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Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (>60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS-like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or DTRs). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype-phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population.

RATIONALE: Acute respiratory failure is a life-threatening clinical outcome in critically ill pediatric patients. In severe cases, patients can require mechanical ventilation (MV) for survival. Early recognition of these patients can potentially help clinicians alter the clinical course and lead to improved outcomes. OBJECTIVES: To build a data-driven model for early prediction of the need for mechanical ventilation in pediatric intensive care unit (PICU) patients. METHODS: The study consists of a single-center retrospective observational study on a cohort of 13,651 PICU patients admitted between 1/01/2010 and 5/15/2018 with a prevalence of 8.06% for MV due to respiratory failure. XGBoost (extreme gradient boosting) and a convolutional neural network (CNN) using medication history were used to develop a prediction model that could yield a time-varying risk-score-a continuous probability of whether a patient will receive MV-and an ideal global threshold was calculated from the receiver operating characteristics (ROC) curve. The early prediction point (EPP) was the first time the risk-score surpassed the optimal threshold, and the interval between the EPP and the start of the MV was the early warning period (EWT). Spectral clustering identified patient groups based on risk-score trajectories after EPP. RESULTS: A clinical and medication history-based model achieved a 0.89 area under the ROC curve (AUROC), 0.6 sensitivity, 0.95 specificity, 0.55 positive predictive value (PPV), and 0.95 negative predictive value (NPV). Early warning time (EWT) median [inter-quartile range] of this model was 9.9[4.2-69.2] hours. Clustering risk-score trajectories within a six-hour window after the early prediction point (EPP) established three patient groups, with the highest risk groups PPV being 0.92. CONCLUSIONS: This study uses a unique method to extract and apply medication history information, such as time-varying variables, to identify patients who may need mechanical ventilation for respiratory failure and provide an early warning period to avert it.

BackgroundThrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19.MethodsIn an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge.ResultsThe trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support-free days was 1 (interquartile range, -1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, -1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio

BackgroundThrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19.MethodsIn this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care-level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level.ResultsThe trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support-free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis.ConclusionsIn noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589, NCT04505774, NCT04359277, and NCT02735707.).

BackgroundThrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19.MethodsIn an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge.ResultsThe trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support-free days was 1 (interquartile range, -1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, -1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio

BackgroundThrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19.MethodsIn this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care-level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level.ResultsThe trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support-free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis.ConclusionsIn noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589, NCT04505774, NCT04359277, and NCT02735707.).

All aspects of medical education were affected by the COVID-19 pandemic. Several challenges were experienced by trainees and programs alike, including economic repercussions of the pandemic; social distancing affecting the delivery of medical education, testing, and interviewing; the surge of patients affecting redeployment of personnel and potential compromises in core training; and the overall impact on the wellness and mental health of trainees and educators. The ability of medical teams and researchers to peer review, conduct clinical research, and keep up with literature was similarly challenged by the rapid growth in peer-reviewed and preprint literature. This article reviews these challenges and shares strategies that institutions, educators, and learners adopted, adapted, and developed to provide quality education during these unprecedented times.

BackgroundPressure ulcers/injuries (PU/Is) negatively affect patients by causing pain and increasing morbidity and mortality risks. Care teams have a heightened sense of awareness of the condition and may feel confident in their ability to appropriately identify and manage PU/Is, but the potential for, and consequences of, a misdiagnosis always should be considered.PurposeThe purpose of this compendium is to describe and illustrate conditions that may mimic PU/Is.MethodsAdvanced practice wound care nurses were asked to identify and describe conditions that may mimic PU/Is. Permission was obtained from all patients to use their cases and photos in this article.ResultsSixteen (16) different skin and wound presentations resulting from vascular diseases, systemic infections, trauma, cancer, autoimmune disorders, coagulopathies, and multisystem organ dysfunction were identified and described.ConclusionA complete patient history and assessment will help prevent misidentification of the etiology of a skin lesion or wound and misdiagnosis of these lesions as PU/Is.

Heterochromatin spreading, the propagation of repressive chromatin along the chromosome, is a reaction critical to genome stability and defense, as well as maintenance of unique cell fates. Here, we discuss the intrinsic properties of the spreading reaction and circumstances under which its products, formed distal to DNA-encoded nucleation sites, can be epigenetically maintained. Finally, we speculate that the epigenetic properties of heterochromatin evolved together with the need to stabilize cellular identity.

