Smokeless tobacco - a substantial risk for oral potentially malignant disorders in South Asia

Data sources: Medline, the Science Citation Index (SCI) via Web of Science, Scopus, CINAHL, Global Index Medicus, Google Scholar and SLT-related reports of the International Agency for Research on Cancer and the National Cancer Institute of the United States. Study selection: Observational studies on the use of SLT and the risk of developing OPMDs in South Asian Populations. Data extraction and synthesis: Duplicate selection of studies was undertaken with two reviewers undertaking data abstraction and quality assessment independently. Risk and odds ratios were extracted or calculated for studies where possible. Meta odds ratios (mOR) were calculated using a random effects analysis. Results: Fifteen papers reporting 18 studies were included. The majority (12) were from India. All the studies were case-control designs. MOR for any OPMD with the use of any SLT product was 15.5 (95% CI; 9.9–24.2). Risk was higher in women; mOR = 22.2 (95% CI, 9.1–54.1) than men; mOR = 8.7 (95% CI, 2.1–34.8). Betel quid with tobacco carried the highest risk for OPMD, mOR = 16.1 (95% CI, 7.8–33.5). Conclusions: The findings of our study point towards a strong association between some forms of OPMDs and SLT use in South Asia. The risk estimates are high, irrespective of controlling for confounders such as smoking and alcohol or stratification by sex, country or source of controls. There is also an exposure-response relationship between OPMDs and SLT use

Direct observation of intermediates in a thermodynamically controlled solid-state dynamic covalent reaction.

We present the first polymorph interconversion study that uses solid-state dynamic covalent chemistry (DCC). This system exhibits unexpected and rich behavior, including the observation that under appropriate conditions the polymorph interconversion of a heterodimer proceeds through reversible covalent chemistry intermediates, and this route is facilitated by one of the two disulfide homodimers involved in the reaction. Furthermore, we demonstrate experimentally that in all cases a dynamic equilibrium is reached, meaning that changing the milling conditions affects the free energy difference between the two polymorphs and thus their relative stability. We suggest that this effect is due to the surface solvation energy combined with the high surface to volume ratio of the nanocrystalline powder.We are grateful to the EPSRC (AMB, JKMS and DJW) and ERC(DJW) for financial support.This is the accepted manuscript. The final version is available from ACS at http://pubs.acs.org/doi/abs/10.1021/ja500707z

The role of aspirin, heparin, and other interventions in the prevention and treatment of fetal growth restriction

Fetal growth restriction and related placental pathologies such as preeclampsia, stillbirth, and placental abruption are believed to arise in early pregnancy when inadequate remodeling of the maternal spiral arteries leads to persistent high-resistance and low-flow uteroplacental circulation. The consequent placental ischaemia, reperfusion injury, and oxidative stress are associated with an imbalance in angiogenic/antiangiogenic factors. Many interventions have centered on the prevention and/or treatment of preeclampsia with results pertaining to fetal growth restriction and small-for-gestational-age pregnancy often included as secondary outcomes because of the common pathophysiology. This renders the study findings less reliable for determining clinical significance. For the prevention of fetal growth restriction, a recent large-study level meta-analysis and individual patient data meta-analysis confirm that aspirin modestly reduces small-for-gestational-age pregnancy in women at high risk (relative risk, 0.90, 95% confidence interval, 0.81-1.00) and that a dose of ≥100 mg should be recommended and to start at or before 16 weeks of gestation. These findings support national clinical practice guidelines. In vitro and in vivo studies suggest that low-molecular-weight heparin may prevent fetal growth restriction; however, evidence from randomized control trials is inconsistent. A meta-analysis of multicenter trial data does not demonstrate any positive preventative effect of low-molecular-weight heparin on a primary composite outcome of placenta-mediated complications including fetal growth restriction (18% vs 18%; absolute risk difference, 0.6%; 95% confidence interval, 10.4-9.2); use of low-molecular-weight heparin for the prevention of fetal growth restriction should remain in the research setting. There are even fewer treatment options once fetal growth restriction is diagnosed. At present the only management option if the risk of hypoxia, acidosis, and intrauterine death is high is iatrogenic preterm birth, with the use of peripartum maternal administration of magnesium sulphate for neuroprotection and corticosteroids for fetal lung maturity, to prevent adverse neonatal outcomes. The pipeline of potential therapies use different strategies, many aiming to increase fetal growth by improving poor placentation and uterine blood flow. Phosphodiesterase type 5 inhibitors that potentiate nitric oxide availability such as sildenafil citrate have been extensively researched both in preclinical and clinical studies; results from the Sildenafil Therapy In Dismal Prognosis Early-Onset Intrauterine Growth Restriction consortium of randomized control clinical trials are keenly awaited. Targeting the uteroplacental circulation with novel therapeutics is another approach, the most advanced being maternal vascular endothelial growth factor gene therapy, which is being translated into the clinic via the doEs Vascular endothelial growth factor gene therapy safEly impRove outcome in seveRe Early-onset fetal growth reSTriction consortium. Other targeting approaches include nanoparticles and microRNAs to deliver drugs locally to the uterine arterial endothelium or trophoblast. In vitro and in vivo studies and animal models have demonstrated effects of nitric oxide donors, dietary nitrate, hydrogen sulphide donors, statins, and proton pump inhibitors on maternal blood pressure, uteroplacental resistance indices, and angiogenic/antiangiogenic factors. Data from human pregnancies and, in particular, pregnancies with fetal growth restriction remain very limited. Early research into melatonin, creatine, and N-acetyl cysteine supplementation in pregnancy suggests they may have potential as neuro- and cardioprotective agents in fetal growth restriction

