Creation and Expansion of a Mixed Patient Intermediate Care Unit to Improve ICU Capacity.

OBJECTIVES: ICU capacity strain is associated with worsened outcomes. Intermediate care units (IMCs) comprise one potential option to offload ICUs while providing appropriate care for intermediate acuity patients, but their impact on ICU capacity has not been thoroughly characterized. The aims of this study are to describe the creation of a medical-surgical IMC and assess how the IMC affected ICU capacity. DESIGN: Descriptive report with retrospective cohort review. SETTING: Six hundred seventy-three-bed tertiary care academic medical center with 77 ICU beds. PATIENTS: Adult inpatients who were admitted to the IMC. INTERVENTIONS: An interdisciplinary working group created an IMC which was located on a general ward. The IMC was staffed by hospitalists and surgeons and supported by critical care consultants. The initial maximum census was three, but this number increased to six in response to heightened critical care demand. IMC admission criteria also expanded to include advanced noninvasive respiratory support defined as patients requiring high-flow nasal cannula, noninvasive positive pressure ventilation, or mechanical ventilation in patients with tracheostomies. MEASUREMENTS AND MAIN RESULTS: The primary outcome entailed the number of ICU bed-days saved. Adverse outcomes, including ICU transfer, intubation, and death, were also recorded. From August 2021 to July 2022, 230 patients were admitted to the IMC. The most frequent IMC indications were respiratory support for medical patients and post-operative care for surgical patients. A total of 1023 ICU bed-days were made available. Most patients were discharged from the IMC to a general ward, while 8% of all patients required transfer to an ICU within 48 hours of admission. Intubation (2%) and death (1%) occurred infrequently within 48 hours of admission. Respiratory support was the indication associated with the most ICU transfers. CONCLUSIONS: Despite a modest daily census, an IMC generated substantial ICU bed capacity during a time of peak critical care demand.

"A Lot to Offer": Nurses as Educators for Medical Residents in an Academic Medical Center Intensive Care Unit.

INTRODUCTION: The role of fully trained interprofessional clinicians in educating residents has not been rigorously explored. The intensive care unit (ICU), where multiprofessional teamwork is essential to patient care, represents an ideal training environment in which to study this role. This study aimed to describe the practices, perceptions, and attitudes of ICU nurses regarding teaching medical residents and to identify potential targets to facilitate nurse teaching. METHODS: Using a concurrent mixed-methods approach, we administered surveys and focus groups to ICU nurses from September to November 2019 at a single, urban, tertiary, academic medical center. Survey data were analyzed with descriptive and comparative statistics. Focus group data were analyzed using the Framework method of content analysis. RESULTS: Of nurses surveyed, 75 of 96 (78%) responded. Nurses generally held positive attitudes about teaching residents, describing it as both important (52%, 36/69) and enjoyable (64%, 44/69). Nurses reported confidence in both clinical knowledge base (80%, 55/69) and teaching skills (71%, 49/69), but identified time, uncertainty about teaching topics, and trainee receptiveness as potential barriers. Ten nurses participated in focus groups. Qualitative analysis revealed three major themes: nurse-specific factors that impact teaching, the teaching environment, and facilitators of teaching. DISCUSSION: ICU nurses carry positive attitudes about teaching residents, particularly when facilitated by the attending, but this enthusiasm can be attenuated by the learning environment, unknown learner needs, and trainee attitudes. Identified facilitators of nurse teaching, including resident presence at the bedside and structured opportunities for teaching, represent potential targets for interventions to promote interprofessional teaching.

Subtly altered topological asymmetry of brain structural covariance networks in autism spectrum disorder across 43 datasets from the ENIGMA consortium.

