A gene signature based method for identifying subtypes and subtype-specific drivers in cancer with an application to medulloblastoma

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Blood pressure screening during the May Measurement Month 2017 programme in Vietnam-South-East Asia and Australasia.

Elevated blood pressure (BP) is a growing burden worldwide, leading to over 10 million deaths each year. May Measurement Month (MMM) is a global initiative aimed at raising awareness of high BP and to act as a temporary solution to the lack of screening programmes worldwide. Our aim was to screen for hypertension (HTN) and cardiovascular risk factors in people aged ≥18 years in the community, thereby define the proportion of subjects with elevated BP and assess the awareness and the effectiveness of its treatment. An opportunistic cross-sectional survey of volunteers aged ≥18 years was carried out in May 2017. Blood pressure measurement, the definition of HTN and statistical analysis followed the standard MMM protocol. From May 2017 to June 2017, through 10 cities/provinces in Vietnam, 10 993 individuals with mean age 49.1 ± 16.2 years were screened during MMM17. After multiple imputation, 3154 (28.7%) had HTN. Of individuals not receiving antihypertensive medication, 1509 (16.1%) were hypertensive. Of individuals receiving antihypertensive medication, 620 (37.7%) had uncontrolled BP. Raised BP was also associated with additional risk factors including smoking, alcohol, overweight-obesity, and diabetes. May Measurement Month 17 was the largest BP screening campaign ever undertaken in Vietnam. Undiagnosed and uncontrolled HTN in Vietnam remains a substantial health problem. Local campaigns applying standardized methods such as MMM17, will be highly useful to screen for the significant number of individuals with raised BP and increase the awareness of HTN

Effect of clinical and virological parameters on the level of neutralizing antibody against pandemic influenza A virus H1N1 2009

Background. Little is known about the antibody response in natural infection by the novel 2009 influenza A (H1N1) virus and its relationship with clinical and virological parameters. The relative lack of background neutralizing antibody against this novel virus provides a unique opportunity for understanding this issue. Methods. Case patients presenting with influenza-like illness who were positive for the pandemic H1 gene by reverse transcription polymerase chain reaction were identified. The serum antibody response was assayed by neutralizing antibody titer (NAT) against the virus in 881 convalescent donors. We retrospectively analyzed clinical parameters and viral load. Results. Ninety percent of the 881 convalescent donors had seroprotective titer of 1:40 or greater. The geometric mean titer of donors with convalescent NAT measured between day 21 and 42 was 1:101.1. Multivariate analysis by ordinal regression showed that pneumonia (odds ratio, 3.39; 95% confidence interval, 1.49-9-7.61; P=.004) and sputum production (odds ratio, 1.75; 95% CI, 1.01-3.01; P=.046) were the 2 independent factors associated with a higher level of convalescent NAT. Being afebrile on influenza presentation was associated with subsequent poor NAT (<1:40) response (P = .04). A positive correlation between the nasopharyngeal viral load on presentation and the convalescent NAT was demonstrated (Spearman correlation r, 0.238; P = .026). Conclusions. About 10% of these convalescent patients do not have a seroprotective NAT and may benefit from vaccination to prevent reinfection. The convalescent NAT correlated well with the initial viral load and was independently associated with severity of the viral illness, including pneumonia. The findings provide both the clinical and virological markers for identifying potential convalescent plasma donors with high serum NAT, which can be used to produce hyperimmune intravenous immunoglobulin in a randomized treatment trial for patients with severe pandemic H1N1 infection. © 2010 by the Infectious Diseases Society of America. All rights reserved.published_or_final_versio

Prevalence of occult hepatitis B infection in a highly endemic area for chronic hepatitis B: A study of a large blood donor population

Background and aims: The aim of the present study was to determine the population prevalence of occult hepatitis B (OHB) infection and its clinical profile in a highly endemic area of chronic hepatitis B virus disease. Methods: OHB was first identified by individual sample testing for hepatitis B surface antigen (HBsAg) followed by nucleic acid testing (NAT) and vice versa for 3044 (cohort 1, stored sera from donation within 1 year) and 9990 (cohort 2, prospective study) blood donors, respectively. OHB was confirmed meticulously by ≥2 out of 3 tests with detectable hepatitis B virus (HBV) DNA using a sensitive standardised assay. Detailed serology and viral load in the serum and liver were studied. Results: The prevalence of OHB was 0.13% (4/3044) and 0.11% (11/9967) for cohort 1 and 2, respectively. In cohort 2, 10 out of 11 OHB samples were positive for anti-HBc (hepatitis B core antigen) antibody (all were immunoglobulin G). Seven had detectable anti-HBs. The serum HBV DNA levels were extremely low (highest 14.1 IU/ml). Of the six donors who underwent liver biopsies, all had normal liver biochemistry, extremely low liver HBV DNA (highest 6.21 copies/cell) and nearly normal liver histology. For those with viral sequence generation, none had the common HBsAg mutant G145R. Conclusions: The prevalence of OHB in a highly endemic area of chronic HBV was very low, thus implying a low impact on transfusion services. To implement universal screening, the high cost of NAT should be taken into account. OHB blood donors had very low HBV replication, and normal liver biochemistry and histology, conferring a favourable prognosis.published_or_final_versio

