Citations

Background: In patients with heart failure and preserved ejection fraction, little is known about the characteristics of, and outcomes in, those with and without diabetes mellitus. Methods: We examined clinical and echocardiographic characteristics and outcomes in the I-Preserve trial (Irbesartan in Heart Failure With Preserved Ejection Fraction) according to history of diabetes mellitus. Cox regression models were used to estimate hazard ratios for cardiovascular outcomes adjusted for known predictors, including age, sex, natriuretic peptides, and comorbidity. Echocardiographic data were available in 745 patients and were additionally adjusted for in supplementary analyses. Results: Overall, 1134 of 4128 patients (27%) had diabetes mellitus. Compared with those without diabetes mellitus, they were more likely to have a history of myocardial infarction (28% versus 22%), higher body mass index (31 versus 29 kg/m 2 ), worse Minnesota Living With Heart Failure score (48 versus 40), higher median N-terminal pro-B-type natriuretic peptide concentration (403 versus 320 pg/mL; all P <0.01), more signs of congestion, but no significant difference in left ventricular ejection fraction. Patients with diabetes mellitus had a greater left ventricular mass and left atrial area than patients without diabetes mellitus. Doppler E-wave velocity (86 versus 76 cm/s; P <0.0001) and the E/e’ ratio (11.7 versus 10.4; P =0.010) were higher in patients with diabetes mellitus. Over a median follow-up of 4.1 years, cardiovascular death or heart failure hospitalization occurred in 34% of patients with diabetes mellitus versus 22% of those without diabetes mellitus (adjusted hazard ratio, 1.75; 95% confidence interval, 1.49–2.05), and 28% versus 19% of patients with and without diabetes mellitus died (adjusted hazard ratio, 1.59; confidence interval, 1.33–1.91). Conclusions: In heart failure with preserved ejection fraction, patients with diabetes mellitus have more signs of congestion, worse quality of life, higher N-terminal pro-B-type natriuretic peptide levels, and a poorer prognosis. They also display greater structural and functional echocardiographic abnormalities. Further investigation is needed to determine the mediators of the adverse impact of diabetes mellitus on outcomes in heart failure with preserved ejection fraction and whether they are modifiable. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00095238.

AbstractContext:Lipoprotein lipase (LPL) activity is considered the rate-limiting step of very-low-density-lipoprotein triglycerides (VLDL-TG) tissue storage, and has been suggested to relate to the development of obesity as well as insulin resistance and type 2 diabetes.Objective:The objective of the study was to assess the relationship between the quantitative storage of VLDL-TG fatty acids and LPL activity and other storage factors in muscle and adipose tissue. In addition, we examine whether such relations were influenced by type 2 diabetes.Design:We recruited 23 men (12 with type 2 diabetes, 11 nondiabetic) matched for age and body mass index. Postabsorptive VLDL-TG muscle and subcutaneous adipose tissue (abdominal and leg) quantitative storage was measured using tissue biopsies in combination with a primed-constant infusion of ex vivo triolein labeled [1-14C]VLDL-TG and a bolus infusion of ex vivo triolein labeled [9,10-3H]VLDL-TG. Biopsies were analyzed for LPL activity and cellular storage factors.Results:VLDL-TG storage rate was significantly greater in men with type 2 diabetes compared with nondiabetic men in muscle tissue (P = 0.02). We found no significant relationship between VLDL-TG storage rate and LPL activity or other storage factors in muscle or adipose tissue. However, LPL activity correlated with fractional VLDL-TG storage in abdominal fat (P = 0.04).Conclusions:Men with type 2 diabetes have increased VLDL-TG storage in muscle tissue, potentially contributing to increased intramyocellular triglyceride and ectopic lipid deposition. Neither muscle nor adipose tissue storage rates were related to LPL activity. This argues against LPL as a rate-limiting step in the postabsorptive quantitative storage of VLDL-TG.