Small average differences in the left-right asymmetry of cerebral cortical thickness have been reported in individuals with autism spectrum disorder (ASD) compared to typically developing controls, affecting widespread cortical regions. The possible impacts of these regional alterations in terms of structural network effects have not previously been characterized. Inter-regional morphological covariance analysis can capture network connectivity between different cortical areas at the macroscale level. Here, we used cortical thickness data from 1455 individuals with ASD and 1560 controls, across 43 independent datasets of the ENIGMA consortium's ASD Working Group, to assess hemispheric asymmetries of intra-individual structural covariance networks, using graph theory-based topological metrics. Compared with typical features of small-world architecture in controls, the ASD sample showed significantly altered average asymmetry of networks involving the fusiform, rostral middle frontal, and medial orbitofrontal cortex, involving higher randomization of the corresponding right-hemispheric networks in ASD. A network involving the superior frontal cortex showed decreased right-hemisphere randomization. Based on comparisons with meta-analyzed functional neuroimaging data, the altered connectivity asymmetry particularly affected networks that subserve executive functions, language-related and sensorimotor processes. These findings provide a network-level characterization of altered left-right brain asymmetry in ASD, based on a large combined sample. Altered asymmetrical brain development in ASD may be partly propagated among spatially distant regions through structural connectivity.

Consortium neuroscience of attention deficit/hyperactivity disorder and autism spectrum disorder: The ENIGMA adventure.

Neuroimaging has been extensively used to study brain structure and function in individuals with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) over the past decades. Two of the main shortcomings of the neuroimaging literature of these disorders are the small sample sizes employed and the heterogeneity of methods used. In 2013 and 2014, the ENIGMA-ADHD and ENIGMA-ASD working groups were respectively, founded with a common goal to address these limitations. Here, we provide a narrative review of the thus far completed and still ongoing projects of these working groups. Due to an implicitly hierarchical psychiatric diagnostic classification system, the fields of ADHD and ASD have developed largely in isolation, despite the considerable overlap in the occurrence of the disorders. The collaboration between the ENIGMA-ADHD and -ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together. The outcomes of case-control studies of subcortical and cortical structures showed that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case-control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow-up analyses continue that include more imaging modalities (diffusion MRI and resting-state functional MRI), collaborations with other large databases, and samples with dual diagnoses.

NRXN1α+/- is associated with increased excitability in ASD iPSC-derived neurons.

BACKGROUND: NRXN1 deletions are identified as one of major rare risk factors for autism spectrum disorder (ASD) and other neurodevelopmental disorders. ASD has 30% co-morbidity with epilepsy, and the latter is associated with excessive neuronal firing. NRXN1 encodes hundreds of presynaptic neuro-adhesion proteins categorized as NRXN1α/ß/γ. Previous studies on cultured cells show that the short NRXN1ß primarily exerts excitation effect, whereas the long NRXN1α which is more commonly deleted in patients involves in both excitation and inhibition. However, patient-derived models are essential for understanding functional consequences of NRXN1α deletions in human neurons. We recently derived induced pluripotent stem cells (iPSCs) from five controls and three ASD patients carrying NRXN1α+/- and showed increased calcium transients in patient neurons. METHODS: In this study we investigated the electrophysiological properties of iPSC-derived cortical neurons in control and ASD patients carrying NRXN1α+/- using patch clamping. Whole genome RNA sequencing was carried out to further understand the potential underlying molecular mechanism. RESULTS: NRXN1α+/- cortical neurons were shown to display larger sodium currents, higher AP amplitude and accelerated depolarization time. RNASeq analyses revealed transcriptomic changes with significant upregulation glutamatergic synapse and ion channels/transporter activity including voltage-gated potassium channels (GRIN1, GRIN3B, SLC17A6, CACNG3, CACNA1A, SHANK1), which are likely to couple with the increased excitability in NRXN1α+/- cortical neurons. CONCLUSIONS: Together with recent evidence of increased calcium transients, our results showed that human NRXN1α+/- isoform deletions altered neuronal excitability and non-synaptic function, and NRXN1α+/- patient iPSCs may be used as an ASD model for therapeutic development with calcium transients and excitability as readouts.

Supporting Frontline Staff During the COVID-19 Pandemic.

