Allopurinol in Patients with Pulmonary Hypertension Associated with Chronic Lung Disease.

BACKGROUND: Oxidative stress (OS) has been implicated in the development of pulmonary hypertension (PH) and ventricular hypertrophy. Xanthine oxidase is a well-recognised source of reactive oxygen species, which lead to OS. The aim of this proof of concept study was to assess whether allopurinol (xanthine oxidase inhibitor) would reduce right ventricular mass (RVM) in patients with PH-associated chronic lung disease (PH-CLD). METHODS: We conducted a randomised, double-blind, parallel-group, placebo-controlled trial in patients with PH-CLD (93% COPD, 7% IPF) who were randomly assigned to receive allopurinol or placebo for 12 months. The primary outcome was the mean change in RVM, as assessed by cardiac magnetic resonance imaging (CMRI). Secondary outcomes included quality of life (QOL), spirometry and six-minute walk test (6MWT). RESULTS: Seventy-one patients were recruited: mean age 71 years, mean pulmonary arterial pressure 30 mm Hg, FEV1 60% and resting SpO2 96%. After 12 months, there was no significant difference in the change in RVM from baseline (allopurinol 1.85g vs placebo 0.97g with mean difference 0.88g, CI -4.77 to 3.01, p =0.7). There were also no significant changes in other cardiac parameters measured on MRI, in QOL, spirometry and 6MWT. Subgroup analysis showed that allopurinol significantly reduced RVM compared to placebo with -6.16g vs 0.75g and mean difference 6.92g (CI 1.14 to 12.69, p = 0.02) in COPD patients with more severe airflow limitation. CONCLUSION: Allopurinol had no overall impact on patients with PH-CLD but had potential benefit in COPD patients with more severe airflow limitation

Descriptive Analysis of a Baseline Concussion Battery Among U.S. Service Academy Members: Results from the Concussion Assessment, Research, and Education (CARE) Consortium

Introduction The prevalence and possible long-term consequences of concussion remain an increasing concern to the U.S. military, particularly as it pertains to maintaining a medically ready force. Baseline testing is being used both in the civilian and military domains to assess concussion injury and recovery. Accurate interpretation of these baseline assessments requires one to consider other influencing factors not related to concussion. To date, there is limited understanding, especially within the military, of what factors influence normative test performance. Given the significant physical and mental demands placed on service academy members (SAM), and their relatively high risk for concussion, it is important to describe demographics and normative profile of SAMs. Furthermore, the absence of available baseline normative data on female and non-varsity SAMs makes interpretation of post-injury assessments challenging. Understanding how individuals perform at baseline, given their unique individual characteristics (e.g., concussion history, sex, competition level), will inform post-concussion assessment and management. Thus, the primary aim of this manuscript is to characterize the SAM population and determine normative values on a concussion baseline testing battery. Materials and Methods All data were collected as part of the Concussion Assessment, Research and Education (CARE) Consortium. The baseline test battery included a post-concussion symptom checklist (Sport Concussion Assessment Tool (SCAT), psychological health screening inventory (Brief Symptom Inventory (BSI-18) and neurocognitive evaluation (ImPACT), Balance Error Scoring System (BESS), and Standardized Assessment of Concussion (SAC). Linear regression models were used to examine differences across sexes, competition levels, and varsity contact levels while controlling for academy, freshman status, race, and previous concussion. Zero inflated negative binomial models estimated symptom scores due to the high frequency of zero scores. Results Significant, but small, sex effects were observed on the ImPACT visual memory task. While, females performed worse than males (p < 0.0001, pη2 = 0.01), these differences were small and not larger than the effects of the covariates. A similar pattern was observed for competition level on the SAC. There was a small, but significant difference across competition level. SAMs participating in varsity athletics did significantly worse on the SAC compared to SAMs participating in club or intramural athletics (all p’s < 0.001, η2 = 0.01). When examining symptom reporting, males were more than two times as likely to report zero symptoms on the SCAT or BSI-18. Intramural SAMs had the highest number of symptoms and severity compared to varsity SAMs (p < 0.0001, Cohen’s d < 0.2). Contact level was not associated with SCAT or BSI-18 symptoms among varsity SAMs. Notably, the significant differences across competition level on SCAT and BSI-18 were sub-clinical and had small effect sizes. Conclusion The current analyses provide the first baseline concussion battery normative data among SAMs. While statistically significant differences may be observed on baseline tests, the effect sizes for competition and contact levels are very small, indicating that differences are likely not clinically meaningful at baseline. Identifying baseline differences and significant covariates is important for future concussion-related analyses to inform concussion evaluations for all athlete levels

Pulmonary arterial stiffening in COPD and its implications for right ventricular remodelling.

