Diabetes mellitus, blood glucose and the risk of heart failure: A systematic review and meta-analysis of prospective studies.

BACKGROUND AND AIM: The strength of the association between diabetes and risk of heart failure has differed between previous studies and the available studies have not been summarized in a meta-analysis. We therefore quantified the association between diabetes and blood glucose and heart failure in a systematic review and meta-analysis. METHODS AND RESULTS: PubMed and Embase databases were searched up to May 3rd 2018. Prospective studies on diabetes mellitus or blood glucose and heart failure risk were included. A random effects model was used to calculate summary relative risks (RRs) and 95% confidence intervals (CIs). Seventy seven studies were included. Among the population-based prospective studies, the summary RR for individuals with diabetes vs. no diabetes was 2.06 (95% CIs: 1.73-2.46, I2 = 99.8%, n = 30 studies, 401495 cases, 21416780 participants). The summary RR was 1.23 (95% CI: 1.15-1.32, I2 = 78.2%, n = 10, 5344 cases, 91758 participants) per 20 mg/dl increase in blood glucose and there was evidence of a J-shaped association with nadir around 90 mg/dl and increased risk even within the pre-diabetic blood glucose range. Among the patient-based studies the summary RR was 1.69 (95% CI: 1.57-1.81, I2 = 85.5%, pheterogeneity<0.0001) for diabetes vs. no diabetes (n = 41, 100284 cases and >613925 participants) and 1.25 (95% CI: 0.89-1.75, I2 = 95.6%, pheterogeneity<0.0001) per 20 mg/dl increase in blood glucose (1016 cases, 34309 participants, n = 2). In the analyses of diabetes and heart failure there was low or no heterogeneity among the population-based studies that adjusted for alcohol intake and physical activity and among the patient-based studies there was no heterogeneity among studies with ≥10 years follow-up. CONCLUSIONS: These results suggest that individuals with diabetes are at an increased risk of developing heart failure and there is evidence of increased risk even within the pre-diabetic range of blood glucose.

Diabetes mellitus and the risk of sudden cardiac death: A systematic review and meta-analysis of prospective studies.

BACKGROUND: Although diabetes mellitus is an established risk factor for myocardial infarction and stroke, data on the association with sudden cardiac death are less extensive and the findings have not been entirely consistent. We therefore conducted a systematic review and meta-analysis of prospective studies on diabetes mellitus and risk of sudden cardiac death. METHODS AND RESULTS: PubMed and Embase databases were searched up to July 18th 2017. Prospective studies that reported adjusted relative risk (RR) estimates and 95% confidence intervals (CIs) for the association between a diabetes diagnosis or pre-diabetes and risk of sudden cardiac death were included. Summary RRs were estimated by use of a random effects model. Nineteen population-based prospective studies (11 publications) (3610 cases, 249,225 participants) and 10 patient-based prospective studies (2713 cases, 55,098 participants) were included. The summary RR for diabetes patients vs. persons without diabetes was 2.02 (95% CI: 1.81-2.25, I2 = 0%, pheterogeneity = 0.91) in the population-based studies. The summary RR was 1.23 (95% CI: 1.05-1.44, I2 = 6%, pheterogeneity = 0.34) for the association between pre-diabetes and sudden cardiac death (n = 3 studies, 1000 sudden cardiac deaths, 18,360 participants). In the patient-based studies, the summary RR of sudden cardiac death for diabetes patients vs. patients without diabetes was 1.75 (95% CI: 1.51-2.03, I2 = 39%, pheterogeneity = 0.10) for all patients combined, 1.63 (95% CI: 1.36-1.97, I2 = 39%, n = 5) for coronary heart disease patients, and 1.85 (95% CI: 1.48-2.33, I2 = 0%, n = 3) for heart failure patients. CONCLUSIONS: These results suggest that diabetes patients are at an increased risk of sudden cardiac death both in the general population and among different patient groups.

Physical activity and the risk of preterm birth: a systematic review and meta-analysis of epidemiological studies.

