Endothelial dysfunction in neuroprogressive disorders—causes and suggested treatments

Background: Potential routes whereby systemic inflammation, oxidative stress and mitochondrial dysfunction may drive the development of endothelial dysfunction and atherosclerosis, even in an environment of low cholesterol, are examined. Main text: Key molecular players involved in the regulation of endothelial cell function are described, including PECAM-1, VE-cadherin, VEGFRs, SFK, Rho GEF TRIO, RAC-1, ITAM, SHP-2, MAPK/ERK, STAT-3, NF-κB, PI3K/AKT, eNOS, nitric oxide, miRNAs, KLF-4 and KLF-2. The key roles of platelet activation, xanthene oxidase and myeloperoxidase in the genesis of endothelial cell dysfunction and activation are detailed. The following roles of circulating reactive oxygen species (ROS), reactive nitrogen species and pro-inflammatory cytokines in the development of endothelial cell dysfunction are then described: paracrine signalling by circulating hydrogen peroxide, inhibition of eNOS and increased levels of mitochondrial ROS, including compromised mitochondrial dynamics, loss of calcium ion homeostasis and inactivation of SIRT-1-mediated signalling pathways. Next, loss of cellular redox homeostasis is considered, including further aspects of the roles of hydrogen peroxide signalling, the pathological consequences of elevated NF-κB, compromised S-nitrosylation and the development of hypernitrosylation and increased transcription of atherogenic miRNAs. These molecular aspects are then applied to neuroprogressive disorders by considering the following potential generators of endothelial dysfunction and activation in major depressive disorder, bipolar disorder and schizophrenia: NF-κB; platelet activation; atherogenic miRs; myeloperoxidase; xanthene oxidase and uric acid; and inflammation, oxidative stress, nitrosative stress and mitochondrial dysfunction. Conclusions: Finally, on the basis of the above molecular mechanisms, details are given of potential treatment options for mitigating endothelial cell dysfunction and activation in neuroprogressive disorders

End-user involvement in a systematic review of quantitative and qualitative research of non-pharmacological interventions for attention deficit hyperactivity disorder delivered in school settings: reflections on the impacts and challenges.

JOURNAL ARTICLEBACKGROUND: The benefits of end-user involvement in health-care research are widely recognized by research agencies. There are few published evaluations of end-user involvement in systematic reviews. OBJECTIVES: (i) Describe end-user involvement in a complex mixed-methods systematic review of ADHD in schools, (ii) reflect on the impact of end-user involvement, (iii) highlight challenges and benefits experienced and (iv) provide suggestions to inform future involvement. METHODS: End-users were involved in all stages of the project, both as authors and as members of an advisory group. In addition, several events were held with groups of relevant end-users during the project. RESULTS: End-user input (i) guided the direction of the research, (ii) contributed to a typology of interventions and outcomes, (iii) contributed to the direction of data analysis and (iv) contributed to the robustness of the syntheses by demonstrating the alignment of interim findings with lived experiences. Challenges included (i) managing expectations, (ii) managing the intensity of emotion, (iii) ensuring that involvement was fruitful for all not just the researcher, (iv) our capacity to communicate and manage the process and (v) engendering a sense of involvement amongst end-users. CONCLUSIONS: End-user involvement was an important aspect of this project. To minimize challenges in future projects, a recognition by the project management team and the funding provider that end-user involvement even in evidence synthesis projects is resource intensive is essential to allow appropriate allocation of time and resources for meaningful engagement.NIHR HTA programmeNIHRExeter NHS Foundation Trus

