Weight change and sulfonylurea therapy are related to 3 year change in microvascular function in people with type 2 diabetes

Aims/hypothesis: Although cardiovascular disease is the biggest cause of death in people with diabetes, microvascular complications have a significant impact on quality of life and financial burden of the disease. Little is known about the progression of microvascular dysfunction in the early stages of type 2 diabetes before the occurrence of clinically apparent complications. We aimed to explore the determinants of endothelial-dependent and -independent microvascular function progression over a 3 year period, in people with and without both diabetes and few clinical microvascular complications. Methods: Demographics were collected in 154 participants with type 2 diabetes and in a further 99 participants without type 2 diabetes. Skin microvascular endothelium-dependent response to iontophoresis of acetylcholine and endothelium-independent responses to sodium nitroprusside were measured using laser Doppler fluximetry. All assessments were repeated 3 years later. Results: People with type 2 diabetes had impaired endothelial-dependent microvascular response compared with those without (AUC 93.9 [95% CI 88.1, 99.4] vs 111.9 [102.3, 121.4] arbitrary units [AU] × min, p < 0.001, for those with vs without diabetes, respectively). Similarly, endothelial-independent responses were attenuated in those with diabetes (63.2 [59.2, 67.2] vs 75.1 [67.8, 82.4] AU × min, respectively, p = 0.002). Mean microvascular function declined over 3 years in both groups to a similar degree (pinteraction 0.74 for response to acetylcholine and 0.69 for response to sodium nitroprusside). In those with diabetes, use of sulfonylurea was associated with greater decline (p = 0.022 after adjustment for co-prescriptions, change in HbA1c and weight), whereas improving glycaemic control was associated with less decline of endothelial-dependent microvascular function (p = 0.03). Otherwise, the determinants of microvascular decline were similar in those with and without diabetes. The principal determinant of change in microvascular function in the whole population was weight change over 3 years, such that those that lost ≥5% weight had very little decline in either endothelial-dependent or -independent function compared with those that were weight stable, whereas those who gained weight had a greater decline in function (change in endothelial-dependent function was 1.2 [95% CI -13.2, 15.7] AU × min in those who lost weight; -15.8 [-10.5, -21.0] AU × min in those with stable weight; and -37.8 [-19.4, -56.2] AU × min in those with weight gain; ptrend < 0.001). This association of weight change with change in endothelial function was driven by people with diabetes; in people without diabetes, the relationship was nonsignificant. Conclusions/interpretation: Over 3 years, physiological change in weight was the greatest predictor of change in microvascular function.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.This work was supported by the Innovative Medicines Initiative (the SUMMIT consortium, IMI-2008/115006).published version, accepted version (12 month embargo

Opportunities for refinement in neuroscience: Indicators of wellness and post-operative pain in laboratory macaques

Being able to assess pain in nonhuman primates undergoing biomedical procedures is important for preventing and alleviating pain, and for developing better guidelines to minimise the impacts of research on welfare in line with the 3Rs principle of Refinement. Nonhuman primates are routinely used biomedical models however it remains challenging to recognise negative states, including pain, in these animals. This study aimed to identify behavioural and facial changes that could be used as pain or general wellness indicators in the rhesus macaque (Macaca mulatta). Thirty-six macaques scheduled for planned neuroscience procedures were opportunistically monitored at four times: Pre-Operative (PreOp), Post-Operative (PostOp) once the effects of anaesthesia had dissipated, Pre-Analgesia (PreAn) on the subsequent morning prior to repeating routine analgesic treatment, and Post-Analgesia (PostAn) following administration of analgesia. Pain states were expected to be absent in PreOp, moderate in PreAn, and mild or absent in PostOp and PostAn when analgesia had been administered. Three potential pain indicators were identified: lip tightening and chewing, which were most likely to occur in PreAn, and running which was least likely in PreAn. Arboreal behaviour indicated general wellness, while half-closed eyes, leaning of the head or body shaking indicated the opposite. Despite considerable individual variation, behaviour and facial expressions could offer important indicators of pain and wellness and should be routinely quantified, and appropriate interventions applied to prevent or alleviate pain, and promote positive welfare

Exogenous Metabolic Modulators Improve Response to Carboplatin in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) lacks targeted therapies, leaving cytotoxic chemotherapy as the current standard treatment. However, chemotherapy resistance remains a major clinical challenge. Increased insulin-like growth factor 1 signaling can potently blunt chemotherapy response, and lysosomal processes including the nutrient scavenging pathway autophagy can enable cancer cells to evade chemotherapy-mediated cell death. Thus, we tested whether inhibition of insulin receptor/insulin-like growth factor 1 receptor with the drug BMS-754807 and/or lysosomal disruption with hydroxychloroquine (HCQ) could sensitize TNBC cells to the chemotherapy drug carboplatin. Using in vitro studies in multiple TNBC cell lines, in concert with in vivo studies employing a murine syngeneic orthotopic transplant model of TNBC, we show that BMS-754807 and HCQ each sensitized TNBC cells and tumors to carboplatin and reveal that exogenous metabolic modulators may work synergistically with carboplatin as indicated by Bliss analysis. Additionally, we demonstrate the lack of overt in vivo toxicity with our combination regimens and, therefore, propose that metabolic targeting of TNBC may be a safe and effective strategy to increase sensitivity to chemotherapy. Thus, we conclude that the use of exogenous metabolic modulators, such as BMS-754807 or HCQ, in combination with chemotherapy warrants additional study as a strategy to improve therapeutic responses in women with TNBC

Financial considerations in the conduct of multi-centre randomised controlled trials: evidence from a qualitative study.