Beta cell replacement has the potential to restore euglycemia in patients with insulin-dependent diabetes. Although great progress has been made in establishing allogeneic islet transplantation from deceased donors as the standard of care for those with the most labile diabetes, it is also clear that the deceased donor organ supply cannot possibly treat all those who could benefit from restoration of a normal beta cell mass, especially if immunosuppression were not required. Against this background, the International Pancreas and Islet Transplant Association in collaboration with the Harvard Stem Cell Institute, the Juvenile Diabetes Research Foundation (JDRF), and the Helmsley Foundation held a 2-day Key Opinion Leaders Meeting in Boston in 2016 to bring together experts in generating and transplanting beta cells derived from stem cells. The following summary highlights current technology, recent significant breakthroughs, unmet needs and roadblocks to stem cell-derived beta cell therapies, with the aim of spurring future preclinical collaborative investigations and progress toward the clinical application of stem cell-derived beta cells.

OBJECTIVE: To systematically review evidence regarding ataxia treatment. METHODS: A comprehensive systematic review was performed according to American Academy of Neurology methodology. CONCLUSIONS: For patients with episodic ataxia type 2, 4-aminopyridine 15 mg/d probably reduces ataxia attack frequency over 3 months (1 Class I study). For patients with ataxia of mixed etiology, riluzole probably improves ataxia signs at 8 weeks (1 Class I study). For patients with Friedreich ataxia or spinocerebellar ataxia (SCA), riluzole probably improves ataxia signs at 12 months (1 Class I study). For patients with SCA type 3, valproic acid 1,200 mg/d possibly improves ataxia at 12 weeks. For patients with spinocerebellar degeneration, thyrotropin-releasing hormone possibly improves some ataxia signs over 10 to 14 days (1 Class II study). For patients with SCA type 3 who are ambulatory, lithium probably does not improve signs of ataxia over 48 weeks (1 Class I study). For patients with Friedreich ataxia, deferiprone possibly worsens ataxia signs over 6 months (1 Class II study). Data are insufficient to support or refute the use of numerous agents. For nonpharmacologic options, in patients with degenerative ataxias, 4-week inpatient rehabilitation probably improves ataxia and function (1 Class I study); transcranial magnetic stimulation possibly improves cerebellar motor signs at 21 days (1 Class II study). For patients with multiple sclerosis-associated ataxia, the addition of pressure splints possibly has no additional benefit compared with neuromuscular rehabilitation alone (1 Class II study). Data are insufficient to support or refute use of stochastic whole-body vibration therapy (1 Class III study).

Gyrification is a fundamental property of the human cortex that is increasingly studied by basic and clinical neuroscience. However, it remains unclear if and how the global architecture of cortical folding varies with 3 interwoven sources of anatomical variation: brain size, sex, and sex chromosome dosage (SCD). Here, for 375 individuals spanning 7 karyotype groups (XX, XY, XXX, XYY, XXY, XXYY, XXXXY), we use structural neuroimaging to measure a global sulcation index (SI, total sulcal/cortical hull area) and both determinants of sulcal area: total sulcal length and mean sulcal depth. We detail large and patterned effects of sex and SCD across all folding metrics, but show that these effects are in fact largely consistent with the normative scaling of cortical folding in health: larger human brains have disproportionately high SI due to a relative expansion of sulcal area versus hull area, which arises because disproportionate sulcal lengthening overcomes a lack of proportionate sulcal deepening. Accounting for these normative allometries reveals 1) brain size-independent sulcal lengthening in males versus females, and 2) insensitivity of overall folding architecture to SCD. Our methodology and findings provide a novel context for future studies of human cortical folding in health and disease.

The cerebellum is a large hindbrain structure that is increasingly recognized for its contribution to diverse domains of cognitive and affective processing in human health and disease. Although several of these domains are sex biased, our fundamental understanding of cerebellar sex differences-including their spatial distribution, potential biological determinants, and independence from brain volume variation-lags far behind that for the cerebrum. Here, we harness automated neuroimaging methods for cerebellar morphometrics in 417 individuals to (1) localize normative male-female differences in raw cerebellar volume, (2) compare these to sex chromosome effects estimated across five rare sex (X/Y) chromosome aneuploidy (SCA) syndromes, and (3) clarify brain size-independent effects of sex and SCA on cerebellar anatomy using a generalizable allometric approach that considers scaling relationships between regional cerebellar volume and brain volume in health. The integration of these approaches shows that (1) sex and SCA effects on raw cerebellar volume are large and distributed, but regionally heterogeneous, (2) human cerebellar volume scales with brain volume in a highly nonlinear and regionally heterogeneous fashion that departs from documented patterns of cerebellar scaling in phylogeny, and (3) cerebellar organization is modified in a brain size-independent manner by sex (relative expansion of total cerebellum, flocculus, and Crus II-lobule VIIIB volumes in males) and SCA (contraction of total cerebellar, lobule IV, and Crus I volumes with additional X- or Y-chromosomes; X-specific contraction of Crus II-lobule VIIIB). Our methods and results clarify the shifts in human cerebellar organization that accompany interwoven variations in sex, sex chromosome complement, and brain size.SIGNIFICANCE STATEMENT Cerebellar systems are implicated in diverse domains of sex-biased behavior and pathology, but we lack a basic understanding of how sex differences in the human cerebellum are distributed and determined. We leverage a rare neuroimaging dataset to deconvolve the interwoven effects of sex, sex chromosome complement, and brain size on human cerebellar organization. We reveal topographically variegated scaling relationships between regional cerebellar volume and brain size in humans, which (1) are distinct from those observed in phylogeny, (2) invalidate a traditional neuroimaging method for brain volume correction, and (3) allow more valid and accurate resolution of which cerebellar subcomponents are sensitive to sex and sex chromosome complement. These findings advance understanding of cerebellar organization in health and sex chromosome aneuploidy.