BACKGROUND: Physical activity has been inconsistently associated with risk of preterm birth, and the strength of the association and the shape of the dose-response relationship needs clarification. OBJECTIVES: To conduct a systematic review and dose-response meta-analysis to clarify the association between physical activity and risk of preterm birth. SEARCH STRATEGY: PubMed, Embase and Ovid databases were searched for relevant studies up to 9 February 2017. SELECTION CRITERIA: Studies with a prospective cohort, case-cohort, nested case-control or randomized study design were included. DATA COLLECTION AND ANALYSIS: Data were extracted by one reviewer and checked for accuracy by a second reviewer. Summary relative risks (RRs) were estimated using a random effects model. MAIN RESULTS: Forty-one studies (43 publications) including 20 randomized trials and 21 cohort studies were included. The summary RR for high versus low activity was 0.87 [95% confidence interval (CI): 0.70-1.06, I2 = 17%, n = 5] for physical activity before pregnancy, and it was 0.86 (95% CI: 0.78-0.95, I2 = 0%, n = 30) for early pregnancy physical activity. The summary RR for a 3 hours per week increment in leisure-time activity was 0.90 (95% CI: 0.85-0.95, I2 = 0%, n = 5). There was evidence of a nonlinear association between physical activity and preterm birth, Pnonlinearity < 0.0001, with the lowest risk observed at 2-4 hours per week of activity. CONCLUSION: This meta-analysis suggests that higher leisure-time activity is associated with reduced risk of preterm birth. Further randomized controlled trials with sufficient frequency and duration of activity to reduce the risk and with larger sample sizes are needed to conclusively demonstrate an association. TWEETABLE ABSTRACT: Physically active compared with inactive women have an 10-14% reduction in the risk of preterm birth.

Serum metabolomic profiling highlights pathways associated with liver fat content in a general population sample.

BACKGROUND/OBJECTIVES: Fatty liver disease (FLD) is an important intermediate trait along the cardiometabolic disease spectrum and strongly associates with type 2 diabetes. Knowledge of biological pathways implicated in FLD is limited. An untargeted metabolomic approach might unravel novel pathways related to FLD. SUBJECTS/METHODS: In a population-based sample (n=555) from Northern Germany, liver fat content was quantified as liver signal intensity using magnetic resonance imaging. Serum metabolites were determined using a non-targeted approach. Partial least squares regression was applied to derive a metabolomic score, explaining variation in serum metabolites and liver signal intensity. Associations of the metabolomic score with liver signal intensity and FLD were investigated in multivariable-adjusted robust linear and logistic regression models, respectively. Metabolites with a variable importance in the projection >1 were entered in in silico overrepresentation and pathway analyses. RESULTS: In univariate analysis, the metabolomics score explained 23.9% variation in liver signal intensity. A 1-unit increment in the metabolomic score was positively associated with FLD (n=219; odds ratio: 1.36; 95% confidence interval: 1.27-1.45) adjusting for age, sex, education, smoking and physical activity. A simplified score based on the 15 metabolites with highest variable importance in the projection statistic showed similar associations. Overrepresentation and pathway analyses highlighted branched-chain amino acids and derived gamma-glutamyl dipeptides as significant correlates of FLD. CONCLUSIONS: A serum metabolomic profile was associated with FLD and liver fat content. We identified a simplified metabolomics score, which should be evaluated in prospective studies.

Adult weight gain and colorectal adenomas-a systematic review and meta-analysis.

