scholarly journals Proactive Variant Effect Mapping to Accelerate Genetic Diagnosis for Pediatric Cardiac Arrest

2022 ◽  
Author(s):  
Brendan Floyd ◽  
Jochen Weile ◽  
Prince Kannankeril ◽  
Andrew Glazer ◽  
Chloe Reuter ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Medical Center ◽  
Genetic Diagnosis ◽  
Family Care ◽  
Standard Of Care ◽  
Variant Interpretation ◽  
Uncertain Significance ◽  
Retrospective Data Collection ◽  
Variant Effect ◽  
Vanderbilt University

While genetic testing is becoming standard of care for patients with potentially inherited cardiovascular disease, the prevalence of uncertain results severely limits its utility. One promising approach is to generate variant effect maps that report the function of all possible variants in a gene prospectively. The proactive clinical application of these maps is nascent, and requires careful integration with current American College of Medical Genetics guidelines for variant interpretation. Here, we describe three pediatric cases of cardiac arrest or sudden cardiac death with variants of uncertain significance in calmodulin genes. We demonstrate the prospective clinical utility of a calmodulin variant effect map to inform variant interpretation, and therefore diagnosis and family care, in each case. This study was approved by the Stanford University and Vanderbilt University Medical Center IRBs. Consent was waived based on low risk of de-identified retrospective data collection per the IRB.

scholarly journals Prioritizing genes for systematic variant effect mapping

2020 ◽  
Author(s):  
Da Kuang ◽  
Rebecca Truty ◽  
Jochen Weile ◽  
Britt Johnson ◽  
Keith Nykamp ◽  
...  
Keyword(s):  
Protein Function ◽  
Supplementary Information ◽  
Functional Testing ◽  
Variant Interpretation ◽  
Missense Variants ◽  
Clinical Variant ◽  
Uncertain Significance ◽  
Missense Variation ◽  
Variant Effect ◽  
Extra Weight

Abstract Motivation When rare missense variants are clinically interpreted as to their pathogenicity, most are classified as variants of uncertain significance (VUS). Although functional assays can provide strong evidence for variant classification, such results are generally unavailable. Multiplexed assays of variant effect can generate experimental ‘variant effect maps’ that score nearly all possible missense variants in selected protein targets for their impact on protein function. However, these efforts have not always prioritized proteins for which variant effect maps would have the greatest impact on clinical variant interpretation. Results Here, we mined databases of clinically interpreted variants and applied three strategies, each building on the previous, to prioritize genes for systematic functional testing of missense variation. The strategies ranked genes (i) by the number of unique missense VUS that had been reported to ClinVar; (ii) by movability- and reappearance-weighted impact scores, to give extra weight to reappearing, movable VUS and (iii) by difficulty-adjusted impact scores, to account for the more resource-intensive nature of generating variant effect maps for longer genes. Our results could be used to guide systematic functional testing of missense variation toward greater impact on clinical variant interpretation. Availability and implementation Source code available at: https://github.com/rothlab/mave-gene-prioritization Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Local Laboratory Testing of Germline BRCA Mutations vs. Myriad: A Single-Institution Experience in Korea

Diagnostics ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 370
Author(s):  
Joohyun Hong ◽  
Jiyun Lee ◽  
Minsuk Kwon ◽  
Ji-Yeon Kim ◽  
Jong-Won Kim ◽  
...  
Keyword(s):  
Genetic Testing ◽  
High Risk ◽  
Salt Lake ◽  
Medical Center ◽  
Brca Mutation ◽  
Genetic Diagnosis ◽  
Metastatic Breast ◽  
Breast Cancer Patients ◽  
Brca 1 ◽  
Local Laboratory

Genetic diagnosis for human epidermal growth factor receptor 2-negative metastatic breast cancer patients with the germline BRCA (gBRCA) mutation has been emphasized since the development of polyadenosine diphosphate-ribose polymerase inhibitors. Myriad Genetics, Inc.’s (Salt Lake City, UT, USA) companion diagnostics service is almost exclusively used for genetic testing. The aim of this study was to compare the results of germline BRCA mutation tests returned by a local laboratory and those performed by Myriad. Between April 2014 and February 2018, 31 patients with gBRCA 1/2 mutation test results from both Samsung Medical Center (Seoul, Korea) and Myriad were enrolled. “Discordant: Opposite classification” was observed for only one among 27 (3.7%). This discrepancy was due to the detection of a deleterious large genomic rearrangement of BRCA 1 by Myriad. Samsung Medical Center performed multiple ligation-dependent probe amplifications (MLPA) to detect large genomic rearrangements only in high-risk patients. This one case was not suspected as high risk and MLPA was not performed. The concordant rate was 74.1% for all 27 patients. “Discordant: Laboratory’s uncertain classification” was found in 22.2% of the sample (six patients). All discrepancies were generated during interpretation of BRCA 2 gene sequencing. Further studies and standardization of genetic testing for BRCA 1/2 genes are required.

