Rett Syndrome: Crossing the Threshold to Clinical Translation

Lying at the intersection between neurobiology and epigenetics, Rett syndrome (RTT) has garnered intense interest in recent years, not only from a broad range of academic scientists, but also from the pharmaceutical and biotechnology industries. In addition to the critical need for treatments for this devastating disorder, optimism for developing RTT treatments derives from a unique convergence of factors, including a known monogenic cause, reversibility of symptoms in preclinical models, a strong clinical research infrastructure highlighted by an NIH-funded natural history study and well-established clinics with significant patient populations. Here, we review recent advances in understanding the biology of RTT, particularly promising preclinical findings, lessons from past clinical trials, and critical elements of trial design for rare disorders

Coastal connectivity and spatial subsidy from a microbial perspective

© 2016 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd. The transfer of organic material from one coastal environment to another can increase production in recipient habitats in a process known as spatial subsidy. Microorganisms drive the generation, transformation, and uptake of organic material in shallow coastal environments, but their significance in connecting coastal habitats through spatial subsidies has received limited attention. We address this by presenting a conceptual model of coastal connectivity that focuses on the flow of microbially mediated organic material in key coastal habitats. Our model suggests that it is not the difference in generation rates of organic material between coastal habitats but the amount of organic material assimilated into microbial biomass and respiration that determines the amount of material that can be exported from one coastal environment to another. Further, the flow of organic material across coastal habitats is sensitive to environmental change as this can alter microbial remineralization and respiration rates. Our model highlights microorganisms as an integral part of coastal connectivity and emphasizes the importance of including a microbial perspective in coastal connectivity studies

New Strong Gravitational Lenses from the DESI Legacy Imaging Surveys Data Release 9

We have conducted a search for strong gravitational lensing systems in the Dark Energy Spectroscopic Instrument (DESI) Legacy Imaging Surveys Data Release 9. This is the third paper in a series (following Huang et al. 2020; Huang et al. 2021, Paper I & II, respectively). These surveys together cover $\sim$ 19,000 deg$^2$ visible from the northern hemisphere, reaching a z-band AB magnitude of $\sim$ 22.5. We use a deep residual neural network, trained on a compilation of known lensing systems and candidates as well as non-lenses in the same footprint. After applying our trained neural networks to the survey data, we visually inspect and rank images with probabilities above a threshold. We have found 1895 lens candidates. Out of these, 1512 are identified for the first time. Combining the discoveries from this work, Paper I (335) and II (1210), the total number of strong lens candidates from the Legacy Surveys that we have discovered is 3057.Comment: 19 pages, 10 figures, 4 tables. arXiv admin note: text overlap with arXiv:2005.0473

Convergent cerebrospinal fluid proteomes and metabolic ontologies in humans and animal models of Rett syndrome

MECP2 loss-of-function mutations cause Rett syndrome, a neurodevelopmental disorder resulting from a disrupted brain transcriptome. How these transcriptional defects are decoded into a disease proteome remains unknown. We studied the proteome of Rett cerebrospinal fluid (CSF) to identify consensus Rett proteome and ontologies shared across three species. Rett CSF proteomes enriched proteins annotated to HDL lipoproteins, complement, mitochondria, citrate/pyruvate metabolism, synapse compartments, and the neurosecretory protein VGF. We used shared Rett ontologies to select analytes for orthogonal quantification and functional validation. VGF and ontologically selected CSF proteins had genotypic discriminatory capacity as determined by receiver operating characteristic analysis in Mecp2(-/y) and Mecp2(−/+). Differentially expressed CSF proteins distinguished Rett from a related neurodevelopmental disorder, CDKL5 deficiency disorder. We propose that Mecp2 mutant CSF proteomes and ontologies inform putative mechanisms and biomarkers of disease. We suggest that Rett syndrome results from synapse and metabolism dysfunction

Three cases of oral hemangioma sclerosis

Hemangiomas or hamartomas are systemic proliferative vascular lesions that often occur in the oral cavity. The lesion usually presents a progressive growth, causing injuries and incontrollable bleeding. Its etiology is multifactorial, and it may occur at any age and there is no gender predilection. Differential diagnosis can involve many different pathologies, including neoplasms. Patients complaints are often related to esthetics. The size, type, and degree of tissue involvement of the hemangioma dictates the need of a specific treatment. The aim of this clinical case series is to present multiple oral hemangioma scenarios managed with sclerotherapy through monoethanolamine oleate at 0.05 g/ml. The diagnosis, treatment, clinical procedures and risks of hemangiomas should be relevant to dental practitioners due to the high prevalence of this type of oral lesion.peer-reviewe

