Showing papers by "Hospital for Sick Children published in 2019"
TL;DR: This guideline update is intended for all clinicians who diagnose or manage adult patients who present with sudden hearing loss and should improve diagnostic accuracy, facilitate prompt intervention, decrease variations in management, reduce unnecessary tests and imaging procedures, and improve hearing and rehabilitative outcomes for affected patients.
Abstract: ObjectiveSudden hearing loss is a frightening symptom that often prompts an urgent or emergent visit to a health care provider. It is frequently but not universally accompanied by tinnitus and/or v...
398 citations
VU University Amsterdam1, University of Leeds2, University of Duisburg-Essen3, University of Texas MD Anderson Cancer Center4, Semmelweis University5, Austrian Academy of Sciences6, Duke University7, Harvard University8, Broad Institute9, Case Western Reserve University10, Medical University of Vienna11, Northwestern University12, University of Liverpool13, University of Connecticut Health Center14, St James's University Hospital15, James Cancer Hospital16, Brigham and Women's Hospital17, Yale University18, Medical College of Wisconsin19, University of California, San Francisco20, German Cancer Research Center21, Erasmus University Rotterdam22, La Trobe University23, University of Melbourne24, National Institutes of Health25, Laval University26, Columbia University Medical Center27, University of Sydney28, Henry Ford Health System29, University of New South Wales30, Samsung Medical Center31, The Chinese University of Hong Kong32, University of Luxembourg33, University of Colorado Denver34, Seoul National University Hospital35, Columbia University36, University of Düsseldorf37, University Hospitals of Cleveland38, Hospital for Sick Children39, University of Tübingen40, Emory University41, University of Birmingham42, University of Zurich43, University Health Network44
TL;DR: The results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.
Abstract: The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear1,2. Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.
264 citations
Istituto Giannina Gaslini1, University Hospital of Lausanne2, National Institutes of Health3, University of Barcelona4, Hebrew University of Jerusalem5, University College London6, University of Siena7, Boston Children's Hospital8, Istanbul University9, University of California, San Diego10, Charité11, Hospital for Sick Children12, Sheba Medical Center13, Hacettepe University14, Radboud University Nijmegen15, Tel Aviv University16, University Medical Center Utrecht17
TL;DR: Eurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity and shows a high accuracy in an independent data set of 1018 patients.
Abstract: Background Different diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)—familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)—and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA. Methods Step 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients’ diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria. Results The panellists achieved consensus to classify 281 of 360 (78%) patients (32 CAPS, 36 FMF, 56 MKD, 37 PFAPA, 39 TRAPS, 81 undefined recurrent fever). Consensus was reached for two sets of criteria for each HRF, one including genetic and clinical variables, the other with clinical variables only, plus new criteria for PFAPA. The four HRF criteria demonstrated sensitivity of 0.94–1 and specificity of 0.95–1; for PFAPA, criteria sensitivity and specificity were 0.97 and 0.93, respectively. Validation of these criteria in an independent data set of 1018 patients shows a high accuracy (from 0.81 to 0.98). Conclusion Eurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity.
249 citations
TL;DR: A strong connection is demonstrated between phase separation, the process underlying the formation of many different types of cellular granules, and in vitro inhibition of translation, which is supportive of phase separation as a general mechanism controlling activity-dependent translation.
Abstract: Activity-dependent translation requires the transport of mRNAs within membraneless protein assemblies known as neuronal granules from the cell body toward synaptic regions. Translation of mRNA is inhibited in these granules during transport but quickly activated in response to neuronal stimuli at the synapse. This raises an important question: how does synaptic activity trigger translation of once-silenced mRNAs? Here, we demonstrate a strong connection between phase separation, the process underlying the formation of many different types of cellular granules, and in vitro inhibition of translation. By using the Fragile X Mental Retardation Protein (FMRP), an abundant neuronal granule component and translational repressor, we show that FMRP phase separates in vitro with RNA into liquid droplets mediated by its C-terminal low-complexity disordered region (i.e., FMRPLCR). FMRPLCR posttranslational modifications by phosphorylation and methylation have opposing effects on in vitro translational regulation, which corroborates well with their critical concentrations for phase separation. Our results, combined with bioinformatics evidence, are supportive of phase separation as a general mechanism controlling activity-dependent translation.
219 citations
TL;DR: The composition of SG and PB proteomes is discussed, supported by a new user-friendly database that curates current literature evidence for genes or proteins associated with SGs or PBs that have a high propensity to contain primary sequence features favoring phase separation.
211 citations
University of Southern California1, National Institutes of Health2, Mayo Clinic3, Cincinnati Children's Hospital Medical Center4, University of Chicago5, University of Oxford6, Paris Diderot University7, Boston Children's Hospital8, Children's Mercy Hospital9, Hospital for Sick Children10, Erasmus University Rotterdam11, New York University12, University of California, San Francisco13, Children's Hospital of Philadelphia14
TL;DR: It is concluded that InO is a well-tolerated, effective therapy for children with relapsed/refractory ALL and prospective studies are warranted.
