Acute Ketone Monoester Supplementation Impairs 20-min Time-Trial Performance in Trained Cyclists: A Randomized, Crossover Trial.

Acute ketone monoester (KE) supplementation can alter exercise responses, but the performance effect is unclear. The limited and equivocal data to date are likely related to factors including the KE dose, test conditions, and caliber of athletes studied. We tested the hypothesis that mean power output during a 20-min cycling time trial (TT) would be different after KE ingestion compared to a placebo (PL). A sample size of 22 was estimated to provide 80% power to detect an effect size dz of 0.63 at an alpha level of .05 with a two-tailed paired t test. This determination considered 2.0% as the minimal important difference in performance. Twenty-three trained cyclists (N = 23; peak oxygen uptake: 65 ± 12 ml·kg-1 min-1; M ± SD), who were regularly cycling >5 hr/week, completed a familiarization trial followed by two experimental trials. Participants self-selected and replicated their diet and exercise for ∼24 hr before each trial. Participants ingested either 0.35 g/kg body mass of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate KE or a flavor-matched PL 30 min before exercise in a randomized, triple-blind, crossover manner. Exercise involved a 15-min warm-up followed by the 20-min TT on a cycle ergometer. The only feedback provided was time elapsed. Preexercise venous [ß-hydroxybutyrate] was higher after KE versus PL (2.0 ± 0.6 vs. 0.2 ± 0.1 mM, p < .0001). Mean TT power output was 2.4% (0.6% to 4.1%; mean [95% confidence interval]) lower after KE versus PL (255 ± 54 vs. 261 ± 54 W, p < .01; dz = 0.60). The mechanistic basis for the impaired TT performance after KE ingestion under the present study conditions remains to be determined.

Characteristics and Prognosis of Patients With Nonvalvular Atrial Fibrillation and Significant Valvular Heart Disease Referred for Electrical Cardioversion.

Valvular atrial fibrillation (AF) is defined as AF in the presence of mitral stenosis or mechanical valve prosthesis. However, there are patients with AF who have significant native valvular heart disease (VHD) others than mitral stenosis that are classified as nonvalvular AF. The characteristics and prognostic implications of these entities have not been extensively studied. Of 1,885 AF patients referred for electrical cardioversion (64 ± 13years, 71% male), 171 (9.1%) had valvular AF (any grade of mitral stenosis or mechanical/biological valve prostheses) and 1,714 patients were identified as nonvalvular AF, of whom 329 (17.5%) had significant left-sided VHD. Patients with nonvalvular AF but with significant left-sided VHD were older, more frequently women and had more co-morbidities compared with the other groups. Furthermore, nonvalvular AF patients with significant left-sided VHD showed the worst left ventricular systolic function and largest left atrial volumes. During a median follow-up of 64 months (interquartile range: 33 to 96 months), 488 patients presented with the combined endpoint of all-cause mortality, heart failure hospitalization, and ischemic stroke. Patients with nonvalvular AF and with significant left-sided VHD had more events of heart failure whereas patients with valvular AF had higher all-cause mortality events. There were no differences in ischemic stroke events. Type of AF was not associated with outcomes after correcting for echocardiographic variables. In conclusion, the frequency of AF patients with significant VHD is relatively high. The consequences of VHD and AF on cardiac structure and function are more important determinants of adverse outcome than the type of AF.

Daclatasvir and sofosbuvir treatment of decompensated liver disease or post-liver transplant hepatitis C virus recurrence in patients with advanced liver disease/cirrhosis in a real-world cohort.

