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Hepatitis C virus (HCV) replication requires annealing of a liver specific small-RNA, miR-122 to 2 sites on 5′ untranslated region (UTR). Annealing has been reported to (a) stabilize the genome, (b) stimulate translation and (c) promote the formation of translationally active Internal Ribosome Entry Site (IRES) RNA structure. In this report, we map the RNA element to which small RNA annealing promotes HCV to nucleotides 1-44 and identify the relative impact of small RNA annealing on virus translation promotion and genome stabilization. We mapped the optimal region on the HCV genome to which small RNA annealing promotes virus replication to nucleotides 19-37 and found the efficiency of viral RNA accumulation decreased as annealing moved away from this region. Then, by using a panel of small RNAs that promote replication with varying efficiencies we link the efficiency of lifecycle promotion with translation stimulation. By contrast small RNA annealing stabilized the viral genome even if they did not promote virus replication. Thus, we propose that miR-122 annealing promotes HCV replication by annealing to an RNA element that activates the HCV IRES and stimulates translation, and that miR-122 induced HCV genome stabilization is insufficient alone but enhances virus replication.

To estimate the association between biological DMARDs (bDMARDs; overall and by drug) as used in RA and the risk of malignant lymphomas including subtypes.

By linking nationwide Swedish registers we identified cohorts of patients with RA initiating treatment with a bDMARD (n = 16392), bDMARD-naïve (n = 55253), an age- and sex-matched general population comparator cohort (n = 229047), and all incident lymphomas 2001-16. We used Cox regression to calculate hazard ratios (HRs) of lymphoma taking calendar period and other factors into account.

There were 82 lymphomas among the bDMARD-treated patients with RA, crude incidence rate 76/100000 person-years, and 310 lymphomas among the bDMARD-naïve patients with RA, crude incidence rate 90/100000 person-years. This resulted in an adjusted HR (aHR) associated with bDMARD treatment (vs not) of 1.08 (95% CI 0.83, 1.41). The corresponding aHR for bDMARD-treated and bDMARD-naïve vs the general population was 1.65 (95% CI 1.31, 2.08) and 1.56 (95% CI 1.37, 1.78) respectively. Restricting follow-up period to after 2006, the aHR of lymphoma for patients with RA starting a first bDMARD vs bDMARD-naïve was 0.69 (95% CI 0.47, 1.00), and for bDMARD treated vs patients with RA switching from one conventional synthetic DMARDs to another, aHR was 0.46 (95% CI 0.28, 0.73). There were no signals of different risks with any particular TNF inhibitor (TNFi) agent. We found no different lymphoma subtype pattern following bDMARD therapy.

Treatment with bDMARDs, including both TNFi and non-TNFi bDMARDs, does not further increase the lymphoma risk in RA; instead, bDMARD treatment may actually reduce the excess lymphoma risk in RA.

Treatment with bDMARDs, including both TNFi and non-TNFi bDMARDs, does not further increase the lymphoma risk in RA; instead, bDMARD treatment may actually reduce the excess lymphoma risk in RA.

The diagnosis of hypoglycemia and the use of diazoxide have risen in the last decade. Diazoxide is the only Food and Drug Agency-approved pharmacologic treatment for neonatal hypoglycemia caused by hyperinsulinism (HI). Recent publications have highlighted that diazoxide has serious adverse effects (AEs) such as pulmonary hypertension (2-3%) and neutropenia (15%). Despite its increasing use, there is little information regarding dosing of diazoxide and/or monitoring for AEs.

We convened a working group of pediatric endocrinologists who were members of the Drug and Therapeutics Committee of the Pediatric Endocrine Society (PES) to review the available literature. Our committee sent a survey to its PES members regarding the use of diazoxide in their endocrine practices. Our review of the results concluded that there was substantial heterogeneity in usage and monitoring for AEs for diazoxide among pediatric endocrinologists.

Based on our extensive literature review and on the lack of consensus regarding use of diazoxide noted in our PES survey, our group graded the evidence using the framework of the Grading of Recommendations, Assessment, Development and Evaluation Working Group, and has proposed expert consensus practice guidelines for the appropriate use of diazoxide in infants and children with HI. We summarized the information on AEs reported to date and have provided practical ideas for dosing and monitoring for AEs in infants treated with diazoxide.

