Clinical Exome Gene Panel Analysis of a Cohort of Urothelial Bladder Cancer Patients from Sri Lanka.

BACKGROUND: Bladder cancer has a high rate of recurrence and high mortality rates in those who progress to muscle invasive disease. Biomarkers and molecular sub classification of tumours beyond standard histopathology has been proposed to address therapeutic dilemmas. The Cancer Genome Atlas project and other studies have contributed to the enhanced knowledge base of the mutational landscape of urothelial bladder cancer. Once again, these are mostly from Caucasian and Chinese patients, with data from the rest of Asia and Sri Lanka being sparse. The objective of this study was to assess the genomic variations of a cohort of urothelial bladder cancer patients in Sri Lanka. METHODS: The molecular genetic study was conducted on formalin fixed paraffin embedded tumour samples of 24 patients, prospectively enrolled from 2013 to 2017. The samples were sequenced and variant distribution performed based on a 70-gene panel. RESULTS: Total number of filtered mutations in the 24 patients was 10453. Median mutations per patient were 450 (range 22-987). The predominant mutational change was C>T and G>A. The top 5 mutated genes in our cohort were SYNE1, SYNE2, KMT2C, LRP2, and ANK2. The genes were clustered into 3 groups dependent on the number of mutations per patient per gene. The genes of cluster 1 and 2 mapped to Chromatin modifying enzymes and Generic Transcription Pathway. The chromatin remodelling pathway accounted for the largest proportion (22%) of mutations. CONCLUSIONS: Clinical exome sequencing utilising a gene panel yielded a high mutation rate in our patients. The predominant mutational change was C>T and G>A. Three clusters of genes were identified. SYNE1 was the gene with the most mutations. The mutations comprised predominantly of genes of the chromatin remodelling pathway.

Simultaneous Acquisition of Diffusion Tensor and Dynamic Diffusion MRI.

BACKGROUND: Dynamic diffusion magnetic resonance imaging (ddMRI) metrics can assess transient microstructural alterations in tissue diffusivity but requires additional scan time hindering its clinical application. PURPOSE: To determine whether a diffusion gradient table can simultaneously acquire data to estimate dynamic and diffusion tensor imaging (DTI) metrics. STUDY TYPE: Prospective. SUBJECTS: Seven healthy subjects, 39 epilepsy patients (15 female, 31 male, age ± 15). FIELD STRENGTH/SEQUENCE: Two-dimensional diffusion MRI (b = 1000 s/mm2 ) at a field strength of 3 T. Sessions in healthy subjects-standard ddMRI (30 directions), standard DTI (15 and 30 directions), and nested cubes scans (15 and 30 directions). Sessions in epilepsy patients-two 30 direction (standard ddMRI, 10 nested cubes) or two 15 direction scans (standard DTI, 5 nested cubes). ASSESSMENT: Fifteen direction DTI was repeated twice for within-session test-retest measurements in healthy subjects. Bland-Altman analysis computed bias and limits of agreement for DTI metrics using test-retest scans and standard 15 direction vs. 5 nested cubes scans. Intraclass correlation (ICC) analysis compared tensor metrics between 15 direction DTI scans (standard vs. 5 nested cubes) and the coefficients of variation (CoV) of trace and apparent diffusion coefficient (ADC) between 30 direction ddMRI scans (standard vs. 10 nested cubes). STATISTICAL TESTS: Bland-Altman and ICC analysis using a P-value of 0.05 for statistical significance. RESULTS: Correlations of mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were strong and significant in gray (ICC > 0.95) and white matter (ICC > 0.95) between standard vs. nested cubes DTI acquisitions. Correlation of white matter fractional anisotropy was also strong (ICC > 0.95) and significant. ICCs of the CoV of dynamic ADC measured using repeated cubes and nested cubes acquisitions were modest (ICC >0.60), but significant in gray matter. CONCLUSION: A nested cubes diffusion gradient table produces tensor-based and dynamic diffusion measurements in a single acquisition. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 1.

Demographics and distribution of australia's medical immigrant workforce.