Structural magnetic resonance imaging (MRI) scans at high spatial resolution can detect potential foci of early brain dysmaturation in children with autism spectrum disorders (ASD). In addition, comparison between MRI and behavior measures over time can identify patterns of brain change accompanying specific outcomes. We report structural MRI data from two time points for a total of 84 scans in children with ASD and 30 scans in typical controls (mean age time one = 4.1 years, mean age at time two = 6.6 years). Surface-based cortical morphometry and linear mixed effects models were used to link changes in cortical anatomy to both diagnostic status and individual differences in changes in language and autism severity. Compared with controls, children with ASD showed accelerated gray matter volume gain with age, which was driven by a lack of typical age-related cortical thickness (CT) decrease within 10 cortical regions involved in language, social cognition, and behavioral control. Greater expressive communication gains with age in children with ASD were associated with greater CT gains in a set of right hemisphere homologues to dominant language cortices, potentially identifying a compensatory system for closer translational study. Hum Brain Mapp 37:2616-2629, 2016. © 2016 Wiley Periodicals, Inc.

BackgroundMucopolysaccharidosis VII (MPS VII) is an ultra-rare disease characterised by the deficiency of β-glucuronidase (GUS). Patients' phenotypes vary from severe forms with hydrops fetalis, skeletal dysplasia and mental retardation to milder forms with fewer manifestations and mild skeletal abnormalities. Accurate assessments on the frequency and clinical characteristics of the disease have been scarce. The aim of this study was to collect such data.MethodsWe have conducted a survey of physicians to document the medical history of patients with MPS VII. The survey included anonymous information on patient demographics, family history, mode of diagnosis, age of onset, signs and symptoms, severity, management, clinical features and natural progression of the disease.ResultsWe collected information on 56 patients from 11 countries. Patients with MPS VII were classified based on their phenotype into three different groups: (1) neonatal non-immune hydrops fetalis (NIHF) (n=10), (2) Infantile or adolescent form with history of hydrops fetalis (n=13) and (3) Infantile or adolescent form without known hydrops fetalis (n=33). Thirteen patients with MPS VII who had the infantile form with history of hydrops fetalis and survived childhood, had a wide range of clinical manifestations from mild to severe. Five patients underwent bone marrow transplantation and one patient underwent enzyme replacement therapy with recombinant human GUS.ConclusionsMPS VII is a pan-ethnic inherited lysosomal storage disease with considerable phenotypical heterogeneity. Most patients have short stature, skeletal dysplasia, hepatosplenomegaly, hernias, cardiac involvement, pulmonary insufficiency and cognitive impairment. In these respects it resembles MPS I and MPS II. In MPS VII, however, one unique and distinguishing clinical feature is the unexpectedly high proportion of patients (41%) that had a history of NIHF. Presence of NIHF does not, by itself, predict the eventual severity of the clinical course, if the patient survives infancy.

Owing to their unique evolutionary history, modern mammalian X- and Y-chromosomes have highly divergent gene contents counterbalanced by regulatory features, which preferentially restrict expression of X- and Y-specific genes. These 2 characteristics make opposing predictions regarding the expected dissimilarity of X- vs. Y-chromosome influences on biological structure and function. Here, we quantify this dissimilarity using in vivo neuroimaging within a rare cohort of humans with diverse sex chromosome aneuploidies (SCAs). We show that X- and Y-chromosomes have opposing effects on overall brain size but exert highly convergent influences on local brain anatomy, which manifest across biologically distinct dimensions of the cerebral cortex. Large-scale online meta-analysis of functional neuroimaging data indicates that convergent sex chromosome dosage effects preferentially impact centers for social perception, communication, and decision-making. Thus, despite an almost complete lack of sequence homology, and opposing effects on overall brain size, X- and Y-chromosomes exert congruent effects on the proportional size of cortical systems involved in adaptive social functioning. These convergent X-Y effects (i) track the dosage of those few genes that are still shared by X- and Y-chromosomes, and (ii) may provide a biological substrate for the link between SCA and increased rates of psychopathology.