BACKGROUND: Colorectal adenomas are known as precursors for the majority of colorectal carcinomas. While weight gain during adulthood has been identified as a risk factor for colorectal cancer, the association is less clear for colorectal adenomas. We conducted a systematic review and meta-analysis to quantify the evidence on this association. METHODS: We searched Medline up to September 2016 to identify observational (prospective, cross-sectional and retrospective) studies on weight gain during adulthood and colorectal adenoma occurrence and recurrence. We conducted meta-analysis on high weight gain versus stable weight, linear and non-linear dose-response meta-analyses to analyze the association. Summary odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using a random effects model. RESULTS: For colorectal adenoma occurrence, the summary OR was 1.39 (95% CI: 1.17-1.65; I2: 43%, N = 9 studies, cases = 5507) comparing high (midpoint: 17.4 kg) versus stable weight gain during adulthood and with each 5 kg weight gain the odds increased by 7% (2%-11%; I2: 65%, N = 7 studies). Although there was indication of non-linearity (Pnon-linearity < 0.001) there was an increased odds of colorectal adenoma throughout the whole range of weight gain. Three studies were identified investigating the association between weight gain and colorectal adenoma recurrence and data were limited to draw firm conclusions. CONCLUSIONS: Even a small amount of adult weight gain was related to a higher odds of colorectal adenoma occurrence. Our findings add to the benefits of weight control in adulthood regarding colorectal adenoma occurrence, which might be relevant for early prevention of colorectal cancer.

Does Implant Insertion with a Funnel Decrease Capsular Contracture? A Preliminary Report.

BACKGROUND: Capsular contracture remains a common and dreaded complication of breast augmentation. The etiology of capsular contracture is believed to be multi-factorial, and its causes may include biofilm formation due to implant/pocket contamination with skin flora. It has been shown that insertion funnel use reduces skin contact and potential contamination by 27-fold in a cadaver model. After incorporating the funnel into our surgical protocols, we anecdotally believed we were experiencing fewer capsular contractures in our augmentation practices. OBJECTIVES: The purpose of this study was to test the hypothesis that capsular contracture related reoperation rates decreased after insertion funnel adoption using data from multiple practices. METHODS: At seven participating centers, we retrospectively reviewed the surgical records from March 2006 to December 2012 for female patients who had undergone primary breast augmentation with silicone gel implants. Group 1 consisted of consecutive augmentations done without the insertion funnel, and Group 2 consisted of consecutive augmentations done with the insertion funnel. The primary outcome variable was development of grade III or IV capsular contracture that led to reoperation within 12 months. RESULTS: A total of 1177 breast augmentations met inclusion criteria for Group 1 and 1620 breast augmentations for Group 2. The rate of reoperation due to capsular contracture was higher without use of the insertion funnel (1.49%), compared to Group 2 with funnel use (0.68%), a 54% reduction (P = 0.004). CONCLUSIONS: The insertion funnel group experienced a statistically significant reduction in the incidence of reoperations performed due to capsular contracture within 12 months of primary breast augmentation.

Changes in body weight and obesity status in German adults: results of seven population-based prospective studies.

BACKGROUND/OBJECTIVES: The objective of this study was to quantify body weight changes in German adult populations during the past decades. SUBJECTS/METHODS: Longitudinal analysis of seven cohort studies covering different age ranges between 18 and 83 years. Baseline examinations were between 1994 and 2007 and follow-up durations between 4.0 and 11.9 years. For each study, mean change in body weight per year and 10-year change in body mass index (BMI) classification were analyzed. For the middle age group of 45-64 years, meta-analysis was conducted to obtain an overall estimate for Germany. RESULTS: Among men weight gain was highest in the youngest participants and decreased with advancing age. Among women weight gain was on a stable high level among those younger than 45 years and decreased at older age. Within 10 years, 30-40% of middle-aged participants with normal baseline weight became pre-obese or obese and 20-25% of those with pre-obesity at baseline became obese, whereas >80% of persons who were obese at baseline remained obese over time. The estimated average weight change in adults aged 45-64 years was 0.25 (95% confidence interval (CI): 0.18-0.33) kg/year among men and 0.24 (0.17-0.30) kg/year among women. CONCLUSIONS: We could observe a moderate weight gain over the past years in German middle-aged populations of 0.25 kg/year. Obesity prevention needs to be targeted to specific subgroups in the population, especially to younger adults, who seem to be most vulnerable for gaining weight. Obesity intervention needs to be improved, as the majority of obese adults remained obese over time.