Establishment of a pipeline to analyse non-synonymous SNPs in Bos taurus

BACKGROUND: Single nucleotide polymorphisms (SNPs) are an abundant form of genetic variation in the genome of every species and are useful for gene mapping and association studies. Of particular interest are non-synonymous SNPs, which may alter protein function and phenotype. We therefore examined bovine expressed sequences for non-synonymous SNPs and validated and tested selected SNPs for their association with measured traits. RESULTS: Over 500,000 public bovine expressed sequence tagged (EST) sequences were used to search for coding SNPs (cSNPs). A total of 15,353 SNPs were detected in the transcribed sequences studied, of which 6,325 were predicted to be coding SNPs with the remaining 9,028 SNPs presumed to be in untranslated regions. Of the cSNPs detected, 2,868 were predicted to result in a change in the amino acid encoded. In order to determine the actual number of non-synonymous polymorphic SNPs we designed assays for 920 of the putative SNPs. These SNPs were then genotyped through a panel of cattle DNA pools using chip-based MALDI-TOF mass spectrometry. Of the SNPs tested, 29% were found to be polymorphic with a minor allele frequency >10%. A subset of the SNPs was genotyped through animal resources in order to look for association with age of puberty, facial eczema resistance or meat yield. Three SNPs were nominally associated with resistance to the disease facial eczema (P < 0.01). CONCLUSION: We have identified 15,353 putative SNPs in or close to bovine genes and 2,868 of these SNPs were predicted to be non-synonymous. Approximately 29% of the non-synonymous SNPs were polymorphic and common with a minor allele frequency >10%. Of the SNPs detected in this study, 99% have not been previously reported. These novel SNPs will be useful for association studies or gene mapping

Fukushima Daiichi-derived radionuclides in the ocean: Transport, fate, and impacts

The events that followed the Tohoku earthquake and tsunami on March 11, 2011, included the loss of power and overheating at the Fukushima Daiichi nuclear power plants, which led to extensive releases of radioactive gases, volatiles, and liquids, particularly to the coastal ocean. The fate of these radionuclides depends in large part on their oceanic geochemistry, physical processes, and biological uptake. Whereas radioactivity on land can be resampled and its distribution mapped, releases to the marine environment are harder to characterize owing to variability in ocean currents and the general challenges of sampling at sea. Five years later, it is appropriate to review what happened in terms of the sources, transport, and fate of these radionuclides in the ocean. In addition to the oceanic behavior of these contaminants, this review considers the potential health effects and societal impacts

Precompetitive data sharing as a catalyst to address unmet needs in Parkinson's disease

Parkinson's disease is a complex heterogeneous disorder with urgent need for disease-modifying therapies. Progress in successful therapeutic approaches for PD will require an unprecedented level of collaboration. At a workshop hosted by Parkinson's UK and co-organized by Critical Path Institute's (C-Path) Coalition Against Major Diseases (CAMD) Consortiums, investigators from industry, academia, government and regulatory agencies agreed on the need for sharing of data to enable future success. Government agencies included EMA, FDA, NINDS/NIH and IMI (Innovative Medicines Initiative). Emerging discoveries in new biomarkers and genetic endophenotypes are contributing to our understanding of the underlying pathophysiology of PD. In parallel there is growing recognition that early intervention will be key for successful treatments aimed at disease modification. At present, there is a lack of a comprehensive understanding of disease progression and the many factors that contribute to disease progression heterogeneity. Novel therapeutic targets and trial designs that incorporate existing and new biomarkers to evaluate drug effects independently and in combination are required. The integration of robust clinical data sets is viewed as a powerful approach to hasten medical discovery and therapies, as is being realized across diverse disease conditions employing big data analytics for healthcare. The application of lessons learned from parallel efforts is critical to identify barriers and enable a viable path forward. A roadmap is presented for a regulatory, academic, industry and advocacy driven integrated initiative that aims to facilitate and streamline new drug trials and registrations in Parkinson's disease

Flux of particulate elements in the North Atlantic Ocean constrained by multiple radionuclides