The Role of Parvalbumin-positive Interneurons in Auditory Steady-State Response Deficits in Schizophrenia

© The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Despite an increasing body of evidence demonstrating subcellular alterations in parvalbumin-positive (PV+) interneurons in schizophrenia, their functional consequences remain elusive. Since PV+ interneurons are involved in the generation of fast cortical rhythms, these changes have been hypothesized to contribute to well-established alterations of beta and gamma range oscillations in patients suffering from schizophrenia. However, the precise role of these alterations and the role of different subtypes of PV+ interneurons is still unclear. Here we used a computational model of auditory steady-state response (ASSR) deficits in schizophrenia. We investigated the differential effects of decelerated synaptic dynamics, caused by subcellular alterations at two subtypes of PV+ interneurons: basket cells and chandelier cells. Our simulations suggest that subcellular alterations at basket cell synapses rather than chandelier cell synapses are the main contributor to these deficits. Particularly, basket cells might serve as target for innovative therapeutic interventions aiming at reversing the oscillatory deficits.Peer reviewe

Seeing two faces together: preference formation in humans and rhesus macaques

Humans, great apes and old world monkeys show selective attention to faces depending on conspecificity, familiarity, and social status supporting the view that primates share similar face processing mechanisms. Although many studies have been done on face scanning strategy in monkeys and humans, the mechanisms influencing viewing preference have received little attention. To determine how face categories influence viewing preference in humans and rhesus macaques (Macaca mulatta), we performed two eye-tracking experiments using a visual preference task whereby pairs of faces from different species were presented simultaneously. The results indicated that viewing time was significantly influenced by the pairing of the face categories. Humans showed a strong bias towards an own-race face in an Asian–Caucasian condition. Rhesus macaques directed more attention towards non-human primate faces when they were paired with human faces, regardless of the species. When rhesus faces were paired with faces from Barbary macaques (Macaca sylvanus) or chimpanzees (Pan troglodytes), the novel species’ faces attracted more attention. These results indicate that monkeys’ viewing preferences, as assessed by a visual preference task, are modulated by several factors, species and dominance being the most influential

A Dynamic Knowledge Management Framework for the High Value Manufacturing Industry

Dynamic Knowledge Management (KM) is a combination of cultural and technological factors, including the cultural factors of people and their motivations, technological factors of content and infrastructure and, where these both come together, interface factors. In this paper a Dynamic KM framework is described in the context of employees being motivated to create profit for their company through product development in high value manufacturing. It is reported how the framework was discussed during a meeting of the collaborating company’s (BAE Systems) project stakeholders. Participants agreed the framework would have most benefit at the start of the product lifecycle before key decisions were made. The framework has been designed to support organisational learning and to reward employees that improve the position of the company in the market place

