Faculty Bibliography

BACKGROUND:ASH1L-related intellectual developmental disorder represents an emerging neurodevelopmental syndrome with significant phenotypic heterogeneity (Cordova et al. in Genes (Basel). 15(4):423, 2024). Comprehensive genomic analysis demonstrates superior diagnostic yield compared with targeted approaches in complex neurodevelopmental presentations (Srivastava et al. in Genet Med. 21(11):2413-2421, 2019). CASE PRESENTATION/METHODS:This report describes a 6-year-old Central Asian (Uzbek) male patient with a history of global developmental delay who was diagnosed with mild autism spectrum disorder, attention-deficit/hyperactivity disorder, and a developmental expressive language disorder. Neuropsychological assessment revealed an uneven cognitive profile with average verbal abilities but below-average nonverbal reasoning. After uninformative targeted genetic panels, trio whole-genome sequencing identified a novel de novo heterozygous missense variant in ASH1L c.4043A > G (p.Lys1348Arg). This variant, absent in population databases, was classified as a variant of uncertain significance. However, in silico analysis predicted this variant to be probably damaging, and therefore, it emerged as the strongest candidate to explain the patient's phenotype. CONCLUSION/CONCLUSIONS:This case expands the known phenotypic spectrum of ASH1L-related disorders, demonstrating that a de novo missense variant can be associated with a milder neurodevelopmental phenotype, including borderline-to-average intellectual ability. These findings challenge suggestions that missense variants uniformly lead to more severe outcomes and underscores the importance of comprehensive genomic and deep clinical characterization to refine our understanding of gene-disease relationships.

The kidneys contribute to glucose homeostasis by gluconeogenesis and glucose reabsorption. Herein, we identified previously unknown fasting-induced, glucagon-mediated inhibitory effect of the circadian clock gene basic helix-loop-helix ARNT like 1 (Bmal1) on the expression of the main proximal tubule glucose transporter solute carrier family 5 member 2 (Sglt2) in mice. During fasting, glucagon induces Bmal1, which increases expression of nuclear receptor subfamily 1, group D, member 1 (Rev-erbα). Rev-erbα represses nuclear respiratory factor 1, a transcriptional activator of Sglt2, and diminishes Sglt2 expression and thereby kidney glucose reabsorption capacity. During refeeding (lower glucagon) this process is attenuated, thereby inducing glucose reabsorption. The physiological role of this mechanism appears to ensure optimal temporal retrieval of filtered glucose during fasting/refeeding. Thus, this study demonstrates that during fasting and refeeding, glucagon regulates renal glucose reabsorption by utilizing the local cellular circadian machinery.

OBJECTIVE:Induction of labor (IOL) and hospitalist coverage is becoming more common. While hospitalist coverage has been associated with improved maternal outcomes and lower cesarean delivery rates, its impact on IOL remains unclear. The objective of this study was to compare the induction time to vaginal delivery across three obstetric coverage models: hospitalists, faculty generalists, and private practice generalists. STUDY DESIGN/METHODS:This single-site retrospective cohort study analyzed singleton, term (≥39 weeks), vertex patients undergoing induction of labor at NYU Langone Hospital- Long Island from January 1 to September 30, 2022. Hospitalists at this institution managed high-risk obstetric patients including those under maternal-fetal medicine care, resident clinic, and unregistered patients who presented to labor and delivery, along with serving as labor and delivery safety officer on the labor floor. Faculty and private practice generalists managed their respective groups. Outcomes included induction time to vaginal delivery, mode of delivery, induction methods, and maternal and neonatal complications. Statistical analyses included chi-square, ANOVA, and multivariable linear regression. A p-value <0.05 was statistically significant. RESULTS:Among 403 patients, 92 (22.8%) were managed by hospitalists, 115 (28.5%) by faculty, and 196 (48.6%) by private generalists. Median (IQR) induction-to-delivery times were similar across groups-hospitalists 20.5 (15.3-27.5) h, faculty 23.4 (16.5-31.1) h, and private 19.7 (14.1-25.6) h (p = 0.004). However, when limited to vaginal deliveries, no significant difference was observed in induction-to-vaginal-delivery time (p = 0.17). Private generalists had the shortest induction-to-cesarean time and time to membrane rupture leading to cesarean. There were no differences in intrapartum complications. Hospitalists had more NICU admissions after vaginal delivery, mostly unrelated to labor. CONCLUSION/CONCLUSIONS:Induction-to-vaginal delivery times and complication rates were similar across coverage models, but differences in NICU admissions and cesarean delivery times highlight care variations. Collaboration and evidence based standardized induction protocols may optimize outcomes across coverage models.