Based on our extensive literature review and on the lack of consensus regarding use of diazoxide noted in our PES survey, our group graded the evidence using the framework of the Grading of Recommendations, Assessment, Development and Evaluation Working Group, and has proposed expert consensus practice guidelines for the appropriate use of diazoxide in infants and children with HI. We summarized the information on AEs reported to date and have provided practical ideas for dosing and monitoring for AEs in infants treated with diazoxide.G-quadruplex (GQ) is formed at various regions of DNA, including telomeres of chromosomes and regulatory regions of oncogenes. Since GQ is important in both gene regulation and genome instability, the biological and medical implications of this abnormal DNA structure have been intensively studied. Its formation mechanisms, however, are not clearly understood yet. We report single-molecule fluorescence experiments to monitor the cotranscriptional GQ formation coupled with R-loop formation using T7 RNA polymerase. The GQ is formed very rarely per single-round transcription. R-loop formation precedes and facilitates GQ formation. Once formed, some GQs are extremely stable, resistant even to RNase H treatment, and accumulate in multiple-round transcription conditions. On the other hand, GQ existing in the non-template strand promotes the R-loop formation in the next rounds of transcription. Our study clearly shows the existence of a positive feedback mechanism of GQ and R-loop formations, which may possibly contribute to gene regulation and genome instability.Although cancer is the leading cause of disease-related mortality in children, the relative rarity of pediatric cancers poses a significant challenge for developing novel therapeutics to further improve prognosis. Patient-derived xenograft (PDX) models, which are usually developed from high-risk tumors, are a useful platform to study molecular driver events, identify biomarkers and prioritize therapeutic agents. Here, we develop PDX for Childhood Cancer Therapeutics (PCAT), a new integrated portal for pediatric cancer PDX models. Distinct from previously reported PDX portals, PCAT is focused on pediatric cancer models and provides intuitive interfaces for querying and data mining. The current release comprises 324 models and their associated clinical and genomic data, including gene expression, mutation and copy number alteration. Importantly, PCAT curates preclinical testing results for 68 models and 79 therapeutic agents manually collected from individual agent testing studies published since 2008. To facilitate comparisons of patterns between patient tumors and PDX models, PCAT curates clinical and molecular data of patient tumors from the TARGET project. In addition, PCAT provides access to gene fusions identified in nearly 1000 TARGET samples. PCAT was built using R-shiny and MySQL. The portal can be accessed at http//pcat.zhenglab.info or http//www.pedtranscriptome.org.

Transient hyperglycaemia in the context of illness with or without known diabetes has been termed as ‘stress hyperglycaemia’. Stress hyperglycaemia can result in poor functional outcomes in patients with acute ischaemic stroke who underwent mechanical thrombectomy. We investigated the association between stress hyperglycaemia and clinical outcomes in acute ischaemic stroke patients undergoing intravenous thrombolysis (IVT).

We examined 666 consecutive patients with acute ischaemic stroke who underwent IVT from 2006-2018. All patients had a glycated haemoglobin level (HbA1c) and fasting venous blood glucose measured within 24 hours of admission. Stress hyperglycaemia ratio (SHR) was defined as the ratio of the fasting glucose to the HbA1c. Univariate and multivariate analyses were employed to identify predictors of poor functional outcomes (modified Rankin Scale 3-6 at 3 months) after IVT.

Three-hundred and sixty-one patients (54.2%) had good functional outcomes. These patients tended to be younger (60.7±12.7 vs 70 ±14.4 years, p < 0.001), male (70.7% vs 51.5%, p < 0.001), had lower prevalence of atrial fibrillation (13.0% vs 20.7%, p = 0.008) and lower SHR (0.88±0.20 vs 0.99±26, p < 0.001). Patients with high SHR (≥0.97) were slightly older than those with low SHR (<0.97), and were more likely to have diabetes mellitus. On multivariate analysis, higher SHR was independently associated with poor functional outcomes (adjusted odds ratio 3.85, 95% CI 1.59 – 9.09, p = 0.003).

SHR appears to be an important predictor of functional outcomes in patients with AIS undergoing IVT. This may have important implications on the role of glycaemic control in the acute management of ischaemic stroke.

SHR appears to be an important predictor of functional outcomes in patients with AIS undergoing IVT. This may have important implications on the role of glycaemic control in the acute management of ischaemic stroke.

Interest in the clinical usefulness of machine learning for risk prediction has bloomed recently. Cardiac surgery patients are at high risk of complications and therefore presurgical risk assessment is of crucial relevance. We aimed to compare the performance of machine learning algorithms over traditional logistic regression (LR) model to predict in-hospital mortality following cardiac surgery.

A single-centre data set of prospectively collected information from patients undergoing adult cardiac surgery from 1996 to 2017 was split into 70% training set and 30% testing set. Prediction models were developed using neural network, random forest, naive Bayes and retrained LR based on features included in the EuroSCORE. Adavosertib Discrimination was assessed using area under the receiver operating characteristic curve, and calibration analysis was undertaken using the calibration belt method. Model calibration drift was assessed by comparing Goodness of fit χ2 statistics observed in 2 equal bins from the testing sample ordered by procedure date.

A total of 28 761 cardiac procedures were performed during the study period. The in-hospital mortality rate was 2.7%. Retrained LR [area under the receiver operating characteristic curve 0.80; 95% confidence interval (CI) 0.77-0.83] and random forest model (0.80; 95% CI 0.76-0.83) showed the best discrimination. All models showed significant miscalibration. Retrained LR proved to have the weakest calibration drift.

Our findings do not support the hypothesis that machine learning methods provide advantage over LR model in predicting operative mortality after cardiac surgery.

Our findings do not support the hypothesis that machine learning methods provide advantage over LR model in predicting operative mortality after cardiac surgery.