Abstract: Although inotuzumab ozogamicin (InO) is recognized as an effective agent in relapsed acute lymphoblastic leukemia (ALL) in adults, data on safety and efficacy in pediatric patients are scarce. We report the use of InO in 51 children with relapsed/refractory ALL treated in the compassionate use program. In this heavily pretreated cohort, complete remission was achieved in 67% of patients with overt marrow disease. The majority (71%) of responders were negative for minimal residual disease. Responses were observed irrespective of cytogenetic subtype or number or type of prior treatment regimens. InO was well-tolerated; grade 3 hepatic transaminitis or hyperbilirubinemia were noted in 6 (12%) and grade 3/4 infections in 11 (22%) patients. No patient developed sinusoidal obstruction syndrome (SOS) during InO therapy; however, 11 of 21 (52%) patients who underwent hematopoietic stem cell transplantation (HSCT) following InO developed SOS. Downregulation of surface CD22 was detected as a possible escape mechanism in three patients who developed a subsequent relapse after InO. We conclude that InO is a well-tolerated, effective therapy for children with relapsed ALL and prospective studies are warranted. Identification of risk factors for developing post-HSCT SOS and strategies to mitigate this risk are ongoing.
149 citations
TL;DR: Eight patients from six unrelated pedigrees with biallelic loss-of-function mutations in RIPK1 presenting with primary immunodeficiency and/or intestinal inflammation are reported, highlighting the essential role ofRIPK1 in controlling human immune and intestinal homeostasis.
Abstract: Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a critical regulator of cell death and inflammation, but its relevance for human disease pathogenesis remains elusive. Studies of monogenic disorders might provide critical insights into disease mechanisms and therapeutic targeting of RIPK1 for common diseases. Here, we report on eight patients from six unrelated pedigrees with biallelic loss-of-function mutations in RIPK1 presenting with primary immunodeficiency and/or intestinal inflammation. Mutations in RIPK1 were associated with reduced NF-κB activity, defective differentiation of T and B cells, increased inflammasome activity, and impaired response to TNFR1-mediated cell death in intestinal epithelial cells. The characterization of RIPK1-deficient patients highlights the essential role of RIPK1 in controlling human immune and intestinal homeostasis, and might have critical implications for therapies targeting RIPK1.
115 citations
North Bristol NHS Trust1, Imperial College Healthcare2, University of Texas Southwestern Medical Center3, Oslo University Hospital4, University of Virginia5, University of Bern6, University Hospital of Bern7, McGill University8, Beth Israel Deaconess Medical Center9, University of Texas at Arlington10, James Cook University Hospital11, Aarhus University12, University of Iowa13, University of Alberta14, University of Newcastle15, Saginaw Valley State University16, McMaster University17, Great Ormond Street Hospital for Children NHS Foundation Trust18, University of São Paulo19, University of Cologne20, Alfred Hospital21, University of Zurich22, Queen's University23, University of Toronto24, University of Pittsburgh25, Allegheny Health Network26, International Federation of Red Cross and Red Crescent Societies27, Helsinki University Central Hospital28, National Taiwan University29, Alberta Children's Hospital30, Yonsei University31, Deakin University32, University of Warwick33, Northern General Hospital34, Royal Women's Hospital35, Federal University of São Paulo36, University of Southampton37, St. Michael's GAA, Sligo38, Boston Children's Hospital39, American Red Cross40, National Heart Foundation of Australia41, Rosalind Franklin University of Medicine and Science42, Aarhus University Hospital43, Hospital for Sick Children44, Monash Medical Centre45, Jichi Medical University46, Kyoto University47, Dalhousie University48, University of Washington Medical Center49, University of Calgary50, Denver Health Medical Center51, Mater Health Services52, Singapore General Hospital53, European Resuscitation Council54, Stanford University55, Middlemore Hospital56, University of Melbourne57, Royal Melbourne Hospital58, Children's Hospital of Philadelphia59, University of Michigan60, Waikato Hospital61, Wayne State University62, Liverpool Hospital63, Heart of England NHS Foundation Trust64, Cornell University65, Michigan State University66, University of Milan67, University of Oxford68, Teikyo University69, Catholic University of the Sacred Heart70, Agostino Gemelli University Polyclinic71, Arkansas Children's Hospital72, University of Arkansas73, University of Birmingham74, St. Marianna University School of Medicine75, University of Helsinki76, London Health Sciences Centre77, University of Padua78, Ottawa Hospital79, University of Ottawa80, Ghent University81, Memorial Hospital of South Bend82, Hamilton Health Sciences83, Vanderbilt University84
TL;DR: This summary addresses the role of cardiac arrest centers and dispatcher-assisted cardiopulmonary resuscitation, the role for presyncope by first aid providers, advanced airway interventions in adults and children, targeted temperature management in children after cardiac arrest, and initial oxygen concentration during resuscitation of newborns.