ABSTRACT: The coronavirus disease 2019 (COVID-19) pandemic that emerged in early 2020 put unprecedented physical, mental, and emotional strain on the staff of health care organizations, who have been caring for a critically ill patient population for more than a year and a half. Amid the ongoing pandemic, health care workers have struggled to keep up with new information about the disease, while also coping with the anxiety associated with caring for affected patients. It has also been a continual challenge for nurse leaders to provide adequate support for staff members and keep them informed about frequently changing practices and protocols. In this article, nursing leaders at an academic medical center in Boston reflect on the initial COVID-19 patient surge, which occurred from March to June 2020, and identify key actions taken to provide clinical and emotional support to frontline staff who cared for these patients. Lessons learned in this period provide insight into the management of redeployed staff, use of emotional support and debriefing, and relationship between access to information and staff morale. The knowledge gained through these initial experiences has been a vital resource as health care workers continue to face challenges associated with the ongoing pandemic.

Parental stress and adjustment in the context of rare genetic syndromes: A scoping review.

Chromosomal abnormalities are now considered a common cause of intellectual disability. With increased genetic testing, phenotyping and technological advancements, many new syndromes have been identified. This review sought to explore parental stress and adjustment in the context of rare genetic syndromes to evaluate their clinical impact. A systematic review of English peer-reviewed literature across three databases (PsycINFO, Medline, CINAHL) was completed and 69 articles were included. Parents of children with rare genetic syndromes experienced greater distress relative to other disabilities. Differences in parental wellbeing were syndrome-specific relative to ASD thus demonstrating the need to consider the contribution of syndrome-specific phenotypes. Child emotional and behavioural difficulties were the most consistent predictor of parental distress. Research reflecting other factors such as physical health, syndrome-specific behaviours, benefit finding and, parental appraisal in the context of a rare genetic aetiology is required in order to support parental adjustment in these conditions.

'More than a box of puzzles': Understanding the parental experience of having a child with a rare genetic condition".

BACKGROUND: Chromosomal microarray (CMA) testing has been adopted as the first-tier diagnostic test for developmental disabilities. However, determining the clinical significance of the results is often complex. This qualitative study seeks to explore parental interpretation, adaption and coping in the context of ambiguous rare genetic findings in order to support parental adjustment and wellbeing. METHODS: In-depth interviews were conducted with parents (n = 30) of children identified with a rare genetic chromosomal abnormality. RESULTS: Three major themes were identified following a thematic analysis: 'Learning of the Genetic Diagnosis', "The Reality of the Rarity' and 'Beyond Genetics: The Child Takes Centre Stage'. Findings demonstrated that parental adjustment to their child's genetic results are mediated by several factors including child difficulties and stage of development, clinician communication, perception of genetics, intrinsic coping strategies, access to practical and emotional support as well as broader contextual experiences. CONCLUSION: This study highlights the importance of considering the parental perspective in the context of genetic testing in clinical practice.

Derivation of iPSC lines from two patients with autism spectrum disorder carrying NRXN1α deletion (NUIGi041-A, NUIG041-B; NUIGi045-A) and one sibling control (NUIGi042-A, NUIGi042-B).

NRXN1 encodes thousands of splicing variants categorized into long NRXN1α, short NRXN1ß and extremely short NRXN1γ, which exert differential roles in neuronal excitation/inhibition. NRXN1α deletions are common in autism spectrum disorder (ASD) and other neurodevelopmental/neuropsychiatric disorders. We derived induced pluripotent stem cells (iPSCs) from one sibling control and two ASD probands carrying NRXN1α+/-, using non-integrating Sendai viral method. All iPSCs highly expressed pluripotency markers and could be differentiated into ectodermal/mesodermal/endodermal cells. The genotype and karyotype of the iPSCs were validated by whole genome SNP array. The availability of the iPSCs offers an opportunity for understanding NRXN1α function in human neurons and in ASD.

The clinical relevance of intragenic NRXN1 deletions.

