Seasonal Training Load Quantification and Comparison in College Male Soccer Players.

ABSTRACT: Ryan, GA, Snarr, RL, Eisenman, ML, and Rossi, SJ. Seasonal training load quantification and comparison in college male soccer players. J Strength Cond Res 36(4): 1038-1045, 2022-Monitoring and quantification of training load (TL) throughout a competitive soccer season is important to ensure players are able to perform throughout the season. The intent of this study was to examine the positional demands and patterns of select measures of TL during a 14-week season in collegiate male soccer players. Heart rate (HR), running performance (SZ), and perceived recovery data were collected daily using a bioharness for each subject (n = 21). Data were grouped into 2- to 3-week training blocks (Pre1, Pre2, In1, In2, In3, and In4). Continuous variables were analyzed using a multivariate analysis of variance, with post hoc Least Squared Difference pairwise comparisons. Significant positional differences were observed across the season. During Pre1, center midfielders (CM) spent more time in %HRlow compared to center backs (CB) (p < 0.01), wide midfielders (p < 0.01), and center forwards (p = 0.04). Center midfielders spent greater time in SZlower than CB (p < 0.01) and wide backs (WB) (p = 0.01). Wide backs spent greater time in SZupper compared to other positions (all p < 0.01). During Pre2, WB spent more time in %HRhigh and SZupper compared to other positions (all p < 0.01). Positional differences were more varied throughout in-season comparisons, but generally, WB and CB demonstrated higher intensities in variables compared to other positions. Tracking variations in positional TLs across the season is important for coaching and training staffs to determine player readiness and plan future training sessions, while helping to mitigate overuse injuries during a long competitive season.

NGM282 Improves Liver Fibrosis and Histology in 12 Weeks in Patients With Nonalcoholic Steatohepatitis.

NGM282, an engineered fibroblast growth factor 19 analogue, rapidly and significantly reduced liver fat content in a multicenter, randomized, double-blind, placebo-controlled study in patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH). However, it is unclear whether these changes would be accompanied by histological improvement. In this open-label study, we assessed the histological efficacy of NGM282 in patients with biopsy-confirmed nonalcoholic steatohepatitis. Paired liver biopsies from 43 patients who received subcutaneous NGM282 (1 mg, n = 24; 3 mg, n = 19) once daily for 12 weeks were evaluated blinded to time point, subject, and clinical information. At week 12, NGM282 significantly reduced nonalcoholic fatty liver disease activity score (NAS; -1.9; 95% confidence interval, -2.6 to -1.2; P < 0.001 in the 1 mg group; -2.2, -3.1 to -1.3; P < 0.001 in the 3 mg group) and fibrosis (-0.5; -0.9 to 0; P = 0.035 in the 3 mg group) scores. Overall, 50% and 63% of the patients receiving NGM282 1 mg or 3 mg, respectively, improved NAS by 2 or more points without fibrosis worsening. Of the patients receiving NGM282 1 mg or 3 mg, 25% and 42%, respectively, improved liver fibrosis by one stage or more without worsening of steatohepatitis. Treatment with NGM282 led to relative reductions in liver fat content (-58% and -67% in the 1 mg and 3 mg groups, respectively), corrected T1 (cT1; -8% and -9%), alanine aminotransferase (ALT) (-67% and -60%), aspartate aminotransferase (-57% and -52%), and fibrogenesis biomarkers neoepitope-specific N-terminal propeptide of type III collagen (Pro-C3; -22% and -33%) and enhanced liver fibrosis score (ELF; -3% and -6%) at week 12. Greater reductions in Pro-C3, ELF, and cT1, but not in liver fat content, 7alpha-hydroxy-4-cholesten-3-one, or ALT, were observed in histological responders than in nonresponders. Conclusion: In this open-label study, NGM282 improved the histological features of NASH in 12 weeks with significant reductions in NAS and fibrosis scores, accompanied by improvements in noninvasive imaging and serum markers.

Therapeutic FGF19 promotes HDL biogenesis and transhepatic cholesterol efflux to prevent atherosclerosis.

