Publications by Year: 2026

Schizophrenia and related psychoses occur in all human populations, with the highest rates of diagnosis among Black individuals and those of mainly African ancestry1. Decades of research have established a highly heritable and polygenic basis for schizophrenia, which is mostly shared across populations2-4. However, a recruitment bias towards European cohorts5 has led to discoveries that are poorly generalizable to African populations. This exclusion of the world's most genetically diverse populations narrows our understanding of disease biology and risks exacerbating health disparities. Here we show that electronic health records linked with genomic data from the Million Veteran Program (MVP)6-a national research programme that looks at the effects of genes, lifestyle, military experiences and exposures on the health and wellness of veterans-enable a comprehensive assessment of schizophrenia genetics in populations of African ancestry in the USA. We identify ancestry-independent associations in African populations and expand the catalogue of implicated regions by more than 100 loci. Through statistical fine-mapping and integrative transcriptomic analyses, we refine disease-associated signals to consensus genes with convergent neurobiological functions. These findings provide a much-needed view of schizophrenia's genetic architecture in populations of African ancestry, and offer biological insights that both extend previous work and broaden its global relevance.

The mammalian cerebral cortex comprises a complex neuronal network that maintains a precise balance between excitatory pyramidal neurons and inhibitory interneurons. Accumulating evidence indicates that specific interneuron subtypes form stereotyped microcircuits with distinct pyramidal neuron classes1-3. Here we show that pyramidal neurons have an active role in this process by promoting the survival and terminal differentiation of their associated interneuron subtypes. In the wild-type cortex, interneuron subtype abundance mirrors the prevalence of their pyramidal neuron partners. In Fezf2 mutants, which lack L5b pyramidal neurons and are expanded in L6 intratelencephalic neurons, corresponding subtype-specific shifts occur through two distinct mechanisms: somatostatin interneurons adjust their programmed cell death, whereas parvalbumin interneurons switch their subtype identity. Silencing neuronal activity or blocking vesicular release in L5b pyramidal neurons revealed that their communication with interneurons does not require voltage-gated synaptic activity but engages both tetanus toxin-sensitive and tetanus toxin-insensitive pathways. Moreover, a targeted bioinformatic screen for ligand-receptor pairs displaying subtype-specific expression and reduced expression of pyramidal neuron-derived ligand in Fezf2 mutants identified candidate secreted factors and adhesion molecules. These findings reveal distinct, pyramidal neuron-driven mechanisms for sculpting interneuron diversity and integrating them into local cortical circuits.

Evening residential illumination possesses the capacity to impair sleep quality via the suppression of endogenous melatonin production, a process largely driven by short-wavelength (blue) light. In this investigation, we characterized the light emissions from 52 distinct examples across three common lamp technologies: light-emitting diodes (LED), incandescent, and compact fluorescent (CFL) lamps. To estimate the differential circadian impact of these sources, we determined the Melatonin Suppression Value (MSV), melanopic illuminance, and photopic illuminance for each. Our findings reveal that "cool" white LED (median 12.3% MSV) and "cool" white CFL (12.1% MSV) lamps induce considerably greater melatonin suppression than "warm" white LED (3.6%), "warm" white CFL (2.6%), or traditional incandescent (1.5%) lamps. As potential countermeasures, we examined the efficacy of tunable Correlated Color Temperature (CCT) lamps and "blue-light-filtering" (BLF) lenses. The four tunable LED lamps demonstrated a profound ability to mitigate circadian disruption, reducing estimated melatonin suppression from 10% at a 5700 K (cool white) setting to 0.1% at 2100 K (warm white). An analysis of eight BLF lenses identified variable performance; while six had moderate impacts compared to uncorrected vision, their benefit was limited relative to standard clear lenses. Only two BLF lenses, distinguished by a "brown" tint, proved highly effective, reducing estimated suppression to below 0.3%. These results suggest that cool white CFL and LED lamps may exert a greater disruptive influence on sleep physiology than other lamp types. Conversely, tunable lamps adjusted to warm settings and "brown"-tinted BLF lenses represent beneficial strategies for ameliorating this effect. (Detailed measurement methodologies are available in a previously published study, with supplementary calculations provided separately).

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.

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.

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.

INTRODUCTION/AIMS: Although classically characterized as a motor neuron disease, spinal muscular atrophy (SMA) is increasingly recognized as a multisystem disorder. We previously showed hepatocyte-intrinsic steatosis in SMA, raising the question of whether SMA carriers, who are typically asymptomatic, may also exhibit subclinical hepatic abnormalities.

METHODS: We generated induced hepatocyte-like cells (iHeps) from induced pluripotent stem cells (iPSCs) derived from an SMA Type 2 proband, his isogenic wild-type (Iso-WT) line, and both carrier parents, comprised of three carrier lines from the father and one from the mother. Steatosis was assessed by Oil Red O staining and image analysis. Survival motor neuron (SMN) expression was evaluated by immunoblotting. Proteotranscriptomic profiling and mitochondrial respiration assays were performed. Risdiplam, an SMN2 splicing modulator, was used to assess reversibility of observed phenotypes.

RESULTS: SMA and carrier iHeps demonstrated increased lipid accumulation compared to Iso-WT. Risdiplam reduced steatosis by 65.9% in SMA patient-derived iHeps and by 43.6% and 56.9% in father- and mother carrier-derived iHeps, respectively. Carrier and SMA iHeps exhibited downregulation of genes involved in lipid metabolism and liver function, along with altered expression of lipid-related proteins. Mitochondrial dysfunction was present only in SMA iHeps. Carrier-derived induced motor neurons showed normal viability under oxidative stress, consistent with preserved neuromuscular function clinically.

DISCUSSION: Our data reveal hepatocyte-intrinsic lipid metabolic defects in SMA carriers, partially reversible with risdiplam. These findings suggest subclinical hepatic involvement in carriers and support further investigation into the systemic impact of SMN deficiency.

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.

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.