110 citations
Stanford University1, Seattle Children's2, University of Washington3, Baylor College of Medicine4, University of Pittsburgh5, Cincinnati Children's Hospital Medical Center6, University of Cincinnati Academic Health Center7, University of Colorado Denver8, Boston Children's Hospital9, University of Miami10, United States Public Health Service11, Michigan State University12, Washington University in St. Louis13, University of Pennsylvania14, Children's Hospital of Philadelphia15, Metro Health Hospital16, University of Michigan17, Harvard University18, University of Southern California19, Children's Hospital Los Angeles20, Children's of Alabama21, University of Alabama at Birmingham22, Columbia University Medical Center23, Yale University24, Vanderbilt University25, Hackensack University Medical Center26, The Chinese University of Hong Kong27, University of Missouri–Kansas City28, Children's Mercy Hospital29, University of Utah30, Georgia Regents University31, Northwestern University32, Albert Einstein College of Medicine33, All Children's Hospital34, Kaiser Permanente35, Cornell University36, Hospital for Special Surgery37, Hacettepe University38, Northeast Ohio Medical University39, Emory University40, University of California, San Diego41, University of Nebraska Medical Center42, University of Minnesota43, Children's Hospital of Eastern Ontario44, Hospital for Sick Children45, University of Toronto46, University of Amsterdam47, University of Wisconsin-Madison48
TL;DR: A rare, life-threatening lung disease in sJIA is defined by a constellation of unusual clinical characteristics, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the interleukin (IL)-6 inhibitor, tocilizumab.
Abstract: Objective To investigate the characteristics and risk factors of a novel parenchymal lung disease (LD), increasingly detected in systemic juvenile idiopathic arthritis (sJIA). Methods In a multicentre retrospective study, 61 cases were investigated using physician-reported clinical information and centralised analyses of radiological, pathological and genetic data. Results LD was associated with distinctive features, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the interleukin (IL)-6 inhibitor, tocilizumab. Serum ferritin elevation and/or significant lymphopaenia preceded LD detection. The most prevalent chest CT pattern was septal thickening, involving the periphery of multiple lobes ± ground-glass opacities. The predominant pathology (23 of 36) was pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia (PAP/ELP), with atypical features including regional involvement and concomitant vascular changes. Apparent severe delayed drug hypersensitivity occurred in some cases. The 5-year survival was 42%. Whole exome sequencing (20 of 61) did not identify a novel monogenic defect or likely causal PAP-related or macrophage activation syndrome (MAS)-related mutations. Trisomy 21 and young sJIA onset increased LD risk. Exposure to IL-1 and IL-6 inhibitors (46 of 61) was associated with multiple LD features. By several indicators, severity of sJIA was comparable in drug-exposed subjects and published sJIA cohorts. MAS at sJIA onset was increased in the drug-exposed, but was not associated with LD features. Conclusions A rare, life-threatening lung disease in sJIA is defined by a constellation of unusual clinical characteristics. The pathology, a PAP/ELP variant, suggests macrophage dysfunction. Inhibitor exposure may promote LD, independent of sJIA severity, in a small subset of treated patients. Treatment/prevention strategies are needed.
96 citations
TL;DR: This paper identified ZIKV host genes in human pluripotent stem cell (hPSC)-derived neural progenitors (NPs) using a genome-wide CRISPR-Cas9 knockout screen.
Abstract: Zika virus (ZIKV) is a neurotropic and neurovirulent arbovirus that has severe detrimental impact on the developing human fetal brain. To date, little is known about the factors required for ZIKV infection of human neural cells. We identified ZIKV host genes in human pluripotent stem cell (hPSC)-derived neural progenitors (NPs) using a genome-wide CRISPR-Cas9 knockout screen. Mutations of host factors involved in heparan sulfation, endocytosis, endoplasmic reticulum processing, Golgi function, and interferon activity conferred resistance to infection with the Uganda strain of ZIKV and a more recent North American isolate. Host genes essential for ZIKV replication identified in human NPs also provided a low level of protection against ZIKV in isogenic human astrocytes. Our findings provide insights into host-dependent mechanisms for ZIKV infection in the highly vulnerable human NP cells and identify molecular targets for potential therapeutic intervention.
81 citations
TL;DR: This guideline update provides evidence-based recommendations for the diagnosis, management, and follow-up of patients who present with sudden hearing loss and focuses on those with idiopathic sudden sensorineural hearing loss.