Fibroblast growth factor (FGF)19, an endocrine hormone produced in the gut, acts in the liver to control bile acid synthesis. NGM282, an engineered FGF19 analog, is currently in clinical development for treating nonalcoholic steatohepatitis. However, the molecular mechanisms that integrate FGF19 with cholesterol metabolic pathways are incompletely understood. Here, we report that FGF19 and NGM282 promote HDL biogenesis and cholesterol efflux from the liver by selectively modulating LXR signaling while ameliorating hepatic steatosis. We further identify ABCA1 and FGF receptor 4 as mediators of this effect, and that administration of a HMG-CoA reductase inhibitor or a blocking antibody against proprotein convertase subtilisin/kexin type 9 abolished FGF19-associated elevations in total cholesterol, HDL cholesterol (HDL-C), and LDL cholesterol in db/db mice. Moreover, we show that a constitutively active MEK1, but not a constitutively active STAT3, mimics the effect of FGF19 and NGM282 on cholesterol change. In dyslipidemic Apoe-/- mice fed a Western diet, treatment with NGM282 dramatically reduced atherosclerotic lesion area in aortas. Administration of NGM282 to healthy volunteers for 7 days resulted in a 26% increase in HDL-C levels compared with placebo. These findings outline a previously unrecognized role for FGF19 in the homeostatic control of cholesterol and may have direct impact on the clinical development of FGF19 analogs.

Rosuvastatin improves the FGF19 analogue NGM282-associated lipid changes in patients with non-alcoholic steatohepatitis.

BACKGROUND: NGM282, an engineered analogue of the gut hormone FGF19, improves hepatic steatosis and fibrosis biomarkers in patients with non-alcoholic steatohepatitis (NASH). However, NGM282 increases serum cholesterol levels by inhibiting CYP7A1, which encodes the rate-limiting enzyme in the conversion of cholesterol to bile acids. Herein, we investigate whether administration of a statin can manage the cholesterol increase seen in patients with NASH receiving treatment with NGM282. METHODS: In this phase II, open-label, multicenter study, patients with biopsy-confirmed NASH were treated with subcutaneous NGM282 once daily for 12 weeks. After 2 weeks, rosuvastatin was added in stepwise, biweekly incremental doses to a maximum of 40 mg daily. Both drugs were continued until the end of treatment at week 12. We evaluated plasma lipids, lipoprotein particles and liver fat content. RESULTS: In 66 patients who received NGM282 0.3 mg (n = 23), NGM282 1 mg (n = 21), or NGM282 3 mg (n = 22), circulating cholesterol increased from baseline at week 2. Initiation of rosuvastatin resulted in rapid decline in plasma levels of total cholesterol and low-density lipoprotein cholesterol. At week 12, reductions from baseline in total cholesterol levels of up to 18% (p <0.001), low-density lipoprotein cholesterol of up to 28% (p <0.001), triglycerides of up to 34% (p <0.001) and an increase in high-density lipoprotein cholesterol of up to 16% (p <0.001), with similar changes in lipoprotein particles, were observed in these patients. Robust decreases from baseline in 7alpha-hydroxy-4-cholesten-3-one (p <0.001) and liver fat content (p <0.001) were also observed. Rosuvastatin was safe and well-tolerated when co-administered with NGM282 in patients with NASH. CONCLUSIONS: In this multicenter study, NGM282-associated elevation of cholesterol was effectively managed with rosuvastatin. Co-administration of rosuvastatin with NGM282 may be a reasonable strategy to optimize the cardiovascular risk profile in patients with NASH. LAY SUMMARY: Non-alcoholic steatohepatitis (NASH) represents a large and growing public health concern with no approved therapy. NGM282, an engineered analogue of the gut hormone FGF19, reduces liver fat, liver injury and inflammation in patients with NASH. However, NGM282 increases cholesterol levels. Here we show that co-administration of a statin can manage the cholesterol increase seen in patients with NASH receiving treatment with NGM282, producing a favorable overall lipid profile.

Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: A multicenter, randomized, double-blind, placebo-controlled phase II trial.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is an inflammatory, cholestatic and progressively fibrotic liver disease devoid of effective medical intervention. NGM282, an engineered, non-tumorigenic FGF19 analogue, potently regulates CYP7A1-mediated bile acid homeostasis. We assessed the activity and safety of NGM282 in patients with PSC. METHODS: In this double-blind, placebo-controlled phase II trial, 62 patients who had PSC confirmed by cholangiography or biopsy and an elevated alkaline phosphatase (ALP) >1.5 × the upper limit of normal were randomly assigned 1:1:1 to receive NGM282 1 mg, 3 mg or placebo once daily for 12 weeks. The primary outcome was the change in ALP from baseline to week 12. Secondary and exploratory outcomes included changes in serum biomarkers of bile acid metabolism and fibrosis. Efficacy analysis was by intention-to-treat. RESULTS: At 12 weeks, there were no significant differences in the mean change from baseline in ALP between the NGM282 and placebo groups, and therefore, the primary endpoint was not met. However, NGM282 significantly reduced levels of 7alpha-hydroxy-4-cholesten-3-one (a marker of hepatic CYP7A1 activity, LS mean differences -6.2 ng/ml (95% CI -10.7 to -1.7; p = 0.008) and -9.4 ng/ml (-14.0 to -4.9; p <0.001) in the NGM282 1 mg and 3 mg groups, respectively, compared with placebo) and bile acids. Importantly, fibrosis biomarkers that predict transplant-free survival, including Enhanced Liver Fibrosis score and Pro-C3, were significantly improved following NGM282 treatment. Most adverse events were mild to moderate in severity, with gastrointestinal symptoms more frequent in the NGM282 treatment groups. CONCLUSIONS: In patients with PSC, NGM282 potently inhibited bile acid synthesis and decreased fibrosis markers, without significantly affecting ALP levels. LAY SUMMARY: We present for the first time, the clinical and laboratory effects of a first-in-class, engineered analogue of the endocrine hormone FGF19 in patients with primary sclerosing cholangitis (PSC). By incorporating non-invasive markers of fibrosis, beyond standard liver injury markers, we show that NGM282 impacted on fibrosis turnover and hepatic inflammation without changing alkaline phosphatase. Our findings demonstrate the complexities of using highly potent rational agents in PSC, and furthermore challenge the dogma about what the appropriate endpoints should be for trials in PSC.

NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Non-alcoholic steatohepatitis is a chronic liver disease characterised by the presence of hepatic steatosis, inflammation, and hepatocellular injury, for which no Food and Drug Administration (FDA)-approved treatment exists. FGF19 is a hormone that regulates bile acid synthesis and glucose homoeostasis. We aimed to assess the safety and efficacy of NGM282, an engineered FGF19 analogue, for the treatment of non-alcoholic steatohepatitis. METHODS: In this randomised, double-blind, placebo-controlled, phase 2 study, we recruited patients aged 18-75 years with biopsy-confirmed non-alcoholic steatohepatitis as defined by the non-alcoholic steatohepatitis clinical research network histological scoring system, from hospitals and gastroenterology and liver clinics in Australia and the USA. Key eligibility criteria included a non-alcoholic fatty liver disease activity score of 4 or higher, stage 1-3 fibrosis, and at least 8% liver fat content. Patients were randomly assigned (1:1:1) via a web-based system and stratified by diabetic status to receive either 3 mg or 6 mg subcutaneous NGM282 or placebo. The primary endpoint was the absolute change from baseline to week 12 in liver fat content. Responders were patients who achieved a 5% or larger reduction in absolute liver fat content as measured by MRI-proton density fat fraction. Efficacy analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02443116. FINDINGS: Between July 14, 2015, and Aug 30, 2016, 166 patients were screened across 18 sites in Australia and the USA. 82 patients were randomly assigned to receive 3 mg NGM282 (n=27), 6 mg NGM282 (n=28), or placebo (n=27). At 12 weeks, 20 (74%) patients in the 3 mg dose group and 22 (79%) in the 6 mg dose group achieved at least a 5% reduction in absolute liver fat content from baseline (relative risk 10·0 [95% CI 2·6-38·7] vs 11·4 [3·0-43·8], respectively; p<0·0001 for both comparisons) versus two (7%) in the placebo group. Overall, 76 (93%) of 82 patients experienced at least one adverse event, most of which were grade 1 (55 [67%]), and only five (6%) were grade 3 or worse. The most commonly (≥10%) reported adverse events were injection site reactions (28 [34%]), diarrhoea (27 [33%]), abdominal pain (15 [18%]), and nausea (14 [17%]). These adverse events were reported more frequently in the NGM282 groups compared with the placebo group. No life-threatening events or patient deaths occurred during the study. INTERPRETATION: NGM282 produced rapid and significant reductions in liver fat content with an acceptable safety profile in patients with non-alcoholic steatohepatitis. Further study of NGM282 is warranted in this patient population. FUNDING: NGM Biopharmaceuticals.

Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice.

Alcoholic liver disease (ALD) is associated with changes in the intestinal microbiota. Functional consequences of alcohol-associated dysbiosis are largely unknown. The aim of this study was to identify a mechanism of how changes in the intestinal microbiota contribute to ALD. Metagenomic sequencing of intestinal contents demonstrated that chronic ethanol feeding in mice is associated with an over-representation of bacterial genomic DNA encoding choloylglycine hydrolase, which deconjugates bile acids in the intestine. Bile acid analysis confirmed an increased amount of unconjugated bile acids in the small intestine after ethanol administration. Mediated by a lower farnesoid X receptor (FXR) activity in enterocytes, lower fibroblast growth factor (FGF)-15 protein secretion was associated with increased hepatic cytochrome P450 enzyme (Cyp)-7a1 protein expression and circulating bile acid levels. Depletion of the commensal microbiota with nonabsorbable antibiotics attenuated hepatic Cyp7a1 expression and reduced ALD in mice, suggesting that increased bile acid synthesis is dependent on gut bacteria. To restore intestinal FXR activity, we used a pharmacological intervention with the intestine-restricted FXR agonist fexaramine, which protected mice from ethanol-induced liver injury. Whereas bile acid metabolism was only minimally altered, fexaramine treatment stabilized the gut barrier and significantly modulated hepatic genes involved in lipid metabolism. To link the beneficial metabolic effect to FGF15, a nontumorigenic FGF19 variant-a human FGF15 ortholog-was overexpressed in mice using adeno-associated viruses. FGF19 treatment showed similarly beneficial metabolic effects and ameliorated alcoholic steatohepatitis. CONCLUSION: Taken together, alcohol-associated metagenomic changes result in alterations of bile acid profiles. Targeted interventions improve bile acid-FXR-FGF15 signaling by modulation of hepatic Cyp7a1 and lipid metabolism, and reduce ethanol-induced liver disease in mice. (Hepatology 2018;67:2150-2166).

Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis.

BACKGROUND & AIMS: The degree of cholestasis is an important disease driver in alcoholic hepatitis, a severe clinical condition that needs new biomarkers and targeted therapies. We aimed to identify the largely unknown mechanisms and biomarkers linked to cholestasis in alcoholic hepatitis. METHODS: Herein, we analyzed a well characterized cohort of patients with alcoholic hepatitis and correlated clinical and histological parameters and outcomes with serum bile acids and fibroblast growth factor 19 (FGF19), a major regulator of bile acid synthesis. RESULTS: We found that total and conjugated bile acids were significantly increased in patients with alcoholic hepatitis compared with controls. Serum FGF19 levels were strongly increased and gene expression of FGF19 was induced in biliary epithelial cells and ductular cells of patients with alcoholic hepatitis. De novo bile acid synthesis (CYP7A1 gene expression and C4 serum levels) was significantly decreased in patients with alcoholic hepatitis. Importantly, total and conjugated bile acids correlated positively with FGF19 and with disease severity (model for end-stage liver disease score). FGF19 correlated best with conjugated cholic acid, and model for end-stage liver disease score best with taurine-conjugated chenodeoxycholic acid. Univariate analysis demonstrated significant associations between FGF19 and bilirubin as well as gamma glutamyl transferase, and negative correlations between FGF19 and fibrosis stage as well as polymorphonuclear leukocyte infiltration, in all patients with alcoholic hepatitis. CONCLUSION: Serum FGF19 and bile acids are significantly increased in patients with alcoholic hepatitis, while de novo bile acid synthesis is suppressed. Modulation of bile acid metabolism or signaling could represent a promising target for treatment of alcoholic hepatitis in humans. LAY SUMMARY: Understanding the underlying mechanisms that drive alcoholic hepatitis is important for the development of new biomarkers and targeted therapies. Herein, we describe a molecule that is increased in patients with alcoholic hepatitis. Modulating the molecular pathway of this molecule might lead to promising targets for the treatment of alcoholic hepatitis.

Effects of NGM282, an FGF19 variant, on colonic transit and bowel function in functional constipation: a randomized phase 2 trial.

OBJECTIVE: NGM282 is an analog of fibroblast growth factor 19 (FGF19), a potent inhibitor of bile acid (BA) synthesis in animals and humans. In phase 2 trials in type 2 diabetes and primary biliary cholangitis, NGM282 was associated with dose-related abdominal cramping and diarrhea. We aimed to examine effects of NGM282 on colonic transit, stool frequency and consistency, hepatic BA synthesis (fasting serum C4), fecal fat, and BA in functional constipation (FC). METHODS: Two-dose NGM282 (1 and 6 mg, subcutaneously daily), parallel-group, randomized, placebo-controlled, 14-day study in patients with FC (Rome III criteria) and baseline colonic transit 24 h geometric center (GC) <3.0. We explored treatment interaction with SNPs in genes KLB, FGFR4, and TGR5 (GPBAR1). STATISTICAL ANALYSIS: overall ANCOVA at α = 0.025 (baseline as covariate where available), with three pairwise comparisons among the three groups (α = 0.008). RESULTS: Overall, NGM282 altered bowel function (number of bowel movements, looser stool form, and increased ease of passage) and significantly accelerated gastric and colonic transit. Dose-related effects were seen with GC 24 h, but not with gastric emptying (GE) and GC 48 h. There were no differences in fecal fat or weight, but there was reduced fecal total BA excretion with NGM282. The most common adverse events were increased appetite (n = 0 with placebo, 2 with 1 mg, 9 with 6 mg), injection site reaction (n = 2 placebo, 4 with 1 mg, 8 with 6 mg), and diarrhea (n = 1 with 1 mg and 4 with 6 mg NGM282). There was treatment interaction with KLB SNP, with greater increase in colonic transit in participants with the minor A allele (p = 0.056). CONCLUSION: NGM282 significantly impacts GE and colonic transit, consistent with the observed clinical symptoms. The specific mechanism of prokinetic activity requires further research.

