Super Natural II - a database of natural products

Natural products play a significant role in drug discovery and development. Many topological pharmacophore patterns are common between natural products and commercial drugs. A better understanding of the specific physicochemical and structural features of natural products is important for corresponding drug development. Several encyclopedias of natural compounds have been composed, but the information remains scattered or not freely available. The first version of the Supernatural database containing ∼50 000 compounds was published in 2006 to face these challenges. Here we present a new, updated and expanded version of natural product database, Super Natural II (http://bioinformatics.charite.de/supernatural), comprising ∼326 000 molecules. It provides all corresponding 2D structures, the most important structural and physicochemical properties, the predicted toxicity class for ∼170 000 compounds and the vendor information for the vast majority of compounds. The new version allows a template-based search for similar compounds as well as a search for compound names, vendors, specific physical properties or any substructures. Super Natural II also provides information about the pathways associated with synthesis and degradation of the natural products, as well as their mechanism of action with respect to structurally similar drugs and their target proteins

A clinical and cost-effectiveness trial of a parent group intervention to manage challenging restricted and repetitive behaviours in young children with autism spectrum disorder: study protocol for a randomised controlled trial

Background Restricted and repetitive behaviours vary greatly across the autism spectrum, and although not all are problematic some can cause distress and interfere with learning and social opportunities. We have, alongside parents, developed a parent group based intervention for families of young children with autism, which aims to offer support to parents and carers; helping them to recognise, understand and learn how to respond to their child’s challenging restricted repetitive behaviours. Methods The study is a clinical and cost-effectiveness, multi-site randomised controlled trial of the Managing Repetitive Behaviours (MRB) parent group intervention versus a psychoeducation parent group Learning About Autism (LAA) (n = 250; 125 intervention/125 psychoeducation; ~ 83/site) for parents of young children aged 3–9 years 11 months with a diagnosis of autism. All analyses will be done under intention-to-treat principle. The primary outcome at 24 weeks will use generalised estimating equation (GEE) to compare proportion of children with improved RRB between the MRB group and the LAA group. The GEE model will account for the clustering of children by parent groups using exchangeable working correlation. All secondary outcomes will be analysed in a similar way using appropriate distribution and link function. The economic evaluation will be conducted from the perspective of both NHS costs and family access to local community services. A ‘within trial’ cost-effectiveness analysis with results reported as the incremental cost per additional child achieving at least the target improvement in CGI-I scale at 24 weeks. Discussion This is an efficacy trial to investigate the clinical and cost-effectiveness of a parent group based intervention designed to help parents understand and manage their child’s challenging RRB. If found to be effective, this intervention has the potential to improve the well-being of children and their families, reduce parental stress, greatly enhance community participation and potential for learning, and improve longer-term outcomes

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Kaleidoscope of oral artifacts: A vivid picture through light and polarizing microscope

Background: This study is based on finding of an inexplicable artifact that was seen in the tissue received as periapical granuloma. Aim: To observe the histological appearance of different commonly implanted food particles and easily incorporated substances from a laboratory in the oral biopsy tissues. Materials and Methods: Various food particles such as wheat chapatti, beans, peas, pulses, and coriander leaves and substances such as a suture, cotton, and paper that can easily gain entry during biopsy and histotechnical procedures were intentionally introduced in the tissue specimens of a uterus from outside. Both light and polarizing microscopes were utilized to view them. Results: Different food particles and substances gave different appearances that could lead to misdiagnosis. Some of these also exhibited positive birefringence under the polarizing microscope. Conclusion: Knowledge and familiarity with probable foreign substances which can appear in tissues may help prevent misdiagnosis or erroneous diagnosis of biopsy specimens

Health Care Utilization and Burden of Diabetic Ketoacidosis in the U.S. Over the Past Decade: A Nationwide Analysis

