidepressant data, 16.6% reported current antidepressant use, and of 30 098 respondents with psychotherapy data, 10.4% reported current psychotherapy. Use of both treatments was significantly greater among White respondents compared with all other racial groups. When asked about potential federal restrictions on doctors prescribing antidepressants, 16.4% of respondents supported and 48.0% opposed such regulation, with lesser opposition among those of male gender (OR 0.69, 95% CI 0.65 to 0.73), and greater opposition among those with lifetime antidepressant treatment (OR 2.37, 95% CI 2.21 to 2.54).

CONCLUSIONS: Antidepressant and psychotherapy use remains unevenly distributed across demographic groups. A significant proportion of adults in every US state oppose efforts to restrict access to antidepressant prescribing, reflecting broad public support for maintaining access to treatment.

CLINICAL IMPLICATIONS: Findings from this study suggest that restrictive policies on antidepressant prescribing are unlikely to align with public sentiment and may risk exacerbating existing inequities in care.

As the world's population ages, the focus of healthcare is shifting from extending life span to promoting health span. There is an unmet need to identify sensitive and reliable markers of health span through more cost-effective and non-invasive methods, to enable early and effective intervention on modifiable aging factors. The eye offers a unique window into systemic health, providing direct visualization of the body's vascular and neural health. This review presents an overview of how various ocular structures can serve as biomarkers of health span-drawing on insights from ocular imaging, metabolomics, and proteomics, with evidence from basic science, animal models, and human clinical trials. The role of artificial intelligence (AI) in predicting biological age and the risk of age-related systemic conditions is also highlighted, with a focus on current applications and how AI is being integrated to synthesize and interpret multimodal data.

BACKGROUND: Routine deltoid ligament repair (DLR) during operative management of ankle fractures remains controversial.

PURPOSE: To compare patient-reported outcomes (PROs), complications, and radiographic outcomes in patients with bimalleolar equivalent ankle fractures treated with or without DLR.

STUDY DESIGN: Retrospective cohort study.

METHODS: Adult patients who underwent operative fixation of bimalleolar equivalent ankle fractures at two level 1 trauma centers between 2010 and 2023 were retrospectively identified. The primary outcome was the Olerud-Molander Ankle Score (OMAS). Secondary outcomes included additional PROs, complications, and radiographic measurements. Multivariable logistic regression assessed the association between DLR and the odds of achieving an excellent (≥91) versus non-excellent OMAS.

RESULTS: A total of 260 patients (median age 36.4 years, 38.4% female) were included. Thirty-one (12%) patients underwent DLR and 229 (88%) did not. PROs were obtained from 92 patients (18 DLR, 74 non-repair) at a median of 7.0 years postoperatively. Median OMAS was similar between cohorts (90 vs. 90, P = 0.79). DLR was not associated with increased odds of achieving an excellent OMAS (adjusted OR 1.89, 95% CI: 0.52-7.08, P = 0.335). Secondary PROs and complications were comparable between cohorts. Radiographic measurements in 111 patients (26 DLR, 85 non-repair) revealed a decreased median tibiofibular clear space in the DLR group (4.50 mm vs. 5.09 mm, P = 0.012). Medial clear space and tibiofibular overlap were similar between cohorts.

CONCLUSION: Patients with bimalleolar equivalent ankle fractures had comparable long-term PROs and complication rates regardless of DLR. Radiographic findings suggested adequate restoration of ankle joint congruity and medial stability in both cohorts.

INTRODUCTION: Biallelic variants in Fanconi Anemia-associated Nuclease 1 (FAN1) cause karyomegalic tubulointerstitial nephropathy (KIN), a condition poorly characterized in terms of kidney survival, patient survival, and clinical characteristics. Therefore, we undertook a cross-sectional collaborative study to better characterize KIN-FAN1.

METHODS: To gather data, we distributed a REDCap survey on clinical characteristics and genetic variants of KIN-FAN1 to colleagues and case report authors.

RESULTS: Based on the survey, we identified 86 families affected (122 individuals) from 22 countries. There were 56 families (83 individuals) with a genetic diagnosis of KIN-FAN1, including 38 distinct FAN1 variants, and 30 families (39 individuals) with KIN with no predisposing risk factors and without molecular FAN1 testing. The median age at presentation was 38.5 years (interquartile range: 29-43), 62% male. Of the cohort, 46% had asymptomatic elevation of liver function tests, 39% had pulmonary complications, and 6% developed cancer. The median age of kidney failure was 45 years (95% confidence interval (CI): 38-56). Of the cohort, 27.1% died at a median age of 55 years (95% CI: 43-75). Pulmonary complications was/were the cause of death in 15.4% of patients on dialysis and 23.1% of kidney transplant recipients. Compared to other variants, patients with the p.W707X-FAN1 variant were at a significantly higher risk of pulmonary complications (adjusted odds ratio: 8.26 (95% CI: 1.7-40.1) and had a significantly shorter lifespan (hazard ratio: 3.24 (95% CI: 1.13-9.28). No genetic covariates were statistically associated with the progression to kidney failure.