Background: International medical graduates (IMGs) have made important contributions to Australian healthcare since colonization. Recent published data have documented source countries and characteristics of IMGs undertaking the examinations of the Australian Medical Council. However, information about those currently practicing in Australia is limited. Objective: To analyze a cross section of IMGs currently practicing in Australia to determine patterns of change in donor countries, other demographic characteristics, geographical locations, and their areas of specialization. Methods: A random sample of all practitioners on a national database was interrogated for their country of first medical qualification. Those who qualified outside Australia were then analyzed for demographic variables such as age, gender, country of origin, and years of graduation and immigration. Their practice locations were matched to the Australian Bureau of Statistics geographical framework, and their specialties compared with those of a random sample of graduates from Australian medical schools. Results: Over the approximately 60 years since those surveyed arrived in Australia, IMGs' countries/regions of origin have changed from mainly the UK and Ireland to Southern Asia, in line with demographic changes in Australia as a whole. Most arrived soon after graduation, and IMGs are twice IMGs as likely as local graduates to be working in a rural area of workforce shortage. Compared with local graduates, significantly more IMGs are working in general practice. Conclusions: IMGs currently practicing in Australia make up a substantial proportion of the workforce and are more likely than local graduates to provide health services in regional and remote areas.

Highly Efficient and Accurate Deep Learning-Based Classification of MRI Contrast on a CPU and GPU.

Classifying MR images based on their contrast mechanism can be useful in image segmentation where additional information from different contrast mechanisms can improve intensity-based segmentation and help separate the class distributions. In addition, automated processing of image type can be beneficial in archive management, image retrieval, and staff training. Different clinics and scanners have their own image labeling scheme, resulting in ambiguity when sorting images. Manual sorting of thousands of images would be a laborious task and prone to error. In this work, we used the power of transfer learning to modify pretrained residual convolution neural networks to classify MRI images based on their contrast mechanisms. Training and validation were performed on a total of 5169 images belonging to 10 different classes and from different MRI vendors and field strengths. Time for training and validation was 36 min. Testing was performed on a different data set with 2474 images. Percentage of correctly classified images (accuracy) was 99.76%. (A deeper version of the residual network was trained for 103 min and showed slightly lower accuracy of 99.68%.) In consideration of model deployment in the real world, performance on a single CPU computer was compared with GPU implementation. Highly accurate classification, training, and testing can be achieved without use of a GPU in a relatively short training time, through proper choice of a convolutional neural network and hyperparameters, making it feasible to improve accuracy by repeated training with cumulative training sets. Techniques to improve accuracy further are discussed and demonstrated. Derived heatmaps indicate areas of image used in decision making and correspond well with expert human perception. The methods used can be easily extended to other classification tasks with minimal changes.

A case report of post-surgical page kidney due to extensive renal hematoma following percutaneous nephrolithotomy.

INTRODUCTION AND IMPORTANCE: Post-surgical Page kidney due to large renal hematoma following percutaneous nephrolithotomy (PCNL) is a rare significant complication that may lead to loss of a kidney. CASE PRESENTATION: A 50-year-old lady underwent elective left side PCNL for a 3 cm renal pelvis stone, and one week later, she presented back with a massive renal hematoma with high blood pressure. CLINICAL DISCUSSION: The ultrasound abdomen and computed tomography diagnosed a page kidney due to massive intrarenal and perirenal hematoma as a complication of PCNL. Angioembolization and percutaneous aspiration were failed, and the antihypertensives also failed to control the blood pressure. Therefore, she underwent a left-side simple nephrectomy and had an uneventful recovery with reversal of normal blood pressure. CONCLUSION: Post-surgical page kidney needs to identify early to facilitate the percutaneous radiological interventions that may preserve the renal parenchyma and avoid further surgeries. Nevertheless, late cases or the failed radiologically intervened cases need open renal exploration and simple nephrectomy, which may be the bailed-out procedure to reverse the consequence of page kidney.

A qualitative exploration of psychosocial well-being experiences in a South African rural community.

The aim of this study was to explore and describe the psychosocial well-being experiences of a South African rural community. The study employed a qualitative explorative-descriptive research design in which participants (n = 20) were sampled through purposive sampling and participated in a world café session. Data were analyzed thematically. The findings identify three main themes with subthemes, namely contributing factors to psychosocial well-being (such as spirituality/religion and community cohesion), hindering factors to psychosocial well-being (such as crime and unemployment), and means to promote psychosocial well-being (such as provision of infrastructure). The findings provide insight into the psychosocial well-being experiences of an understudied and vulnerable South African rural community and makes recommendations for future research.

Quality, nutrient and sensory characteristics of aged meat from lambs supplemented with selenomethionine.

