Advancing Mental Health Research Through Strategic Integration of Transdiagnostic Dimensions and Genomics.

Genome-wide studies are yielding a growing catalog of common and rare variants that confer risk for psychopathology. However, despite representing unprecedented progress, emerging data also indicate that the full promise of psychiatric genetics-including understanding pathophysiology and improving personalized care-will not be fully realized by targeting traditional dichotomous diagnostic categories. The current article provides reflections on themes that emerged from a 2021 National Institute of Mental Health-sponsored conference convened to address strategies for the evolving field of psychiatric genetics.

A genome-first study of sex chromosome aneuploidies provides evidence of Y chromosome dosage effects on autism risk.

A female protective effect has long been postulated as the primary explanation for the four-fold increase of autism spectrum disorder (ASD) diagnoses in males versus females. However, genetic and epidemiological investigations of this hypothesis have so far failed to explain the large difference in ASD prevalence between the sexes. To address this knowledge gap, we examined sex chromosome aneuploidy in a large ASD case-control cohort to evaluate the relationship between X and Y chromosome dosage and ASD risk.

Facilitating Repeat Intracarotid Injections in Mouse Models by a Novel Injection Site Repair Technique.

Given recent advances in the delivery of novel antitumor therapeutics using endovascular selective intraarterial delivery methods in neuro-oncology, there is an urgent need to develop methods for intracarotid injections in mouse models, including methods to repair the carotid artery in mice after injection to allow for subsequent injections. We developed a method of intracarotid injection in a mouse model to deliver therapeutics into the internal carotid artery (ICA) with two alternative procedures. During injection, the needle is inserted into the common carotid artery (CCA) after tying a suture around the external carotid artery (ECA) and injected therapeutics are delivered into the ICA.

Tumor treating fields suppress tumor cell growth and neurologic decline in models of spinal metastases.

Spinal metastases can result in severe neurologic compromise and decreased overall survival. Despite treatment advances, local disease progression is frequent, highlighting the need for novel therapies. Tumor treating fields (TTFields) impair tumor cell replication and are influenced by properties of surrounding tissue.

Prehospitalization Trauma and Physiologic Factors Associated with the Presence of Post-traumatic Stress 3 Months After PICU Discharge.

Background: Children admitted to the pediatric intensive care unit (PICU) have post-traumatic stress (PTS) rates up to 64%, and up to 28% of them meet criteria for PTS disorder (PTSD). We aim to examine whether a prior trauma history and increased physiologic parameters due to a heightened sympathetic response are associated with later PTS. Our hypothesis was children with history of prehospitalization trauma, higher heart rates, blood pressures, cortisol, and extrinsic catecholamine administration during PICU admission are more likely to have PTS after discharge.

Ventilator Weaning and Terminal Extubation: Withdrawal of Life-Sustaining Therapy in Children. Secondary Analysis of the Death One Hour After Terminal Extubation Study.

Objective: Terminal extubation (TE) and terminal weaning (TW) during withdrawal of life-sustaining therapies (WLSTs) have been described and defined in adults. The recent Death One Hour After Terminal Extubation study aimed to validate a model developed to predict whether a child would die within 1 hour after discontinuation of mechanical ventilation for WLST. Although TW has not been described in children, pre-extubation weaning has been known to occur before WLST, though to what extent is unknown.

Tumor-specific polycistronic miRNA delivered by engineered exosomes for the treatment of glioblastoma.

Background: Glioblastoma (GBM) has poor prognosis due to ineffective agents and poor delivery methods. MicroRNAs (miRs) have been explored as novel therapeutics for GBM, but the optimal miRs and the ideal delivery strategy remain unresolved. In this study, we sought to identify the most effective pan-subtype anti-GBM miRs and to develop an improved delivery system for these miRs.

A Novel Application of Spectrograms with Machine Learning Can Detect Patient Ventilator Dyssynchrony.

Patients in intensive care units are frequently supported by mechanical ventilation. There is increasing awareness of patient-ventilator dyssynchrony (PVD), a mismatch between patient respiratory effort and assistance provided by the ventilator, as a risk factor for infection, narcotic exposure, lung injury, and adverse neurocognitive effects. One of the most injurious consequences of PVD are double cycled (DC) breaths when two breaths are delivered by the ventilator instead of one.

Narrowing the gap: expected versus deployment performance.

Objectives: Successful model development requires both an accurate a priori understanding of future performance and high performance on deployment. Optimistic estimations of model performance that are unrealized in real-world clinical settings can contribute to nonuse of predictive models. This study used 2 tasks, predicting ICU mortality and Bi-Level Positive Airway Pressure failure, to quantify: (1) how well internal test performances derived from different methods of partitioning data into development and test sets estimate future deployment performance of Recurrent Neural Network models and (2) the effects of including older data in the training set on models' performance.