Engineered fibroblast growth factor 19 reduces liver injury and resolves sclerosing cholangitis in Mdr2-deficient mice.

UNLABELLED: Defects in multidrug resistance 3 gene (MDR3), which encodes the canalicular phospholipid flippase, cause a wide spectrum of cholangiopathy phenotypes in humans. Mice deficient in Mdr2 (murine ortholog of MDR3) develop liver diseases that closely reproduce the biochemical, histological, and clinical features of human cholangiopathies such as progressive familial intrahepatic cholestasis and primary sclerosing cholangitis. We hypothesized that modulating bile acid metabolism by the gut hormone fibroblast growth factor 19 (FGF19) may represent a novel approach for treating cholangiopathy and comorbidities. We introduced adeno-associated virus carrying the gene for either the endocrine hormone FGF19 or engineered FGF19 variant M70 to 12-week old Mdr2-deficient mice with fully established disease. Effects on serum levels of liver enzymes, liver histology, and bile acid homeostasis were evaluated. FGF19 and M70 rapidly and effectively reversed liver injury, decreased hepatic inflammation, attenuated biliary fibrosis, and reduced cholecystolithiasis in Mdr2-deficient mice. Mechanistically, FGF19 and M70 significantly inhibited hepatic expression of Cyp7a1 and Cyp27a1, which encode enzymes responsible for the rate-limiting steps in the classic and alternate bile acid synthetic pathways, thereby reducing the hepatic bile acid pool and blood levels of bile acids. Importantly, prolonged exposure to FGF19, but not M70, led to the formation of hepatocellular carcinomas in the Mdr2-deficient mice. Furthermore, M70 ameliorated the hepatosplenomegaly and ductular proliferation that are associated with cholangiopathy. CONCLUSION: These results demonstrate the potential for treating cholangiopathy by safely harnessing FGF19 biology to suppress bile acid synthesis.

Relationship Between Running Performance and Recovery-Stress State in Collegiate Soccer Players.

Coker, NA, Wells, AJ, Ake, KM, Griffin, DL, Rossi, SJ, and McMillan, JL. Relationship between running performance and recovery-stress state in collegiate soccer players. J Strength Cond Res 31(8): 2131-2140, 2017-The purpose of this study was to evaluate the relationship between changes in running performance and the stress-recovery state in collegiate soccer players. Running performance was evaluated in 7 National Collegiate Athletic Association Division I male soccer players (179.39 ± 5.24 cm; 75.46 ± 5.98 kg; 20.37 ± 1.41 years) through global positioning systems over the course of 12 competitive games in a single season. The regular season was divided into 4 competitive blocks: B1 (n = 3), B2 (n = 3), B3 (n = 3), and B4 (n = 3). Total distance and distance covered while engaging in walking, jogging, low-speed running, high-speed running, sprinting, low-intensity running, and high-intensity running were assessed during each block. The Recovery-Stress Questionnaire (RESTQ) 52 Sport was administered twice during each block to evaluate measures of stress and recovery. Total distance was greater during B4 compared with B1 (p = 0.027). Jogging and low-speed running were greater during B4 compared with all other time points (p's ≤ 0.05). Low-intensity running distance was greater during B4 compared with B1 (p = 0.034). Sport-specific recovery decreased significantly during B4 compared with B1 (p = 0.035). Correlational analysis indicated that high-velocity running was associated with increased stress, whereas low-velocity running was associated with greater recovery. However, changes in sport-specific recovery did not correlate with changes in running performance from B1 to B4. Results of this study indicate that running performance decreased across the season. Changes in running performance coincided with a decrease in sport-specific recovery. Practitioners may benefit from including the RESTQ as part of an assessment battery to monitor the stress/recovery state of athletes.

The Impact of Gloves and Occupational Tasks on Handgrip Strength in Structural Firefighters.