Selenium (Se) as a co-factor of antioxidant enzymes is metabolically essential for animals. Its presence in muscle can improve the oxidative stability of meat and is a desirable nutrient for consumers. A novel approach to Se supplementation for meat-producing livestock was demonstrated in a 95-day study of young lambs. DL-selenomethionine (SeMet) was administered by subcutaneous injection at day 0 (3-4 weeks of age) and again at day 54. A Control group (n = 9) received carrier only, whilst Medium and High groups (n = 10) received graded levels of Se. Physicochemical attributes of meat quality and sensory characteristics were measured at 1, 3, 14 and 42 days of ageing (vacuum packaged at -1.5 °C), followed by instrumental colour measurements after 7 days of simulated retail display. There were no significant interactions between SeMet treatment and ageing. Muscle pH, drip and cooking losses, initial display colour and sensory evaluations by trained and consumer panels were unaffected by treatment. Smaller changes in colour during display were observed for the Medium group compared to Control (P < 0.05). The shorter range of ageing times improved meat tenderness however extended ageing decreased colour stability. SeMet markedly increased Se concentrations in muscle, blood, kidney and liver (P < 0.05), resulting in Se enriched meat without appreciable changes in meat quality.

Nonhuman primates exposed to Zika virus in utero are not protected against reinfection at 1 year postpartum.

There is limited information about the impact of Zika virus (ZIKV) exposure in utero on the anti-ZIKV immune responses of offspring. We infected six rhesus macaque dams with ZIKV early or late in pregnancy and studied four of their offspring over the course of a year postpartum. Despite evidence of ZIKV exposure in utero, we observed no structural brain abnormalities in the offspring. We detected infant-derived ZIKV-specific immunoglobulin A antibody responses and T cell memory responses during the first year postpartum in the two offspring born to dams infected with ZIKV early in pregnancy. Critically, although the infants had acquired some immunological memory of ZIKV, it was not sufficient to protect them against reinfection with ZIKV at 1 year postpartum. The four offspring reexposed to ZIKV at 1 year postpartum all survived but exhibited acute viremia and viral tropism to lymphoid tissues; three of four reexposed offspring exhibited spinal cord pathology. These data suggest that macaque infants born to dams infected with ZIKV during pregnancy remain susceptible to postnatal infection and consequent neuropathology.

Rapid Diagnosis of Meningococcal Meningitis in a Patient With Familial Mediterranean Fever by the FilmArray Meningitis/Encephalitis Panel: A Case Report.

Familial Mediterranean fever (FMF) is a rare autoinflammatory disorder of the innate immune system. Patients with innate immune system defects are at a high risk of meningococcal disease, although it is unclear if patients with FMF also have increased susceptibility to invasive infection. Herein, we present a diagnostically challenging case of a male adolescent with a past medical history of FMF stabilized on colchicine who presented with some of the early clinical features of community-acquired bacterial meningitis. To our knowledge, this is the first case of meningococcal meningitis in a patient with FMF diagnosed with the FilmArray Meningitis/Encephalitis (ME) Panel. This case report demonstrates that rapid detection of Neisseria meningitidis by the ME Panel can aid in the early diagnosis and prompt treatment of patients with suspected meningitis and may be the only positive test in patients with early presentation and/or prior antimicrobial therapy.

Systematic review with meta-analysis: sirolimus- or everolimus-based immunosuppression following liver transplantation for hepatocellular carcinoma.

BACKGROUND: Calcineurin-inhibitor immunosuppressants (tacrolimus and ciclosporin) have been associated with an exposure-related increase in tumour recurrence following liver transplantation for hepatocellular carcinoma (HCC). Conversely, mechanistic target of rapamycin (mTOR) inhibitors (sirolimus and everolimus) have been suggested to reduce recurrence rates and improve survival in this patient group. AIM: To clarify the potential benefit of mTOR-inhibitors in HCC transplant patients by comparing recurrence and survival outcomes with calcineurin-inhibitor-based immunosuppression. METHODS: A systematic review and meta-analysis was performed. The inclusion criteria were observational or interventional studies reporting the effect of early-initiated (<6 months post-transplant) mTOR-inhibitor-based immunosuppression on survival or tumour recurrence in patients transplanted with HCC, compared to a control of calcineurin-inhibitor-based therapy. RESULTS: Meta-analysis demonstrated that compared with calcineurin-inhibitor controls, recurrence-free-survival was significantly increased with mTOR-inhibitor-based therapy at 1-year (Risk-Ratio (RR): 1.09, 95% CI: 1.01-1.18) and 3-years (RR: 1.1, 95% CI: 1.01-1.21) post-transplant, with a nonsignificant increase at 5-years (RR: 1.15, 95% CI: 0.99-1.35). Overall survival was improved at 1-year (RR: 1.07, 95% CI: 1.02-1.12), 3-years (RR: 1.1, 95% CI: 1.02-1.19), and 5-years (RR: 1.18, 95% CI: 1.08-1.29). Recurrence-rate was lower in the mTOR-inhibitor arm (RR: 0.67, 95% CI: 0.56-0.82), with no significant increase in acute rejection (RR: 1.1, 95% CI: 0.94-1.28). CONCLUSIONS: mTOR-inhibitor-based immunosuppression may be a preferable option in patients transplanted with HCC. It improves recurrence-free-survival over at least three years and reduces the recurrence rate compared with standard calcineurin-inhibitor-based therapy, with no significant increase in the rate of acute rejection. Future research should clarify the effect in higher vs lower risk cohorts.

