The First Evaluation of a Geroscience Biomarker Index (TAME-BI) in a Trial of Caloric Restriction and Exercise

We leveraged the WF OAIC biorepository to measure a consensus-derived panel of blood-based biomarkers of aging and constructed a geroscience-guided biomarker index (TAME-BI), testing it for the first time in a clinical trial. We measured IL-6, TNF-α-receptor-I, growth differentiating factor-15, cystatin C, and N-terminal pro-B-type natriuretic peptide in a 20-week randomized trial of caloric restriction (CR), aerobic exercise (EX), CR+EX, or attention-control in 88 patients (67±5years) with heart failure with preserved ejection fraction (HFpEF). We calculated TAME-BI (analyte levels ranked, binned by quintile, and summed) and found a time×treatment interaction for improved TAME-BI with intervention (p≤0.05) and detected associations between change in TAME-BI and change in six-minute walk distance (r= -0.24), usual walk speed (r= -0.23), and left ventricular relative wall thickness (r= 0.31). In sum, CR+EX intervention improved TAME-BI and changes in TAME-BI were associated with changes in key functional measures in older HFpEF patients.

A frequentist one-step model for a simple network meta-analysis of time-to-event data in presence of an effect modifier

Introduction Individual patient data (IPD) present particular advantages in network meta-analysis (NMA) because interactions may lead an aggregated data (AD)-based model to wrong a treatment effect (TE) estimation. However, fewer works have been conducted for IPD with time-to-event contrary to binary outcomes. We aimed to develop a general frequentist one-step model for evaluating TE in the presence of interaction in a three-node NMA for time-to-event data. Methods One-step, frequentist, IPD-based Cox and Poisson generalized linear mixed models were proposed. We simulated a three-node network with or without a closed loop with (1) no interaction, (2) covariate-treatment interaction, and (3) covariate distribution heterogeneity and covariate-treatment interaction. These models were applied to the NMA (Meta-analyses of Chemotherapy in Head and Neck Cancer [MACH-NC] and Radiotherapy in Carcinomas of Head and Neck [MARCH]), which compared the addition of chemotherapy or modified radiotherapy (mRT) to loco-regional treatment with two direct comparisons. AD-based (contrast and meta-regression) models were used as reference. Results In the simulated study, no IPD models failed to converge. IPD-based models performed well in all scenarios and configurations with small bias. There were few variations across different scenarios. In contrast, AD-based models performed well when there were no interactions, but demonstrated some bias when interaction existed and a larger one when the modifier was not distributed evenly. While meta-regression performed better than contrast-based only, it demonstrated a large variability in estimated TE. In the real data example, Cox and Poisson IPD-based models gave similar estimations of the model parameters. Interaction decomposition permitted by IPD explained the ecological bias observed in the meta-regression. Conclusion The proposed general one-step frequentist Cox and Poisson models had small bias in the evaluation of a three-node network with interactions. They performed as well or better than AD-based models and should also be undertaken whenever possible.

Prevalence of evidence of inconsistency and its association with network structural characteristics in 201 published networks of interventions

Background Network meta-analysis (NMA) has attracted growing interest in evidence-based medicine. Consistency between different sources of evidence is fundamental to the reliability of the NMA results. The purpose of the present study was to estimate the prevalence of evidence of inconsistency and describe its association with different NMA characteristics. Methods We updated our collection of NMAs with articles published up to July 2018. We included networks with randomised clinical trials, at least four treatment nodes, at least one closed loop, a dichotomous primary outcome, and available arm-level data. We assessed consistency using the design-by-treatment interaction (DBT) model and testing all the inconsistency parameters globally through the Wald-type chi-squared test statistic. We estimated the prevalence of evidence of inconsistency and its association with different network characteristics (e.g., number of studies, interventions, intervention comparisons, loops). We evaluated the influence of the network characteristics on the DBT p-value via a multivariable regression analysis and the estimated Pearson correlation coefficients. We also evaluated heterogeneity in NMA (consistency) and DBT (inconsistency) random-effects models. Results We included 201 published NMAs. The p-value of the design-by-treatment interaction (DBT) model was lower than 0.05 in 14% of the networks and lower than 0.10 in 20% of the networks. Networks including many studies and comparing few interventions were more likely to have small DBT p-values (less than 0.10), which is probably because they yielded more precise estimates and power to detect differences between designs was higher. In the presence of inconsistency (DBT p-value lower than 0.10), the consistency model displayed higher heterogeneity than the DBT model. Conclusions Our findings show that inconsistency was more frequent than what would be expected by chance, suggesting that researchers should devote more resources to exploring how to mitigate inconsistency. The results of this study highlight the need to develop strategies to detect inconsistency (because of the relatively high prevalence of evidence of inconsistency in published networks), and particularly in cases where the existing tests have low power.