Author Posting. © American Geophysical Union, 2019. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Global Biogeochemical Cycles 32(12), (2019): 1738-1758, doi:10.1029/2018GB005994.Sinking particles strongly regulate the distribution of reactive chemical substances in the ocean, including particulate organic carbon and other elements (e.g., P, Cd, Mn, Cu, Co, Fe, Al, and 232Th). Yet, the sinking fluxes of trace elements have not been well described in the global ocean. The U.S. GEOTRACES campaign in the North Atlantic (GA03) offers the first data set in which the sinking flux of carbon and trace elements can be derived using four different radionuclide pairs (238U:234Th ;210Pb:210Po; 228Ra:228Th; and 234U:230Th) at stations co‐located with sediment trap fluxes for comparison. Particulate organic carbon, particulate P, and particulate Cd fluxes all decrease sharply with depth below the euphotic zone. Particulate Mn, Cu, and Co flux profiles display mixed behavior, some cases reflecting biotic remineralization, and other cases showing increased flux with depth. The latter may be related to either lateral input of lithogenic material or increased scavenging onto particles. Lastly, particulate Fe fluxes resemble fluxes of Al and 232Th, which all have increasing flux with depth, indicating a dominance of lithogenic flux at depth by resuspended sediment transported laterally to the study site. In comparing flux estimates derived using different isotope pairs, differences result from different timescales of integration and particle size fractionation effects. The range in flux estimates produced by different methods provides a robust constraint on the true removal fluxes, taking into consideration the independent uncertainties associated with each method. These estimates will be valuable targets for biogeochemical modeling and may also offer insight into particle sinking processes.This study grew out of a synthesis workshop at the Lamont‐Doherty Earth Observatory of Columbia University in August 2016. This workshop was sponsored by the U.S. GEOTRACES Project Office (NSF 1536294) and the Ocean Carbon and Biogeochemistry (OCP) Project Office (NSF 1558412 and NASA NNX17AB17G). The U.S. National Science Foundation supported all of the analytical work on GA03. Kuanbo Zhou measured 228Th in the large size class particles (NSF 0925158 to WHOI). NSF 1061128 to Stony Brook University supported the BaRFlux project, for which Chistina Heilbrun is acknowledged for laboratory and field work. The lead author acknowledges support from a start‐up grant from the University of Southern Mississippi. Two anonymous reviewers are thanked for their constructive comments. All GEOTRACES GA03 data used in this study are accessible through the Biological and Chemical Oceanography Data Management Office (http://data.bco‐dmo.org/jg/dir/BCO/GEOTRACES/NorthAtlanticTransect/), and derived parameters are reported in the supporting information.2019-05-2

EXPLICIT: a feasibility study of remote expert elicitation in health technology assessment

This is the final version of the article. Available from BioMed Central via the DOI in this recordBACKGROUND: Expert opinion is often sought to complement available information needed to inform model-based economic evaluations in health technology assessments. In this context, we define expert elicitation as the process of encoding expert opinion on a quantity of interest, together with associated uncertainty, as a probability distribution. When availability for face-to-face expert elicitation with a facilitator is limited, elicitation can be conducted remotely, overcoming challenges of finding an appropriate time to meet the expert and allowing access to experts situated too far away for practical face-to-face sessions. However, distance elicitation is associated with reduced response rates and limited assistance for the expert during the elicitation session. The aim of this study was to inform the development of a remote elicitation tool by exploring the influence of mode of elicitation on elicited beliefs. METHODS: An Excel-based tool (EXPLICIT) was developed to assist the elicitation session, including the preparation of the expert and recording of their responses. General practitioners (GPs) were invited to provide expert opinion about population alcohol consumption behaviours. They were randomised to complete the elicitation by either a face-to-face meeting or email. EXPLICIT was used in the elicitation sessions for both arms. RESULTS: Fifteen GPs completed the elicitation session. Those conducted by email were longer than the face-to-face sessions (13 min 30 s vs 10 min 26 s, p = 0.1) and the email-elicited estimates contained less uncertainty. However, the resulting aggregated distributions were comparable. CONCLUSIONS: EXPLICIT was useful in both facilitating the elicitation task and in obtaining expert opinion from experts via email. The findings support the opinion that remote, self-administered elicitation is a viable approach within the constraints of HTA to inform policy making, although poor response rates may be observed and additional time for individual sessions may be required.This paper presents independent research funded by the National Institute of Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsula

