Citations

ABSTRACT Brain lesions classically cause contralateral sensorimotor and postural deficits, attributed to the decussation of descending neural pathways. However, recent findings reveal that, beyond neural mechanisms, contralateral effects can also be mediated by the neuroendocrine system via humoral pathways. This raises the possibility that the brain regulates left- and right-sided peripheral processes through hypothalamic neurohormones released into the bloodstream. For such spatially targeted endocrine signaling to occur, hemisphere-specific neural activity must be encoded into side-specific hormonal output—requiring a lateralized organization of hypothalamic neuroendocrine systems. Here, we report molecular asymmetries in the rat hypothalamus that support this mechanism. Transcriptomic analysis revealed asymmetric expression of eleven neurohormonal genes, including Gnrh1 , Cck , and Trh , along with distinct left-right side-specific gene co-expression networks. Chemogenetic stimulation of Arg-vasopressin neurons in vasopressin-hM3Dq-mCherry transgenic rats produced generalized changes in these networks—predominantly in the right hypothalamus—suggesting that hypothalamic neurohormonal circuits function as integrated, lateralized ensembles. Stereological analysis revealed asymmetric coordination of vasopressin neurons within the paraventricular nucleus, with the left rostral region decoupled from the right rostral and caudal subregions. Functionally, gonadotropin-releasing hormone, cholecystokinin-8, and thyrotropin-releasing hormone—administered intracisternally in rats with complete spinal cord transection—elicited side-specific peripheral responses, measured as hindlimb postural asymmetry in a binary left–right output model. These neurohormonal effects were therefore transmitted via the humoral route. These findings suggest that multiple hypothalamic neurohormones and their integrated networks are asymmetrically organized, and that their lateralization may be necessary for hemisphere-specific hormonal regulation of peripheral systems.

ABSTRACT The objective of this study is to describe outcomes of rapid exome (rES) and rapid genome sequencing (rGS) in an inpatient setting. This is a retrospective cohort of inpatients with rES or rGS during their hospitalization between April 2016 and November 2023. Medical records were reviewed to measure primary outcomes: diagnostic yield, medical management changes, and anticipatory guidance updates. Descriptive analysis and formal comparisons (Welch's t ‐test with post hoc power analysis, Fischer's exact test) were performed, with rES and rGS comparisons limited to 2023 due to test distribution. Of 95 patients, most (74.7% [71/95]) were < 12 months old and admitted in neonatal (44.2% [42/95]) or pediatric (29.5% [28/95]) intensive care units. Common indications for rapid sequencing included multiple congenital anomalies (24.2% [23/95]), neurological concerns (23.3% [22/95]), and acute illness (16.8% [16/95]). Mean turnaround time of testing significantly shortened for rES from 2021 (13.2 [SD = 5.9] days) to 2023 (8.1 [SD = 4.1] days) ( p ‐value = 0.018; power = 0.74). Diagnostic yield was 29.5% (28/95) and did not significantly differ between rES (13.6% [3/22]) and rGS (35.0% [7/20]) ( p ‐value = 0.15). Sequencing led to medical management changes (86.0% [74/86]) and anticipatory guidance updates (41.4% [39/95]) with similar rates observed in diagnostic and non‐diagnostic tests. Our findings suggest rES or rGS implementation may influence diagnosis and care strategies in critically ill patients.

Background Vocal cord dysfunction (VCD) is an underrecognized differential diagnosis for asthma and is often influenced by psychological factors. The COVID-19 pandemic introduced new stressors and disrupted access to pediatric care, potentially affecting VCD incidence and recognition. Objectives This study aimed to determine whether the incidence of pediatric VCD at Nemours Children's Hospital in Orlando changed during the COVID-19 pandemic and to identify psychological diagnoses most associated with VCD. Methods A retrospective chart review was conducted for patients diagnosed with VCD between January 2017 and July 2022, including 2.5 years before and 2.5 years during the pandemic. Demographics, diagnostic methods, triggers, comorbidities, and psychological conditions were extracted from the electronic medical record. Results Among 74,022 patients (45,199 pre-pandemic; 28,823 pandemic), VCD incidence significantly decreased during the pandemic (0.7% vs. 0.3%, p &lt; 0.001). Psychological diagnoses also declined modestly: anxiety (2.6% vs. 2.0%), depression (0.3% vs. 0.2%), and ADHD (4.4% vs. 3.5%). Compared with non-VCD patients, those with VCD were older (median 14 vs. 9 years), predominantly female (71% vs. 47%), and more often White/non-Hispanic. They had higher rates of asthma (41% vs. 16%), allergic rhinitis (20% vs. 11%), gastroesophageal reflux (31% vs. 4%), and psychological conditions, including anxiety (8.5% vs. 2.3%), depression (1.5% vs. 0.2%), and panic attacks (0.8% vs. 0.1%). Conclusions In contrast to prior reports, VCD incidence declined during the pandemic, likely reflecting reduced healthcare access or underdiagnosis. Persistent associations with psychological conditions highlight the biopsychosocial nature of VCD and the importance of multidisciplinary evaluation in pediatric populations.