scholarly journals A case report of individualized ventilation in a COVID-19 patient – new possibilities and caveats to consider with flow-controlled ventilation

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Patrick Spraider ◽  
Gabriel Putzer ◽  
Robert Breitkopf ◽  
Julia Abram ◽  
Simon Mathis ◽  
...  
Keyword(s):  
Medical Center ◽  
Standard Of Care ◽  
Dynamic Compliance ◽  
Dissipated Energy ◽  
Lung Protective Ventilation ◽  
Controlled Ventilation ◽  
Ventilation Modes ◽  
Personalized Ventilation ◽  
Ventilator Settings

Abstract Background Flow-controlled ventilation (FCV) is a novel ventilation method increasingly being used clinically, particularly during the current COVID-19 pandemic. However, the continuous flow pattern in FCV during inspiration and expiration has a significant impact on respiratory parameters and ventilatory settings compared to conventional ventilation modes. In addition, the constant flow combined with direct intratracheal pressure measurement allows determination of dynamic compliance and ventilation settings can be adjusted accordingly, reflecting a personalized ventilation approach. Case presentation A 50-year old women with confirmed SARS-CoV-2 infection suffering from acute respiratory distress syndrome (ARDS) was admitted to a tertiary medical center. Initial ventilation occurred with best standard of care pressure-controlled ventilation (PCV) and was then switched to FCV, by adopting PCV ventilator settings. This led to an increase in oxygenation by 30 %. Subsequently, to reduce invasiveness of mechanical ventilation, FCV was individualized by dynamic compliance guided adjustment of both, positive end-expiratory pressure and peak pressure; this intervention reduced driving pressure from 18 to 12 cm H2O. However, after several hours, compliance further deteriorated which resulted in a tidal volume of only 4.7 ml/kg. Conclusions An individualized FCV approach increased oxygenation parameters in a patient suffering from severe COVID-19 related ARDS. Direct intratracheal pressure measurements allow for determination of dynamic compliance and thus optimization of ventilator settings, thereby reducing applied and dissipated energy. However, although desirable, this personalized ventilation strategy may reach its limits when lung function is so severely impaired that patient’s oxygenation has to be ensured at the expense of lung protective ventilation concepts.

scholarly journals Genotypes Predispose Phenotypes—Clinical Features and Genetic Spectrum of ABCA4-Associated Retinal Dystrophies

Genes ◽  
2020 ◽  
Vol 11 (12) ◽  
pp. 1421
Author(s):  
Yu-Chi Sung ◽  
Chang-Hao Yang ◽  
Chung-May Yang ◽  
Chao-Wen Lin ◽  
Ding-Siang Huang ◽  
...  
Keyword(s):  
Visual Acuity ◽  
Retinal Degeneration ◽  
Medical Center ◽  
Fundus Autofluorescence ◽  
Genetic Diagnosis ◽  
Common Disease ◽  
Genetic Characteristics ◽  
Retinal Dystrophies ◽  
High Prevalence ◽  
Abca4 Gene

The ABCA4 gene is one of the most common disease-causing genes of inherited retinal degeneration. In this study, we report different phenotypes of ABCA4-associated retinal dystrophies in the Taiwanese population, its clinical progression, and its relationship with genetic characteristics. Thirty-seven subjects were recruited and all patients underwent serial ophthalmic examinations at a single medical center. Fundus autofluorescence (FAF) images were quantified for clinical evaluation, and panel-based next-generation sequencing testing was performed for genetic diagnosis. Visual preservation, disease progression, and genotype–phenotype correlation were analyzed. In this cohort, ABCA4-associated retinal degeneration presented as Stargardt disease 1 (STGD1, 62.16%), retinitis pigmentosa (32.43%), and cone-rod dystrophy (5.41%). STGD1 could be further divided into central and dispersed types. In each phenotype, the lesion areas quantified by FAF increased with age (p < 0.01) and correlated with poorer visual acuity. However, three patients had the foveal sparing phenotype and had relatively preserved visual acuity. Forty-two ABCA4 variants were identified as disease-causing, with c.1804C>T (p.Arg602Trp) the most frequent (37.84%). Patients with a combination of severe/null variants could have more extensive phenotypes, such as arRP and dispersed STGD1. This is the first cohort study of ABCA4-associated retinal degeneration in Taiwan with wide spectrums of both genotypic and phenotypic characteristics. An extremely high prevalence of c.1804C>T, which has not been reported in East Asia before, was noted. The extensiveness of retinal involvement might be regarded as a spectrum of ABCA4-associated retinal dystrophies. Different types of genetic variations could lead to distinctive phenotypes, according to the coding impact of variants.