Determining the optimal postlabeling delay for arterial spin labeling using subject-specific estimates of blood velocity in the carotid artery.

BACKGROUND: Arterial spin labeling with 3D acquisition requires determining a single postlabeling delay (PLD) value. PLD affects the signal-to-noise ratio (SNR) per unit time as well as quantitative cerebral blood flow (CBF) values due to its bearing on the presence of a vascular signal. PURPOSE: To search for an optimal PLD for pseudocontinuous arterial spin labeling (pCASL) using patient-specific carotid artery blood velocity measurements. STUDY TYPE: Prospective. SUBJECTS: A control group of 11 volunteers with no known pathology. Corroboration was through a separate group of six volunteers and a noncontrol group of five sickle cell disease (SCD) patients. FIELD STRENGTH/SEQUENCE: Pseudocontinuous arterial spin labeling with 3D nonsegmented echo planar imaging acquisition at 3T. ASSESSMENT: A perfusion-based measure was determined over a range of PLDs for each of 11 volunteers. A third-order polynomial was used to find the optimal PLD where the defined measure was maximum. This was plotted against the corresponding carotid artery velocity to determine a relationship between the perfusion measure and velocity. Corroboration was done using a group of six volunteers and a noncontrol group of five patients with SCD. PLD was determined from the carotid artery velocity and derived relationship and compared with optimal PLD obtained from measured perfusion over a range of PLD values. Error between the perfusion measure at predicted and measured optimal PLD was determined. STATISTICAL TESTS: Chi-squared goodness of fit; Pearson correlation; Bland-Altman. RESULTS: Carotid artery velocity was 63.8 ± 6.6 cm/s (53.1 ≤ v ≤ 72.3 cm/s) while optimal PLD was 1374 ± 226.5 msec (1102 ≤ PLD ≤ 1787 msec) across the 11 volunteers. PLD as a function of carotid velocity was determined to be PLD = -31.94. v + 3410 msec (Pearson correlation -0.93). In six volunteers, mean error between the perfusion measure at predicted and measured optimal PLD was 1.35%. Pearson correlation between the perfusion measure at the predicted PLD and the measure obtained experimentally was r = 0.96 (P < 0.001). Bland-Altman revealed a slight bias of 1.3%. For the test case of five SCD patients, the mean error was 1.3%. DATA CONCLUSION: Carotid artery velocity was used to determine optimal PLD for pCASL with 3D acquisition. The derived relationship was used to predict optimal PLD and the associated perfusion measure, which was found to be accurate when compared with its measured counterpart. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;50:951-960.

Systematic Review and Meta-analysis: Optimal Salvage Therapy in Acute Severe Ulcerative Colitis.

BACKGROUND: Infliximab is an effective salvage therapy in acute severe ulcerative colitis; however, the optimal dosing strategy is unknown. We performed a systematic review and meta-analysis to examine the impact of infliximab dosage and intensification on colectomy-free survival in acute severe ulcerative colitis. METHODS: Studies reporting outcomes of hospitalized steroid-refractory acute severe ulcerative colitis treated with infliximab salvage were identified. Infliximab use was categorized by dose, dose number, and schedule. The primary outcome was colectomy-free survival at 3 months. Pooled proportions and odds ratios with 95% confidence intervals were reported. RESULTS: Forty-one cohorts (n = 2158 cases) were included. Overall colectomy-free survival with infliximab salvage was 79.7% (95% confidence interval [CI], 75.48% to 83.6%) at 3 months and 69.8% (95% CI, 65.7% to 73.7%) at 12 months. Colectomy-free survival at 3 months was superior with 5-mg/kg multiple (≥2) doses compared with single-dose induction (odds ratio [OR], 4.24; 95% CI, 2.44 to 7.36; P < 0.001). However, dose intensification with either high-dose or accelerated strategies was not significantly different to 5-mg/kg standard induction at 3 months (OR, 0.70; 95% CI, 0.39 to 1.27; P = 0.24) despite being utilized in patients with a significantly higher mean C-reactive protein and lower albumin levels. CONCLUSIONS: In acute severe ulcerative colitis, multiple 5-mg/kg infliximab doses are superior to single-dose salvage. Dose-intensified induction outcomes were not significantly different compared to standard induction and were more often used in patients with increased disease severity, which may have confounded the results. This meta-analysis highlights the marked variability in the management of infliximab salvage therapy and the need for further studies to determine the optimal dose strategy.