246 Examining Melatonin-induced Changes in Uterine Blood Flow and Vaginal Temperatures in Nutrient Restricted Pregnant Heifers

The objectives were to examine melatonin mediated changes in temporal uterine blood flow (UBF) and vaginal temperatures (VT) in 54 Brangus heifers (Fall, n = 29; Summer, n = 25) during compromised pregnancy. At d160 of gestation, heifers were assigned to 1 of 4 groups consisting of adequately fed (ADQ-CON; 100% NRC; n=13), global nutrient restricted (RES-CON; 60% NRC; n = 13), and ADQ or RES supplemented with 20 mg of melatonin (ADQ-MEL, n = 13; RES-MEL, n = 15). In the morning (0500h) and afternoon (1300h) of d220 of gestation, temperature dataloggers (Onset Computer Corporation) attached to progesterone-free CIDRs were used to record VT, while UBF was determined via Doppler ultrasonography. Data were analyzed using repeated measures of ANOVA (SAS). Significant differences were found in UBF and VT between Fall and Summer groups (P< 0.05), therefore seasons were individually analyzed. In Fall, a nutrition by treatment interaction was significant, where the RES-CON heifers exhibited reduced total UBF compared to ADQ-CON (5.67±0.68 vs. 7.97±0.54 L/min; P = 0.012). In Summer, there was not a main effect of nutrition (P = 0.390); nevertheless, the MEL heifers exhibited increased total UBF compared to the CON counterparts (8.16±0.73 vs. 6.00±0.70 L/min; P = 0.048). Moreover, there was a nutrition by treatment by time interaction in VT for Fall and Summer heifers (P < 0.0001). In Fall, all groups had decreased VT in the morning compared to the afternoon (P < 0.0001). Whereas, in Summer, VT increased for ADQ-CON, RES-CON, and ADQ-MEL from morning to afternoon (P < 0.0001), while the RES-MEL remained constant throughout the day (P = 0.649). Furthermore, during the afternoon RES-MEL heifers exhibited decreased VT compared to ADQ-CON (38.91±0.09 vs. 39.26±0.09°C, respectively; P=0.039). In summary, nutrient restriction and melatonin supplementation altered UBF in a season dependent manner. Additionally, with the VT differences observed in Summer, future studies should evaluate the potential of melatonin supplementation for mitigating heat stress in farm animals.

PSIII-26 The effects of maternal melatonin supplementation during pregnancy on longissimus dorsi muscle morphometrics in bovine fetuses at 240 days of gestation

Melatonin is a multifunctional hormone that positively impacts postnatal growth and weaning weight in cattle offspring when supplemented to adequately fed dams during gestation. However, it is unclear whether supplemental melatonin is effective as a countermeasure to decrease effects of a nutritionally compromised pregnancy on fetal tissues. The current study evaluated the efficacy of maternal melatonin supplementation during gestation, as a therapeutic in nutrient restricted beef heifers using fetal LM morphometrics for evaluation of carcass tissue growth. On gestational d 160, 25 Brangus heifers were assigned to one of four groups in a 2 x 2 factorial: nutrient restricted (RES-CON: 60% NRC; n = 6), adequate fed (ADQ-CON; 100% NRC; n = 6), nutrient restricted supplemented with 20 mg melatonin (RES-MEL; n = 7), or adequate fed supplemented with 20 mg melatonin (ADQ-MEL; n = 6). Treatments were top-dressed with 2 mL of melatonin dissolved in 100% ethanol (10 mg/mL) or 2 mL of ethanol (control). At gestational d 240, Caesarean sections and fetal necropsies were performed, both fetal LM were dissected to determine weight, length, and midline circumference. Data were analyzed using the MIXED procedure of SAS. There was a diet by treatment interaction wherein the mass of the left and right LM was increased (P0.035) by an average of 42.46 g in RES-MEL offspring compared to RES-CON fetuses, but no differences (P0.0812) among ADQ groups. Restricted nutrition decreased left LM circumference (10.21 vs. 10.95 cm; P = 0.0445). Treatment had no effect on LM length (P0.1139). In the present study, maternal melatonin supplementation during the Summer promoted muscle growth and mitigated the adverse effects of a nutritionally compromised pregnancy on LM morphometrics. These data are indicative of the potential for melatonin as a gestational therapeutic for prenatal muscle growth and improved efficiency of meat animal production.