Mixture models for distance sampling detection functions

Funding: EPSRC DTGWe present a new class of models for the detection function in distance sampling surveys of wildlife populations, based on finite mixtures of simple parametric key functions such as the half-normal. The models share many of the features of the widely-used “key function plus series adjustment” (K+A) formulation: they are flexible, produce plausible shapes with a small number of parameters, allow incorporation of covariates in addition to distance and can be fitted using maximum likelihood. One important advantage over the K+A approach is that the mixtures are automatically monotonic non-increasing and non-negative, so constrained optimization is not required to ensure distance sampling assumptions are honoured. We compare the mixture formulation to the K+A approach using simulations to evaluate its applicability in a wide set of challenging situations. We also re-analyze four previously problematic real-world case studies. We find mixtures outperform K+A methods in many cases, particularly spiked line transect data (i.e., where detectability drops rapidly at small distances) and larger sample sizes. We recommend that current standard model selection methods for distance sampling detection functions are extended to include mixture models in the candidate set.Publisher PDFPeer reviewe

Referral management and the care of patients with diabetes: the Translating Research Into Action for Diabetes (TRIAD) study.

OBJECTIVE: To examine the effect of referral management on diabetes care. STUDY DESIGN: Cross-sectional analysis. PATIENTS AND METHODS: Translating Research Into Action for Diabetes (TRIAD) is a multicenter study of managed care enrollees with diabetes. Prospective referral management was defined as "gatekeeping" and mandatory preauthorization from a utilization management office, and retrospective referral management as referral profiling and appropriateness reviews. Outcomes included dilated eye exam; self-reported visit to specialists; and perception of difficulty in getting referrals. Hierarchical models adjusted for clustering and patient age, gender, race, ethnicity, type and duration of diabetes treatment, education, income, health status, and comorbidity. RESULTS: Referral management was commonly used by health plans (55%) and provider groups (52%). In adjusted analyses, we found no association between any referral management strategies and any of the outcome measures. CONCLUSIONS: Referral management does not appear to have an impact on referrals or perception of referrals related to diabetes care

Activity of the DNA minor groove cross-linking agent SG2000 (SJG-136) against canine tumours

BACKGROUND: Cancer is the leading cause of death in older dogs and its prevalence is increasing. There is clearly a need to develop more effective anti-cancer drugs in dogs. SG2000 (SJG-136) is a sequence selective DNA minor groove cross-linking agent. Based on its in vitro potency, the spectrum of in vivo and clinical activity against human tumours, and its tolerability in human patients, SG2000 has potential as a novel therapeutic against spontaneously occurring canine malignancies. RESULTS: In vitro cytotoxicity was assessed using SRB and MTT assays, and in vivo activity was assessed using canine tumour xenografts. DNA interstrand cross-linking (ICL) was determined using a modification of the single cell gel electrophoresis (comet) assay. Effects on cell cycle distribution were assessed by flow cytometry and measurement of γ-H2AX by immunofluorescence and immunohistochemistry. SG2000 had a multi-log differential cytotoxic profile against a panel of 12 canine tumour cell lines representing a range of common tumour types in dogs. In the CMeC-1 melanoma cell line, DNA ICLs increased linearly with dose following a 1 h treatment. Peak ICL was achieved within 1 h and no removal was observed over 48 h. A relationship between DNA ICL formation and cytotoxicity was observed across cell lines. The formation of γ-H2AX foci was slow, becoming evident after 4 h and reaching a peak at 24 h. SG2000 exhibited significant anti-tumour activity against two canine melanoma tumour models in vivo. Anti-tumour activity was observed at 0.15 and 0.3 mg/kg given i.v. either once, or weekly x 3. Dose-dependent DNA ICL was observed in tumours (and to a lower level in peripheral blood mononuclear cells) at 2 h and persisted at 24 h. ICL increased following the second and third doses in a repeated dose schedule. At 24 h, dose dependent γ-H2AX foci were more numerous than at 2 h, and greater in tumours than in peripheral blood mononuclear cells. SG2000-induced H2AX phosphorylation measured by immunohistochemistry showed good correspondence, but less sensitivity, than measurement of foci. CONCLUSIONS: SG2000 displayed potent activity in vitro against canine cancer cell lines as a result of the formation and persistence of DNA ICLs. SG2000 also had significant in vivo antitumour activity against canine melanoma xenografts, and the comet and γ-H2AX foci methods were relevant pharmacodynamic assays. The clinical testing of SG2000 against spontaneous canine cancer is warranted. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12917-015-0534-2) contains supplementary material, which is available to authorized users