Helicobacter pylori and low-dose aspirin ulcer risk: A meta-analysis.

BACKGROUND AND AIM: Owing to wide-spread use, low-dose aspirin (LDA) produces a substantial amount of peptic ulcer disease. Current guidelines are ambivalent about the need for Helicobacter pylori eradication to protect against LDA ulcers. This study aimed to determine, through meta-analysis, if (and by how much) infection alters the baseline risk of peptic ulcers during LDA therapy. METHODS: Literature screening was performed in MEDLINE and EMBASE from inception to May 2018. Original studies reporting prevalence or incidence of uncomplicated ulcers in LDA users were included. Ulcer endpoints needed to be specified separately, according to H. pylori infection status. Meta-analysis was performed in MIX 2.0 Pro. RESULTS: Ten cross-sectional studies and seven randomized controlled trials were included (n = 5964). The pooled odds ratios with 95% confidence intervals (CI) for the risk of LDA ulcers in H. pylori-positive versus H. pylori-negative individuals were 1.68 (95%CI 1.40-2.02) and 1.65 (95%CI 1.29-2.08) under fixed-effects and random-effects models, respectively. Heterogeneity among studies was minimal (I2  = 26.9%). After adjusting for the protective effects of antisecretory drugs, the odds ratios increased to 1.94 (95%CI 1.54-2.46). CONCLUSION: This analysis suggests that H. pylori increases the risk of LDA ulcers by almost 70% in a population where some were taking proton pump inhibitors and/or other acid suppressants. Without antisecretory drugs, the risk almost doubles. Clinically, these findings may support the use of a test-and-treat approach to H. pylori in LDA users, particularly those already at higher risk of developing peptic ulcers.

China's response to a national land-system sustainability emergency.

China has responded to a national land-system sustainability emergency via an integrated portfolio of large-scale programmes. Here we review 16 sustainability programmes, which invested US$378.5 billion (in 2015 US$), covered 623.9 million hectares of land and involved over 500 million people, mostly since 1998. We find overwhelmingly that the interventions improved the sustainability of China's rural land systems, but the impacts are nuanced and adverse outcomes have occurred. We identify some key characteristics of programme success, potential risks to their durability, and future research needs. We suggest directions for China and other nations as they progress towards the Sustainable Development Goals of the United Nations' Agenda 2030.

The potential benefits of aspirin for primary cardiovascular prevention in rheumatoid arthritis: a secondary analysis of the PRECISION Trial.

Objective: Guidelines exist for the use of low-dose aspirin in the general population for primary cardiovascular (CV) prevention, but the risk-benefit considerations may differ in RA. While RA confers an increased CV risk, such patients more likely use NSAIDs and corticosteroids. Methods: We conducted a cohort study to assess potential risks and benefits of low-dose aspirin. We estimated incidence rates and hazard ratios (HRs) using Cox regression among subjects with RA but no known CV disease in the Prospective Randomized Evaluation of Celecoxib Integrated Safety Vs Ibuprofen Or Naproxen trial. The primary exposure of interest was low-dose aspirin, and all enrolled patients were provided open-label esomeprazole. The primary composite outcome was major NSAID toxicity, including major adverse CV event (MACE), clinically significant gastrointestinal events, renal events and all-cause mortality. Results: We found 1852 subjects with RA in Prospective Randomized Evaluation of Celecoxib Integrated Safety Vs Ibuprofen Or Naproxen without known CV disease; 540 reported using low-dose aspirin for CV prevention and 1312 did not. Any major NSAID toxicity was observed in 79 (6.0%) non-aspirin users and 37 (6.9%) aspirin users (P = 0.50). Aspirin users experienced all components of the primary outcome at a similar rate to non-users. In fully adjusted models, the risk for major NSAID toxicity was similar between aspirin exposure groups (HR = 1.08, 95% CI: 0.69, 1.69). The risk for MACE was also similar between exposure groups in age- and gender-adjusted models (HR = 1.23, 95% CI: 0.72, 2.10). Conclusion: RA patients using low-dose aspirin with chronic NSAIDs and esomeprazole had a similar risk of major NSAID toxicity and MACE as patients who did not.