HOXB13 is a prostate-specific transcription factor best known for its role as an androgen receptor (AR) cofactor. Recent evidence suggests that HOXB13 plays critical AR-independent functions in repressing lipogenic programs and promoting prostate cancer (PCa) metastasis. However, the mechanisms linking HOXB13 loss to tumor metastasis remain unclear. Here, we show that p300 and CBP co-occupy lipogenic enhancers suppressed by HOXB13 and HDAC3 and are essential for enhancer activation and target gene expression following HOXB13 depletion. Loss of HOXB13 induces lipid-sensitive matrix metalloproteinases (MMPs), promoting increased cell motility. Importantly, pharmacological inhibition of p300 and CBP blocks HOXB13-loss-driven lipogenesis, reduces MMP expression, and decreases cell migration in vitro and tumor metastasis in vivo. Analysis of clinical samples revealed that HOXB13 expression is reduced in metastatic hormone-sensitive PCa compared with matched primary tumors, further supporting its role in tumor metastasis. These findings demonstrate that HOXB13 downregulation promotes PCa metastasis through p300- and CBP-dependent lipogenic and motility pathways, which may be targeted by p300 inhibition.

BACKGROUND:This study assessed whether there is a correlation between the grade of splenic injury and the semiquantitative assessment of the amount of the hemoperitoneum (HP) by a modified Federle score (mFS), and which of the 2 factors is more predictive of the need for intervention in adult patients with isolated blunt splenic injury (iBSI). METHODS:Retrospective cohort study of patients admitted (1/1/2019-12/31/2022) with iBSI. Continuous data are presented as means ± standard deviation and non-parametric data as frequencies with percentages. A test-retest analysis for intra- and inter-class reliability of HP assessment was done in a 10-patient subgroup. RESULTS:Among the 62 patients, 47 (75.8%) were managed nonoperatively (23 observation, 24 splenic artery embolization [SAE]), and 15 underwent splenectomy. The grade of splenic injury and mFS scores were 3.6 ± 1.3 and 4.1 ± 1.9, respectively. The 22 patients who underwent SAE were more severely injured in terms of grade of splenic injury (4.0 ± 1.2 vs 2.6 ± 1.1), amount of HP by mFS (4.1 ± 1.8 vs 3.1 ± 1.7) and ISS (21 ± 11 vs 15 ± 12) compared to the observed patients (P < .05). Mortality was 8%. SAE and splenectomy groups differed only by the quantity of HP (4.1 ± 1.8 vs 5.5 ±1.3). While there was a correlation between AAST grade and mFS, only mFS was predictive of splenectomy. CONCLUSION/CONCLUSIONS:The quantity of HP as assessed by mFS may be more predictive than the grade of splenic injury regarding the need for splenectomy in patients with iBSI.