BACKGROUND: Pulmonary pulse wave velocity (PWV) allows the non-invasive measurement of pulmonary arterial stiffening, but has not previously been assessed in COPD. The aim of the current study was to assess PWV in COPD and its association with right ventricular (RV) remodelling. METHODS: Fifty-eight participants with COPD underwent pulmonary function tests, 6-min walk test and cardiac MRI, while 21 healthy controls (HCs) underwent cardiac MRI. Thirty-two COPD patients underwent a follow-up MRI to assess for longitudinal changes in RV metrics. Cardiac MRI was used to quantify RV mass, volumes and PWV. Differences in continuous variables between the COPD and HC groups was tested using an independent t-test, and associations between PWV and right ventricular parameters was examined using Pearson's correlation coefficient. RESULTS: Those with COPD had reduced pulsatility (COPD (mean±SD):24.88±8.84% vs. HC:30.55±11.28%, p=0.021), pulmonary acceleration time (COPD:104.0±22.9ms vs. HC: 128.1±32.2ms, p<0.001), higher PWV (COPD:2.62±1.29ms-1 vs. HC:1.78±0.72ms-1, p=0.001), lower RV end diastolic volume (COPD:53.6±11.1ml vs. HC:59.9±13.0ml, p=0.037) and RV stroke volume (COPD:31.9±6.9ml/m2 vs. HC:37.1±6.2ml/m2, p=0.003) with no difference in mass (p=0.53). PWV was not associated with right ventricular parameters. CONCLUSIONS: While pulmonary vascular remodelling is present in COPD, cardiac remodelling favours reduced filling rather than increased afterload. Treatment of obstructive lung disease may have greater effect on cardiac function than treatment of pulmonary vascular disease in most COPD patients KEY POINTS: • Pulmonary pulse wave velocity (PWV) is elevated in COPD. • Pulmonary PWV is not associated with right ventricular remodelling. • Right ventricular remodelling is more in keeping with that of reduced filling

Disconnection of pulmonary and systemic arterial stiffness in COPD.

BACKGROUND: Both pulmonary arterial stiffening and systemic arterial stiffening have been described in COPD. The aim of the current study was to assess pulse wave velocity (PWV) within these two arterial beds to determine whether they are separate or linked processes. MATERIALS AND METHODS: In total, 58 participants with COPD and 21 healthy volunteers (HVs) underwent cardiac magnetic resonance imaging (MRI) and were tested with a panel of relevant biomarkers. Cardiac MRI was used to quantify ventricular mass, volumes, and pulmonary (pulse wave velocity [pPWV] and systemic pulse wave velocity [sPWV]). RESULTS: Those with COPD had higher pPWV (COPD: 2.62 vs HV: 1.78 ms-1, p=0.006), higher right ventricular mass/volume ratio (RVMVR; COPD: 0.29 vs HV: 0.25 g/mL, p=0.012), higher left ventricular mass/volume ratio (LVMVR; COPD: 0.78 vs HV: 0.70 g/mL, p=0.009), and a trend toward a higher sPWV (COPD: 8.7 vs HV: 7.4 ms-1, p=0.06). Multiple biomarkers were elevated: interleukin-6 (COPD: 1.38 vs HV: 0.58 pg/mL, p=0.02), high-sensitivity C-reactive protein (COPD: 6.42 vs HV: 2.49 mg/L, p=0.002), surfactant protein D (COPD: 16.9 vs HV: 9.13 ng/mL, p=0.001), N-terminal pro-brain natriuretic peptide (COPD: 603 vs HV: 198 pg/mL, p=0.001), and high-sensitivity troponin I (COPD: 2.27 vs HV: 0.92 pg/mL, p<0.001). There was a significant relationship between sPWV and LVMVR (p=0.01) but not pPWV (p=0.97) nor between pPWV and RVMVR (p=0.27). CONCLUSION: Pulmonary arterial stiffening and systemic arterial stiffening appear to be disconnected and should therefore be considered independent processes in COPD. Further work is warranted to determine whether both these cause an increased morbidity and mortality and whether both can be targeted by similar pharmacological therapy or whether different strategies are required for each