The Effects of Escalation of Respiratory Support and Prolonged Invasive Ventilation on Outcomes of Cardiac Surgical Patients: A Retrospective Cohort Study

Abstract Objectives: The aim of this study was to determine the effects of escalation of respiratory support and prolonged postoperative invasive ventilation on patient–centered outcomes, and identify perioperative factors associated with these two respiratory complications. Design: A retrospective cohort analysis of cardiac surgical patients admitted to cardiothoracic intensive care unit (ICU) between August 2015 and January 2018. Escalation of respiratory support was defined as ‘unplanned continuous positive airway pressure’, ‘non-invasive ventilation’ or ‘reintubation’ following surgery; prolonged invasive ventilation was defined as ‘invasive ventilation beyond the first 12 hours following surgery’. The primary endpoint was the composite of escalation of respiratory support and prolonged ventilation. Setting: Tertiary cardiothoracic ICU. Participants: A total of 2,098 patients were included and analyzed. Interventions: None. Measurements and Main Results: The composite of escalation of support or prolonged ventilation occurred in 509 patients (24.3%). Patients who met the composite had higher mortality (2.9% vs 0.1%; P<0.001) and longer median [interquartile range] length of ICU (2.1 [1.0–4.9] vs 0.9 [0.8–1.0] days; P<0.0001) and hospital (10.6 [8.0–16.0] vs 7.2 [6.2–10.0] days; P<0.0001) stay. Hypoxemia and anemia on admission to ICU were the only two factors independently associated with need for escalation of respiratory support or prolonged invasive ventilation. Conclusions: Escalation of respiratory support or prolonged invasive ventilation are frequently seen in cardiac surgery patients, and are highly associated with increased mortality and morbidity. Hypoxemia and anemia on admission to ICU are potentially modifiable factors associated with escalation of respiratory support or prolonged invasive ventilation.ACM is supported by a Clinical Research Career Development Fellowship from the Wellcome Trust (WT 2055214/Z/16/Z). VZ is supported by an Academic Clinical Fellowship from the National Institute for Health Research (ACF-2016-09-011)

Sixty-five common genetic variants and prediction of type 2 diabetes.

We developed a 65 type 2 diabetes (T2D) variant-weighted gene score to examine the impact on T2D risk assessment in a U.K.-based consortium of prospective studies, with subjects initially free from T2D (N = 13,294; 37.3% women; mean age 58.5 [38-99] years). We compared the performance of the gene score with the phenotypically derived Framingham Offspring Study T2D risk model and then the two in combination. Over the median 10 years of follow-up, 804 participants developed T2D. The odds ratio for T2D (top vs. bottom quintiles of gene score) was 2.70 (95% CI 2.12-3.43). With a 10% false-positive rate, the genetic score alone detected 19.9% incident cases, the Framingham risk model 30.7%, and together 37.3%. The respective area under the receiver operator characteristic curves were 0.60 (95% CI 0.58-0.62), 0.75 (95% CI 0.73 to 0.77), and 0.76 (95% CI 0.75 to 0.78). The combined risk score net reclassification improvement (NRI) was 8.1% (5.0 to 11.2; P = 3.31 × 10(-7)). While BMI stratification into tertiles influenced the NRI (BMI ≤24.5 kg/m(2), 27.6% [95% CI 17.7-37.5], P = 4.82 × 10(-8); 24.5-27.5 kg/m(2), 11.6% [95% CI 5.8-17.4], P = 9.88 × 10(-5); >27.5 kg/m(2), 2.6% [95% CI -1.4 to 6.6], P = 0.20), age categories did not. The addition of the gene score to a phenotypic risk model leads to a potentially clinically important improvement in discrimination of incident T2D