Adequate handgrip strength (HGS) is important to safely perform fireground tasks. However, there is limited research describing the deleterious impact of glove use and fatigue from occupational tasks on HGS. Therefore, the aims of this investigation were to quantify the impact of glove use and occupational tasks on HGS, to explore the relationship between HGS versus the glove and task-induced decrement in HGS, and to evaluate the relationship between HGS and decrement in HGS versus occupational performance. Fourteen (Male: n = 13) career structural firefighters (Age: 35.5 ± 7.2 yr) performed a maximal isometric HGS assessment with and without gloves before and immediately following completion of a simulated fireground test (SFGT). General linear model with written contrast was used to identify significant differences in HGS between conditions. Pearson Correlations were used to describe bivariate relationships between the decrements in HGS and occupational task times. Significance was set at p < 0.05. There were significant main effects indicating that gloves, performing occupational tasks, and their combined effects decreased HGS (p < 0.001 for all). There were strong inverse relationships between baseline (barehanded) HGS versus the decrement in HGS from donning gloves (r = -0.82, p < 0.001) and from performing occupational tasks with gloves (r = -0.61, p = 0.021). Baseline HGS and the decrement in HGS due to wearing gloves and performing occupational tasks were not correlated to the timed completion of occupational tasks (p ≥ 0.27). These findings suggest that the use of regulation fire gloves and work-induced fatigue reduces HGS and these decrements are related to HGS. Practitioners are encouraged to utilize training strategies to optimize HGS among structural firefighters.

Comparison of two different resistance training intensities on excess post-exercise oxygen consumption in African American women who are overweight.

The purpose of this study was to compare a low- and high-intensity resistance exercise session of equal work on excess post-exercise oxygen consumption (EPOC). Ten African American (AA) overweight women performed a no-exercise control (CN) session, 3 sets of 9 resistance training exercises, for 15 repetitions (reps) at 45% of their 8-repetition maximum (RM) during 1 session (LO) and for 8 reps at 85% of their 8-RM during another session (HI). For each session heart rate (HR), ventilation volume (VE), oxygen consumption (VO2), and respiratory exchange ratio, were collected continuously from 15 minutes pre exercise until 30 minutes post exercise. Blood lactate ([Lac]b) was collected pre, immediately post, 15 and 30 minutes post exercise. No significant differences were found between sessions for any pre-exercise measurements (p > 0.05). During exercise, there was no significant difference between the HI and LO sessions, as expected. The [Lac]b immediately post and 15-minute post were significantly higher in both HI and LO sessions compared with the CN session, however; no significant differences were found between the HI and LO sessions. Post-exercise HR for the HI session was significantly greater than the CN session (p = 0.006) but not different from the LO session. There were no significant differences in post-exercise VO2 between the HI and LO sessions. A trend was observed between exercise sessions with EPOC for HI (1.26 ± 0.567 L·O2) vs. LO (0.870 ± 0.394 L·O2) sessions. These data suggest that resistance training at either a low or high intensity with an equated work volume will produce similar exercise and post-exercise oxygen consumption for AA overweight women. Both of these resistance training programs were well tolerated and could be used for sedentary populations without a preconditioning program.

Efficacy and safety of peginterferon alfa-2a/ribavirin in methadone maintenance patients: randomized comparison of direct observed therapy and self-administration.

BACKGROUND: Adherence to chronic hepatitis C (CHC) treatment may be particularly challenging in methadone maintenance patients. We assessed the safety, tolerability, and efficacy of peginterferon alfa-2a/ribavirin treatment in methadone maintenance patients previously untreated for CHC. METHODS: Patients were randomized 1:1 to direct observed therapy (DOT) or self-administration (SA) of peginterferon alfa-2a. DOT patients were seen weekly at methadone clinics; SA patients were seen less frequently, only at investigative sites. Genotype 1-infected patients were treated for 48 wk with peginterferon alfa-2a (180 microg/wk)/ribavirin (1,000/1,200 mg/day); genotypes 2- and 3-infected patients were treated for 24 wk with peginterferon alfa-2a (180 microg/wk)/ribavirin (800 mg/day). RESULTS: Based on defined efficacy stopping rules, 77% (37/48) completed their targeted length of treatment, and 44% (21/48) achieved sustained virologic response (SVR). Two DOT and 3 SA patients were withdrawn for safety reasons and 6 and 9, respectively, for nonsafety reasons. Over 60% and 50% of each group were >80% compliant with the planned cumulative doses of peginterferon alfa-2a and ribavirin, respectively, and over 60% with overall treatment duration. SVR rates were 54% (13/24) for DOT and 33% (8/24) for SA; 23% (3/13) and 38% (6/16), respectively, for genotype 1 and 91% (10/11) and 25% (2/8), respectively, for genotypes 2 and 3. Stepwise logistic regression analysis, showed that DOT (vs SA; OR 3.27, 95% CI 0.90-11.91, P = 0.073) and Caucasian race (vs Other; OR 13.31, 95% CI 1.42-124.71, P = 0.023) were predictors of SVR. CONCLUSION: Peginterferon alfa-2a/ribavirin can be used safely and successfully in CHC patients receiving methadone maintenance.

