Recovirus NS1-2 Has Viroporin Activity That Induces Aberrant Cellular Calcium Signaling To Facilitate Virus Replication.

Enteric viruses in the Caliciviridae family cause acute gastroenteritis in humans and animals, but the cellular processes needed for virus replication and disease remain unknown. A common strategy among enteric viruses, including rotaviruses and enteroviruses, is to encode a viral ion channel (i.e., viroporin) that is targeted to the endoplasmic reticulum (ER) and disrupts host calcium (Ca2+) homeostasis. Previous reports have demonstrated genetic and functional similarities between the nonstructural proteins of caliciviruses and enteroviruses, including the calicivirus NS1-2 protein and the 2B viroporin of enteroviruses. However, it is unknown whether caliciviruses alter Ca2+ homeostasis for virus replication or whether the NS1-2 protein has viroporin activity like its enterovirus counterpart. To address these questions, we used Tulane virus (TV), a rhesus enteric calicivirus, to examine Ca2+ signaling during infection and determine whether NS1-2 has viroporin activity that disrupts Ca2+ homeostasis. We found that TV increases Ca2+ signaling during infection and that increased cytoplasmic Ca2+ levels are important for efficient replication. Further, TV NS1-2 localizes to the endoplasmic reticulum, the predominant intracellular Ca2+ store, and the NS2 region has characteristics of a viroporin domain (VPD). NS1-2 had viroporin activity in a classic bacterial functional assay and caused aberrant Ca2+ signaling when expressed in mammalian cells, but truncation of the VPD abrogated these activities. Together, our data provide new mechanistic insights into the function of the NS2 region of NS1-2 and support the premise that enteric viruses, including those within Caliciviridae, exploit host Ca2+ signaling to facilitate their replication.IMPORTANCE Tulane virus is one of many enteric caliciviruses that cause acute gastroenteritis and diarrheal disease. Globally, enteric caliciviruses affect both humans and animals and amass >65 billion dollars per year in treatment and health care-associated costs, thus imposing an enormous economic burden. Recent progress has resulted in several cultivation systems (B cells, enteroids, and zebrafish larvae) to study human noroviruses, but mechanistic insights into the viral factors and host pathways important for enteric calicivirus replication and infection are still largely lacking. Here, we used Tulane virus, a calicivirus that is biologically similar to human noroviruses and can be cultivated by conventional cell culture, to identify and functionally validate NS1-2 as an enteric calicivirus viroporin. Viroporin-mediated calcium signaling may be a broadly utilized pathway for enteric virus replication, and its existence within caliciviruses provides a novel approach to developing antivirals and comprehensive therapeutics for enteric calicivirus diarrheal disease outbreaks.

Bridging the Gap Between Consumers' Medication Questions and Trusted Answers.

This paper addresses the task of answering consumer health questions about medications. To better understand the challenge and needs in terms of methods and resources, we first introduce a gold standard corpus for Medication Question Answering created using real consumer questions. The gold standard (https://github.com/abachaa/Medication_QA_MedInfo2019) consists of six hundred and seventy-four question-answer pairs with annotations of the question focus and type and the answer source. We first present the manual annotation and answering process. In the second part of this paper, we test the performance of recurrent and convolutional neural networks in question type identification and focus recognition. Finally, we discuss the research insights from both the dataset creation process and our experiments. This study provides new resources and experiments on answering consumers' medication questions and discusses the limitations and directions for future research efforts.

Wood Dust in Joineries and Furniture Manufacturing: An Exposure Determinant and Intervention Study.

Objectives: To assess wood dust exposures and determinants in joineries and furniture manufacturing and to evaluate the efficacy of specific interventions on dust emissions under laboratory conditions. Also, in a subsequent follow-up study in a small sample of joinery workshops, we aimed to develop, implement, and evaluate a cost-effective and practicable intervention to reduce dust exposures. Methods: Personal inhalable dust (n = 201) was measured in 99 workers from 10 joineries and 3 furniture-making factories. To assess exposure determinants, full-shift video exposure monitoring (VEM) was conducted in 19 workers and task-based VEM in 32 workers (in 7 joineries and 3 furniture factories). We assessed the efficacy of vacuum extraction on hand tools and the use of vacuum cleaners instead of sweeping and dry wiping under laboratory conditions. These measures were subsequently implemented in three joinery workshops with 'high' (>4 mg m-3) and one with 'low' (<2 mg m-3) baseline exposures. We also included two control workshops (one 'low' and one 'high' exposure workshop) in which no interventions were implemented. Exposures were measured 4 months prior and 4 months following the intervention. Results: Average (geometric means) exposures in joinery and furniture making were 2.5 mg m-3 [geometric standard deviations (GSD) 2.5] and 0.6 mg m-3 (GSD 2.3), respectively. In joinery workers cleaning was associated with a 3.0-fold higher (P < 0.001) dust concentration compared to low exposure tasks (e.g. gluing), while the use of hand tools showed 3.0- to 11.0-fold higher (P < 0.001) exposures. In furniture makers, we found a 5.4-fold higher exposure (P < 0.001) with using a table/circular saw. Laboratory efficiency experiments showed a 10-fold decrease in exposure (P < 0.001) when using a vacuum cleaner. Vacuum extraction on hand tools combined with a downdraft table reduced exposures by 42.5% for routing (P < 0.1) and 85.5% for orbital sanding (P < 0.001). Following intervention measures in joineries, a borderline statistically significant (P < 0.10) reduction in exposure of 30% was found in workshops with 'high' baseline exposures, but no reduction was shown in the workshop with 'low' baseline exposures. Conclusions: Wood dust exposure is high in joinery workers and (to a lesser extent) furniture makers with frequent use of hand tools and cleaning being key drivers of exposure. Vacuum extraction on hand tools and alternative cleaning methods reduced workplace exposures substantially, but may be insufficient to achieve compliance with current occupational exposure limits.