A rare cause of chronic mesenteric ischemia from fibromuscular dysplasia: a case report

<p>Abstract</p> <p>Introduction</p> <p>Chronic mesenteric ischemia is a condition that is classically associated with significant atherosclerosis of the abdominal arteries, causing postprandial abdominal pain out of proportion to physical examination. The abdominal pain is exacerbated after meals due to the shunting of blood away from the intestines to the stomach, causing relative ischemia. More than 95% of chronic mesenteric ischemia cases are due to atherosclerosis. We report the first known case of chronic mesenteric ischemia from fibromuscular dysplasia. To the best of our knowledge, this is also the first known case in the literature where postprandial abdominal pain was the presenting symptom of fibromuscular dysplasia.</p> <p>Case presentation</p> <p>A 44-year-old Caucasian woman with a history of hypertension and preeclampsia, who had taken oral contraceptive pills for 15 years, presented with an intractable, colicky abdominal pain of two weeks duration. This abdominal pain worsened with oral intake. It was also associated with diarrhea and vomiting. Physical examination revealed stage III hypertension out of proportion to her risk factors and diffuse abdominal pain without peritoneal signs. An abdominal computed tomography scan, completed in the emergency room, revealed nonspecific colitis. Laboratory work revealed leukocytosis with a left shift, an erythrocyte sedimentation rate of 79 and a C-reactive protein level of 100. She was started on intravenous flagyl and intravenous ciprofloxacin. However, all microbial cultures were negative including three cultures for clostridium difficile. Urine analysis revealed nephritic range proteinuria. The laboratory profile was within normal limits for perinuclear-anti-neutrophil cytoplasmic antibody, cytoplasmic-anti-neutrophil cytoplasmic antibody, anti-saccharomyces cerevisiae antibody, antinuclear antibody test, celiac profile, lactate, carbohydrate antigen-125 and thyroid stimulating hormone. A colonoscopy was completed, which revealed diffuse colonic lymphoid reactive hyperplasia. A small bowel series was negative for any inflammation. An indium scan, pan-computed tomography scan and transvaginal ultrasound were also negative. Magnetic resonance angiography of her abdomen revealed proximal superior mesenteric artery stenosis, which was confirmed by computed tomography angiogram findings of severe proximal and distal superior mesenteric artery stenosis, consistent with the appearance of fibromuscular dysplasia on angiography in the absence of vasculitis or atherosclerotic disease. The patient's superior mesenteric artery stenosis was subsequently angioplastied suboptimally and had to be stented with an Angioplus stent. One month after she was admitted, her abdominal pain and tolerance to oral feeds improved tremendously.</p> <p>Conclusion</p> <p>Fibromuscular dysplasia most commonly presents with renal artery stenosis, which rarely causes abdominal pain. This case illustrates how fibromuscular dysplasia can present as a rare cause of chronic mesenteric ischemia, similar to chronic mesenteric ischemia from atherosclerosis.</p

A cohort study: temporal trends in prevalence of antecedents, comorbidities and mortality in Aboriginal and non-Aboriginal Australians with first heart failure hospitalization, 2000-2009

Abstract Background/objectives: Little is known about trends in risk factors and mortality for Aboriginal Australians with heart failure (HF). This population-based study evaluated trends in prevalence of risk factors, 30-day and 1-year all-cause mortality following first HF hospitalization among Aboriginal and non-Aboriginal Western Australians in the decade 2000-2009. Methods: Linked-health data were used to identify patients (20-84 years), with a first-ever HF hospitalization. Trends in demographics, comorbidities, interventions and risk factors were evaluated. Logistic and Cox regression models were fitted to test and compare trends over time in 30-day and 1-year mortality. Results: Of 17,379 HF patients, 1,013 (5.8 %) were Aboriginal. Compared with 2000-2002, the prevalence (as history) of myocardial infarction and hypertension increased more markedly in 2006-2009 in Aboriginal (versus non-Aboriginal) patients, while diabetes and chronic kidney disease remained disproportionately higher in Aboriginal patients. Risk factor trends, including the Charlson comorbidity index, increased over time in younger Aboriginal patients. Risk-adjusted 30-day mortality did not change over the decade in either group. Risk-adjusted 1-year mortality (in 30-day survivors) was non-significantly higher in Aboriginal patients in 2006-2008 compared with 2000-2002 (hazard ratio (HR) 1.44; 95 % CI 0.85-2.41; p-trend = 0.47) whereas it decreased in non-Aboriginal patients (HR 0.87; 95 % CI 0.78-0.97; p-trend = 0.01). Conclusions: Between 2000 and 2009, the prevalence of HF antecedents increased and remained disproportionately higher in Aboriginal (versus non-Aboriginal) HF patients. Risk-adjusted 1-year mortality did not improve in Aboriginal patients over the period in contrast with non-Aboriginal patients. These findings highlight the need for better prevention and post-HF care in Aboriginal Australians

The positions of TFIIF and TFIIE in the RNA polymerase II transcription preinitiation complex.