NGM282 for Treatment of Patients With Primary Biliary Cholangitis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

Patients with primary biliary cholangitis (PBC) who had an inadequate response to ursodiol have few treatment options. Alkaline phosphatase (ALP) and bilirubin levels correlate with the risk of liver transplant or death in PBC patients. Fibroblast growth factor (FGF) 19 is a hormone that acts directly in the liver to regulate bile acid synthesis. We evaluated NGM282, an engineered analogue of FGF19, for the treatment of PBC. In this 28-day, double-blind, placebo-controlled phase 2 trial, 45 PBC patients who had an inadequate response to ursodiol were randomly assigned 1:1:1 to receive subcutaneous daily doses of either NGM282 at 0.3 mg (n = 14), 3 mg (n = 16), or placebo (n = 15). The primary endpoint was a change in ALP from baseline after 28 days of treatment. At day 28, ALP was significantly reduced with NGM282 treatment at both 0.3 mg (least-squares mean -51.0 IU/L [standard error (SE) 15.4]) and 3 mg (-66.0 IU/L [SE 16.0]) versus placebo (3.3 IU/L [SE 14.8]), with least-squares mean differences of -54.3 IU/L (95% confidence interval -104.2 to -4.5; P = 0.0149) and -69.3 IU/L (95% confidence interval -120.5 to -18.3; P = 0.0030), respectively. Fifty percent (7 of 14) of patients receiving NGM282 0.3 mg and 46% (6 of 13) of those receiving NGM282 3mg achieved 15% or greater reduction in ALP levels from baseline, compared with 7% (1 of 15) of patients receiving placebo. NGM282 also significantly reduced serum concentrations of transaminases and immunoglobulins. Most adverse events were grade 1 (mild) to grade 2 (moderate) in severity, with gastrointestinal disorders more frequent in the NGM282 treatment groups. No worsening of pruritus was observed with NGM282 treatment. Conclusion: NGM282 administered for 28 days resulted in significant improvements in ALP and transaminase levels compared with placebo, with an acceptable safety profile in patients with PBC. (Hepatology Communications 2018; 00:000-000).

A comparison of periodization models during nine weeks with equated volume and intensity for strength.

The purpose of the present investigation was to determine if significant differences exist among 3 different periodization programs in eliciting changes in strength. Twenty-eight recreationally trained college-aged volunteers (mean +/- SD; 22.29 +/- 3.98) of both genders were tested for bench press, leg press, body fat percentage, chest circumference, and thigh circumference during initial testing. After initial testing, subjects were randomly assigned to 1 of 3 training groups: (a) linear periodization (n = 9), (b) daily undulating periodization (n = 10), or (c) weekly undulating periodization (n = 9). The training regimen for each group consisted of a 9-week, 3-day-per-week program. Training loads were assigned as heavy (90%, 4 repetition maximum [4RM]), medium (85%, 6RM), or light (80%, 8RM) for bench press and leg press exercises. Subjects were familiarized with the CR-10 rated perceived exertion scale and instructed to achieve an 8 or 9 on the final repetition of each set for all other exercises. Subjects were then retested after 4 weeks of training. Training loads were then adjusted according to the new 1RM. Subjects were then retested after 5 more weeks of exercise. For all subjects, significant (p < 0.05) increases in bench press and leg press strength were demonstrated at all time points (T1-T3). No significant differences (p > 0.05) were observed between groups for bench press, leg press, body fat percentage, chest circumference, or thigh circumference at all time points. These results indicate that no separation based on periodization model is seen in early-phase training.

Engineered FGF19 eliminates bile acid toxicity and lipotoxicity leading to resolution of steatohepatitis and fibrosis in mice.

Nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent chronic liver disease for which no approved therapies are available. Despite intensive research, the cellular mechanisms that mediate NAFLD pathogenesis and progression are poorly understood. Although obesity, diabetes, insulin resistance, and related metabolic syndrome, all consequences of a Western diet lifestyle, are well-recognized risk factors for NAFLD development, dysregulated bile acid metabolism is emerging as a novel mechanism contributing to NAFLD pathogenesis. Notably, NAFLD patients exhibit a deficiency in fibroblast growth factor 19 (FGF19), an endocrine hormone in the gut-liver axis that controls de novo bile acid synthesis, lipogenesis, and energy homeostasis. Using a mouse model that reproduces the clinical progression of human NAFLD, including the development of simple steatosis, nonalcoholic steatohepatitis (NASH), and advanced "burnt-out" NASH with hepatocellular carcinoma, we demonstrate that FGF19 as well as an engineered nontumorigenic FGF19 analogue, M70, ameliorate bile acid toxicity and lipotoxicity to restore liver health. Mass spectrometry-based lipidomics analysis of livers from mice treated with FGF19 or M70 revealed significant reductions in the levels of toxic lipid species (i.e., diacylglycerols, ceramides and free cholesterol) and an increase in levels of unoxidized cardiolipins, an important component of the inner mitochondrial membrane. Furthermore, treatment with FGF19 or M70 rapidly and profoundly reduced levels of liver enzymes, resolved the histologic features of NASH, and enhanced insulin sensitivity, energy homeostasis, and lipid metabolism. Whereas FGF19 induced hepatocellular carcinoma formation following prolonged exposure in these mice, animals expressing M70 showed no evidence of liver tumorigenesis in this model. Conclusion: We have engineered an FGF19 hormone that is capable of regulating multiple pathways to deliver antisteatotic, anti-inflammatory, and antifibrotic activities and that represents a potentially promising therapeutic for patients with NASH. (Hepatology Communications 2017;1:1024-1042).

