Blood circulating proteins are confounded readouts of the biological processes that occur in different tissues and organs. Many proteins have been linked to complex disorders and are also under ...substantial genetic control. Here, we investigate the associations between over 1000 blood circulating proteins and body mass index (BMI) in three studies including over 4600 participants. We show that BMI is associated with widespread changes in the plasma proteome. We observe 152 replicated protein associations with BMI. 24 proteins also associate with a genome-wide polygenic score (GPS) for BMI. These proteins are involved in lipid metabolism and inflammatory pathways impacting clinically relevant pathways of adiposity. Mendelian randomization suggests a bi-directional causal relationship of BMI with LEPR/LEP, IGFBP1, and WFIKKN2, a protein-to-BMI relationship for AGER, DPT, and CTSA, and a BMI-to-protein relationship for another 21 proteins. Combined with animal model and tissue-specific gene expression data, our findings suggest potential therapeutic targets further elucidating the role of these proteins in obesity associated pathologies.
Aim
To establish if alpha‐7 nicotinic acetylcholine receptor (α7nAChR) agonist GTS‐21 exerts a blood glucose‐lowering action in db/db mice, and to test if this action requires coordinate α7nAChR and ...GLP‐1 receptor (GLP‐1R) stimulation by GTS‐21 and endogenous GLP‐1, respectively.
Materials and Methods
Blood glucose levels were measured during an oral glucose tolerance test (OGTT) using db/db mice administered intraperitoneal GTS‐21. Plasma GLP‐1, peptide tyrosine tyrosine 1‐36 (PYY1‐36), glucose‐dependent insulinotropic peptide (GIP), glucagon, and insulin levels were measured by ELISA. A GLP‐1R–mediated action of GTS‐21 that is secondary to α7nAChR stimulation was evaluated using α7nAChR and GLP‐1R knockout (KO) mice, or by co‐administration of GTS‐21 with the dipeptidyl peptidase‐4 inhibitor, sitagliptin, or the GLP‐1R antagonist, exendin (9‐39). Insulin sensitivity was assessed in an insulin tolerance test.
Results
Single or multiple dose GTS‐21 (0.5‐8.0 mg/kg) acted in a dose‐dependent manner to lower levels of blood glucose in the OGTT using 10‐14 week‐old male and female db/db mice. This action of GTS‐21 was reproduced by the α7nAChR agonist, PNU‐282987, was enhanced by sitagliptin, was counteracted by exendin (9‐39), and was absent in α7nAChR and GLP‐1R KO mice. Plasma GLP‐1, PYY1‐36, GIP, glucagon, and insulin levels increased in response to GTS‐21, but insulin sensitivity, body weight, and food intake were unchanged.
Conclusions
α7nAChR agonists improve oral glucose tolerance in db/db mice. This action is contingent to coordinate α7nAChR and GLP‐1R stimulation. Thus α7nAChR agonists administered in combination with sitagliptin might serve as a new treatment for type 2 diabetes.
ObjectivesAs part of the PIONEER Consortium objectives, we have explored which diagnostic and prognostic factors (DPFs) are available in relation to our previously defined clinician and ...patient-reported outcomes for prostate cancer (PCa).DesignWe performed a systematic review to identify validated and non-validated studies.Data sourcesMEDLINE, Embase and the Cochrane Library were searched on 21 January 2020.Eligibility criteriaOnly quantitative studies were included. Single studies with fewer than 50 participants, published before 2014 and looking at outcomes which are not prioritised in the PIONEER core outcome set were excluded.Data extraction and synthesisAfter initial screening, we extracted data following the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of prognostic factor studies (CHARMS-PF) criteria and discussed the identified factors with a multidisciplinary expert group. The quality of the included papers was scored for applicability and risk of bias using validated tools such as PROBAST, Quality in Prognostic Studies and Quality Assessment of Diagnostic Accuracy Studies 2.ResultsThe search identified 6604 studies, from which 489 DPFs were included. Sixty-four of those were internally or externally validated. However, only three studies on diagnostic and seven studies on prognostic factors had a low risk of bias and a low risk concerning applicability.ConclusionMost of the DPFs identified require additional evaluation and validation in properly designed studies before they can be recommended for use in clinical practice. The PIONEER online search tool for DPFs for PCa will enable researchers to understand the quality of the current research and help them design future studies.Ethics and disseminationThere are no ethical implications.
•The CAP consists of the vagus nerve, spleen, acetylcholine, and α7nAchR.•The CAP involves in balancing immune regulation and inflammation during sepsis.•CAP reduces inflammatory response in ...myocardial cells during sepsis.•CAP improves mitochondrial dysfunction in septic cardiomyopathy.•α7nAchR is the core regulator of CAP in septic cardiomyopathy.
Septic cardiomyopathy (SCM)is common in septic patients and results in cardiovascular failure. The pathogenesis of SCM is complicated, and patients with SCM have high mortality because current treatment methods are limited. The cholinergic anti-inflammatory pathway (CAP) modulates inflammatory responses through vagus nerve stimulation that leads to the release of acetylcholine (ACh), which binds to the alpha7 nicotinic acetylcholine receptor (α7nAChR). Moreover, α7nAChR activation by its agonists at the tissue level inhibits inflammatory mediators and regulates the function of immune cells in sepsis. Therefore, the α7nAChR can maintain balance of the inflammatory-immune response in sepsis. CAP has been elucidated as a critical regulator of anti-inflammation in many diseases, including rheumatoid arthritis, inflammatory boweldisease and SCM. Additionally, some clinical and preclinical trials show therapeutic potential via regulating CAP. There are excellent studies regarding the beneficial role of CAP activation, especially α7nAChR, in experimental SCM. This review aims to discuss the CAP in attenuating inflammation and the potential role of α7nAChR activation in regulating immune and reducing inflammation in SCM.