OBJECTIVE: Diabetes is one of the most common chronic diseases and a leading cause of morbidity and mortality in the U.S. Although our ability to treat diabetes and its associated complications has significantly improved, presentation with uncontrolled diabetes leading to ketoacidosis remains a significant problem. RESEARCH DESIGN AND METHODS: We aimed to determine the incidence and costs of hospital admissions associated with diabetic ketoacidosis (DKA). We reviewed the National Inpatient Sample Database for all hospitalizations in which DKA (ICD-9 codes 250.10, 250.11, 250.12, and 250.13) was the principal discharge diagnosis during 2003-2014 and calculated the population incidence by using U.S. census data. Patients with ICD-9 codes for diabetic coma were excluded because the codes do not distinguish between hypoglycemic and DKA-related coma. We then analyzed changes in temporal trends of incidence, length of stay, costs, and in-hospital mortality by using the Cochrane-Armitage test. RESULTS: There were 1,760,101 primary admissions for DKA during the study period. In-hospital mortality for the cohort was 0.4% (n = 7,031). The total number of hospital discharges with the principal diagnosis of DKA increased from 118,808 in 2003 to 188,965 in 2014 (P \u3c 0.001). The length of stay significantly decreased from an average of 3.64 days in 2003 to 3.24 days in 2014 (P \u3c 0.01). During this period, the mean hospital charges increased significantly from $18,987 (after adjusting for inflation) per admission in 2003 to$26,566 per admission in 2014. The resulting aggregate charges (i.e., national bill) for diabetes with ketoacidosis increased dramatically from $2.2 billion (after adjusting for inflation) in 2003 to$ 5.1 billion in 2014 (P \u3c 0.001). However, there was a significant reduction in mortality from 611 (0.51%) in 2003 to 620 (0.3%) in 2014 (P \u3c 0.01). CONCLUSIONS: Our analysis shows that the population incidence for DKA hospitalizations in the U.S. continues to increase, but the mortality of this condition has significantly decreased, indicating advances in early diagnosis and better inpatient care. Despite decreases in the length of stay, the costs of hospitalizations have increased significantly, indicating opportunities for value-based care intervention in this vulnerable population

Molecular similarity-based predictions of the Tox21 screening outcome

To assess the toxicity of new chemicals and drugs, regulatory agencies require in vivo testing for many toxic endpoints, resulting in millions of animal experiments conducted each year. However, following the Replace, Reduce, Refine (3R) principle, the development and optimization of alternative methods, in particular in silico methods, has been put into focus in the recent years. It is generally acknowledged that the more complex a toxic endpoint, the more difficult it is to model. Therefore, computational toxicology is shifting from modelling general and complex endpoints to the investigation and modelling of pathways of toxicity and the underlying molecular effects.The U.S. Toxicology in the 21st Century (Tox21) initiative has screened a large library of compounds, including approximately 10K environmental chemicals and drugs, for different mechanisms responsible for eliciting toxic effects, and made the results publicly available. Through the Tox21 Data Challenge, the consortium has established a platform for computational toxicologists to develop and validate their predictive models.Here, we present a fast and successful method for the prediction of different outcomes of the nuclear receptor and stress response pathway screening from the Tox21 Data Challenge 2014. The method is based on the combination of molecular similarity calculations and a naïve Bayes machine learning algorithm and has been implemented as a KNIME pipeline. Molecules are represented as binary vectors consisting of a concatenation of common two-dimensional molecular fingerprint types with topological compound properties. The prediction method has been optimized individually for each modelled target and evaluated in a cross-validation as well as with the independent Tox21 validation set. Our results show that the method can achieve good prediction accuracies and rank among the top algorithms submitted to the prediction challenge, indicating its broad applicability in toxicity prediction

Efficacy of modified Tochen’s formula for optimum endotracheal tube placement in low birth weight neonates- an RCT