BACKGROUND: Intragenic NRXN1 deletions are susceptibility variants for neurodevelopmental disorders; however, their clinical interpretation is often unclear. Therefore, a literature study and an analysis of 43 previously unpublished deletions are provided. METHODS: The literature cohort covered 629 heterozygous NRXN1 deletions: 148 in controls, 341 in probands and 140 in carrier relatives, and was used for clinical hypothesis testing. Exact breakpoint determination was performed for 43 in-house deletions. RESULTS: The prevalence of exonic NRXN1 deletions in controls was ~1/3000 as compared with ~1/800 in patients with neurodevelopmental/neuropsychiatric disorders. The differential distribution of deletions across the gene between controls and probands allowed to distinguish distinct areas within the gene. Exon 6-24 deletions appeared only twice in over 100000 control individuals, had an estimated penetrance for neurodevelopmental disorders of 32.43%, a de novo rate of 50% and segregated mainly with intellectual disability (ID) and schizophrenia. In contrast, exon 1-5 deletions appeared in 20 control individuals, had an estimated penetrance of 12.59%, a de novo rate of 32.5% and were reported with a broad range of neurodevelopmental phenotypes. Exact breakpoint determination revealed six recurrent intron 5 deletions. CONCLUSION: Exon 6-24 deletions have a high penetrance and are mainly associated with ID and schizophrenia. In contrast, the actual contribution of exon 1-5 deletions to a neurodevelopmental/neuropsychiatric disorder in an individual patient and family remains very difficult to assess. To enhance the clinical interpretation, this study provides practical considerations for counselling and an interactive table for comparing a deletion of interest with the available literature data.

NRXN1 deletion syndrome; phenotypic and penetrance data from 34 families.

The spectrum of phenotypes associated with heterozygous deletions of neurexin-1 (NRXN1) is diverse and includes: autism spectrum disorder, attention deficit hyperactivity disorder, intellectual disability, seizures, schizophrenia, mood disorders and congenital malformations. Reduced penetrance and variable expressivity of deletions in this gene remain a challenge for genetic counselling. We clinically reviewed 67 NRXN1 deletions from 34 families to document the phenotype and determine odds ratio. Thirty-four probands (5 adults, 29 children (<16 years)) were initially identified from a cohort clinically referred for arrayCGH. A further 33 NRXN1 deletions (16 with established phenotype) from the families were identified following cascade screening. Speech and language delay was a consistent clinical presentation. Pedigree analysis of the inherited group revealed numerous untested relatives with a history of mental health and developmental issues, most notably in the NRXN1ß isoform patients. Our study highlights the complex nature of the NRXN1 phenotype in this population.

Widespread Disrupted White Matter Microstructure in Autism Spectrum Disorders.

Autism Spectrum Disorders (ASDs) are characterised by impaired social communication and restricted repetitive behaviours. Researchers posit that these core features may be underpinned by disrupted structural connectivity. A tract based spatial statistical analysis of diffusion MRI data was performed to investigate white matter organisation (an indication of structural connectivity) in a well-defined cohort of 45 ASD and 45 age and IQ matched control participants. Aberrant structural connectivity characterised by reduced fractional anisotropy was observed in several fiber pathways in ASD relative to controls. Disrupted white matter organisation was associated with social deficits and restricted repetitive behaviours in ASD. Abnormal structural connectivity is apparent in ASD and may be linked to the core behavioural features of the disorder.

Increased Ca2+ signaling in NRXN1α+/- neurons derived from ASD induced pluripotent stem cells.

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a high co-morbidity of epilepsy and associated with hundreds of rare risk factors. NRXN1 deletion is among the commonest rare genetic factors shared by ASD, schizophrenia, intellectual disability, epilepsy, and developmental delay. However, how NRXN1 deletions lead to different clinical symptoms is unknown. Patient-derived cells are essential to investigate the functional consequences of NRXN1 lesions to human neurons in different diseases. Methods: Skin biopsies were donated by five healthy donors and three ASD patients carrying NRXN1α+/- deletions. Seven control and six NRXN1α+/- iPSC lines were derived and differentiated into day 100 cortical excitatory neurons using dual SMAD inhibition. Calcium (Ca2+) imaging was performed using Fluo4-AM, and the properties of Ca2+ transients were compared between two groups of neurons. Transcriptome analysis was carried out to undercover molecular pathways associated with NRXN1α+/- neurons. Results: NRXN1α+/- neurons were found to display altered calcium dynamics, with significantly increased frequency, duration, and amplitude of Ca2+ transients. Whole genome RNA sequencing also revealed altered ion transport and transporter activity, with upregulated voltage-gated calcium channels as one of the most significant pathways in NRXN1α+/- neurons identified by STRING and GSEA analyses. Conclusions: This is the first report to show that human NRXN1α+/- neurons derived from ASD patients' iPSCs present novel phenotypes of upregulated VGCCs and increased Ca2+ transients, which may facilitate the development of drug screening assays for the treatment of ASD.