Gastrointestinal bleeding (GIB) is a common and potentially life-threatening clinical event. To date, the literature on the long-term global epidemiology of GIB has not been systematically reviewed.
...To systematically review the published literature on the worldwide epidemiology of upper and lower GIB.
EMBASE
and MEDLINE were queried from 01 January 1965 to September 17, 2019 to identify population-based studies reporting incidence, mortality, or case-fatality rates of upper GIB (UGIB) or lower GIB (LGIB) in the general adult population, worldwide. Relevant outcome data were extracted and summarized (including data on rebleeding following initial occurrence of GIB when available). All included studies were assessed for risk of bias based upon reporting guidelines.
Of 4203 retrieved database hits, 41 studies were included, comprising a total of around 4.1 million patients with GIB worldwide from 1980-2012. Thirty-three studies reported rates for UGIB, four for LGIB, and four presented data on both. Incidence rates ranged from 15.0 to 172.0/100000 person-years for UGIB, and from 20.5 to 87.0/100000 person-years for LGIB. Thirteen studies reported on temporal trends, generally showing an overall decline in UGIB incidence over time, although a slight increase between 2003 and 2005 followed by a decline was shown in 5/13 studies. GIB-related mortality data were available from six studies for UGIB, with rates ranging from 0.9 to 9.8/100000 person-years, and from three studies for LGIB, with rates ranging from 0.8 to 3.5/100000 person-years. Case-fatality rate ranged from 0.7% to 4.8% for UGIB and 0.5% to 8.0% for LGIB. Rates of rebleeding ranged from 7.3% to 32.5% for UGIB and from 6.7% to 13.5% for LGIB. Two main areas of potential bias were the differences in the operational GIB definition used and inadequate information on how missing data were handled.
Wide variation was seen in estimates of GIB epidemiology, likely due to high heterogeneity between studies however, UGIB showed a decreasing trend over the years. Epidemiological data were more widely available for UGIB than for LGIB.
•Activation of UT, MT, and LT increased following 60min of computer work.•UT activation differed between genders following 60min of computer work.•Clavicular/upper trapezius ratio decreased following ...60min of computer work.
The aim of this study was to provide a description of gender differences of the activation patterns of the four subdivisions of the trapezius (clavicular, upper, middle, lower) following a 60min computer work task. Surface EMG was collected from these subdivisions from 21 healthy subjects during bilateral arm elevation pre-/post- task. Subjects completed a standardized 60min computer work task at a standard, ergonomic workstation. Normalized activation and activation ratios of each trapezius subdivision were compared between genders and condition with repeated measures ANOVAs. The interaction effect of Gender×Condition for upper trapezius% activation approached significance at p=0.051with males demonstrating greater activation post-task. The main effect of Condition was statistically significant for% activation of middle and lower trapezius (p<0.05), with both muscles demonstrating increase activation post-task. There was a statistically significant interaction effect of Gender×Condition for the Middle Trapezius/Upper Trapezius ratio and main effect of Condition for the Clavicular Trapezius/Upper Trapezius ratio, with a decreased ratio post-typing. Gender differences exist following 60min of a low force computer typing task. Imbalances in muscle activation and activation ratios following computer work may affect total shoulder kinematics and should be further explored.
Abstract
Background
Heart failure (HF) trials have stringent inclusion and exclusion criteria, but limited data exist regarding generalizability of trials. We compared patient characteristics and ...outcomes between patients with HF and reduced ejection fraction (HFrEF) in trials and observational registries.
Methods and Results
Individual patient data for 16 922 patients from five randomized clinical trials and 46 914 patients from two HF registries were included. The registry patients were categorized into trial-eligible and non-eligible groups using the most commonly used inclusion and exclusion criteria. A total of 26 104 (56%) registry patients fulfilled the eligibility criteria. Unadjusted all-cause mortality rates at 1 year were lowest in the trial population (7%), followed by trial-eligible patients (12%) and trial-non-eligible registry patients (26%). After adjustment for age and sex, all-cause mortality rates were similar between trial participants and trial-eligible registry patients standardized mortality ratio (SMR) 0.97; 95% confidence interval (CI) 0.92–1.03 but cardiovascular mortality was higher in trial participants (SMR 1.19; 1.12–1.27). After full case-mix adjustment, the SMR for cardiovascular mortality remained higher in the trials at 1.28 (1.20–1.37) compared to RCT-eligible registry patients.
Conclusion
In contemporary HF registries, over half of HFrEF patients would have been eligible for trial enrolment. Crude clinical event rates were lower in the trials, but, after adjustment for case-mix, trial participants had similar rates of survival as registries. Despite this, they had about 30% higher cardiovascular mortality rates. Age and sex were the main drivers of differences in clinical outcomes between HF trials and observational HF registries.
IntroductionAs part of the PIONEER (Prostate Cancer Diagnosis and Treatment Enhancement Through the Power of Big Data in Europe) Consortium, we will explore which diagnostic and prognostic factors ...(DPFs) are currently being researched to previously defined clinical and patient-reported outcomes for prostate cancer (PCa).Methods and analysisThis research project will follow the following four steps: (1) a broad systematic literature review of DPFs for all stages of PCa, covering evidence from 2014 onwards; (2) discussion of systematic review findings by a multidisciplinary expert panel; (3) risk of bias assessment and applicability with Prediction model Risk Of Bias Assessment Tool criteria, Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) and the Quality In Prognosis Studies tool (QUIPS) and (4) additional quantitative assessments if required.Ethics and disseminationWe aim to develop an online tool to present the DPFs identified in this research and make them available across all stakeholders. There are no ethical implications.
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