Body weight gain and risk of colorectal cancer: a systematic review and meta-analysis of observational studies.

While the relationship between body mass index as an indicator of excess body weight and the risk of colorectal cancer (CRC) is well established, the association between body weight gain in adulthood and risk of CRC remains unresolved. We quantified this association in a meta-analysis of 12 observational studies published until November 2014 with a total of 16,151 incident CRC cases. Random effect models were used to obtain summary relative risks (RR) and 95% confidence intervals (95% CIs). Between-study heterogeneity was assessed using I(2) statistics. Overall, the summary RR (95% CI) was 1.22 (1.14-1.30) for high body weight gain (midpoint: 15.2 kg) compared with stable weight (P for heterogeneity = 0.182; I(2) = 21.2%). In a dose-response analysis, each 5 kg weight gain was associated with a 4% (95% CI: 2%-5%) higher risk of CRC. The association persisted after adjustment for body weight at younger age and was present for both men and women, as well as for colon and rectal cancer. Differences by sex were detected for colon cancer (P for interaction = 0.003, with higher risk for men than women), but not for rectal cancer (P for interaction = 0.613). In conclusion, these data underscore the importance of body weight management from early adulthood onwards for the prevention of CRC development.

Efficacy and safety of CDX-301, recombinant human Flt3L, at expanding dendritic cells and hematopoietic stem cells in healthy human volunteers.

Fms-like tyrosine kinase-3 ligand (Flt3L) uniquely binds the Flt3 (CD135) receptor expressed on hematopoietic stem cells (HSCs), early progenitor cells, immature thymocytes and steady-state dendritic cells (DCs) and induces their proliferation, differentiation, development and mobilization in the bone marrow, peripheral blood and lymphoid organs. CDX-301 has an identical amino-acid sequence and comparable biological activity to the previously tested rhuFlt3L, which ceased clinical development over a decade ago. This Phase 1 trial assessed the safety, pharmacokinetic, pharmacodynamic and immunologic profile of CDX-301, explored alternate dosing regimens and examined the impact of rhuFlt3L on key immune cell subsets. Thirty healthy volunteers received CDX-301 (1-75 µg/kg/day) over 5-10 days. One event of Grade 3 community-acquired pneumonia occurred. There were no other infections, dose-limiting toxicities or serious adverse events. CDX-301 resulted in effective peripheral expansion of monocytes, hematopoietic stem and progenitor cells and key subsets of myeloid DCs and plasmacytoid DCs, with no clear effect on regulatory T cells. These data from healthy volunteers support the potential for CDX-301, as monotherapy or in combination with other agents, in various indications including allogeneic HSC transplantation and immunotherapy, but the effects of CDX-301 will need to be investigated in each of these patient populations.

Diabetes mellitus, insulin treatment, diabetes duration, and risk of biliary tract cancer and hepatocellular carcinoma in a European cohort.

BACKGROUND: Evidence on associations between self-reported diabetes mellitus, diabetes duration, age at diabetes diagnosis, insulin treatment, and risk of biliary tract cancer (BTC) and hepatocellular carcinoma (HCC), independent of general and abdominal obesity is scarce. PATIENTS AND METHODS: We conducted a prospective analysis in the EPIC-cohort study among 363 426 participants with self-reported diabetes data. Multivariable adjusted relative risks and 95% confidence intervals were estimated from Cox regression models. In a nested case-control subset, analyses were carried out in HCV/HBV-negative individuals. RESULTS: During 8.5 years of follow-up, 204 BTC cases [including 75 gallbladder cancer (GBC) cases], and 176 HCC cases were identified. Independent of body mass index and waist-to-height ratio diabetes status was associated with higher risk of BTC and HCC [1.77 (1.00-3.13) and 2.17 (1.36-3.47)]. For BTC, the risk seemed to be higher in participants with shorter diabetes duration and those not treated with insulin. Regarding cancer subsites, diabetes was only associated with GBC [2.72 (1.17-6.31)]. The risk for HCC was particularly higher in participants treated with insulin. The results were not appreciably different in HCV/HBV-negative individuals. CONCLUSION(S): This study supports the hypothesis that diabetes is a risk factor for BTC (particularly GBC) and HCC. Further research is required to establish whether diabetes treatment or duration is associated with these cancers.