Abstract: ObjectiveSudden hearing loss is a frightening symptom that often prompts an urgent or emergent visit to a health care provider. It is frequently, but not universally, accompanied by tinnitus and/or...
University of Washington1, University of Calgary2, Imperial College London3, University of Colorado Denver4, Queen's University Belfast5, University of San Diego6, Hospital for Sick Children7, QIMR Berghofer Medical Research Institute8, Medical University of South Carolina9, Case Western Reserve University10
TL;DR: There is little evidence that AST predicts the clinical outcome of CF antimicrobial treatment, suggesting a need for careful consideration of current AST use by the CF community.
TL;DR: To develop core outcome sets (COS) for studies evaluating interventions for prevention and treatment of postpartum haemorrhage (PPH), and recommendations on how to report the COS.
TL;DR: It is shown that purified V-ATPase complexes containing Vph1p have higher ATPase activity than complexes containing Stv1p and that the relative difference in activity depends on the presence of lipids.
Abstract: Proton-translocating vacuolar-type ATPases (V-ATPases) are necessary for numerous processes in eukaryotic cells, including receptor-mediated endocytosis, protein maturation, and lysosomal acidification. In mammals, V-ATPase subunit isoforms are differentially targeted to various intracellular compartments or tissues, but how these subunit isoforms influence enzyme activity is not clear. In the yeast Saccharomyces cerevisiae, isoform diversity is limited to two different versions of the proton-translocating subunit a: Vph1p, which is targeted to the vacuole, and Stv1p, which is targeted to the Golgi apparatus and endosomes. We show that purified V-ATPase complexes containing Vph1p have higher ATPase activity than complexes containing Stv1p and that the relative difference in activity depends on the presence of lipids. We also show that VO complexes containing Stv1p could be readily purified without attached V1 regions. We used this effect to determine structures of the membrane-embedded VO region with Stv1p at 3.1-A resolution, which we compare with a structure of the VO region with Vph1p that we determine to 3.2-A resolution. These maps reveal differences in the surface charge near the cytoplasmic proton half-channel. Both maps also show the presence of bound lipids, as well as regularly spaced densities that may correspond to ergosterol or bound detergent, around the c-ring.
TL;DR: Fertility is a low current and future life priority for transgender YP and the majority of YP wish to become parents but are open to alternative strategies for building a family, which may explain in part the reported low rates of fertility preservation.
Abstract: Objective The aim of this study was to investigate the views of young people (YP) with gender dysphoria and their parents concerning fertility preservation and reproductive and life priorities. Design A cross-sectional questionnaire-based study assessed knowledge of potential effects of treatments for gender dysphoria on fertility, current and future life priorities and preferences regarding future fertility/parenting options among YP and parents. Results A total of 79 YP (81% assigned female at birth [AFAB], 19% assigned male at birth [AMAB], aged 12–18 years, 68% between ages 16 years and 18 years) and 73 parents participated. The top current life priority for YP among eight options was being in good health; the least important priority was having children. Anticipated life priorities 10 years from now were ranked similarly. Parents’ rankings paralleled the YP responses; however, parents ranked having children as a significantly higher priority for AFAB compared with AMAB YP in 10 years. The majority of YP (66% AFAB, 67% AMAB) want to be a parent in the future. However, most do not envision having a biological child. A large majority (72% AFAB, 80% AMAB) were open to adoption. None of the YP surveyed pursued fertility preservation. Conclusion Fertility is a low current and future life priority for transgender YP. The majority of YP wish to become parents but are open to alternative strategies for building a family. These data may explain in part the reported low rates of fertility preservation among this population. Further studies are needed to assess if life priorities change over time.
Johns Hopkins University1, University of Southern California2, Children's Oncology Group3, St. Jude Children's Research Hospital4, Stony Brook University5, Amgen6, University of Colorado Boulder7, Hospital for Sick Children8, Children's Hospital Los Angeles9, University of Pennsylvania10, Boston Children's Hospital11
TL;DR: Brown et al. as discussed by the authors showed that blinatumomab is superior to standard chemotherapy as post-reinduction consolidation prior to HSCT, resulting in fewer and less severe toxicities, higher rates of MRD response, greater likelihood of proceeding to HLCT and improved disease-free and overall survival.
TL;DR: This study shows that ECHO improved providers’ self-efficacy and knowledge, and suggests that this project may be used as a template for creating other educational programs on other medical topics.
Abstract: IntroductionInadequate knowledge and training of healthcare providers are obstacles to effective chronic pain management. ECHO (extension for community healthcare outcomes) uses case-based learning...
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TL;DR: In this article, the authors surveyed clinicians from two distinct acute care specialties (Intenstive Care Unit and Emergency Department) to identify specific aspects of explainability that may catalyze building trust in ML models.
