Evaluation of in silico pathogenicity prediction tools for the classification of small in-frame indels

This is the final version. Available from BMC via the DOI in this record.All variants in the final dataset are included in Additional file 2. The publicly available variant datasets are available from gnomAD [22] or ClinVar [10]. Genomic datasets from the DDD Study are available under managed access for research into developmental disorders via the European Genome-phenome Archive (EGAS00001000775). Individual pathogenic/likely pathogenic variants are openly accessible with phenotypes via DECIPHER [38].Background: The use of in silico pathogenicity predictions as evidence when interpreting genetic variants is widely accepted as part of standard variant classification guidelines. Although numerous algorithms have been developed and evaluated for classifying missense variants, in-frame insertions/deletions (indels) have been much less well studied. Methods: We created a dataset of 3964 small (< 100 bp) indels predicted to result in in-frame amino acid insertions or deletions using data from gnomAD v3.1 (minor allele frequency of 1–5%), ClinVar and the Deciphering Developmental Disorders (DDD) study. We used this dataset to evaluate the performance of nine pathogenicity predictor tools: CADD, CAPICE, FATHMM-indel, MutPred-Indel, MutationTaster2021, PROVEAN, SIFT-indel, VEST-indel and VVP. Results: Our dataset consisted of 2224 benign/likely benign and 1740 pathogenic/likely pathogenic variants from gnomAD (n = 809), ClinVar (n = 2882) and, DDD (n = 273). We were able to generate scores across all tools for 91% of the variants, with areas under the ROC curve (AUC) of 0.81–0.96 based on the published recommended thresholds. To avoid biases caused by inclusion of our dataset in the tools’ training data, we also evaluated just DDD variants not present in either gnomAD or ClinVar (70 pathogenic and 81 benign). Using this subset, the AUC of all tools decreased substantially to 0.64–0.87. Several of the tools performed similarly however, VEST-indel had the highest AUCs of 0.93 (full dataset) and 0.87 (DDD subset). Conclusions: Algorithms designed for predicting the pathogenicity of in-frame indels perform well enough to aid clinical variant classification in a similar manner to missense prediction tools.Medical Research Council (MRC)Health Innovation Challenge FundWellcome Trust Sanger Institut

Standardization of epidemiological surveillance of acute rheumatic fever

Acute rheumatic fever (ARF) is a multiorgan inflammatory disorder that results from the body’s autoimmune response to pharyngitis or a skin infection caused by Streptococcus pyogenes (Strep A). Acute rheumatic fever mainly affects those in low- and middle-income nations, as well as in indigenous populations in wealthy nations, where initial Strep A infections may go undetected. A single episode of ARF puts a person at increased risk of developing long-term cardiac damage known as rheumatic heart disease. We present case definitions for both definite and possible ARF, including initial and recurrent episodes, according to the 2015 Jones Criteria, and we discuss current tests available to aid in the diagnosis. We outline the considerations specific to ARF surveillance methodology, including discussion on where and how to conduct active or passive surveillance (eg, early childhood centers/schools, households, primary healthcare, administrative database review), participant eligibility, and the surveillance population. Additional considerations for ARF surveillance, including implications for secondary prophylaxis and follow-up, ARF registers, community engagement, and the impact of surveillance, are addressed. Finally, the core elements of case report forms for ARF, monitoring and audit requirements, quality control and assurance, and the ethics of conducting surveillance are discussed

Standardization of epidemiological surveillance of rheumatic heart disease

Rheumatic heart disease (RHD) is a long-term sequela of acute rheumatic fever (ARF), which classically begins after an untreated or undertreated infection caused by Streptococcus pyogenes (Strep A). RHD develops after the heart valves are permanently damaged due to ARF. RHD remains a leading cause of morbidity and mortality in young adults in resource-limited and low- and middle-income countries. This article presents case definitions for latent, suspected, and clinical RHD for persons with and without a history of ARF, and details case classifications, including differentiating between definite or borderline according to the 2012 World Heart Federation echocardiographic diagnostic criteria. This article also covers considerations specific to RHD surveillance methodology, including discussions on echocardiographic screening, where and how to conduct active or passive surveillance (eg, early childhood centers/schools, households, primary healthcare), participant eligibility, and the surveillance population. Additional considerations for RHD surveillance, including implications for secondary prophylaxis and follow-up, RHD registers, community engagement, and the negative impact of surveillance, are addressed. Finally, the core elements of case report forms for RHD, monitoring and audit requirements, quality control and assurance, and the ethics of conducting surveillance are discussed

Static platelet adhesion, flow cytometry and serum TXB2 levels for monitoring platelet inhibiting treatment with ASA and clopidogrel in coronary artery disease: a randomised cross-over study