Glycemic index, glycemic load, dietary carbohydrate, and dietary fiber intake and risk of liver and biliary tract cancers in Western Europeans.

BACKGROUND: The type and quantity of dietary carbohydrate as quantified by glycemic index (GI) and glycemic load (GL), and dietary fiber may influence the risk of liver and biliary tract cancers, but convincing evidence is lacking. PATIENTS AND METHODS: The association between dietary GI/GL and carbohydrate intake with hepatocellular carcinoma (HCC; N = 191), intrahepatic bile duct (IBD; N = 66), and biliary tract (N = 236) cancer risk was investigated in 477 206 participants of the European Prospective Investigation into Cancer and Nutrition cohort. Dietary intake was assessed by country-specific, validated dietary questionnaires. Hazard ratios and 95% confidence intervals were estimated from proportional hazard models. HBV/HCV status was measured in a nested case-control subset. RESULTS: Higher dietary GI, GL, or increased intake of total carbohydrate was not associated with liver or biliary tract cancer risk. For HCC, divergent risk estimates were observed for total sugar = 1.43 (1.17-1.74) per 50 g/day, total starch = 0.70 (0.55-0.90) per 50 g/day, and total dietary fiber = 0.70 (0.52-0.93) per 10 g/day. The findings for dietary fiber were confirmed among HBV/HCV-free participants [0.48 (0.23-1.01)]. Similar associations were observed for IBD [dietary fiber = 0.59 (0.37-0.99) per 10 g/day], but not biliary tract cancer. CONCLUSIONS: Findings suggest that higher consumption of dietary fiber and lower consumption of total sugars are associated with lower HCC risk. In addition, high dietary fiber intake could be associated with lower IBD cancer risk.

Dendritic cell-targeted protein vaccines: a novel approach to induce T-cell immunity.

Current vaccines primarily work by inducing protective antibodies. However, in many infections like HIV, malaria and tuberculosis as well as cancers, there remains a need for durable and protective T-cell immunity. Here, we summarize our efforts to develop a safe T-cell-based protein vaccine that exploits the pivotal role of dendritic cells (DC) in initiating adaptive immunity. Focusing on HIV, gag-p24 protein antigen is introduced into a monoclonal antibody (mAb) that efficiently and specifically targets the DEC-205 antigen uptake receptor on DC. When administered together with synthetic double-stranded RNA, polyriboinosinic:polyribocytidylic acid (poly IC) or its analogue poly IC stabilized with carboxymethylcellulose and poly-L-lysine (poly ICLC), as adjuvant, HIV gag-p24 within anti-DEC-205 mAb is highly immunogenic in mice, rhesus macaques, and in ongoing research, healthy human volunteers. Human subjects form both T- and B-cell responses to DC-targeted protein. Thus, DC-targeted protein vaccines are a potential new vaccine platform, either alone or in combination with highly attenuated viral vectors, to induce integrated immune responses against microbial or cancer antigens, with improved ease of manufacturing and clinical use.

Reactivation versus primary CMV infection after splenectomy in immunocompetent patients.

Acute CMV infection in the immunocompetent host is usually asymptomatic or produces only mild symptoms. CMV infection in immunocompromized patients, especially transplant recipients and those infected with HIV, is a result of profound lymphopenia or dysfunction of CD4+/CD8+ cells and can cause substantial rates of complication and death. We present a case of CMV infection in a previously healthy man who just had splenectomy for blunt trauma: a short incubation of the CMV disease, a strongly positive CMV antigenemia, severity of the disease including prominent lymphocytosis, massive hepatic sinusoidal infiltration, and retinitis. Splenectomy changed the immunological defense against the virus and brought the infection to nearly fulminant scale.