CHA2DS2-VASc score predicts atrial fibrillation recurrence after cardioversion: systematic review and individual patient pooled meta-analysis

BackgroundDespite progresses in the treatment of the thromboembolic risk related to atrial fibrillation (AF), the management of recurrences remains a challenge.HypothesisTo assess if congestive heart failure or left ventricular systolic dysfunction (CHA2DS2‐VASc) score is predictive of early arrhythmia recurrence after AF cardioversion.MethodsSystematic review and individual patient pooled meta‐analysis following Preferred Reporting Items for Systematic reviews and Meta‐Analyses guidelines. Inclusion criteria: observational trials in patients with AF undergoing cardioversion, available data on recurrence of AF and available data on CHA2DS2‐VASc score. Clinical studies of interest were retrieved by PubMed, Cochrane Library, and Biomed Central. Seven authors were contacted for joining the patient level meta‐analysis, and three shared data regarding anthropometric measurements, risk factors, major comorbidities, and CHA2DS2‐VASc score. The primary outcome was the recurrence of AF after cardioversion in patients free from antiarrhythmic prophylaxis. Univariate and multivariate logistic regression was performed.ResultsOverall, we collect data of 2889 patients: 61% were male, 50% with hypertension, 12% with diabetes, and 23% with history of ischemic heart disease. The median CHA2DS2‐VASc score was 2.. At the multivariate analysis, chronic kidney disease (odds ratio [OR] 1.94; 95% confidence interval [CI] 1.12‐3.27; P = 0.01), peripheral artery disease (OR 1.65; 95% CI 1.23‐2.19; P P  2 (OR 1.37; 95% CI 1.1‐1.68; P = 0.002) were independent predictors of early recurrence of AF.ConclusionsCHA2DS2‐VASc score predicts early recurrence of AF in the first 30 days after electrical or pharmacological cardioversion.N

Risk Factors for Noninvasive Ventilation Failure in Children Post-Hematopoietic Cell Transplant

Rationale: Little is known on the use of noninvasive ventilation (NIPPV) in pediatric hematopoietic cell transplant (HCT) patients. Objective: We sought to describe the landscape of NIPPV use and to identify risk factors for failure to inform future investigation or quality improvement. Methods: This is a multicenter, retrospective observational cohort of 153 consecutive children post-HCT requiring NIPPV from 2010-2016. Results: 97 (63%) failed NIPPV. Factors associated with failure on univariate analysis included: longer oxygen use prior to NIPPV (p=0.04), vasoactive agent use (p40 at 4 hours [aOR=6.3 9(95% CI: 2.4, 16.4), p<0.001] and vasoactive use [aOR=4.9 (95% CI: 1.9, 13.1), p=0.001]. Of note, 11 patients had a cardiac arrest during intubation (11%) and 3 others arrested prior to intubation. These 14 patients were closer to HCT [14 days (IQR:4, 73) vs 54 (IQR:21,117), p<0.01] and there was a trend toward beginning NIPPV outside of the PICU and arrest during/prior to intubation (p=0.056). Conclusions: In this cohort respiratory rate at 4 hours and vasoactive use are independent risk factors of NIPPV failure. An objective model to predict which children may benefit from a trial of NIPPV, may also inform the timing of both NIPPV initiation and uncomplicated intubation

Exuberant fibroblast activity compromises lung function via ADAMTS4

© 2020, The Author(s), under exclusive licence to Springer Nature Limited. Severe respiratory infections can result in acute respiratory distress syndrome (ARDS)1. There are no effective pharmacological therapies that have been shown to improve outcomes for patients with ARDS. Although the host inflammatory response limits spread of and eventually clears the pathogen, immunopathology is a major contributor to tissue damage and ARDS1,2. Here we demonstrate that respiratory viral infection induces distinct fibroblast activation states, which we term extracellular matrix (ECM)-synthesizing, damage-responsive and interferon-responsive states. We provide evidence that excess activity of damage-responsive lung fibroblasts drives lethal immunopathology during severe influenza virus infection. By producing ECM-remodelling enzymes—in particular the ECM protease ADAMTS4—and inflammatory cytokines, damage-responsive fibroblasts modify the lung microenvironment to promote robust immune cell infiltration at the expense of lung function. In three cohorts of human participants, the levels of ADAMTS4 in the lower respiratory tract were associated with the severity of infection with seasonal or avian influenza virus. A therapeutic agent that targets the ECM protease activity of damage-responsive lung fibroblasts could provide a promising approach to preserving lung function and improving clinical outcomes following severe respiratory infections