Analgesia and Sedation at Terminal Extubation: A Secondary Analysis From Death One Hour After Terminal Extubation Study Data.

Objectives: To describe the doses of opioids and benzodiazepines administered around the time of terminal extubation (TE) to children who died within 1 hour of TE and to identify their association with the time to death (TTD).

Design: Secondary analysis of data collected for the Death One Hour After Terminal Extubation study.

Setting: Nine U.

Association of Supernumerary Sex Chromosome Aneuploidies With Venous Thromboembolism.

Importance: An increased risk of venous thromboembolism (VTE) has been reported in men with an additional sex chromosome. The association between other sex chromosome aneuploidies and VTE is not well characterized.

Objective: To determine if sex chromosome aneuploidy is associated with VTE.

Phenotypic shift in copy number variants: Evidence in 16p11.2 duplication syndrome.

Purpose: Recurrent 16p11.2 duplications produce a wide range of clinical outcomes with varying effects on cognition and social functioning. Family-based studies of copy number variants (CNVs) have revealed significant contributions of genomic background on variable expressivity.

Prevalence and Penetrance of Rare Pathogenic Variants in Neurodevelopmental Psychiatric Genes in a Health Care System Population.

Objective: Autism, schizophrenia, and other clinically distinct neurodevelopmental psychiatric disorders (NPDs) have shared genetic etiologies, including single-gene and multigenic copy number variants (CNVs). Because rare variants are primarily investigated in clinical cohorts, population-based estimates of their prevalence and penetrance are lacking. The authors determined the prevalence, penetrance, and NPD risk of pathogenic single-gene variants in a large health care system population.

Predicting Time to Death After Withdrawal of Life-Sustaining Treatment in Children.

Unlabelled: Accurately predicting time to death after withdrawal of life-sustaining treatment is valuable for family counseling and for identifying candidates for organ donation after cardiac death. This topic has been well studied in adults, but literature is scant in pediatrics. The purpose of this report is to assess the performance and clinical utility of the available tools for predicting time to death after treatment withdrawal in children.

Frequency of truncating FLCN variants and Birt-Hogg-Dubé-associated phenotypes in a health care system population.

Purpose: Penetrance estimates of Birt-Hogg-Dubé syndrome (BHD)-associated cutaneous, pulmonary, and kidney manifestations are based on clinically ascertained families. In a health care system population, we used a genetics-first approach to estimate the prevalence of pathogenic/likely pathogenic (P/LP) truncating variants in FLCN, which cause BHD, and the penetrance of BHD-related phenotypes.

Methods: Exomes from 135,990 patient-participants in Geisinger's MyCode cohort were assessed for P/LP truncating FLCN variants.

Development of a deep learning model that predicts Bi-level positive airway pressure failure.

Delaying intubation for patients failing Bi-Level Positive Airway Pressure (BIPAP) may be associated with harm. The objective of this study was to develop a deep learning model capable of aiding clinical decision making by predicting Bi-Level Positive Airway Pressure (BIPAP) failure. This was a retrospective cohort study in a tertiary pediatric intensive care unit (PICU) between 2010 and 2020.

Predicting High Flow Nasal Cannula Failure in an Intensive Care Unit Using a Recurrent Neural Network With Transfer Learning and Input Data Perseveration: Retrospective Analysis.

Background: High flow nasal cannula (HFNC) provides noninvasive respiratory support for children who are critically ill who may tolerate it more readily than other noninvasive ventilation (NIV) techniques such as bilevel positive airway pressure and continuous positive airway pressure. Moreover, HFNC may preclude the need for mechanical ventilation (intubation). Nevertheless, NIV or intubation may ultimately be necessary for certain patients.

Genes To Mental Health (G2MH): A Framework to Map the Combined Effects of Rare and Common Variants on Dimensions of Cognition and Psychopathology.

Rare genomic disorders (RGDs) confer elevated risk for neurodevelopmental psychiatric disorders. In this era of intense genomics discoveries, the landscape of RGDs is rapidly evolving. However, there has not been comparable progress to date in scalable, harmonized phenotyping methods.

Medical manifestations and health care utilization among adult MyCode participants with neurodevelopmental psychiatric copy number variants.

Purpose: Recurrent pathogenic copy number variants (pCNVs) have large-effect impacts on brain function and represent important etiologies of neurodevelopmental psychiatric disorders (NPDs), including autism and schizophrenia. Patterns of health care utilization in adults with pCNVs have gone largely unstudied and are likely to differ in significant ways from those of children.

Methods: We compared the prevalence of NPDs and electronic health record-based medical conditions in 928 adults with 26 pCNVs to a demographically-matched cohort of pCNV-negative controls from >135,000 patient-participants in Geisinger's MyCode Community Health Initiative.