Increased Hepatic Insulin Action in Diet-Induced Obese Mice Following Inhibition of Glucosylceramide Synthase

Obesity is characterized by the accumulation of fat in the liver and other tissues, leading to insulin resistance. We have previously shown that a specific inhibitor of glucosylceramide synthase, which inhibits the initial step in the synthesis of glycosphingolipids (GSLs), improved glucose metabolism and decreased hepatic steatosis in both ob/ob and diet-induced obese (DIO) mice. Here we have determined in the DIO mouse model the efficacy of a related small molecule compound, Genz-112638, which is currently being evaluated clinically for the treatment of Gaucher disease, a lysosomal storage disorder.DIO mice were treated with the Genz-112638 for 12 to 16 weeks by daily oral gavage. Genz-112638 lowered HbA1c levels and increased glucose tolerance. Whole body adiposity was not affected in normal mice, but decreased in drug-treated obese mice. Drug treatment also significantly lowered liver triglyceride levels and reduced the development of hepatic steatosis. We performed hyperinsulinemic-euglycemic clamps on the DIO mice treated with Genz-112638 and showed that insulin-mediated suppression of hepatic glucose production increased significantly compared to the placebo treated mice, indicating a marked improvement in hepatic insulin sensitivity.These results indicate that GSL inhibition in obese mice primarily results in an increase in insulin action in the liver, and suggests that GSLs may have an important role in hepatic insulin resistance in conditions of obesity

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Education is associated with lower levels of abdominal obesity in women with a non-agricultural occupation: an interaction study using China's Four Provinces survey.

The prevalence of obesity is increasing rapidly in low- and middle-income countries (LMICs) as their populations become exposed to obesogenic environments. The transition from an agrarian to an industrial and service-based economy results in important lifestyle changes. Yet different socioeconomic groups may experience and respond to these changes differently. Investigating the socioeconomic distribution of obesity in LMICs is key to understanding the causes of obesity but the field is limited by the scarcity of data and a uni-dimensional approach to socioeconomic status (SES). This study splits socioeconomic status into two dimensions to investigate how educated women may have lower levels of obesity in a context where labour market opportunities have shifted away from agriculture to other forms of employment. The Four Provinces Study in China 2008/09 is a household-based community survey of 4,314 people aged ≥60  years (2,465 women). It was used to investigate an interaction between education (none/any) and occupation (agricultural/non-agricultural) on high-risk central obesity defined as a waist circumference ≥80 cm. An interaction term between education and occupation was incorporated in a multivariate logistic regression model, and the estimates adjusted for age, parity, urban/rural residence and health behaviours (smoking, alcohol, meat and fruit & vegetable consumption). Complete case analyses were undertaken and results confirmed using multiple imputation to impute missing data. An interaction between occupation and education was present (P = 0.02). In the group with no education, the odds of central obesity in the sedentary occupation group were more than double those of the agricultural occupation group even after taking age group and parity into account (OR; 95%CI: 2.21; 1.52, 3.21), while in the group with any education there was no evidence of such a relationship (OR; 95%CI: 1.25; 0.92, 1.70). Health behaviours appeared to account for some of the association. These findings suggest that education may have a protective role in women against the higher odds of obesity associated with occupational shifts in middle-income countries, and that investment in women's education may present an important long term investment in obesity prevention. Further research could elucidate the mechanisms behind this association

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

What can health inequalities researchers learn from an intersectionality perspective?:Understanding social dynamics with an inter-categorical approach

The concept of intersectionality was developed by social scientists seeking to analyse the multiple interacting influences of social location, identity and historical oppression. Despite broad take-up elsewhere, its application in public health remains underdeveloped. We consider how health inequalities research in the United Kingdom has predominantly taken class and later socioeconomic position as its key axis in a manner that tends to overlook other crucial dimensions. We especially focus on international research on ethnicity, gender and caste to argue that an intersectional perspective is relevant for health inequalities research because it compels researchers to move beyond (but not ignore) class and socioeconomic position in analysing the structural determinants of health. Drawing on these theoretical developments, we argue for an inter-categorical conceptualisation of social location that recognises differentiation without reifying social groupings – thus encouraging researchers to focus on social dynamics rather than social categories, recognising that experiences of advantage and disadvantage reflect the exercise of power across social institutions. Such an understanding may help address the historic tendency of health inequalities research to privilege methodological issues and consider different axes of inequality in isolation from one another, encouraging researchers to move beyond micro-level behaviours to consider the structural drivers of inequalities

Phase II trial of vatalanib in patients with advanced or metastatic pancreatic adenocarcinoma after first-line gemcitabine therapy (PCRT O4-001)

PURPOSE: Vatalanib (PTK 787/ZK22584) is an oral polytyrosine kinase inhibitor with strong affinity for platelet-derived growth factor and vascular endothelial growth factor (VEGF) receptors. We conducted an open-label, phase II multicenter therapeutic trial investigating the efficacy and tolerability of vatalanib in patients with metastatic or advanced pancreatic cancer who failed first-line gemcitabine-based therapy. METHODS: Vatalanib treatment consisted of a twice daily oral dosing using a “ramp-up schedule,” beginning with 250 mg bid during week 1,500 mg bid during week 2, and 750 mg bid on week three and thereafter. the primary objective of this study was to evaluate the 6-month survival rate. RESULTS: Sixty-seven patients were enrolled. The median age was 64, and 66 %(N = 43) had only one prior regimen. Common grade 3/4 adverse events included hypertension (20 %; N = 13), fatigue (17 %; N = 11), abdominal pain (17 %; N = 11), and elevated alkaline phosphatase (15 %; N = 10). among the 65 evaluable patients, the 6-month survival rate was 29 % (95 % CI 18–41 %) and the median progression-free survival was 2 months. Fifteen patients survived 6 months or more. two patients had objective partial responses, and 28 % of patients had stable disease. Changes in biomarkers including soluble VEGF and vascular endothelial growth factor receptor did not correlate with response to drug. CONCLUSION: Vatalanib was well tolerated as a second-line therapy and resulted in favorable 6-month survival rate in patients with metastatic pancreatic cancer, compared with historic controls