Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Evaluation of EPI distortion correction methods for quantitative MRI of the brain at high magnetic field

High field MRI has been applied to high-resolution structural and functional imaging of the brain. Echo planar imaging (EPI) is an ultrafast acquisition technique widely used in diffusion imaging, functional MRI and perfusion imaging. However, it suffers from geometric and intensity distortions caused by static magnetic field inhomogeneity, which is worse at higher field strengths. Such susceptibility artifacts are particularly severe in relation to the small size of the mouse brain. In this study we compared different distortion correction methods, including nonlinear registration, field map-based, and reversed phase-encoding-based approaches, on quantitative imaging of T1 and perfusion in the mouse brain acquired by spin-echo EPI with inversion recovery and pseudo-continuous arterial spin labeling, respectively, at 7. T. Our results showed that the 3D reversed phase-encoding correction outperformed other methods in terms of geometric fidelity, and that conventional field map-based correction could be improved by combination with affine transformation to reduce the bias in the field map. Both methods improved quantification with smaller fitting error and regional variation. These approaches offer robust correction of EPI distortions at high field strengths and hence could lead to more accurate co-registration and quantification of imaging biomarkers in both clinical and preclinical applications

A cross-sectional study on the rate of non-adherence to anti-seizure medications and factors associated with non-adherence among patients with epilepsy.

BackgroundNon-adherence to anti-seizure medication (ASM) therapy is an important contributing factor to the higher mortality rate and treatment failure of epilepsy. This study aimed to determine the rate and factors associated with non-adherence to ASM therapy through the WHO five dimensions of medication adherence framework.MethodsWe conducted a cross-sectional study at an outpatient Neurology Clinic of a tertiary government hospital in Malaysia. Between March and July 2019, we identified 217 patients with a confirmed diagnosis of epilepsy, receiving oral ASM therapy and able to administer their medications. We performed a semi-structured interview to gather information on sociodemographic background, clinical and medication history, and perceptions on healthcare services. Adherence to ASM therapy was evaluated using the Medication Compliance Questionnaire (MCQ). Patient's illness perception was assessed by the Brief Illness Perception Questionnaire (B-IPQ).Results208 patients participated in this study. The median age of the study participants was 35 years (IQR 26-44). 58.2% were females and majority, 55.8%, were from the Malay ethnic group. Based on the MCQ scoring, 89 patients (42.8%) were non-adherent. Multiple logistic regression demonstrated that being employed or students (adjusted odds ratio [aOR] 2.26, 95%CI: 1.19-4.29 p = 0.012) and having an average or below average perceived access to pharmacy services (aOR 2.94, 95%CI: 1.38-6.24, p = 0.005) were significant contributors to non-adherence.ConclusionBeing employed or students and having an average or below average perceived access to pharmacy services were associated with ASM non-adherence Efforts to improve ASM adherence should adopt a comprehensive approach considering the success of adherence is contingent on the interrelationship of multiple dimensions

A double whammy:the association between comorbidities and severe dengue among adult patients-a matched case-control study

BACKGROUND: Dengue infection is the most prevalent mosquito-borne viral infection globally. Concurrently, there has also been an upsurge of non-communicable comorbidities. We aimed to investigate the association between these comorbidities and the development of severe dengue. METHODS: We performed a retrospective, case-control study involving 117 cases with severe dengue and 351 controls with non-severe dengue; matched according to gender, age (+/- 5 years old), and admission date (+/- 2 weeks). We analyzed the data using conditional odds ratio (cOR) and adjusted conditional odds ratio (AcOR) using univariate and multivariable conditional logistic regression respectively. RESULTS: Six main comorbidities namely obesity, diabetes mellitus, hypertension, hyperlipidemia, chronic pulmonary disease, and ischemic heart disease were observed among cases and controls. Multivariable conditional logistic regression model found only hypertension to be independently associated with the development of severe dengue (ACOR 2.46; 95% CI:1.09–5.53). Among symptoms at presentation, lethargy, vomiting, bleeding manifestations, and abdominal pain were associated with increased odds of severe dengue, although the associations were not statistically significant. Headache (ACOR: 0:32; 95% CI: 0.21–0.51) and skin rash (ACOR: 0.42; 95% CI: 0.22–0.81) were associated with significantly lower odds of severe dengue. Severe dengue patients were also found to have significantly higher white cell count, urea, creatinine, alanine aminotransferase, aspartate aminotransferase, creatine kinase, and lactate dehydrogenase on admission, while platelet and albumin were significantly lower compared to non-severe dengue patients. CONCLUSIONS: Our study found a significant association between hypertension and the development of severe dengue in adult patients. For clinical practice, this finding suggests that dengue patients with underlying hypertension warrant closer clinical monitoring for deterioration. The association between significant derangement in various laboratory parameters and severe dengue as shown in this study is in keeping with previous reports. While further substantiation by larger prospective studies will be desirable, this association may serve to inform the dengue triaging process

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Conditional odds ratio (cOR) and adjusted conditional odds ratio (AcOR) for the association between comorbidities and severe dengue.

Conditional odds ratio (cOR) and adjusted conditional odds ratio (AcOR) for the association between comorbidities and severe dengue.</p

Baseline Characteristics of cases (severe dengue) and controls (non-severe dengue).

Baseline Characteristics of cases (severe dengue) and controls (non-severe dengue).</p

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Admission laboratory parameters of cases (severe dengue) compared to controls (non-severe dengue).

Admission laboratory parameters of cases (severe dengue) compared to controls (non-severe dengue).</p

Clinical presentation on admission of cases (severe dengue) compared to controls (non-severe dengue).

Clinical presentation on admission of cases (severe dengue) compared to controls (non-severe dengue).</p