We incorporated the non-natural photoreactive amino acid p-benzoyl-L-phenylalanine (Bpa) into the RNA polymerase II (Pol II) surface surrounding the central cleft formed by the Rpb1 and Rpb2 subunits. Photo-cross-linking of preinitiation complexes (PICs) with these Pol II derivatives and hydroxyl-radical cleavage assays revealed that the TFIIF dimerization domain interacts with the Rpb2 lobe and protrusion domains adjacent to Rpb9, while TFIIE cross-links to the Rpb1 clamp domain on the opposite side of the Pol II central cleft. Mutations in the Rpb2 lobe and protrusion domains alter both Pol II-TFIIF binding and the transcription start site, a phenotype associated with mutations in TFIIF, Rpb9 and TFIIB. Together with previous biochemical and structural studies, these findings illuminate the structural organization of the PIC and the network of protein-protein interactions involved in transcription start site selection

Using Unsupervised Patterns to Extract Gene Regulation Relationships for Network Construction

BACKGROUND: The gene expression is usually described in the literature as a transcription factor X that regulates the target gene Y. Previously, some studies discovered gene regulations by using information from the biomedical literature and most of them require effort of human annotators to build the training dataset. Moreover, the large amount of textual knowledge recorded in the biomedical literature grows very rapidly, and the creation of manual patterns from literatures becomes more difficult. There is an increasing need to automate the process of establishing patterns. METHODOLOGY/PRINCIPAL FINDINGS: In this article, we describe an unsupervised pattern generation method called AutoPat. It is a gene expression mining system that can generate unsupervised patterns automatically from a given set of seed patterns. The high scalability and low maintenance cost of the unsupervised patterns could help our system to extract gene expression from PubMed abstracts more precisely and effectively. CONCLUSIONS/SIGNIFICANCE: Experiments on several regulators show reasonable precision and recall rates which validate AutoPat's practical applicability. The conducted regulation networks could also be built precisely and effectively. The system in this study is available at http://ikmbio.csie.ncku.edu.tw/AutoPat/

Artemether-Lumefantrine versus Dihydroartemisinin-Piperaquine for Treating Uncomplicated Malaria: A Randomized Trial to Guide Policy in Uganda

BACKGROUND: Uganda recently adopted artemether-lumefantrine (AL) as the recommended first-line treatment for uncomplicated malaria. However, AL has several limitations, including a twice-daily dosing regimen, recommendation for administration with fatty food, and a high risk of reinfection soon after therapy in high transmission areas. Dihydroartemisinin-piperaquine (DP) is a new alternative artemisinin-based combination therapy that is dosed once daily and has a long post-treatment prophylactic effect. We compared the efficacy and safety of AL with DP in Kanungu, an area of moderate malaria transmission. METHODOLOGY/PRINCIPAL FINDINGS: Patients aged 6 months to 10 years with uncomplicated falciparum malaria were randomized to therapy and followed for 42 days. Genotyping was used to distinguish recrudescence from new infection. Of 414 patients enrolled, 408 completed follow-up. Compared to patients treated with artemether-lumefantrine, patients treated with dihydroartemisinin-piperaquine had a significantly lower risk of recurrent parasitaemia (33.2% vs. 12.2%; risk difference = 20.9%, 95% CI 13.0-28.8%) but no statistically significant difference in the risk of treatment failure due to recrudescence (5.8% vs. 2.0%; risk difference = 3.8%, 95% CI -0.2-7.8%). Patients treated with dihydroartemisinin-piperaquine also had a lower risk of developing gametocytaemia after therapy (4.2% vs. 10.6%, p = 0.01). Both drugs were safe and well tolerated. CONCLUSIONS/SIGNIFICANCE: DP is highly efficacious, and operationally preferable to AL because of a less intensive dosing schedule and requirements. Dihydroartemisinin-piperaquine should be considered for a role in the antimalarial treatment policy of Uganda. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN75606663

Association of Polymorphisms in Oxidative Stress Genes with Clinical Outcomes for Bladder Cancer Treated with Bacillus Calmette-Guérin

Genetic polymorphisms in oxidative stress pathway genes may contribute to carcinogenesis, disease recurrence, treatment response, and clinical outcomes. We applied a pathway-based approach to determine the effects of multiple single nucleotide polymorphisms (SNPs) within this pathway on clinical outcomes in non-muscle-invasive bladder cancer (NMIBC) patients treated with Bacillus Calmette-Guérin (BCG). We genotyped 276 SNPs in 38 genes and evaluated their associations with clinical outcomes in 421 NMIBC patients. Twenty-eight SNPs were associated with recurrence in the BCG-treated group (P<0.05). Six SNPs, including five in NEIL2 gene from the overall and BCG group remained significantly associated with recurrence after multiple comparison adjustments (q<0.1). Cumulative unfavorable genotype analysis showed that the risk of recurrence increased with increasing number of unfavorable genotypes. In the analysis of risk factors associated with progression to disease, rs3890995 in UNG, remained significant after adjustment for multiple comparison (q<0.1). These results support the hypothesis that genetic variations in host oxidative stress genes in NMIBC patients may affect response to therapy with BCG