The Diagnostic Yield of Prenatal Genetic Technologies in Congenital Heart Disease: A Prospective Cohort Study

2021 ◽  
pp. 1-8
Author(s):  
Fionnuala Mone ◽  
Bethany K. Stott ◽  
Susan Hamilton ◽  
Anna N. Seale ◽  
Elizabeth Quinlan-Jones ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Cohort Study ◽  
Heart Disease ◽  
Prospective Cohort Study ◽  
Prospective Cohort ◽  
Congenital Heart ◽  
Diagnostic Yield ◽  
Genetic Diagnosis ◽  
Uncertain Significance ◽  
Conotruncal Anomalies

<b><i>Introduction:</i></b> The objective was to evaluate: (i) the proportion of prenatally diagnosed congenital heart disease (CHD) associated with an abnormal quantitative fluorescence-PCR (QF-PCR), chromosome microarray (CMA), and exome sequencing (ES) result; and (ii) the diagnostic yield of these technologies based on CHD category and presence of extra-cardiac anomalies (ECAs). <b><i>Methods:</i></b> This prospective cohort study was set across 12 UK foetal medicine centres. All cases underwent QF-PCR, CMA, and ES, and the diagnostic yield in <i>n</i> = 147 cases of prenatally diagnosed CHD was assessed. <b><i>Results:</i></b> In 34.7% (<i>n</i> = 51/147), a genetic diagnosis was obtained. Using a stepwise testing strategy, the diagnostic yield for QF-PCR, CMA, and ES was 15.6% (<i>n</i> = 23/147), 13.7% (<i>n</i> = 17/124), and 10.2% (<i>n</i> = 11/107), respectively. Abnormal QF-PCR/shunt (septal) defects 31.4% (<i>n</i> = 11/35), <i>p</i> = 0.046, and abnormal CMA/conotruncal anomalies 22.7% (<i>n</i> = 10/44), <i>p</i> = 0.04, had significant associations. Monogenic variants were commonest in complex CHD 36.4% (<i>n</i> = 4/11). Multisystem CHD had a greater diagnostic yield overall compared to isolated OR 2.41 (95% CI, 1.1–5.1), particularly in association with brain and gastrointestinal tract anomalies. The proportion of variants of uncertain significance was 4.7% (<i>n</i> = 5/107) with ES, with none in the CMA group. <b><i>Conclusion:</i></b> In the era of prenatal ES, there remains an important role for QF-PCR and CMA. Identification of monogenic pathologic variants further allows delineation of prognosis in CHD.

NEWS AND ANNOUNCEMENTS

PEDIATRICS ◽  
1959 ◽  
Vol 23 (1) ◽  
pp. 179-183
Keyword(s):  
Medical Center ◽  
Ohio State University ◽  
City Hospital ◽  
State University ◽  
University Of Michigan ◽  
Contagious Diseases ◽  
Ann Arbor ◽  
The University ◽  
Vanderbilt University ◽  
Michigan Medical

Postgraduate Courses—AAP The first two of a series of postgraduate courses being sponsored by the American Academy of Pediatrics will be held at the University of Michigan Medical Center, Ann Arbor, Michigan, March 2, 3, 4, and 5, 1959; and at Vanderbilt University Medical Center, Nashville, Tennessee, on March 17, 18, and 19, 1959. Tuition for these courses is $50 and $40, respectively, for Academy members. Fees for nonmembers will be $70 and $60, respectively. These courses will both be organized so that each day will be devoted to papers and discussions on a different pediatric problem. At the University of Michigan, Dr. James Wilson and the pediatric staff will be hosts, as well as part of the faculty for the course. Other speakers will include members of other departments and the guest speakers, Dr. Warren Wheeler, Professor of Pediatrics and Bacteriology, Ohio State University Medical School, and Dr. Frederick C. Robbins, Director, Department of Pediatrics and Contagious Diseases, Cleveland City Hospital.

News and Announcements

PEDIATRICS ◽  
1974 ◽  
Vol 53 (6) ◽  
pp. 955-955
Keyword(s):  
Annual Meeting ◽  
International Society ◽  
Medical Center ◽  
Pediatric Gastroenterology ◽  
University Of Minnesota ◽  
School Of Medicine ◽  
Common Problems ◽  
Sick Children ◽  
Nutrition Diagnosis ◽  
Vanderbilt University

PAEDIATIC NEUROSURGERY: The International Society for Paediatric Neurosurgery, annual meeting, London, England, September 13-14. For information write Kenneth Till, The Hospital for Sick Children, Great Ormond Street, London WC IN 3JH, England. PEDIATRIC GASTROENTEROLOCY AND NUTRITION: The Children's Hospital of Vanderbilt University, Fifth Annual Autumn Pediatric Symposium on Pediatric Gastroenterology and Nutrition-Diagnosis and Management of Common Problems, September 20-21. Guest faculty: Dr. William Schubert, Department of Pediatrics, University of Cincinnati School of Medicine; Dr. Phil Sunshine, Department of Pediatrics, Stanford University Medical Center; and Dr. Harvey Sharp, Department of Pediatrics, University of Minnesota Medical Center. For information write Harry L. Greene, M.D., Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.