National Coordinating Centre for Research Methodology; Medical Research Council, UK Department of Health; Chief Scientist OfficeNot peer reviewedPublisher PD

Hearing Ability with Age in Northern European Women: A New Web-Based Approach to Genetic Studies

Age-related hearing impairment (ARHI) affects 25–40% of individuals over the age of 65. Despite the high prevalence of this complex trait, ARHI is still poorly understood. We hypothesized that variance in hearing ability with age is largely determined by genetic factors. We collected audiologic data on females of Northern European ancestry and compared different audiogram representations. A web-based speech-to-noise ratio (SNR) hearing test was compared with pure-tone thresholds to see if we could determine accurately hearing ability on people at home and the genetic contribution to each trait compared. Volunteers were recruited from the TwinsUK cohort. Hearing ability was determined using pure-tone audiometry and a web-based hearing test. Different audiogram presentations were compared for age-correlation and reflection of audiogram shape. Using structural equation modelling based on the classical twin model the heritability of ARHI, as measured by the different phenotypes, was estimated and shared variance between the web-based SNR test and pure-tone audiometry determined using bivariate modelling. Pure-tone audiometric data was collected on 1033 older females (age: 41–86). 1970 volunteers (males and females, age: 18–85) participated in the SNR. In the comparison between different ARHI phenotypes the difference between the first two principle components (PC1–PC2) best represented ARHI. The SNR test showed a sensitivity and specificity of 89% and 80%, respectively, in comparison with pure-tone audiogram data. Univariate heritability estimates ranged from 0.70 (95% CI: 0.63–0.76) for (PC1–PC2) to 0.56 (95% CI: 0.48–0.63) for PC2. The genetic correlation of PC1–PC2 and SNR was −0.67 showing that the 2 traits share variances attributed to additive genetic factors. Hearing ability showed considerable heritability in our sample. We have shown that the SNR test provides a useful surrogate marker of hearing. This will enable a much larger sample to be collected at a fraction of the cost, facilitating future genetic association studies

Effective dementia education and training for the health and social care workforce: A systematic review of the literature

Ensuring an informed and effective dementia workforce is of international concern, however there remains limited understanding of how this can be achieved. This systematic review aimed to identify factors associated with effective dementia educational programmes. Critical Interpretive Synthesis underpinned by Kirkpatrick’s return on investment model for evaluation of education was applied. One hundred and fifty-two papers of variable quality were included in the review. Common features of more efficacious educational programmes included the need for educational programmes to: be relevant to participants’ role and experience; involve active face-to-face participation; underpin practice-based learning with theory; be delivered by an experienced facilitator; have a total duration of at least eight hours with individual sessions of 90 minutes or more; support application of learning in practice; and provide a structured tool or practice guideline to underpin care practice. Further robust research is required to develop the evidence base; however, the findings of this review have relevance for all working in workforce education

Injection Drug Use Is a Risk Factor for HCV Infection in Urban Egypt

OBJECTIVE: To identify current risk factors for hepatitis C virus (HCV) transmission in Greater Cairo. DESIGN AND SETTING: A 1:1 matched case-control study was conducted comparing incident acute symptomatic hepatitis C patients in two "fever" hospitals of Greater Cairo with two control groups: household members of the cases and acute hepatitis A patients diagnosed at the same hospitals. Controls were matched on the same age and sex to cases and were all anti-HCV antibody negative. Iatrogenic, community and household exposures to HCV in the one to six months before symptoms onset for cases, and date of interview for controls, were exhaustively assessed. RESULTS: From 2002 to 2007, 94 definite acute symptomatic HCV cases and 188 controls were enrolled in the study. In multivariate analysis, intravenous injections (OR = 5.0; 95% CI = 1.2-20.2), medical stitches (OR = 4.2; 95% CI = 1.6-11.3), injection drug use (IDU) (OR = 7.9; 95% CI = 1.4-43.5), recent marriage (OR = 3.3; 95% CI = 1.1-9.9) and illiteracy (OR = 3.9; 95% CI = 1.8-8.5) were independently associated with an increased HCV risk. CONCLUSION: In urban Cairo, invasive health care procedures remain a source of HCV transmission and IDU is an emerging risk factor. Strict application of standard precautions during health care is a priority. Implementation of comprehensive infection prevention programs for IDU should be considered

Being Moved: Louis XIV’s Triumphant Tenderness and the Protestant Object

This essay examines the place of affect in Le Triomphe de la Religion, a text from 1687 that praises Louis XIV for the Revocation of the Edict of Nantes and the forced conversion of French Protestants. It explores the role of the material object in this text and contrasts it with seventeenth-century Protestant fears about the seductive power of Catholic objects. Drawing on the work of affect theory, it suggest how attention to the strange relation between emotion and the material object might better illuminate our sense of what it meant to be religiously different in absolutist France

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Nat Genet

The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms. We developed new statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no previous functional annotation. We captured data from over 27,000 mice, finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. New phenotypes were uncovered for many genes with previously unknown function, providing a powerful basis for hypothesis generation and further investigation in diverse systems.Comment in : Genetic differential calculus. [Nat Genet. 2015] Comment in : Scaling up phenotyping studies. [Nat Biotechnol. 2015