PURPOSE/OBJECTIVE:Chemotherapy-induced alopecia (CIA) affects approximately 65% of patients receiving chemotherapy and has a negative impact on quality of life (QoL). Scalp cooling (SC) is the only FDA-cleared intervention for CIA. This systematic review and meta-analysis evaluated SC adverse events (AEs), reasons for discontinuation, and scalp metastasis incidence. METHODS:Meta-analyses using random-effects models estimated pooled prevalences of SC AEs, SC discontinuation, and reasons for discontinuation. A generalized linear mixed model was used to estimate the incidence of scalp metastasis. RESULTS:Sixty-seven studies met the inclusion criteria. The most common AEs were generalized chills (42%, 95% confidence interval (CI) 26-58%), cap heaviness (35%, 95% CI 18-52%), and headache (30%, 95% CI 21-39%). The SC discontinuation rate was 18% (95% CI 13-23%). The most common reasons for discontinuation were progressive alopecia (15%, 95% CI 10-20%) and reasons unrelated to SC (9%, 95% CI 5-13%). The most frequent AEs leading to SC discontinuation were headache (4%, 95% CI 2-6%), cold intolerance (4%, 95% CI 3-5%), and general discomfort (4%, 95% CI 2-7%). Secondary analysis of scalp metastases yielded an incidence of 0.15% (95% CI 0.05-0.47%). Analysis of FDA Manufacturer and User Facility Device Experience (MAUDE) database medical device reports revealed that user error contributed to cold thermal injuries. Prevalence estimates were limited by significant heterogeneity between studies, reflecting variations in study methodology and real-world SC practices. CONCLUSION/CONCLUSIONS:SC is generally well tolerated with minimal safety concerns. Clinical comfort strategies like supportive medications and improved patient education could enhance SC tolerability and support its implementation.

Atherosclerotic cardiovascular disease is a major contributor to the global disease burden. Atherosclerosis initiation depends on cholesterol accumulation in subendothelial macrophages (Mφs). To clarify the role of Bmal1 in Mφ function and atherosclerosis, we used several global and myeloid-specific Bmal1-deficient mouse models. Myeloid-specific Bmal1-deficient mice had higher Mφ cholesterol and displayed greater atherosclerosis compared with controls. Bmal1-deficient Mφs exhibited: (a) elevated expression of Cd36 and uptake of oxLDL; (b) diminished expression of Abca1 and Abcg1, and decreased cholesterol efflux and reverse cholesterol transport; and (c) reduced Npc1 and Npc2 expression and diminished cholesterol egress from lysosomes. Molecular studies revealed that Bmal1 directly regulates basal and cyclic expression of Npc1 and Npc2 by binding the E-box motif (CANNTG) sequence recognized by Bmal1 in their promoters and indirectly regulates the basal and temporal regulation of Cd36 and Abca1/Abcg1 involving Rev-erbα and Znf202 repressors, respectively. In conclusion, Mφ Bmal1 is a key regulator of the uptake of modified lipoproteins, cholesterol efflux, lysosomal cholesterol egress, and atherosclerosis and, therefore, may be a master regulator of cholesterol metabolism in Mφs. Restoration of Mφ Bmal1 expression or blocking of factors that decrease its activity may be effective in preventing atherosclerosis.

OBJECTIVE:To determine whether administration of antenatal corticosteroids to patients with twin gestations at risk for late preterm delivery is associated with reduced risk for neonatal respiratory morbidity compared with unexposed twins. METHODS:This was a multicenter, retrospective cohort study in a large, urban health network (2013-2022) of patients with twin gestations at risk for preterm delivery between 34 0/7 and 36 6/7 weeks of gestation. Patients were excluded if they received antenatal corticosteroids before 34 weeks of gestation or had pregestational diabetes, single-twin death before 34 weeks, or oral steroid exposure during pregnancy. Neonates were excluded if they had major congenital anomalies. The primary outcome was a composite of neonatal respiratory morbidity requiring respiratory support within 72 hours of birth, including continuous positive airway pressure (CPAP) or high-flow nasal cannula for 2 hours or more, supplemental oxygen of 30% for 2 hours or more, extracorporeal membrane oxygenation, mechanical ventilation, and fetal or neonatal death. Secondary outcomes included neonatal hypoglycemia and indications for neonatal intensive care unit (NICU) admission. Adjusted and unadjusted relative risks with 95% CIs were calculated. RESULTS:During the study period, 366 twin gestations and 722 patient-neonate dyads were included: 162 gestations (321 neonates) in the exposed group and 204 (401 neonates) in the unexposed group. There was no difference in the composite outcome of respiratory morbidity in those exposed to antenatal corticosteroids (23.4% vs 20.4%, P=.40, adjusted relative risk [RR] 1.00, 95% CI, 0.71-1.42). The composite was driven mostly by rates of CPAP use (21.2% vs 18.5%, P=.41, adjusted RR 1.05, 95% CI, 0.73-1.53) and high-flow nasal cannula use (6.2% vs 2.2%, P=.02, RR 2.77, 95% CI, 1.16-6.66). Antenatal corticosteroid exposure was associated with a lower risk of need for supplemental oxygen (0.6% vs 3.5%, P=.02, RR 0.18, 95% CI, 0.04-0.79) and mechanical ventilation (0.6% vs 3.2%, P=.03, RR 0.19, 95% CI, 0.04-0.87). Although antenatal corticosteroids exposure was not associated with higher rates of hypoglycemia (44.2% vs 41.7%, P=.57, adjusted RR 0.99, 95% CI, 0.82-1.19), exposure was associated with a higher risk of having hypoglycemia as the only indication for NICU admission (10.3% vs 5.2%, P=.03, RR 1.96, 95% CI, 1.07-3.59). CONCLUSION/CONCLUSIONS:In a large, multicenter, network-wide retrospective cohort study of patients with twin gestations at risk for late preterm birth, antenatal corticosteroid use was not associated with a decrease in overall respiratory morbidity but was associated with a decreased risk of need for supplemental oxygen and mechanical ventilation, as well as a higher risk of NICU admission for hypoglycemia. These results underscore the ongoing need to elucidate the risks and benefits of late preterm antenatal corticosteroids for patients with twin gestations at risk for late preterm birth.