<p>Abstract</p> <p>Background</p> <p>Despite the use of anti-platelet agents such as acetylsalicylic acid (ASA) and clopidogrel in coronary heart disease, some patients continue to suffer from atherothrombosis. This has stimulated development of platelet function assays to monitor treatment effects. However, it is still not recommended to change treatment based on results from platelet function assays. This study aimed to evaluate the capacity of a static platelet adhesion assay to detect platelet inhibiting effects of ASA and clopidogrel. The adhesion assay measures several aspects of platelet adhesion simultaneously, which increases the probability of finding conditions sensitive for anti-platelet treatment.</p> <p>Methods</p> <p>With a randomised cross-over design we evaluated the anti-platelet effects of ASA combined with clopidogrel as well as monotherapy with either drug alone in 29 patients with a recent acute coronary syndrome. Also, 29 matched healthy controls were included to evaluate intra-individual variability over time. Platelet function was measured by flow cytometry, serum thromboxane B₂(TXB₂)-levels and by static platelet adhesion to different protein surfaces. The results were subjected to Principal Component Analysis followed by ANOVA, t-tests and linear regression analysis.</p> <p>Results</p> <p>The majority of platelet adhesion measures were reproducible in controls over time denoting that the assay can monitor platelet activity. Adenosine 5'-diphosphate (ADP)-induced platelet adhesion decreased significantly upon treatment with clopidogrel compared to ASA. Flow cytometric measurements showed the same pattern (r²= 0.49). In opposite, TXB₂-levels decreased with ASA compared to clopidogrel. Serum TXB₂and ADP-induced platelet activation could both be regarded as direct measures of the pharmacodynamic effects of ASA and clopidogrel respectively. Indirect pharmacodynamic measures such as adhesion to albumin induced by various soluble activators as well as SFLLRN-induced activation measured by flow cytometry were lower for clopidogrel compared to ASA. Furthermore, adhesion to collagen was lower for ASA and clopidogrel combined compared with either drug alone.</p> <p>Conclusion</p> <p>The indirect pharmacodynamic measures of the effects of ASA and clopidogrel might be used together with ADP-induced activation and serum TXB₂for evaluation of anti-platelet treatment. This should be further evaluated in future clinical studies where screening opportunities with the adhesion assay will be optimised towards increased sensitivity to anti-platelet treatment.</p

Introduction revisiting the Argentine crisis a decade on: changes and continuities

This introductory chapter to the book "Argentina Since the 2001 Crisis Recovering the Past, Reclaiming the Future" analyses crisis and its associated responses and subsequent recovery in the context of Argentina’s multiple implosion of 2001-02 whilst also assessing its legacies for the country’s social, cultural, economic and political realms during the last decade. It recognises that "crisis" is a term that is much used in the post-Lehman Brothers world and that the subsequent responses and associated recoveries (or lack of) have been the subject of a cascade of academic, government, media, and think-tank investigation ever since. The chapter instead seeks to understand the nature of how crisis and its impacts should be investigated and interrogated, by rejecting false dichotomies of ‘old’ and ‘new’ and synthesising understanding to form an analysis that draws both elements of continuity and elements of change. Secondly, it argues that crisis manifests itself in a number of realms, and that heuristic devices employed to investigate them must subsequently also be drawn from across a range of disciplinary perspectives. Thirdly, it examines how the 2001-02 crisis in Argentina led to a series of responses that both rejected the neoliberal model yet also recovered elements of it. Finally it outlines the structure of the rest of the book, briefly summarising the chapters in turn

Frequency and severity of myocardial perfusion abnormalities using Tc-99m MIBI SPECT in cardiac syndrome X

BACKGROUND: Cardiac syndrome X is defined by a typical angina pectoris with normal or near normal (stenosis <40%) coronary angiogram with or without electrocardiogram (ECG) change or atypical angina pectoris with normal or near normal coronary angiogram plus a positive none-invasive test (exercise tolerance test or myocardial perfusion scan) with or without ECG change. Studies with myocardial perfusion imaging on this syndrome have indicated some abnormal perfusion scan. We evaluated the role of myocardial perfusion imaging (MPI) and also the severity and extent of perfusion abnormality using Tc-99m MIBI Single Photon Emission Computed Tomography (SPECT) in these patients. METHODS: The study group consisted of 36 patients with cardiac syndrome X. The semiquantitative perfusion analysis was performed using exercise Tc-99m MIBI SPECT. The MPI results were analyzed by the number, location and severity of perfusion defects. RESULTS: Abnormal perfusion defects were detected in 13 (36.10%) cases, while the remaining 23 (63.90%) had normal cardiac imaging. Five of 13 (38.4%) abnormal studies showed multiple perfusion defects. The defects were localized in the apex in 3, apical segments in 4, midventricular segments in 12 and basal segments in 6 cases. Fourteen (56%) of all abnormal segments revealed mild, 7(28%) moderate and 4 (16%) severe reduction of tracer uptake. No fixed defects were identified. The vessel territories were approximately the same in all subjects. The Exercise treadmill test (ETT) was positive in 25(69%) and negative in 11(30%) patients. There was no consistent pattern as related to the extent of MPI defects or exercise test results. CONCLUSION: Our study suggests that multiple perfusion abnormalities with different levels of severity are common in cardiac syndrome X, with more than 30 % of these patients having at least one abnormal perfusion segment. Our findings suggest that in these patients microvascular angina is probably more common than is generally believed