A Randomized Controlled Trial of the Effect of Allopurinol on Left Ventricular Mass Index in Hemodialysis Patients

Introduction: Increased left ventricular mass index (LVMI) is associated with mortality in end-stage renal disease. LVMI regression may improve outcomes. Allopurinol has reduced LVMI in randomized controlled trials in chronic kidney disease, diabetes, and ischemic heart disease. This study investigated whether allopurinol would regress LVMI in hemodialysis patients. Methods: This was a randomized placebo-controlled double-blind multicenter trial. A total of 80 patients undergoing regular maintenance hemodialysis were recruited from NHS Tayside, NHS Greater Glasgow and Clyde and NHS Ayrshire and Arran in Scotland, UK. Participants were randomly assigned on a 1:1 ratio to 12 months of therapy with allopurinol 300 mg or placebo after each dialysis session. The primary outcome was change in LVMI, as assessed by cardiac magnetic resonance imaging (MRI) at baseline and 12 months. Secondary outcomes were change in BP, flow-mediated dilation (FMD), augmentation indices (AIx), and pulse wave velocity (PWV). Results: A total of 53 patients, with a mean age of 58 years, completed the study and had MRI follow-up data for analysis. Allopurinol did not regress LVMI (change in LVMI: placebo +3.6 ± 10.4 g/m2; allopurinol: +1.6 ± 11 g/m2; P = 0.49). Allopurinol had no demonstrable effect on BP, FMD, AIx, or PWV. Conclusion: Compared with placebo, treatment with allopurinol did not regress LVMI in this trial

Impact of target site distribution for Type I restriction enzymes on the evolution of methicillin-resistant Staphylococcus aureus (MRSA) populations.

A limited number of Methicillin-resistant Staphylococcus aureus (MRSA) clones are responsible for MRSA infections worldwide, and those of different lineages carry unique Type I restriction-modification (RM) variants. We have identified the specific DNA sequence targets for the dominant MRSA lineages CC1, CC5, CC8 and ST239. We experimentally demonstrate that this RM system is sufficient to block horizontal gene transfer between clinically important MRSA, confirming the bioinformatic evidence that each lineage is evolving independently. Target sites are distributed randomly in S. aureus genomes, except in a set of large conjugative plasmids encoding resistance genes that show evidence of spreading between two successful MRSA lineages. This analysis of the identification and distribution of target sites explains evolutionary patterns in a pathogenic bacterium. We show that a lack of specific target sites enables plasmids to evade the Type I RM system thereby contributing to the evolution of increasingly resistant community and hospital MRSA

Psychological determinants of whole-body endurance performance

Background: No literature reviews have systematically identified and evaluated research on the psychological determinants of endurance performance, and sport psychology performance-enhancement guidelines for endurance sports are not founded on a systematic appraisal of endurance-specific research. Objective: A systematic literature review was conducted to identify practical psychological interventions that improve endurance performance and to identify additional psychological factors that affect endurance performance. Additional objectives were to evaluate the research practices of included studies, to suggest theoretical and applied implications, and to guide future research. Methods: Electronic databases, forward-citation searches, and manual searches of reference lists were used to locate relevant studies. Peer-reviewed studies were included when they chose an experimental or quasi-experimental research design, a psychological manipulation, endurance performance as the dependent variable, and athletes or physically-active, healthy adults as participants. Results: Consistent support was found for using imagery, self-talk, and goal setting to improve endurance performance, but it is unclear whether learning multiple psychological skills is more beneficial than learning one psychological skill. The results also demonstrated that mental fatigue undermines endurance performance, and verbal encouragement and head-to-head competition can have a beneficial effect. Interventions that influenced perception of effort consistently affected endurance performance. Conclusions: Psychological skills training could benefit an endurance athlete. Researchers are encouraged to compare different practical psychological interventions, to examine the effects of these interventions for athletes in competition, and to include a placebo control condition or an alternative control treatment. Researchers are also encouraged to explore additional psychological factors that could have a negative effect on endurance performance. Future research should include psychological mediating variables and moderating variables. Implications for theoretical explanations of endurance performance and evidence-based practice are described