Progressive white matter impairment as a predictor of outcome in a cohort of opioid-dependent patient's post-detoxification.

White matter impairment is associated with opioid dependence. However, the specific neuropathology related to opioid dependence is still not fully understood. The main aims of this study were to: (1) assess the association between white matter impairment and duration of dependence; (2) examine whether this impairment correlates with treatment outcome measures in opioid-dependent patients post-detoxification. Fifty-eight opioid-dependent patients participated, 20 females and 38 males, across three groups: less than 10 years use (n = 18), 10-15 years use (n = 26) and 16-25+ years use (n = 14). Diffusion tensor imaging was used to assess white matter impairment; whole brain voxel-wise analysis of fractional anisotropy, mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) were performed by Tract-Based-Spatial-Statistics to pinpoint abnormalities in white matter. The longer the subjects were dependent on opioids, the more widespread and severely the white-matter integrity was disrupted. A general linear model was used to examine patients who relapsed compared to those who were abstinent at follow-up. No statistical difference was found between groups (p > 0.05). Partial correlations were performed to investigate the relationship between clinical outcome measures (physical health, psychological well being and quality of life and hope for the future) and white-matter microstructural differences. Significant correlations were found between AD in the posterior corona radiata (L) and MD in the superior longitudinal fasciculus and a clinical measure for HOPE at 9-month follow-up. Nevertheless, it must be noted that the calculation of numerous correlations raises the possibility of a type I error, namely; to incorrectly conclude the occurrence of a significant correlation. The ability to investigate the structure-clinical relationship may improve our understanding of the pathological abnormalities associated with opioid dependence and has promise for use in evaluating future therapeutic outcomes in this population.

Abnormal fronto-parietal white matter organisation in the superior longitudinal fasciculus branches in autism spectrum disorders.

Core features of autism spectrum disorder (ASD) may be underpinned by disrupted functional and structural neural connectivity. Abnormal fronto-parietal functional connectivity has been widely reported in the literature; this may be underpinned by disrupted microstructural organisation of white matter. The superior longitudinal fasciculus (SLF) is a major fronto-parietal white matter tract, the structure of which has been little studied in ASD. The fronto-parietal projections of this tract (SLF I, II and III) are thought to play an important role in a number of cognitive functions including attention and visuospatial processing. To date, the isolation of the fronto-parietal branches of the SLF has been hampered by limitations of traditional tractography approaches. Constrained spherical deconvolution (CSD)-based tractography is an advanced approach that allows valid isolation of the fronto-parietal branches of the SLF. Diffusion MRI data were acquired from 45 participants with ASD and 45 age- and IQ-matched controls. The SLF I, II and III branches were isolated using CSD-based tractography in ExploreDTI. Significantly greater fractional anisotropy (FA) was observed in the right SLF II relative to controls. The ASD group also showed greater linear diffusion coefficient in the left SLF I and the right SLF II. In the SLF II, the ASD group had significantly greater right lateralisation of FA in comparison with the control group. The clinical and functional implications of increased FA in white matter are poorly understood; however, it is possible that this increased white matter organisation in the SLF in ASD may contribute to relative processing advantages in the condition.

Enhancing studies of the connectome in autism using the autism brain imaging data exchange II.