Relationships between cardiorespiratory fitness/muscular strength and 18F-fluorodeoxyglucose uptake in brown adipose tissue after exposure to cold in young, sedentary adults

Humans have metabolically active brown adipose tissue (BAT). However, what is the relation between exercise or physical activity with this tissue remains controversial. Therefore, the main aim of the present study is to examine whether cardiorespiratory fitness and muscular strength are associated with brown adipose tissue (BAT) volume and activity after exposure to cold in young, sedentary adults. Cardiorespiratory fitness was determined in 119 young, healthy, sedentary adults (68% women, age 21.9 ± 2.1 years, body mass index 25 ± 4.8 kg/m2) via the maximum treadmill exercise test, and their muscular strength assessed by the handgrip strength test and the 1-repetition maximum bench and leg press tests. Some days later, all subjects were exposed to 2 h of personalized exposure to cold and their cold-induced BAT volume and activity determined by a combination of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography and computed tomography scan. Cardiorespiratory fitness was associated with neither the BAT volume nor BAT activity (P ≥ 0.05). However, handgrip strength with respect to lean body mass was positively (though weakly) associated with BAT activity as represented by the 18F-FDG mean standardised uptake value (SUV) (β = 3.595, R2 = 0.039, P = 0.031) and SUVpeak value (β = 15.314, R2 = 0.037, P = 0.035). The above relationships remained after adjusting for several confounders. No other associations were found. Handgrip strength with respect to lean body mass is positively associated with BAT activity (SUVmean and SUVpeak) in young adults after exposure to cold - but only weakly. Further studies are needed to reveal the relationship between muscular fitness and human BAT characteristics.This study was supported by the Spanish Ministry of Economy and Competitiveness via the Fondo de Investigación Sanitaria del Instituto de Salud Carlos III (PI13/01393), Retos de la Sociedad (DEP2016-79512-R) and European Regional Development Funds (ERDF), the Spanish Ministry of Education (FPU13/04365 and FPU14/04172), the Fundación Iberoamericana de Nutrición (FINUT), the Redes Temáticas de Investigación Cooperativa RETIC (Red SAMID RD16/0022), the AstraZeneca HealthCare Foundation, the University of Granada Plan Propio de Investigación 2016 -Excellence actions: Unit of Excellence on Exercise and Health (UCEES) - and Plan Propio de Investigación 2018 - Programa Contratos-Puente, and the Junta de Andalucía, Consejería de Conocimiento, Investigación y Universidades (ERDF: SOMM17/6107/UGR)

Bipolar disorders

Bipolar disorder is characterized by (hypo)manic episodes and depressive episodes which alternate with euthymic periods. It causes serious disability with poor outcome, increased suicidality risk, and significant societal costs. This chapter describes the findings of the PET/SPECT research efforts and the current ideas on the pathophysiology of bipolar disorder. First, the cerebral blood flow and cerebral metabolism findings in the prefrontal cortex, limbic system, subcortical structures, and other brain regions are discussed, followed by an overview of the corticolimbic theory of mood disorders that explains these observations. Second, the neurotransmitter studies are discussed. The serotonin transporter alterations are described, and the variation in study results is explained, followed by an overview of the results of the various dopamine receptor and transporter molecules studies, taking into account also the relation to psychosis. Third, a concise overview is given of dominant bipolar disorder pathophysiological models, proposing starting points for future molecular imaging studies. Finally, the most important conclusions are summarized, followed by remarks about the observed molecular imaging study designs specific for bipolar disorder.</p

Blast Shock Wave Mitigation Using the Hydraulic Energy Redirection and Release Technology

A hydraulic energy redirection and release technology has been developed for mitigating the effects of blast shock waves on protected objects. The technology employs a liquid-filled plastic tubing as a blast overpressure transformer to transfer kinetic energy of blast shock waves into hydraulic energy in the plastic tubings. The hydraulic energy is redirected through the plastic tubings to the openings at the lower ends, and then is quickly released with the liquid flowing out through the openings. The samples of the specifically designed body armor in which the liquid-filled plastic tubings were installed vertically as the outer layer of the body armor were tested. The blast test results demonstrated that blast overpressure behind the body armor samples was remarkably reduced by 97% in 0.2 msec after the liquid flowed out of its appropriate volume through the openings. The results also suggested that a volumetric liquid surge might be created when kinetic energy of blast shock wave was transferred into hydraulic energy to cause a rapid physical movement or displacement of the liquid. The volumetric liquid surge has a strong destructive power, and can cause a noncontact, remote injury in humans (such as blast-induced traumatic brain injury and post-traumatic stress disorder) if it is created in cardiovascular system. The hydraulic energy redirection and release technology can successfully mitigate blast shock waves from the outer surface of the body armor. It should be further explored as an innovative approach to effectively protect against blast threats to civilian and military personnel