Macaque dendritic cells infected with SIV-recombinant canarypox ex vivo induce SIV-specific immune responses in vivo.

Dendritic cells (DCs) infected with recombinant avipox vectors express the introduced genes and activate antigen-specific T cells. DCs exhibit distinct differentiation-dependent immune functions. Moreover, immature DCs are readily infected by canarypox vectors, but undergo tumor necrosis factor (TNF)-alpha-dependent death, while fewer mature DCs get infected and resist dying. A pilot study was performed using the rhesus macaque system to explore whether immature and mature DCs infected with SIV-recombinant canarypox (vCP180) ex vivo could induce primary virus-specific immune responses in vivo. After subcutaneous (sc) reinjection, functional monocyte-derived DCs migrated to lymph nodes (LNs) within 1-2 days and primed T cells in vivo. This was observed by monitoring dye-labeled DCs in the draining LNs and tetanus toxoid (TT)-specific T cell responses after injection of TT-loaded DCs. DCs from simian immunodeficiency virus (SIV)-naïve rhesus macaques were infected with vCP180 (SIVmac142 gag, pol, and env genes), and sc reinjected into donor animals. Low-level SIV-specific T cell proliferation, but little if any interferon (IFN)-gamma production was detected. DCs pulsed with vCP180 in combination with TT and keyhole limpet hemocyanin (KLH) (to activate additional T cells and provide "helper" cytokines) induced SIV-, TT-, and KLH-specific T cell responses, including IFN-gamma responses not seen when vCP180-carrying DCs were used alone. Interleukin (IL)-10 and low-level antibody responses were also observed. This pilot study provides the proof of principle that sc injected ex vivo SIV-recombinant canarypox-infected DCs safely induce low-level SIV-specific immune responses in vivo.

Zafirlukast (Accolate): A new treatment for capsular contracture.

BACKGROUND: Capsular contracture after breast augmentation or reconstructive breast surgery is a difficult problem. Previous studies have suggested that alteration of the inflammatory response could have a role in reducing the incidence of capsular contracture. OBJECTIVE: We report a series of patients with Baker class III or IV capsular contracture who underwent treatment with zafirlukast. METHODS: Patients received a regimen of zafirlukast 20 mg by mouth 2 times daily for 3 months. RESULTS: In many cases, dramatic softening of the breast capsule was evident after 1 to 3 months of treatment. CONCLUSIONS: Zafirlukast appears to effectively soften early capsular contracture and may prevent the formation of capsular contracture in those patients at risk. (Aesthetic Surg J 2002;22:329-336.).

Alphavirus vectors: development and potential therapeutic applications.

Alphaviruses are RNA enveloped viruses that are proving their value as expression vectors. They are particularly well-suited for this role as they are easily and quickly engineered and can be used to produce high levels of proteins of interest. A promising and important use is as vaccines against disease-causing agents such as HIV. The three alphaviruses now serving as vectors are Sindbis virus, Semliki Forest virus (SFV) and Venezuelan equine encephalitis (VEE) virus. Sindbis virus and SFV are well-known models for studies in molecular and cell biology; VEE virus is a human pathogen and had received some previous notoriety as a potential biological weapon. It is now becoming a potentially valuable vaccine vector. All three viruses are being tested as vaccines but, at present, only Sindbis virus and SFV have been considered for other uses. Sindbis virus vectors have been developed to screen libraries for the identification of new proteins and to devise sensitive assays to detect viruses more difficult to grow in culture. Both Sindbis virus and SFV vectors are serving as tools for fundamental studies in biology, examples include development in insects and analysis of protein functions in neuronal cells. In this article the replication strategy of alphaviruses and the different ways they can be engineered to serve as expression vectors is described. This provides an introduction to the ways these vectors have been used and illustrates the promise these vectors offer.