Abstract: Translating machine learning (ML) models effectively to clinical practice requires establishing clinicians' trust. Explainability, or the ability of an ML model to justify its outcomes and assist clinicians in rationalizing the model prediction, has been generally understood to be critical to establishing trust. However, the field suffers from the lack of concrete definitions for usable explanations in different settings. To identify specific aspects of explainability that may catalyze building trust in ML models, we surveyed clinicians from two distinct acute care specialties (Intenstive Care Unit and Emergency Department). We use their feedback to characterize when explainability helps to improve clinicians' trust in ML models. We further identify the classes of explanations that clinicians identified as most relevant and crucial for effective translation to clinical practice. Finally, we discern concrete metrics for rigorous evaluation of clinical explainability methods. By integrating perceptions of explainability between clinicians and ML researchers we hope to facilitate the endorsement and broader adoption and sustained use of ML systems in healthcare.
TL;DR: Small-molecule kinetic stabilizers of the native dimeric structure of full-length LCs are introduced, which can slow or stop the amyloidogenicity cascade at its origin, a proven strategy to ameliorate postmitotic tissue degeneration.
Abstract: In Ig light-chain (LC) amyloidosis (AL), the unique antibody LC protein that is secreted by monoclonal plasma cells in each patient misfolds and/or aggregates, a process leading to organ degeneration. As a step toward developing treatments for AL patients with substantial cardiac involvement who have difficulty tolerating existing chemotherapy regimens, we introduce small-molecule kinetic stabilizers of the native dimeric structure of full-length LCs, which can slow or stop the amyloidogenicity cascade at its origin. A protease-coupled fluorescence polarization-based high-throughput screen was employed to identify small molecules that kinetically stabilize LCs. NMR and X-ray crystallographic data demonstrate that at least one structural family of hits bind at the LC-LC dimerization interface within full-length LCs, utilizing variable-domain residues that are highly conserved in most AL patients. Stopping the amyloidogenesis cascade at the beginning is a proven strategy to ameliorate postmitotic tissue degeneration.
TL;DR: By providing an alternative source of innervation in patients with neurotrophic keratopathy treated with minimally invasive corneal neurotisation (MICN), MICN improvesCorneal sensation and stabilises the corneals epithelium, permitting optical keratoplasty for patients with NK-related cornea opacity.
Abstract: Aim To report clinical outcomes and evidence of corneal innervation in patients with neurotrophic keratopathy (NK) treated with minimally invasive corneal neurotisation (MICN) using a sural nerve graft and donor sensory nerves from the face. Methods Patients undergoing MICN at The Hospital for Sick Children, Toronto, Canada were prospectively recruited. Data on central corneal sensation (CCS, measured with Cochet-Bonnet aesthesiometer), best-corrected visual acuity (BCVA) and corneal epithelial integrity were collected. In four patients who subsequently underwent keratoplasty, immunohistochemical analysis was performed on the corneal explants. One patient underwent magnetoencephalography (MEG) after MICN to characterise the neurophysiological pathways involved. Results Between November 2012 and February 2017, 19 eyes of 16 patients underwent MICN. Mean follow-up was 24.0±16.1 months (range, 6–53). Mean CCS significantly improved from 0.8±2.5 mm to 49.7±15.5 mm at final follow-up (p Conclusions By providing an alternative source of innervation, MICN improves corneal sensation and stabilises the corneal epithelium, permitting optical keratoplasty for patients with NK-related corneal opacity.
Saint John Regional Hospital1, Queen's University2, University of British Columbia3, McGill University4, Hospital for Sick Children5, University of Manitoba6, Children's Hospital of Eastern Ontario7, University of Ottawa8, Université de Sherbrooke9, Dalhousie University10, Jewish General Hospital11, University of Alberta12, University of Saskatchewan13
TL;DR: There is still a paucity of prospective POCUS research focused on patient-oriented outcomes, but the authors do believe there is sufficient evidence in the current literature to support the recommendations within this document.
Abstract: The Canadian Association of Emergency Physicians (CAEP) recognizes the role of point-of-care ultrasound (POCUS) as a valuable adjunct to the delivery of excellent emergency care. With this document, the CAEP Emergency Ultrasound Committee (EUC) updates the previous CAEP POCUS position statement and provides an expanded framework and series of recommendations, based on the current evidence, to guide emergency departments (ED) and their POCUS programs in the delivery of high quality patient care. Evaluating and summarizing the evidence for the use of POCUS is challenging because, unlike other diagnostic tests where research is primarily focused on test performance, the value of POCUS is further scrutinized in terms of patient-oriented outcomes and system performance measures, such as time to diagnosis or length of stay. Add to this the operator-dependent nature of POCUS, and, not surprisingly, the application of POCUS literature becomes understandably complex. The recommendations reflect the authors’ synthesis of a combination of test performance metrics, patientoriented outcomes, and system performance measures (when available). To date, there is still a paucity of prospective POCUS research focused on patient-oriented outcomes, but the authors do believe there is sufficient evidence in the current literature to support the recommendations within this document.