Toward a comprehensive drug ontology: extraction of drug-indication relations from diverse information sources.

BACKGROUND: Drug ontologies could help pharmaceutical researchers overcome information overload and speed the pace of drug discovery, thus benefiting the industry and patients alike. Drug-disease relations, specifically drug-indication relations, are a prime candidate for representation in ontologies. There is a wealth of available drug-indication information, but structuring and integrating it is challenging. RESULTS: We created a drug-indication database (DID) of data from 12 openly available, commercially available, and proprietary information sources, integrated by terminological normalization to UMLS and other authorities. Across sources, there are 29,964 unique raw drug/chemical names, 10,938 unique raw indication "target" terms, and 192,008 unique raw drug-indication pairs. Drug/chemical name normalization to CAS numbers or UMLS concepts reduced the unique name count to 91 or 85% of the raw count, respectively, 84% if combined. Indication "target" normalization to UMLS "phenotypic-type" concepts reduced the unique term count to 57% of the raw count. The 12 sources of raw data varied widely in coverage (numbers of unique drug/chemical and indication concepts and relations) generally consistent with the idiosyncrasies of each source, but had strikingly little overlap, suggesting that we successfully achieved source/raw data diversity. CONCLUSIONS: The DID is a database of structured drug-indication relations intended to facilitate building practical, comprehensive, integrated drug ontologies. The DID itself is not an ontology, but could be converted to one more easily than the contributing raw data. Our methodology could be adapted to the creation of other structured drug-disease databases such as for contraindications, precautions, warnings, and side effects.

Effect of Hurricane Sandy on Health Care Services Utilization Under Medicaid.

OBJECTIVE: This investigation assessed changes in utilization of inpatient, outpatient, emergency department, and pharmacy services in the aftermath of Hurricane Sandy in 8 counties in New York affected by the storm. METHODS: Medicaid data for enrollees residing in 8 counties in New York were used to obtain aggregated daily counts of claims for 4 service types over immediate, 3-month, and 1-year periods following the storm. Negative binomial regression was used to compare service utilization in the storm year with the 2 prior years, within areas differentially affected by the storm. RESULTS: Changes in service utilization within areas inside or outside the storm zone were most pronounced over the 1-year effect period. Differences in service utilization by year were the same by storm zone designation over the immediate effect period for all services. CONCLUSIONS: Results are consistent with previous investigations demonstrating that some of the greatest effects of a disaster on health services utilization occur well beyond the initial event. One-year effects, combined with some 3-month effects, suggests that storm recovery, with its effect on health care services utilization, may have followed different paths in areas designated as inside or outside the storm zone. (Disaster Med Public Health Preparedness. 2016;10:472-484).

Poisoning deaths involving opioid analgesics - New York State, 2003-2012.

Deaths involving opioid analgesics have increased dramatically in the United States. Approximately 4,000 such deaths were documented in 1999, increasing to 16,235 in 2013, reflecting a nearly quadrupled death rate from 1.4 to 5.1 deaths per 100,000. To investigate this increase in New York state, trends in poisoning deaths involving opioid analgesics from 2003 to 2012 were examined. Data sources used were New York state vital statistics multiple-cause-of-death data, consisting of data from both the New York City (NYC)* and non-NYC reporting jurisdictions, as well as statewide Medicaid enrollment data. Deaths involving opioid analgesics increased both in number and as a percentage of all drug poisoning deaths, and rates were highest among men, whites, persons aged 45-64 years, persons residing outside of NYC, and Medicaid enrollees. The analysis found that, in 2012, 70.7% of deaths involving opioid analgesics also involved at least one other drug, most frequently a benzodiazepine. These results underscore the potential to mitigate the trend of increasing opioid analgesic-related mortality through initiatives such as New York state's Internet System for Tracking Over-Prescribing (I-STOP) law,† which took effect on August 27, 2013. Provisions under I-STOP include the requirements that providers consult the Prescription Monitoring Program (PMP) Registry when writing prescriptions for controlled substances, and that they use electronic prescribing.

Chronic continuous exenatide infusion does not cause pancreatic inflammation and ductal hyperplasia in non-human primates.