scholarly journals Association of patient-to-emergency department staff ratio with the incidence of cardiac arrest: A retrospective cohort study

2021 ◽  
Keyword(s):  
Emergency Department ◽  
Cardiac Arrest ◽  
Cohort Study ◽  
Length Of Stay ◽  
Retrospective Cohort Study ◽  
Retrospective Cohort ◽  
Medical Center ◽  
Occupancy Rate ◽  
Number Of Patients ◽  
Ed Overcrowding

Background: Emergency department (ED) overcrowding and overuse are global healthcare problems. Despite that substantial pieces of literature have explored quality parameters to monitor the patients’ safety and quality of care in the ED, to the best of our knowledge, no reasonable patient-to-ED staff ratios were established. Objectives: This study aimed to find the association between unexpected emergency department cardiac arrest (EDCA) and the patient-to-ED staff ratio. Methods: A retrospective cohort study was conducted in a medical center in Taiwan. Non-trauma patients (age > 18) who visited the ED from January 1, 2016 to November 30, 2018 were included. The total number of patients in ED, number of patients waiting for boarding, length of stay over 48 hours, and physician/nurse number in ED were collected and analyzed. The primary outcome was the association of each parameter with the incidence of EDCA. Results: A total of 508 patients were included. The total number of patients in ED ( > 361, RR: 1.54; 95% CI {1.239-1.917}), ED occupancy rate (> 280, RR: 1.54; 95% CI {1.245-1.898}), ED bed occupancy rate (> 184, RR: 1.63; 95% CI {1.308-2.034}), number of patients waiting for boarding (> 134, RR: 1.45; 95% CI {1.164-1.805}), number of patients in ED with length of stay over 48 hours (> 36, RR: 1.27; 95% CI {1.029-1.558}) and patient-to-nurse ratio (> 8.5, adjusted RR: 1.33; 95% CI {1.054-1.672}) had significant associations with higher incidence of EDCA. However, the patient-to-physician ratio was not associated with EDCA incidence. Discussions: Regarding loading parameters, the patient-to-nurse ratio is more representative than the patient-to-physician ratio as regards association with higher EDCA incidence. Conclusions: A higher patient-to-nurse ratio (> 8.5) was associated with an increment in the incidence of EDCA. Our findings provide a basis for setting different thresholds for different ED settings to adjust ED staff and develop individually tailored approaches corresponding to the level of ED overcrowding.

scholarly journals Impact of tocilizumab administration on mortality in severe COVID-19

2020 ◽  
Author(s):  
Andrew Tsai ◽  
Oumou Diawara ◽  
Ronald G Nahass ◽  
Luigi Brunetti
Keyword(s):  
Pulmonary Disease ◽  
Propensity Scores ◽  
Medical Center ◽  
Healthcare Providers ◽  
Severity Of Illness ◽  
Standard Of Care ◽  
Care Group ◽  
Chronic Pulmonary Disease ◽  
Cytokine Storm ◽  
Novel Coronavirus

Background The novel coronavirus disease 2019 (COVID-19) worldwide pandemic has placed a significant burden on hospitals and healthcare providers. The immune response to this disease is thought to lead to a cytokine storm, which contributes to the severity of illness. There is an urgent need to confirm whether the use of tocilizumab provides a benefit in individuals with COVID-19. Methods A single-center propensity-score matched cohort study, including all consecutive COVID-19 patients, admitted to the medical center who were either discharged from the medical center or expired between March 1, 2020, and May 5, 2020, was performed. Patients were stratified according to the receipt of tocilizumab for cytokine storm and matched to controls using propensity scores. The primary outcome was in-hospital mortality. Results A total of 132 patients were included in the matched dataset (tocilizumab=66; standard of care=66). Approximately 73% of the patients were male. Hypertension (55%), diabetes mellitus (31%), and chronic pulmonary disease (15%) were the most common comorbidities present. There were 18 deaths (27.3%) in the tocilizumab group and 18 deaths (27.3%) in the standard of care group (odds ratio, 1.0; 95% confidence interval, 0.465 - 2.151; p=1.00). Advanced age, history of myocardial infarction, dementia, chronic pulmonary disease, heart failure, and malignancy were significantly more common in patients who died. Interpretation The current analysis does not support the use of tocilizumab for the management of cytokine storm in patients with COVID-19. Use of this therapeutic agent should be limited to the context of a clinical trial until more evidence is available.

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