TL;DR: Associations are revealed between antibody responses to intestinal microbes and HLA-DR genotype and islet autoantibody specificity and with a future diagnosis of T1D.
Abstract: Microbiome sequence analyses have suggested that changes in gut bacterial composition are associated with autoimmune disease in humans and animal models. However, little is known of the mechanisms through which the gut microbiota influences autoimmune responses to distant tissues. Here, we evaluated systemic antibody responses against cultured human gut bacterial strains to determine whether observed patterns of anticommensal antibody (ACAb) responses are associated with type 1 diabetes (T1D) in two cohorts of pediatric study participants. In the first cohort, ACAb responses in sera collected from participants within 6 months of T1D diagnosis were compared with age-matched healthy controls and also with patients with recent onset Crohn's disease. ACAb responses against multiple bacterial species discriminated among these three groups. In the second cohort, we asked whether ACAb responses present before diagnosis were associated with later T1D development and with HLA genotype in participants who were discordant for subsequent progression to diabetes. Serum IgG2 antibodies against Roseburia faecis and against a bacterial consortium were associated with future T1D diagnosis in an HLA DR3/DR4 haplotype-dependent manner. These analyses reveal associations between antibody responses to intestinal microbes and HLA-DR genotype and islet autoantibody specificity and with a future diagnosis of T1D. Further, we present a platform to investigate antibacterial antibodies in biological fluids that is applicable to studies of autoimmune diseases and responses to therapeutic interventions.
TL;DR: A strategy for multiplexing different features of aperiodic stimuli: Cortical neurons use the rate of asynchronous spiking to encode stimulus intensity while using the timing of synchronous spikes to encode abrupt changes in stimulus intensity.
Abstract: Multiplexing refers to the simultaneous encoding of two or more signals. Neurons have been shown to multiplex, but different stimuli require different multiplexing strategies. Whereas the frequency and amplitude of periodic stimuli can be encoded by the timing and rate of the same spikes, natural scenes, which comprise areas over which intensity varies gradually and sparse edges where intensity changes abruptly, require a different multiplexing strategy. Recording in vivo from neurons in primary somatosensory cortex during tactile stimulation, we found that stimulus onset and offset (edges) evoked highly synchronized spiking, whereas other spikes in the same neurons occurred asynchronously. Stimulus intensity modulated the rate of asynchronous spiking, but did not affect the timing of synchronous spikes. From this, we hypothesized that spikes driven by high- and low-contrast stimulus features can be distinguished on the basis of their synchronization, and that differentially synchronized spiking can thus be used to form multiplexed representations. Applying a Bayesian decoding method, we verified that information about high- and low-contrast features can be recovered from an ensemble of model neurons receiving common input. Equally good decoding was achieved by distinguishing synchronous from asynchronous spikes and applying reverse correlation methods separately to each spike type. This result, which we verified with patch clamp recordings in vitro, demonstrates that neurons receiving common input can use the rate of asynchronous spiking to encode the intensity of low-contrast features while using the timing of synchronous spikes to encode the occurrence of high-contrast features. We refer to this strategy as synchrony-division multiplexing.
TL;DR: A threshold of stability is established, below which aggregation occurs rapidly, suggesting that stabilizing the CL–CL domain interface could prevent aggregation, and the importance of both dimerization strength and intrinsic monomer stability in stabilizing VL domains against aggregation is pointed to.
Abstract: Amyloid light-chain (LC) amyloidosis is a protein misfolding disease in which the aggregation of an overexpressed antibody LC from a clonal plasma cell leads to organ toxicity and patient death if left untreated. While the overall dimeric architecture of LC molecules is established, with each LC composed of variable (VL) and constant (CL) domains, the relative contributions of LC domain-domain interfaces and intrinsic domain stabilities to protection against LC aggregation are not well understood. To address these topics we have engineered a number of domain-destabilized LC mutants and used solution NMR spectroscopy to characterize their structural properties and intrinsic stabilities. Moreover, we used fluorescence spectroscopy to assay their aggregation propensities. Our results point to the importance of both dimerization strength and intrinsic monomer stability in stabilizing VL domains against aggregation. Notably, in all cases considered VL domains aggregate at least 10-fold faster than full-length LCs, establishing the important protective role of CL domains. A strong protective coupling is found between VL-VL and CL-CL dimer interfaces, with destabilization of one interface adversely affecting the stability of the other. Fibril formation is observed when either the VL or CL domain in the full-length protein is severely destabilized (i.e., where domain unfolding free energies are less than 2 kcal/mol). The important role of CL domains in preventing aggregation highlights the potential of the CL-CL interface as a target for the development of drugs to stabilize the dimeric LC structure and hence prevent LC amyloidosis.