T cell fitness has emerged as a critical determinant of the efficacy and persistence of Chimeric Antigen Receptor (CAR)-T cell therapy. Defined by the capacity of T cells to proliferate, resist exhaustion, persist in vivo , and exert sustained effector functions, T cell fitness reflects the integration of a dynamic network of intrinsic and extrinsic regulatory mechanisms. In this review, we present a comprehensive synthesis of the molecular and cellular foundations underlying T cell fitness, emphasizing the influence of differentiation trajectories, signaling pathways, metabolic reprogramming, and epigenetic modifications. We further discuss the impact of patient-specific conditions such as age as well as disease biology, prior therapeutic exposures, and timing and quality of T cell collection, on the phenotypic and functional efficacy of CAR-T cell products. Beyond delineating these determinants, we highlight emerging strategies aimed at enhancing T cell fitness. Importantly, we propose T cell fitness as an integrated, multi-layered systems property emerging from the interaction between differentiation state, signaling architecture, metabolic–mitochondrial competence, epigenetic stability, and host-specific inflammatory and treatment-related pressures. We introduce a mechanistic framework that links these layers across the CAR-T therapeutic timeline from leukapheresis to post-infusion tumor engagement and outline how this framework can be operationalized into measurable parameters to guide patient stratification, manufacturing decisions, and rational therapeutic interventions.

Background: Postoperative emergency department (ED) utilization significantly reduces patient satisfaction and increases health care spending. Purpose: To identify the incidence, risk factors, and reasons for ED visits within 90 days of Achilles tendon repair (ATR). Study Design: Case-control study; Level of evidence, 3 Methods: This study utilized the PearlDiver database to identify all instances of primary ATR. Patient age, sex, Elixhauser comorbidity index (ECI), region, and insurance coverage were extracted. The incidence, timing, and primary diagnoses for those with an ED visit 90 days post-ATR were extracted. Also, the 90-day total cost was determined and compared for those with and without a postoperative ED visit. Welch t test and Pearson chi-square test were used to determine significant differences between groups. Multivariable logistic regressions were used to determine risk factors associated with ED utilization after ATR. Results: Of the 82,604 patients with an ATR identified in the database, 6939 (8.4%) had ≥1 ED visit. Of ED visits, 1506 (21.7%) occurred in the first week after ATR and 3587 (51.7%) occurred in the first 4 weeks after ATR. The mean 90-day cost for those with an ED visit was significantly greater than those without an ED visit ($7330 ± $13,383 vs $3515 ± $5787; P < .001). Independent risk factors associated with ED utilization within 90 days were younger age (odds ratio [OR], 1.02; P < .001), female sex (OR, 1.26; P < .001), higher ECI (OR, 1.17; P < .001), a history of tobacco use (OR, 1.57; P < .001), and having Medicaid insurance (OR, 1.73; P < .001). Most ED visits within the first 2 weeks after ATR were for surgical-site pain (53.6%), with 62.4% of diagnoses being directly related to the surgical site. After 2 weeks following ATR, pain persisted as the most common reason for ED utilization (20.9%). Conclusion: More than 8% of patients had ≥1 ED visit within 90 days of ATR, with over half occurring in the first 4 weeks. This markedly increased health care spending. Addressing regional disparities, improving Medicaid acceptance policies, and enhancing perioperative care plans, such as multimodal pain management and addressing the psychological aspects of pain, may reduce the incidence and economic burden of postoperative ED visits.

ABSTRACT Background Optimal management of direct oral anticoagulants (DOAC) prior to implantation of cardiac implantable electronic devices (CIED) remains controversial. Objective To determine whether a strategy of minimal interruption of DOAC before cardiac CIED implantation is associated with improved clinical outcomes compared to uninterrupted DOAC use. Methods The electronic clinical records of 310 patients who were on DOAC and underwent CIED implantation were evaluated. The patients were separated into 2 groups: patients in Group 1 had minimal DOAC interruption (DOAC held < 24 h before procedure), while patients in Group 2 continued DOAC before procedure. Resumption of DOAC in both groups was on the same day of the procedure or the next morning at the operator's discretion. Clinically significant pocket hematoma and thromboembolic events were compared. Results Among the 310 patients, 71 (22.9%) of them had DOAC held < 24 h before procedure, while DOAC was continued without interruption in 239 (77.1%) in the periprocedural period. Clinically significant pocket hematomas were found in 1 patient (1.4%) in the DOAC interrupted group and 24 (10.0%) in the DOAC continuous group ( p = 0.046). Low thromboembolic events were observed in both groups: 0 in the minimally interrupted group and 1 (0.4%) in the un‐interrupted group ( p > 0.05). Conclusion The bleeding risk in our cohort of patients who underwent CIED implantation with the uninterrupted DOAC approach is higher than previously reported in the literature. A minimally interrupted approach appears to mitigate this risk without significantly increasing the risk of thromboembolism.

Zinc Finger Protein 161 (ZFP161) is a key regulator of Ataxia Telangiectasia and Rad3-related (ATR) signaling, playing a crucial role in maintaining genomic stability. Human ZFP161 activates c-MYC , whereas its murine ortholog, ZF5, serves as a putative transcriptional repressor of c-MYC . In this study, we identified ZFP161 as a direct regulator of c-MYC. We show that ZFP161 binds to the promoter region of c-MYC , modulating its expression and downstream signaling pathways. Additionally, ZFP161 promotes cell proliferation and tumorigenesis through c-MYC regulation and contributes to the malignant transformation of non-cancerous retinal pigment epithelial (RPE-1) cells. Furthermore, high ZFP161 expression is associated with poor survival in patients with mixed colon adenocarcinoma. These findings suggest that the regulation of c-MYC by ZFP161 may represent a potential therapeutic target in c-MYC -driven cancers.

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