PSI-13 Effects of maternal nutrient restriction and melatonin supplementation on fetal mammary gland vascularity

The objective was to determine fetal mammary gland vascularity following dietary melatonin supplementation in late pregnant nutrient restricted Brangus heifers carrying female fetuses from two different seasons (spring calving, n = 12; fall calving, n = 13). Heifers were assigned one of four nutritional treatments at day 160 of gestation; adequate fed (ADQ-CON; 100% NRC; n = 6), nutrient restricted (RES-CON; 60% NRC; n = 6), adequate fed with 20 mg of melatonin (ADQ-MEL; n = 6), and nutrient restricted with 20 mg of melatonin (RES-MEL; n = 7). Fetal mammary glands were collected at day 240 of gestation following Cesarean delivery. Mammary gland vascularity was determined via immunofluorescence staining and analyzed via ANOVA. In spring calving heifers, maternal body weight was decreased (P = 0.002) in RES (528±11 kg) vs ADQ (601±11 kg) fed. Fetal body weight, fetal mammary gland weight, and mammary gland vascularity were not different (P > 0.15) among treatments. In fall calving heifers, a nutrition by treatment interaction (P = 0.048) was observed for maternal body weight, which was increased in ADQ-MEL versus all groups. Fetal body weight and fetal mammary gland weight were not different (P > 0.45) among groups. In fall calving, fetal mammary gland capillary number and average size were not different (P > 0.40) among groups. However, a nutrition by treatment interaction was observed for capillary area (P = 0.05), which was increased in RES-MEL versus ADQ-MEL. In addition, a nutrition by treatment interaction was observed for capillary perimeter (P = 0.001), which was increased in RES-MEL versus all groups. Overall, maternal nutrient restriction and melatonin supplementation did not impact fetal mammary gland vascularity in spring calving heifers; however, melatonin supplementation during nutrient restriction in fall calving heifers may increase fetal mammary gland vascularity. In conclusion, seasonal differences and natural melatonin production may influence melatonin-induced changes in fetal development.

PSXIII-6 Effects of cyclic monensin feeding on ruminally cannulated beef steers consuming low-quality forage

The loss of monensin efficacy when fed continuously requires further study for development of novel feeding strategies that may prolong its effectiveness. In the present study, effects of cyclic monensin feeding on utilization of low-quality forage (LQF; 4.9%CP) were evaluated using ruminally cannulated steers (12 Bos taurus; 260 kg BW). Steers were randomly assigned to one of three treatments: 1) CON (0 mg∙hd-1∙d-1 monensin; Rumensin® 90, Elanco Animal Health, Greenfield, IN), 2) MON (200 mg∙hd-1∙d-1 monensin) or 3) CYC (200 mg∙hd-1∙d-1 monensin for 14 d and 0 mg∙hd-1∙d-1 monensin for subsequent 14 d). Dried distillers grains (1 kg∙hd-1∙d-1) were fed for monensin inclusion. Each of four periods were 28 days in length. Hay, ort, and fecal samples were collected d 10–14 of each period for measures of digestion. Rumen fluid was collected with a suction strainer 0, 2, 4, 8, and 12 h after feeding on d 14 for VFA analysis. Data were analyzed using the MIXED procedure of SAS 9.4 (SAS Inst. Inc., Cary, NC). A period × treatment interaction was not observed for any measure of digestion (DMD, OMD, NDFD; P ≥ 0.39). A period × treatment interaction (P < 0.01) was observed for acetate, propionate, and A:P. An hour effect was observed for all ruminal fermentation parameters (acetate, propionate, A:P ratio, total VFA; P ≤ 0.01). No treatment effects or interactions were observed for any ruminal fermentation parameters by period 4 (P ≥ 0.15), but an hour effect was observed for all parameters (P ≤ 0.03) in period 4. Exploration of novel feeding strategies results in knowledge beef cattle producers can apply in their operations. This data is particularly relevant in cow-calf operations where LQF is often consumed. Although cyclically feeding monensin was similar to continuous feeding, this research furthers our knowledge and understanding of monensin.