Seasonal changes of body mass, body composition, and muscular performance in collegiate wrestlers.

PURPOSE: The purpose of the present investigation was to examine the physiological response of collegiate wrestlers to their competitive season. METHODS: Eleven Division I collegiate wrestlers (mean +/- SD; 19.45 +/- 1.13 y) volunteered and completed 4 testing sessions throughout the course of the collegiate wrestling season. Testing sessions were conducted pre-, mid-, and postseason, as well as before the national tournament. Testing consisted of weigh-in, skinfold body composition testing, and a 50-rep concentric, isokinetic leg extension muscle endurance test (180 degrees /s). Muscular performance variables measured included peak torque, peak torque at fatigue, percent decline, and peak torque/body mass ratio. RESULTS: A significant increase (P < .05) of 2.9% was observed for body mass between midseason and postseason (2.38 kg). From pre- to postseason, a mean increase of 3.8% (3.1 kg) was observed for body mass. An increase (P < .05) in BF% of 2.9% was observed between prenationals and postseason. No significant differences (P > .05) were observed between consecutive time points for quadriceps peak torque; however, there was a significant increase (P < .05) between preseason and prenationals (23.39 N.m). Peak torque at fatigue was greater (P < .05) at midseason than preseason, representing an increase of 9.82 N.m. Between midseason and prenationals testing, we observed an 11% increase (P < .05) in %DCLN. Finally, we noted an increase (P < .05) from 0.6 to 0.69 in peak torque/body mass ratio between preseason and prenationals. CONCLUSIONS: Our results indicate that while force values seem to suffer at midseason, the wrestlers compensated and were strongest just before their national competition.

Bilateral comparison of barbell kinetics and kinematics during a weightlifting competition.

PURPOSE: The primary purpose of this study was to simultaneously analyze both ends of the barbell with 19 weightlifters (age 18.0 +/- 3.2 years, body mass 84.0 +/- 14.2 kg, height 167.3 +/- 8.7 cm) participating in a weightlifting competition to determine whether there were asymmetries in barbell kinematics and kinetics between the right and left sides of the barbell. The second purpose was to compare barbell-trajectory classification of the snatch and clean lifts between the right and left sides of the barbell. METHODS: Barbell kinematic and kinetic data were collected and analyzed with 2 VS-120 weightlifting-analysis systems (Lipman Electronic Engineering Ltd, Ramat Hahayal, Israel). Barbell trajectories (A, B, and C) for the right and left sides were analyzed for each lift. RESULTS: No significant difference was found in trajectory classification between sides of the barbell for either lift. The frequencies analysis revealed that type C barbell trajectories were the most prevalent in each lift. When the right and left sides of the barbell were compared during the snatch and clean, no significant differences were determined for any kinematic or kinetic variables. CONCLUSIONS: The V-scope system appears to facilitate analysis of barbell kinematics, kinetics, and trajectories during weightlifting competition regardless of which side of the barbell is analyzed.

The effect of a competitive wrestling season on body weight, hydration, and muscular performance in collegiate wrestlers.

The purpose of the present investigation was to examine the effects of a collegiate wrestling season on body weight, hydration, and muscular performance. Twelve Division I collegiate wrestlers (mean +/- SE; 20.75 +/- 0.41 year) volunteered to participate in testing sessions during midseason and 3 weeks following the season. Testing consisted of weigh-in, providing a urine sample for hydration analysis, and a measure of isometric leg extension peak torque. Weight significantly increased (p < 0.05) following the completion of the competitive season. No significant change in urine specific gravity (p > 0.05) was observed. Muscular performance was affected by the season as peak torque (PT) and PT-to-body weight ratio increased significantly (p < 0.05). Following the collegiate wrestling season, augmentation in body weight and muscular performance of the wrestlers occurs without alterations in hydration status. Further research is warranted on what type of strength training program would most effectively reduce the decrements in strength associated with weight loss and the strain of a competitive season.