CONCLUSIONS: Patients with KIN-FAN1 develop kidney failure at a median age of 45 years. Survival is compromised with many dying of pulmonary disease.

OBJECTIVE: To assess associations between exposure to intrauterine SARS-CoV-2 and subsequent child neurodevelopment in a large, diverse cohort with confirmation of maternal SARS-CoV-2 status.

STUDY DESIGN: The Researching COVID to Enhance Recovery (RECOVER) Pregnancy Cohort enrolled adults with and without SARS-CoV-2 during pregnancy and their offspring born January 2020 through December 2023 at 23 sites across the US. Neurodevelopment was assessed at 12 months with the Ages & Stages Questionnaire, 3rd edition (ASQ-3) and at 18 months with the ASQ Social-Emotional (ASQ-SE) and the Modified Checklist for Autism in Toddlers-Revised (M-CHAT-R). We compared exposed and unexposed infants' ASQ-3 total and subdomain scores, ASQ-SE and M-CHAT-R scores, and proportions meeting published referral thresholds, using multivariable linear and logistic regression.

RESULTS: Among 1179 participants enrolled, 1008 (85.5%) had exposure, with 806 (80.0%) exposed during Omicron predominance. Of those with known timing, 349 (41.4%) and 295 (35.0%) were exposed in the second and third trimesters of pregnancy, respectively. Exposure was not associated with differences in the ASQ-3 (adjusted difference -0.61, 95% CI -10.03 to 8.81) or ASQ-3 subdomains at 12 months, ASQ-SE at 18 months (adjusted difference 0.19, 95% CI -4.02 to 4.41), or M-CHAT-R scores. Findings were similar for proportions meeting referral thresholds and when stratified by variant or by trimester.

CONCLUSIONS: In this multicenter cohort largely exposed since Omicron and in second or third trimester, intrauterine SARS-CoV-2 exposure was not associated with neurodevelopmental screening outcomes through 18 months of age. Further assessments of the impact of intrauterine SARS-CoV-2 on neurodevelopment beyond 18 months of age are needed.

Basal forebrain cholinergic neurons (BFCNs) densely innervate auditory cortex (ACtx), conveying signals linked to internal brain states and external sensory cues. Acetylcholine (ACh) is known to rapidly modulate cortical circuits through nicotinic ACh receptor (nAChR)-mediated activation of layer 1 inhibitory neurons (L1-INs). However, BFCN terminals are also abundant in deeper layers, where their functional impact has received less attention. Using multi-plex in situ labeling across cortical layers and cell types, we found that layer 6 pyramidal neurons (L6-PNs) are highly enriched in diverse transcripts for nAChR subunits and muscarinic ACh receptors (mAChRs). In vivo optogenetic activation of BFCN axons revealed persistent modulation of regular spiking units in L2-6 but a rapid phasic activation only in L6. In acute slices, optogenetic activation of BFCN axons elicited fast nAChR-mediated excitatory post-synaptic potentials in L6-PNs, comparable to responses in L1-INs, and slower mAChR-mediated inhibitory responses. These findings identify L1-INs and excitatory L6-PNs as two major hubs for BFCN modulation of cortical circuits. By recruiting distinct receptor mechanisms and circuit motifs in L1 and L6, BFCNs may engage parallel pathways of cholinergic control that couple fast, transient modulation with slower, sustained regulation to shape cortical perception and plasticity.

BACKGROUND: Intracranial mesenchymal tumors, FET::CREB fusion-positive (ICMT), show fusions involving FET RNA-binding protein family genes (EWSR1 or FUS) and CREB family of transcription factors (ATF1, CREB1 or CREM). The methylation signature(s), gene expression characteristics and clinical behavior of this important tumor type require further characterization.

METHODS: We study the methylation profiles of 81 ICMT cases (61 newly profiled cases and 20 cases from publicly available sources). Clinicopathologic and genomic data were recorded for each case when available.

RESULTS: ICMT showed a relatively distinct methylation signature compared to related tumors. Among the 65 cases where fusion types were documented, the identified fusions included EWSR1::ATF1 (25 cases), EWSR1::CREB1 (12 cases), EWSR1::CREM (21 cases), FUS::CREM (3 cases) and SMARCA2::CREM (4 cases). We confirmed the prior description of two distinct subgroups of ICMT (subclasses A and B). The majority of the cases belonged to subclass A (n = 69; 85%), which showed higher median age compared to subclass B patients (26 years vs. 15 years). Subclass B cases (n = 12; 15%) showed shorter progression-free survival (p < 0.01). Gene expression analysis of ICMT showed key overexpressed markers in ICMT, with significant CREM overexpression regardless of fusion type, when compared to either meningioma alone, or a larger group of CNS tumors.

CONCLUSIONS: This work provides further characterization of ICMT as an important CNS mesenchymal neoplasm that is prone to tumor recurrence, showing 2 prognostically relevant methylation subclasses, and warranting diagnostic distinction from other epigenetically and histologically related tumors. ICMTs show substantial overexpression of the CREM gene, independent of fusion type.