<div>Abstract:</div><div>Objective: To study the effectiveness of modified Tochen’s formula (hereafter known as the alternative formula) when compared to Tochen’s formula for optimal placement of endotracheal tubes in LBW neonates.</div><div>Study Design: A randomized controlled trial conducted in 70 neonates. Neonates requiring intubation for ventilation, with a confirmatory chest radiograph, were included in the study. They were intubated using Tochen’s formula (birth weight in kg + 6cm) or Alternative formula (birth weight in kg + 5cm). Tube tip placement was verified and modified, if necessary, after auscultation. The incidence of inadequate placement and optimum length of ET insertion were estimated from the chest radiographs. Incidence of adverse events in the two groups were noted.</div><div>Results: A total number of 92 babies were eligible for the study. One family refused consent and twenty-one families could not be approached and hence not included in study. A total of 70 neonates were randomized and included in the study; 34 in Tochen’s group and 33 in alternative formula group. Baseline characteristics between the two groups had no statistically significant differences (p->0.05).</div><div>Measurements in the alternative formula group were significantly (p - 0.006) closer to the optimal position (distance from optimum - 0.50 cm ± 0.41) when compared to Tochen’s group (distance from optimum - 0.86 cm ± 0.06) The adverse events were significantly (p- 0.005) greater in the group that was intubated using Tochen’s formula (16 of 34, 47.05%) when compared to the group where the alternative formula was applied (5 of 33, 15.15%). Though the percentage of optimum (8 of 33, 24.24%) and adequate placements (29 of 33, 87.87%) of the ET tube was higher in the group of the alternative formula when compared to the optimal (3 of 34, 8.82%) and adequate placement (24 of 34, 70.58%) of ET tube in the Tochen’s group, this was not statistically significant (p- >0.05). The depth of ET placement was found to be overestimated in the Tochen’s group as compared to the group of the alternative formula</div><div>Conclusion: The incidence of adequate and optimal placement of ET tube was higher in alternative formula group and the distance from optimal was significantly smaller when compared to the Tochen’s group. The adverse events were significantly fewer in the alternative formula group. Hence, the use of the alternative formula in low birth weight babies may enable the more accurate placement of ET tubes in low birth weight babies when compared to the Tochen’s formula.</div><div><br></div

Comparative analysis of various clinical specimens in detection of SARS-CoV-2 using rRT-PCR in new and follow up cases of COVID-19 infection: Quest for the best choice.

BackgroundAn appropriate specimen is of paramount importance in Real Time reverse transcription-polymerase chain reaction (rRT-PCR) based diagnosis of novel coronavirus (nCoV) disease (COVID-19). Thus, it's pertinent to evaluate various diversified clinical specimens' diagnostic utility in both diagnosis and follow-up of COVID-19.MethodsA total of 924 initial specimens from 130 COVID-19 symptomatic cases before initiation of treatment and 665 follow up specimens from 15 randomly selected cases comprising of equal number of nasopharyngeal swab (NPS), oropharyngeal swab (OPS), combined NPS and OPS (Combined swab), sputum, plasma, serum and urine were evaluated by rRT-PCR.ResultsDemographic analysis showed males (86) twice more affected by COVID-19 than females (44) (p = 0.00001). Combined swabs showed a positivity rate of 100% followed by NPS (91.5%), OPS (72.3%), sputum (63%), while nCoV was found undetected in urine, plasma and serum specimens. The lowest cycle threshold (Ct) values of targeted genes E, ORF1b and RdRP are 10.56, 10.14 and 12.26 respectively and their lowest average Ct values were found in combined swab which indicates high viral load in combined swab among all other specimen types. Analysis of 665 follow-up multi-varied specimens also showed combined swab as the last specimen among all specimen types to become negative, after an average 6.6 (range 4-10) days post-treatment, having lowest (15.48) and average (29.96) Ct values of ORF1b respectively indicating posterior nasopharyngeal tract as primary nCoV afflicted site with high viral load.ConclusionThe combined swab may be recommended as a more appropriate specimen for both diagnosis and monitoring of COVID-19 treatment by rRT-PCR for assessing virus clearance to help physicians in taking evidence-based decision before discharging patients. Implementing combined swabs globally will definitely help in management and control of the pandemic, as it is the need of the hour

Evidence that NLRC4 inflammasome mediates apoptotic and pyroptotic microglial death following ischemic stroke

10.1016/j.bbi.2018.09.001BRAIN BEHAVIOR AND IMMUNITY7534-47BBIM