Environmental risk factors and biomarkers for autism spectrum disorder:an umbrella review of the evidence

Background Numerous studies have identified potential risk factors and biomarkers for autism spectrum disorder. We aimed to study the strength and validity of the suggested environmental risk factors or biomarkers of autism spectrum disorder. Methods We did an umbrella review and systematically appraised the relevant meta-analyses of observational studies. We searched PubMed, Embase, and the Cochrane Database of Systematic Reviews for papers published between database inception and Oct 17, 2018, and screened the reference list of relevant articles. We obtained the summary effect, 95% CI, heterogeneity, and 95% prediction intervals. We examined small study effects and excess significance. We did analyses under credibility ceilings. This review is registered with PROSPERO, number CRD42018091704. Findings 46 eligible articles yielded data on 67 environmental risk factors (544 212 cases, 81 708 787 individuals) and 52 biomarkers (15 614 cases, 15 433 controls). Evidence of association was convincing for maternal age of 35 years or over (relative risk [RR] 1.31, 95% CI 1.18-1.45), maternal chronic hypertension (odds ratio [OR] 1.48, 1.29-1.70), maternal gestational hypertension (OR 1.37, 1.21-1.54), maternal overweight before or during pregnancy (RR 1.28, 1.19-1.36), pre-eclampsia (RR 1.32, 1.20-1.45), prepregnancy maternal antidepressant use (RR 1.48, 1.29-1.71), and maternal selective serotonin reuptake inhibitor (SSRI) use during pregnancy (OR 1.84, 1.60-2.11). Only two associations, maternal overweight before or during pregnancy and SSRI use during pregnancy, retained their high level of evidence under subset sensitivity analyses. Evidence from biomarkers was scarce, being supported by p values close to the significance threshold and too few cases. Interpretation Convincing evidence suggests that maternal factors, such as age and features of metabolic syndrome, are associated with risk of autism spectrum disorder. Although SSRI use during pregnancy was also associated with such risk when exposed and non-exposed groups were compared, this association could be affected by other confounding factors, considering that prepregnancy maternal antidepressant use was also convincingly associated with higher risk of autism spectrum disorder. Findings from previous studies suggest that one possible confounding factor is underlying maternal psychiatric disorders. Copyright (C) 2019 Elsevier Ltd. All rights reserved.Funding Agencies|Health Education England [ICA-CL-2017-03-001]; National Institute for Health Research (NIHR) [ICA-CL-2017-03-001]; NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust; Maudsley Charity; Kings College London; NIHR South London Collaboration for Leadership in Applied Health Research and Care</p

Molecular biomarkers in the context of focal therapy for prostate cancer: Recommendations of a delphi consensus from the focal therapy society

BACKGROUND: Focal therapy (FT) for prostate cancer (PCa) is promising. However, long-term oncological results are awaited and there is no consensus on follow-up strategies. Molecular biomarkers (MB) may be useful in selecting, treating and following up men undergoing FT, though there is limited evidence in this field to guide practice. We aimed to conduct a consensus meeting, endorsed by the Focal Therapy Society, amongst a large group of experts, to understand the potential utility of MB in FT for localized PCa. METHODS: A 38-item questionnaire was built following a literature search. The authors then performed three rounds of a Delphi Consensus using DelphiManager, using the GRADE grid scoring system, followed by a face-to-face expert meeting. Three areas of interest were identified and covered concerning MB for FT, 1) the current/present role; 2) the potential/future role; 3) the recommended features for future studies. Consensus was defined using a 70% agreement threshold. RESULTS: Of 95 invited experts, 42 (44.2%) completed the three Delphi rounds. Twenty-four items reached a consensus and they were then approved at the meeting involving (N.=15) experts. Fourteen items reached a consensus on uncertainty, or they did not reach a consensus. They were re-discussed, resulting in a consensus (N.=3), a consensus on a partial agreement (N.=1), and a consensus on uncertainty (N.=10). A final list of statements were derived from the approved and discussed items, with the addition of three generated statements, to provide guidance regarding MB in the context of FT for localized PCa. Research efforts in this field should be considered a priority. CONCLUSIONS: The present study detailed an initial consensus on the use of MB in FT for PCa. This is until evidence becomes available on the subject

Lupus-related single nucleotide polymorphisms and risk of diffuse large B-cell lymphoma

Objective: Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genome-wide association study (GWAS), we assessed whether certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with DLBCL. Methods: GWAS data on European Caucasians from the International Lymphoma Epidemiology Consortium (InterLymph) provided a total of 3857 DLBCL cases and 7666 general-population controls. Data were pooled in a random-effects meta-analysis. Results: Among the 28 SLE-related SNPs investigated, the two most convincingly associated with risk of DLBCL included the CD40 SLE risk allele rs4810485 on chromosome 20q13 (OR per risk allele=1.09, 95% CI 1.02 to 1.16, p=0.0134), and the HLA SLE risk allele rs1270942 on chromosome 6p21.33 (OR per risk allele=1.17, 95% CI 1.01 to 1.36, p=0.0362). Of additional possible interest were rs2205960 and rs12537284. The rs2205960 SNP, related to a cytokine of the tumour necrosis factor superfamily TNFSF4, was associated with an OR per risk allele of 1.07, 95% CI 1.00 to 1.16, p=0.0549. The OR for the rs12537284 (chromosome 7q32, IRF5 gene) risk allele was 1.08, 95% CI 0.99 to 1.18, p=0.0765. Conclusions: These data suggest several plausible genetic links between DLBCL and SLE

Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes

Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22–1.82, P-value = 8.5 × 10−5]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93–3.51, P-value = 4.0 × 10−10). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk

Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma

Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new geno ..

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of three new genome-wide association studies (GWAS) and one prior scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of nine promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; $P=2.33x10^{-21}$), rs2523607 at 6p21.33 (HLA-B; $2.40x10^{-10}$), rs79480871 at 2p23.3 (NCOA1; $P=4.23x10^{-8}$), and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; $P=9.98x10^{-13}$ and $P=3.63x10^{-11}$, respectively). These data provide substantial new evidence for genetic susceptibility to this B-cell malignancy, and point towards pathways involved in immune recognition and immune function in the pathogenesis of DLBCL

Grammatical Error Correction for L2 Speech Using Publicly Available Data

Over the past decades, the demand for learning English as a second language (L2) has grown consistently, as it has gradually become the lingua franca of business, culture, entertainment, and academia. This aspect has contributed to an increasing demand for systems for automatic feedback for applications in Computer-Assisted Language Learning. In this regard, mastering grammar is a key element of L2 speaking proficiency. In this paper, we illustrate an approach to spoken grammatical error correction (GEC) in a cascaded fashion using only publicly available training data. Specifically, we start from learners' utterances, investigate disfluency detection, and finally explore GEC. We test this pipeline on NICT-JLE, a publicly available L2 corpus, and TLT-GEC, a private dataset that is under preparation for release. We obtain promising results which outperform previous studies that used large proprietary datasets, and we set a potential baseline for future experiments on spoken GEC