The second iteration of the Autism Brain Imaging Data Exchange (ABIDE II) aims to enhance the scope of brain connectomics research in Autism Spectrum Disorder (ASD). Consistent with the initial ABIDE effort (ABIDE I), that released 1112 datasets in 2012, this new multisite open-data resource is an aggregate of resting state functional magnetic resonance imaging (MRI) and corresponding structural MRI and phenotypic datasets. ABIDE II includes datasets from an additional 487 individuals with ASD and 557 controls previously collected across 16 international institutions. The combination of ABIDE I and ABIDE II provides investigators with 2156 unique cross-sectional datasets allowing selection of samples for discovery and/or replication. This sample size can also facilitate the identification of neurobiological subgroups, as well as preliminary examinations of sex differences in ASD. Additionally, ABIDE II includes a range of psychiatric variables to inform our understanding of the neural correlates of co-occurring psychopathology; 284 diffusion imaging datasets are also included. It is anticipated that these enhancements will contribute to unraveling key sources of ASD heterogeneity.

Disrupted functional connectivity in dorsal and ventral attention networks during attention orienting in autism spectrum disorders.

BACKGROUND: Attention orienting is a cognitive process that facilitates the movement of attention focus from one location to another: this may be impaired in autism spectrum disorder (ASD). Dorsal and ventral attention networks (DAN and VAN) sub-serve the process of attention orienting. This study investigated the functional connectivity of attention orienting in these networks in ASD using the Posner Cueing Task. METHOD: Twenty-one adolescents with ASD and 21 age and IQ matched controls underwent functional magnetic resonance imaging. A psychophysical interaction (PPI) analysis was implemented to investigate task-dependent functional connectivity, measuring synchronicity of brain regions during the task. Regions of interest (ROI) were selected to explore functional connectivity in the DAN during cue-only conditions and in the VAN during invalid and valid trials. RESULTS: Behaviourally, the ASD and control groups performed the task in a similar manner. Functional MRI results indicated that the ASD and control groups activated similar brain regions. During invalid trials (VAN), the ASD group showed significant positive functional connectivity to multiple brain regions, whilst the control group demonstrated negative connectivity. During valid trials (VAN), the two groups also showed contrasting patterns of connectivity. In the cue-only conditions (DAN), the ASD group showed weaker functional connectivity. CONCLUSION: The DAN analysis suggests that the ASD group has weaker coherence between brain areas involved in goal-driven, endogenous attention control. The strong positive functional connectivity exhibited by the ASD group in the VAN during the invalid trials suggests that individuals with ASD may generate compensatory mechanisms to achieve neurotypical behaviour. These results support the theory of abnormal cortical connectivity in autism.

Social and monetary reward processing in autism spectrum disorders.

BACKGROUND: Social motivation theory suggests that deficits in social reward processing underlie social impairments in autism spectrum disorders (ASD). However, the extent to which abnormalities in reward processing generalize to other classes of stimuli remains unresolved. The aim of the current study was to examine if reward processing abnormalities in ASD are specific to social stimuli or can be generalized to other classes of reward. Additionally, we sought to examine the results in the light of behavioral impairments in ASD. METHODS: Participants performed adapted versions of the social and monetary incentive delay tasks. Data from 21 unmedicated right-handed male participants with ASD and 21 age- and IQ-matched controls were analyzed using a factorial design to examine the blood-oxygen-level-dependent (BOLD) response during the anticipation and receipt of both reward types. RESULTS: Behaviorally, the ASD group showed less of a reduction in reaction time (RT) for rewarded compared to unrewarded trials than the control group. In terms of the fMRI results, there were no significant group differences in reward circuitry during reward anticipation. During the receipt of rewards, there was a significant interaction between group and reward type in the left dorsal striatum (DS). The ASD group showed reduced activity in the DS compared to controls for social rewards but not monetary rewards and decreased activation for social rewards compared to monetary rewards. Controls showed no significant difference between the two reward types. Increased activation in the DS during social reward processing was associated with faster response times for rewarded trials, compared to unrewarded trials, in both groups. This is in line with behavioral results indicating that the ASD group showed less of a reduction in RT for rewarded compared to unrewarded trials. Additionally, de-activation to social rewards was associated with increased repetitive behavior in ASD. CONCLUSIONS: In line with social motivation theory, the ASD group showed reduced activation, compared to controls, during the receipt of social rewards in the DS. Groups did not differ significantly during the processing of monetary rewards. BOLD activation in the DS, during social reward processing, was associated with behavioral impairments in ASD.