Physiological Adaptations to Progressive Endurance Exercise Training in Adult and Aged Rats: Insights from the Molecular Transducers of Physical Activity Consortium (MoTrPAC)

While regular physical activity is a cornerstone of health, wellness, and vitality, the impact of endurance exercise training on molecular signaling within and across tissues remains to be delineated. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to characterize molecular networks underlying the adaptive response to exercise. Here, we describe the endurance exercise training studies undertaken by the Preclinical Animal Sites Studies component of MoTrPAC, in which we sought to develop and implement a standardized endurance exercise protocol in a large cohort of rats. To this end, Adult (6-mo) and Aged (18-mo) female (n = 151) and male (n = 143) Fischer 344 rats were subjected to progressive treadmill training (5 d/wk, ∼70%-75% VO2max) for 1, 2, 4, or 8 wk; sedentary rats were studied as the control group. A total of 18 solid tissues, as well as blood, plasma, and feces, were collected to establish a publicly accessible biorepository and for extensive omics-based analyses by MoTrPAC. Treadmill training was highly effective, with robust improvements in skeletal muscle citrate synthase activity in as little as 1-2 wk and improvements in maximum run speed and maximal oxygen uptake by 4-8 wk. For body mass and composition, notable age- and sex-dependent responses were observed. This work in mature, treadmill-trained rats represents the most comprehensive and publicly accessible tissue biorepository, to date, and provides an unprecedented resource for studying temporal-, sex-, and age-specific responses to endurance exercise training in a preclinical rat model

Mortality Risk in Pediatric Motor Vehicle Crash Occupants: Accounting for Developmental Stage and Challenging Abbreviated Injury Scale Metrics

<div><p><b>Objective:</b> Survival risk ratios (SRRs) and their probabilistic counterpart, mortality risk ratios (MRRs), have been shown to be at odds with Abbreviated Injury Scale (AIS) severity scores for particular injuries in adults. SRRs have been validated for pediatrics but have not been studied within the context of pediatric age stratifications. We hypothesized that children with similar motor vehicle crash (MVC) injuries may have different mortality risks (MR) based upon developmental stage and that these MRs may not correlate with AIS severity.</p><p><b>Methods:</b> The NASS-CDS 2000–2011 was used to define the top 95% most common AIS 2+ injuries among MVC occupants in 4 age groups: 0–4, 5–9, 10–14, and 15–18 years. Next, the National Trauma Databank 2002–2011 was used to calculate the MR (proportion of those dying with an injury to those sustaining the injury) and the co-injury-adjusted MR (MR_MAIS) for each injury within 6 age groups: 0–4, 5–9, 10–14, 15–18, 0–18, and 19+ years. MR differences were evaluated between age groups aggregately, between age groups based upon anatomic injury patterns and between age groups on an individual injury level using nonparametric Wilcoxon tests and chi-square or Fisher's exact tests as appropriate. Correlation between AIS and MR within each age group was also evaluated.</p><p><b>Results:</b> MR and MR_MAIS distributions of the most common AIS 2+ injuries were right skewed. Aggregate MR of these most common injuries varied between the age groups, with 5- to 9-year-old and 10- to 14-year-old children having the lowest MRs and 0- to 4-year-old and 15- to 18-year-old children and adults having the highest MRs (all <i>P</i> <.05). Head and thoracic injuries imparted the greatest mortality risk in all age groups with median MR_MAIS ranging from 0 to 6% and 0 to 4.5%, respectively. Injuries to particular body regions also varied with respect to MR based upon age. For example, thoracic injuries in adults had significantly higher MR_MAIS than such injuries among 5- to 9-year-olds and 10- to 14-year-olds (<i>P</i> =.04; <i>P</i> <.01). Furthermore, though AIS was positively correlated with MR within each age group, less correlation was seen for children than for adults. Large MR variations were seen within each AIS grade, with some lower AIS severity injuries demonstrating greater MRs than higher AIS severity injuries. As an example, MR_MAIS in 0- to 18-year-olds was 0.4% for an AIS 3 radius fracture versus 1.4% for an AIS 2 vault fracture.</p><p><b>Conclusions:</b> Trauma severity metrics are important for outcome prediction models and can be used in pediatric triage algorithms and other injury research. Trauma severity may vary for similar injuries based upon developmental stage, and this difference should be reflected in severity metrics. The MR-based data-driven determination of injury severity in pediatric occupants of different age cohorts provides a supplement or an alternative to AIS severity classification for pediatric occupants in MVCs.</p></div