We report the findings of an early access program providing treatment for chronic hepatitis C virus infection (any genotype) with daclatasvir and sofosbuvir with/without ribavirin to patients with Child-Pugh class C cirrhosis or prior liver transplant recipients with recurrent hepatitis C virus infection and advanced fibrosis/cirrhosis. Patients had <12-month life expectancies per the local investigator. Patients received daclatasvir 60 mg and sofosbuvir 400 mg once daily, with/without ribavirin, for 24 weeks. Sustained virologic response (SVR) at posttreatment week 12 (SVR12) was measured. Assessments adhered to local standards. One patient (prior Child-Pugh class C who improved to class B) enrolled by exemption was included in the overall data but not the class C cohort efficacy/safety data. Of the 77 treated patients, including 62 liver transplant recipients (genotype 1, n = 43, 69%; genotype 3, n = 16, 26%) and 14 patients with Child-Pugh class C cirrhosis (genotype 1, n = 4, 29%; genotype 3, n = 10, 71%), 63 (82%) completed treatment. SVR12 rates by modified intention-to-treat analysis (excluding nonvirologic failures lost to follow-up and withdrawal [consent/no reason]) in the overall, liver transplant, and Child-Pugh class C cohorts were 84% (n = 64/76), 90% (n = 56/62), and 62% (n = 8/13), respectively. Rates increased to 96% (n = 64/67), 97% (n = 56/58), and 89% (n = 8/9), respectively, in patients with available virologic data (including early discontinuations); 22/23 patients with genotype 3 (96%) achieved SVR12. Single cases of virologic nonresponse and relapse (both in liver transplant recipients with genotype 1) and viral breakthrough (Child-Pugh class C; genotype 3) occurred. Six patients died, 10 had adverse events leading to discontinuation, and 30 experienced serious adverse events. Conclusion: Daclatasvir plus sofosbuvir, with/without ribavirin, provided high SVR12 rates and was generally well tolerated in patients with life-threatening disease and high unmet needs. (Hepatology Communications 2018;2:354-363).

Th17 cells are the dominant T cell subtype primed by Shigella flexneri mediating protective immunity.

The T cell response to Shigella, the causative agent of bacillary dysentery, remains poorly understood. Using a murine model of infection, we report that Shigella flexneri primes predominately IL-17A- and IL-22-producing Th17 cells. Shigella-specific Th1 cells are only significantly induced on secondary infection, whereas specific Th2 and CD8(+) T cells are undetectable. Apart from Th17 cells that are primed in a MHC class II- and IL-6-dependent, but IL12/23p40-independent manner, we identified gammadelta T cells as an additional but minor source of IL-17A. Priming of IL-17A(+) gammadelta T cells is dependent on IL12/23p40, but independent of MHC-class II and IL-6. Th17 cells have emerged as important players in inflammatory, autoimmune, and infectious diseases. Among the yet unresolved questions is their role in long-term immunity to pathogens. In this study, we show that the elicited S. flexneri-specific Th17 pool gives rise to an enhanced recall response up to 12 mo after priming, suggesting the presence of a long-term memory state. The clearance of primary infection is impaired in the absence of T cells, but independently of IL-17A. However, after reinfection, IL-17A produced by S. flexneri-specific Th17 cells becomes important to ultimately restrict bacterial growth. These findings bring new insights into the adaptive immune response to Shigella infection and highlight the importance of pathogen-specific Th17 cell immunity for secondary immune protection.

Intrauterine growth restriction is accompanied by decreased renal volume in the human fetus.

OBJECTIVE: Intrauterine growth-restricted fetuses are at risk for the development of adult hypertension and related cardiovascular diseases. Congenital oligonephropathy has been postulated as the primary mechanism. The objective of our study was to determine whether ultrasonically obtained in utero measurements of renal volume or renal artery Doppler blood flow differ between fetuses that are intrauterine growth restricted and fetuses that are not. STUDY DESIGN: The study population consisted of women who were referred for a prenatal ultrasound evaluation at a large community medical center. The women were divided into two groups: women with fetal biometry that was consistent with intrauterine growth restriction and women with biometry within normal range. Information was collected on maternal demographics and other factors known to affect fetal growth. We performed detailed fetal renal anthropomorphic and Doppler blood flow measurements in addition to standard fetal biometric measurements on all patients, specifically comparing renal volume and renal artery flow data between the two groups. RESULTS: No differences were observed in maternal age, race, parity, or fetal gestational age. Renal volume in the intrauterine growth-restricted fetuses was 31% (95% CI, 20%-40%), which was less than that in the group of fetuses that were not intrauterine growth restricted after an adjustment was made for gestational age. The ratio of renal volume to estimated fetal weight was 15% (95% CI, 1%-26%), which was less than the same ratio in the fetuses that were not intrauterine growth restricted. There were no differences seen in the renal artery Doppler measurements. CONCLUSION: Intrauterine growth restriction appears to be associated with a decrease in fetal renal volume. Because renal volume is a likely proxy for nephron number, this study supports the hypothesis that intrauterine growth restriction may be linked to congenital oligonephropathy and potentially to hypertension in later life.