TL;DR: Intramuscular administration of ACE-083 caused localized, dose-dependent hypertrophy of the injected muscle in wild-type mice and mouse models of Charcot-Marie-Tooth disease and Duchenne muscular dystrophy with no evidence of systemic muscle effects or endocrine perturbation.
Abstract: Skeletal muscle is under inhibitory homeostatic regulation by multiple ligands of the transforming growth factor-β (TGFβ) superfamily. Follistatin is a secreted protein that promotes muscle growth and function by sequestering these ligands extracellularly. In the present study, we evaluated the potential of ACE-083 – a locally acting, follistatin-based fusion protein – as a novel therapeutic agent for focal or asymmetric myopathies. Characterization of ACE-083 in vitro revealed its high affinity for heparin and extracellular matrix while surface plasmon resonance and cell-based assays confirmed that ACE-083 binds and potently neutralizes myostatin, activin A, activin B and growth differentiation factor 11 (GDF11). Intramuscular administration of ACE-083 caused localized, dose-dependent hypertrophy of the injected muscle in wild-type mice and mouse models of Charcot-Marie-Tooth disease (CMT) and Duchenne muscular dystrophy, with no evidence of systemic muscle effects or endocrine perturbation. Importantly, ACE-083 also increased the force of isometric contraction in situ by the injected tibialis anterior muscle in wild-type mice and disease models and increased ankle dorsiflexion torque in CMT mice. Our results demonstrate the potential of ACE-083 as a therapeutic agent for patients with CMT, muscular dystrophy and other disorders with focal or asymmetric muscle atrophy or weakness.
TL;DR: It is suggested that a comprehensive genomic understanding of in vitro and in vivo GBM model systems is crucial for interpreting data from drug screens, and can help control for biases introduced by cell-culture conditions and the microenvironment in mouse models.
Abstract: Glioblastoma multiforme (GBM) is the most deadly brain tumor, and currently lacks effective treatment options. Brain tumor-initiating cells (BTICs) and orthotopic xenografts are widely used in investigating GBM biology and new therapies for this aggressive disease. However, the genomic characteristics and molecular resemblance of these models to GBM tumors remain undetermined. We used massively parallel sequencing technology to decode the genomes and transcriptomes of BTICs and xenografts and their matched tumors in order to delineate the potential impacts of the distinct growth environments. Using data generated from whole-genome sequencing of 201 samples and RNA sequencing of 118 samples, we show that BTICs and xenografts resemble their parental tumor at the genomic level but differ at the mRNA expression and epigenomic levels, likely due to the different growth environment for each sample type. These findings suggest that a comprehensive genomic understanding of in vitro and in vivo GBM model systems is crucial for interpreting data from drug screens, and can help control for biases introduced by cell-culture conditions and the microenvironment in mouse models. We also found that lack of MGMT expression in pretreated GBM is linked to hypermutation, which in turn contributes to increased genomic heterogeneity and requires new strategies for GBM treatment.
TL;DR: No associations were observed between exposure to pH1N1 influenza vaccine during pregnancy and most five year pediatric health outcomes, and residue confounding may explain the small associations observed with increased asthma and reduced gastrointestinal infections.
Abstract: Objective To determine whether any association exists between exposure to 2009 pandemic H1N1 (pH1N1) influenza vaccination during pregnancy and negative health outcomes in early childhood Design Retrospective cohort study Setting Population based birth registry linked with health administrative databases in the province of Ontario, Canada Participants All live births from November 2009 through October 2010 (n=104 249) were included, and children were followed until 5 years of age to ascertain study outcomes Main outcome measures Rates of immune related (infectious diseases, asthma), non-immune related (neoplasms, sensory disorders), and non-specific morbidity outcomes (urgent or inpatient health services use, pediatric complex chronic conditions) were evaluated from birth to 5 years of age; under-5 childhood mortality was also assessed Propensity score weighting was used to adjust hazard ratios, incidence rate ratios, and risk ratios for potential confounding Results Of 104 249 live births, 31 295 (30%) were exposed to pH1N1 influenza vaccination in utero No significant associations were found with upper or lower respiratory infections, otitis media, any infectious diseases, neoplasms, sensory disorders, urgent and inpatient health services use, pediatric complex chronic conditions, or mortality A weak association was observed between prenatal pH1N1 vaccination and increased risk of asthma (adjusted hazard ratio 105, 95% confidence interval 102 to 109) and decreased rates of gastrointestinal infections (adjusted incidence rate ratio 094, 091 to 098) These results were unchanged in sensitivity analyses accounting for any potential differential healthcare seeking behavior or access between exposure groups Conclusions No associations were observed between exposure to pH1N1 influenza vaccine during pregnancy and most five year pediatric health outcomes Residual confounding may explain the small associations observed with increased asthma and reduced gastrointestinal infections These outcomes should be assessed in future studies
TL;DR: New graduate nurses can be an integral part of the team in specialty care provided certain conditions are met during their transition to practice and further evidence that extended orientation enhances new graduates' work readiness as they transit to their professional role is given.