Mid-term outcomes of the COMMENCE trial investigating mitral valve replacement using a bioprosthesis with a novel tissueCentral MessagePerspective

Objective: Novel tissue leaflets (RESILIA tissue) may improve durability of bioprosthetic heart valves. The COMMENCE trial is an ongoing prospective study to evaluate valve replacement using RESILIA tissue. This report describes mid-term outcomes in the mitral cohort of COMMENCE. Methods: Adult patients requiring mitral valve replacement were enrolled in a prospective, single-arm trial at 17 sites in the United States and Canada. An independent clinical events committee adjudicated safety events using definitions from established guidelines, and hemodynamic performance was evaluated by an independent echocardiographic core laboratory. Results: Eighty-two patients (median age 70 years) successfully underwent mitral valve replacement with the study valve. Five-year event-free probabilities for all-cause mortality, structural valve deterioration, and reoperation were 79.9%, 98.7%, and 97.1%, respectively. Hemodynamic valve function measurements were stable through the 5-year follow-up period; valvular leaks were infrequently observed and primarily clinically insignificant/mild. Conclusions: Mitral valve replacement patients implanted with a RESILIA tissue bioprosthesis had a good safety profile and clinically stable hemodynamic performance

Animal study experimental design.

<p>Animal study experimental design.</p

Neutralizing antibody production following intranasal immunization with GelVac^™ dry powder bivalent and monovalent vaccine.

<p>Female Hartley guinea pigs were immunized intranasally with 20 mg of a bivalent vaccine powder formulation containing various amounts of GI and GII.4 VLPs on days 0 and 21. Serum samples were collected on days 0, 14, 21, 42, and 56 and analyzed for GI (A) and GII.4 (B) neutralizing antibodies. Error bars are provided as geometric standard deviation. *<i>p</i><0.05 as compared to the placebo control group. Horizontal dotted line depicts the limit of detection for these assays.</p

Serum norovirus-specific IgG and IgA production following intranasal immunization with GelVac^™ bivalent and monovalent vaccine powders.

<p>Female Hartley guinea pigs were immunized intranasally with 20 mg of a bivalent vaccine powder formulation containing various amounts of GI and GII.4 VLPs on days 0 and 21. Serum samples were collected on day 0, 14, 21, 42, and 56 and analyzed for specific IgG antibodies against GI (A) and GII.4 (B). Serum samples were also analyzed for specific IgA antibodies against GI (C) and GII.4 (D). Error bars are provided as geometric standard deviation. *<i>p</i><0.05 as compared to the placebo control group. Horizontal dotted line depicts the limit of detection for these assays.</p

Intranasal delivery of a bivalent norovirus vaccine formulated in an <i>in situ</i> gelling dry powder

<div><p>The global health community is beginning to understand the burden of norovirus-associated disease, which has a significant impact in both developed and developing countries. Norovirus virus like particle (VLP)-based vaccines are currently under development and have been shown to elicit systemic and mucosal immune responses when delivered intranasally. In the present study, we describe the use of a dry powder formulation (GelVac^™) with an <i>in situ</i> gelling polysaccharide (GelSite^™) extracted from <i>Aloe vera</i> for nasal delivery of a bivalent vaccine formulation containing both GI and GII.4 norovirus VLPs. Dose-ranging studies were performed to identify the optimal antigen dosages based on systemic and mucosal immune responses in guinea pigs and determine any antigenic interference. A dose-dependent increase in systemic and mucosal immunogenicity against each of the VLPs were observed as well as a boosting effect for each VLP after the second dosing. A total antigen dose of ≥50 μg of each GI and GII.4 VLPs was determined to be the maximally immunogenic dose in guinea pigs. The immunogenicity results of this bivalent formulation, taken together with previous work on monovalent GelVac^™ norovirus vaccine formulation, provides a basis for future development of this norovirus VLP vaccine.</p></div

Transmission electron microscopy of norovirus VLPs.

<p>GI (A) and GII.4 (B) VLPs were dissolved in water and imaged at 150,000x magnification (scale bar 100 μm). VLP particles were spherical in appearance at the expected size of 23–38 nm.</p