Objective IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucrase–isomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase–isomaltase ( SI ) gene variants for their potential relevance in IBS. Design We sequenced SI exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p.Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p.Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population. Results CSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case–control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (p<0.05). Conclusions SI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.

Abstract Background Resection with curative intent has been shown to prolong survival of patients with locoregional pancreatic ductal adenocarcinoma (PDAC). However, up to 33 per cent of patients are deemed unresectable at exploratory laparotomy owing to unanticipated locally advanced or metastatic disease. In these patients, prophylactic double bypass (PDB) procedures have been considered the standard of care. The aim of this study was to compare PDB with exploratory laparotomy alone in terms of impact on postoperative course, chemotherapy and overall survival. Methods This retrospective observational cohort study (2004–2013) was conducted using a prospective institutional database. Patients with histologically confirmed, unresectable PDAC were included. Relationships between PDB procedures, exploratory laparotomy alone, postoperative chemotherapy and best supportive care were investigated by means of Cox regression. Overall survival was compared using Kaplan–Meier estimations and log rank test. Results Of 503 patients with PDAC scheduled for resection with curative intent, 104 were deemed unresectable at laparotomy (resection rate 79·3 per cent). Seventy-four patients underwent PDB procedures and 30 had exploratory laparotomy alone. PDB and exploratory laparotomy were similar in terms of perioperative mortality, initiation of chemotherapy and overall survival. Compared with best supportive care, postoperative chemotherapy prolonged survival (8·0 versus 14·4 months in locally advanced PDAC, P = 0·007; 2·3 versus 8·0 months in metastatic PDAC, P &lt; 0·001). Patients undergoing chemotherapy following exploratory laparotomy alone had longer median overall survival than patients undergoing chemotherapy following PDB procedures (16·3 versus 10·3 months; P = 0·040). Conclusion Patients with pancreatic cancer deemed unresectable at laparotomy may derive survival benefit from subsequent chemotherapy as opposed to supportive care alone. At laparotomy, proceeding with a bypass procedure for prophylactic symptom control may be prognostically unfavourable.

Objective The main objective of this pilot study was to investigate the safety of administering onabotulinumtoxinA towards the sphenopalatine ganglion in 10 patients with intractable chronic migraine with an open, uncontrolled design. We also collected efficacy data to provide an indication as to whether future placebo-controlled studies should be performed. Method In a prospective, open-label, uncontrolled study after one-month baseline, we performed bilateral injections of 25 IU onabotulinumtoxinA (total dose 50 IU) toward the sphenopalatine ganglion in a single outpatient session in 10 patients with intractable migraine with a follow-up of 12 weeks. The primary outcome was adverse events and the main efficacy outcome was frequency of moderate and severe headache days in month 2 post-treatment compared to baseline. Results All 10 patients experienced a total of 25 adverse events. The majority of these were different types of local discomfort in the face and jaw, and none were classified as serious. In an intention-to-treat analysis of the main efficacy outcome, a statistically significant reduction of moderate and severe headache days in baseline versus month 2 was observed (16.3 ± 6.2 days baseline versus 7.6 ± 7.6 days month 2, p = 0.009). Eight out of 10 patients experienced an at least 50% reduction of moderate and severe headache days compared to baseline. Conclusion The result warrants randomised, placebo-controlled studies to establish both safety and efficacy of this potential novel treatment of chronic migraine.

Background: Early sport specialization is not a requirement for success at the highest levels of competition and is believed to be unhealthy physically and mentally for young athletes. It also discourages unstructured free play, which has many benefits. Purpose: To review the available evidence on early sports specialization and identify areas where scientific data are lacking. Study Design: Think tank, roundtable discussion. Results: The primary outcome of this think tank was that there is no evidence that young children will benefit from early sport specialization in the majority of sports. They are subject to overuse injury and burnout from concentrated activity. Early multisport participation will not deter young athletes from long-term competitive athletic success. Conclusion: Youth advocates, parents, clinicians, and coaches need to work together with the sport governing bodies to ensure healthy environments for play and competition that do not create long-term health issues yet support athletic competition at the highest level desired.