Serotonergic psychedelics and 3,4-methylendioxtmethamphetamine (MDMA) are promising treatments for mental disorders with a continuously evolving evidence base. We searched Pubmed/Scopus/clinical trial registries up to 08july2025 for double-blind randomized controlled trials (RCTs) testing MDMA or serotonergic psychedelics in patients with mental disorders. Primary outcomes were change in disease-specific symptoms and all-cause discontinuation. Standardized mean differences (SMD) and relative risk (RR) were estimated using random-effects meta-analysis. Risk of bias (RoB) was assessed with Cochrane's RoB-tool version 2 and certainty of evidence with GRADE. The review is maintained as living systematic review (https://ebipsyche-database.org/). We included 30 RCTs (1480 participants; female=45.8 %; with psychological support=83.3 %; high RoB=83.3 %). In post-traumatic stress disorder (PTSD), MDMA reduced PTSD symptoms compared to any control (k = 11; SMD=-0.85 [-1.09; -0.60]; I²=0 %; GRADE=low). In major depressive disorder (MDD), psilocybin/ayahuasca/LSD reduced depressive symptoms (k = 8; SMD=-0.62 [-0.97; -0.28]; I²=55 %; GRADE=very low). In anxiety disorders, both MDMA and serotonergic psychedelics reduced anxiety symptoms (SMD_MDMA=-1.18 [-2.04; -0.32]; I²=0 %; k = 2; GRADE=low and SMD_serotonergic=-0.88 [-1.70; -0.06]; I²=54 %;k = 5; GRADE=very low). In alcohol use disorder, neither psilocybin nor LSD reduced abstinence rates (k = 6; RR=1.42 [0.89; 2.26]; I²=7 %; GRADE=very low). In attention-deficit hyperactivity disorder (ADHD), LSD did not reduce ADHD symptoms (k = 1; SMD=0.22 [-0.32; 0.76]; GRADE=very low). Moderate certainty in evidence was only found for MDMA on PTSD symptoms when compared to placebo. MDMA/serotonergic psychedelics were not associated with higher risk of all-cause discontinuation (RR_MDMA=0.74 [0.32; 1.72]; RR_serotonergic=0.81 [0.56; 1.15]). Overall, MDMA/serotonergic psychedelics are promising for the treatment of PTSD, MDD, and anxiety disorders with moderate to large effect sizes. Pragmatic trials, long-term, head-to-head trials exploring the role of psychological support, aiming to identify predictors of response, and accounting for expectancy and functional unblinding are needed. Studies addressing these limitations will likely be required for regulatory approval of psychedelic drugs.