Abstract: Aim To determine how extended orientation enhances the work readiness of new graduate nurses as they transitioned to their professional role in a specialty care hospital. Background Given increased complexity of care and high-patient acuity, there is concern about the work readiness of new graduate nurses in specialty areas. Design Qualitative exploratory study using an inductive approach. Methods An integrative literature review was conducted to abstract characteristics of work readiness among new graduate nurses. Semistructured interviews were conducted with 41 participants from a large paediatric specialty hospital in Ontario, Canada, in 2014. The sample of nurses was stratified and included nurse managers, new graduates, and preceptors. Interview texts were interpreted using thematic analysis. Results A framework for enhancing work readiness of new graduates transitioning to specialty care was developed from the interview and literature findings. Interview data demonstrate an extended orientation that includes mentorship, a gradual increase in clinical responsibilities, and involvement in the professional role during the early stages of a nurse's career can enhance work readiness of new graduates. Four key areas of work readiness were identified in the literature: personal characteristics, clinical characteristics, relational characteristics, and organizational acuity. Conclusion Based on the study results, new graduate nurses can be an integral part of the team in specialty care provided certain conditions are met during their transition to practice. Our study gives further evidence that extended orientation enhances new graduates' work readiness as they transit to their professional role.
TL;DR: To understand NTD functional dynamics in biologically relevant p97 heterohexamers comprising both WT and disease-causing mutant subunits, a methyl-transverse relaxation optimized spectroscopy (TROSY) NMR study is performed on a series of constructs in which only one of the protomers is NMR-labeled.
Abstract: p97 is an essential hexameric AAA+ ATPase involved in a wide range of cellular processes. Mutations in the enzyme are implicated in the etiology of an autosomal dominant neurological disease in which patients are heterozygous with respect to p97 alleles, containing one copy each of WT and disease-causing mutant genes, so that, in vivo, p97 molecules can be heterogeneous in subunit composition. Studies of p97 have, however, focused on homohexameric constructs, where protomers are either entirely WT or contain a disease-causing mutation, showing that for WT p97, the N-terminal domain (NTD) of each subunit can exist in either a down (ADP) or up (ATP) conformation. NMR studies establish that, in the ADP-bound state, the up/down NTD equilibrium shifts progressively toward the up conformation as a function of disease mutant severity. To understand NTD functional dynamics in biologically relevant p97 heterohexamers comprising both WT and disease-causing mutant subunits, we performed a methyl-transverse relaxation optimized spectroscopy (TROSY) NMR study on a series of constructs in which only one of the protomer types is NMR-labeled. Our results show positive cooperativity of NTD up/down equilibria between neighboring protomers, allowing us to define interprotomer pathways that mediate the allosteric communication between subunits. Notably, the perturbed up/down NTD equilibrium in mutant subunits is partially restored by neighboring WT protomers, as is the two-pronged binding of the UBXD1 adaptor that is affected in disease. This work highlights the plasticity of p97 and how subtle perturbations to its free-energy landscape lead to significant changes in NTD conformation and adaptor binding.
TL;DR: Doccurate is presented, a novel system embodying a curation-based approach for the visualization of large clinical text datasets that offers automation auditing and customizability to physicians while also preserving and extensively linking to the original text.
Abstract: Before seeing a patient, physicians seek to obtain an overview of the patient's medical history. Text plays a major role in this activity since it represents the bulk of the clinical documentation, but reviewing it quickly becomes onerous when patient charts grow too large. Text visualization methods have been widely explored to manage this large scale through visual summaries that rely on information retrieval algorithms to structure text and make it amenable to visualization. However, the integration with such automated approaches comes with a number of limitations, including significant error rates and the need for healthcare providers to fine-tune algorithms without expert knowledge of their inner mechanics. In addition, several of these approaches obscure or substitute the original clinical text and therefore fail to leverage qualitative and rhetorical flavours of the clinical notes. These drawbacks have limited the adoption of text visualization and other summarization technologies in clinical practice. In this work we present Doccurate, a novel system embodying a curation-based approach for the visualization of large clinical text datasets. Our approach offers automation auditing and customizability to physicians while also preserving and extensively linking to the original text. We discuss findings of a formal qualitative evaluation conducted with 6 domain experts, shedding light onto physicians' information needs, perceived strengths and limitations of automated tools, and the importance of customization while balancing efficiency. We also present use case scenarios to showcase Doccurate's envisioned usage in practice.