In this study, we aimed to evaluate the effects of exenatide (EXE) treatment on exocrine pancreas of nonhuman primates. To this end, 52 baboons (Papio hamadryas) underwent partial pancreatectomy, followed by continuous infusion of EXE or saline (SAL) for 14 weeks. Histological analysis, immunohistochemistry, Computer Assisted Stereology Toolbox morphometry, and immunofluorescence staining were performed at baseline and after treatment. The EXE treatment did not induce pancreatitis, parenchymal or periductal inflammatory cell accumulation, ductal hyperplasia, or dysplastic lesions/pancreatic intraepithelial neoplasia. At study end, Ki-67-positive (proliferating) acinar cell number did not change, compared with baseline, in either group. Ki-67-positive ductal cells increased after EXE treatment (P = 0.04). However, the change in Ki-67-positive ductal cell number did not differ significantly between the EXE and SAL groups (P = 0.13). M-30-positive (apoptotic) acinar and ductal cell number did not change after SAL or EXE treatment. No changes in ductal density and volume were observed after EXE or SAL. Interestingly, by triple-immunofluorescence staining, we detected c-kit (a marker of cell transdifferentiation) positive ductal cells co-expressing insulin in ducts only in the EXE group at study end, suggesting that EXE may promote the differentiation of ductal cells toward a ß-cell phenotype. In conclusion, 14 weeks of EXE treatment did not exert any negative effect on exocrine pancreas, by inducing either pancreatic inflammation or hyperplasia/dysplasia in nonhuman primates.

Discovery of novel biomarkers and phenotypes by semantic technologies.

BACKGROUND: Biomarkers and target-specific phenotypes are important to targeted drug design and individualized medicine, thus constituting an important aspect of modern pharmaceutical research and development. More and more, the discovery of relevant biomarkers is aided by in silico techniques based on applying data mining and computational chemistry on large molecular databases. However, there is an even larger source of valuable information available that can potentially be tapped for such discoveries: repositories constituted by research documents. RESULTS: This paper reports on a pilot experiment to discover potential novel biomarkers and phenotypes for diabetes and obesity by self-organized text mining of about 120,000 PubMed abstracts, public clinical trial summaries, and internal Merck research documents. These documents were directly analyzed by the InfoCodex semantic engine, without prior human manipulations such as parsing. Recall and precision against established, but different benchmarks lie in ranges up to 30% and 50% respectively. Retrieval of known entities missed by other traditional approaches could be demonstrated. Finally, the InfoCodex semantic engine was shown to discover new diabetes and obesity biomarkers and phenotypes. Amongst these were many interesting candidates with a high potential, although noticeable noise (uninteresting or obvious terms) was generated. CONCLUSIONS: The reported approach of employing autonomous self-organising semantic engines to aid biomarker discovery, supplemented by appropriate manual curation processes, shows promise and has potential to impact, conservatively, a faster alternative to vocabulary processes dependent on humans having to read and analyze all the texts. More optimistically, it could impact pharmaceutical research, for example to shorten time-to-market of novel drugs, or speed up early recognition of dead ends and adverse reactions.

A framework for characterizing drug information sources.

Drug information is complex, voluminous, heterogeneous, and dynamic. Multiple sources are available, each providing some elements of information about drugs (usually for a given purpose), but there exists no integrated view or directory that could be used to locate sources appropriate to a given purpose. We examined 23 sources that provide drug information in the pharmacy, chemistry, biology, and clinical medicine domains. Their drug information content could be categorized with 39 dimensions. We propose this list of dimensions as a framework for characterizing drug information sources. As an evaluation, we show that this framework is useful for comparing drug information sources and selecting sources most relevant to a given use case.

Quinine levels revisited: the value of routine drug level monitoring for those on parenteral therapy.

Parenteral quinine is the most frequently used first line treatment for severe Plasmodium falciparum malaria in the developed world. Quinine is known to have a number of toxic side effects including cardiotoxicity, ototoxicity and ocular toxicity. Many therefore advocate routine monitoring of quinine levels for patients receiving parenteral therapy. This paper reviews current evidence on the usefulness of quinine level monitoring in the context of 73 adult patients with severe P. falciparum malaria managed by the Hospital for Tropical Diseases in London. Combining data from these patients with a comprehensive literature review, we conclude that routine quinine level monitoring in all patients receiving parenteral therapy is seldom appropriate.

Foot evaluation by infrared imaging.

For better assessment of foot injury severity during basic military training, we evaluated a simple noninvasive technique: thermography. With this infrared imaging method, we determined normal foot parameters (from 30 soldiers before training), thermographic findings in different foot stress fractures (from 30 soldiers so diagnosed), and normal responses to abnormal stresses in 30 trainees who underwent the same training as the previous group but did not have musculoskeletal complaints. We found that normal foot thermograms show onion peel-like progressive cooling on the plantar surface, with a medially located warm center at the instep. Thermograms of injured feet show areas of increased heat, but excessive weight-bearing pressures on feet, new shoes, or boots also cause increased infrared emission even without discomfort. Differentiation remains difficult; however, thermography can detect injury early. It does not reveal exact diagnoses, but its greatest benefit is easy follow-up to monitor severity and healing.