A cohort study to identify and evaluate concussion risk factors across multiple injury settings: findings from the CARE Consortium

BACKGROUND: Concussion, or mild traumatic brain injury, is a major public health concern affecting 42 million individuals globally each year. However, little is known regarding concussion risk factors across all concussion settings as most concussion research has focused on only sport-related or military-related concussive injuries. METHODS: The current study is part of the Concussion, Assessment, Research, and Education (CARE) Consortium, a multi-site investigation on the natural history of concussion. Cadets at three participating service academies completed annual baseline assessments, which included demographics, medical history, and concussion history, along with the Sport Concussion Assessment Tool (SCAT) symptom checklist and Brief Symptom Inventory (BSI-18). Clinical and research staff recorded the date and injury setting at time of concussion. Generalized mixed models estimated concussion risk with service academy as a random effect. Since concussion was a rare event, the odds ratios were assumed to approximate relative risk. RESULTS: Beginning in 2014, 10,604 (n = 2421, 22.83% female) cadets enrolled over 3 years. A total of 738 (6.96%) cadets experienced a concussion, 301 (2.84%) concussed cadets were female. Female sex and previous concussion were the most consistent estimators of concussion risk across all concussion settings. Compared to males, females had 2.02 (95% CI: 1.70-2.40) times the risk of a concussion regardless of injury setting, and greater relative risk when the concussion occurred during sport (Odds Ratio (OR): 1.38 95% CI: 1.07-1.78). Previous concussion was associated with 1.98 (95% CI: 1.65-2.37) times increased risk for any incident concussion, and the magnitude was relatively stable across all concussion settings (OR: 1.73 to 2.01). Freshman status was also associated with increased overall concussion risk, but was driven by increased risk for academy training-related concussions (OR: 8.17 95% CI: 5.87-11.37). Medical history of headaches in the past 3 months, diagnosed ADD/ADHD, and BSI-18 Somatization symptoms increased overall concussion risk. CONCLUSIONS: Various demographic and medical history factors are associated with increased concussion risk. While certain factors (e.g. sex and previous concussion) are consistently associated with increased concussion risk, regardless of concussion injury setting, other factors significantly influence concussion risk within specific injury settings. Further research is required to determine whether these risk factors may aid in concussion risk reduction or prevention

Framing the discussion of microorganisms as a facet of social equity in human health

What do “microbes” have to do with social equity? These microorganisms are integral to our health, that of our natural environment, and even the “health” of the environments we build. The loss, gain, and retention of microorganisms—their flow between humans and the environment—can greatly impact our health. It is well-known that inequalities in access to perinatal care, healthy foods, quality housing, and the natural environment can create and arise from social inequality. Here, we focus on the argument that access to beneficial microorganisms is a facet of public health, and health inequality may be compounded by inequitable microbial exposure

Set Pseudophasors to Stun for Flow Cytometry

Study of signal transduction in live cells benefits from the ability to visualize and quantify light emitted by fluorescent proteins (XFPs) fused to different signaling proteins. However, because cell signaling proteins are often present in small numbers, and because the XFPs themselves are poor fluorophores, the amount of emitted light, and the observable signal in these studies, is often small. An XFP's fluorescence lifetime contains additional information about the immediate environment of the fluorophore that can augment the information from its weak light signal. Here, we constructed and expressed in Saccharomyces cerevisiae variants of Teal Fluorescent Protein (TFP) and Citrine that were isospectral but had shorter fluorescence lifetimes, ∼ 1.5 ns vs ∼ 3 ns. We modified microscopic and flow cytometric instruments to measure fluorescence lifetimes in live cells. We developed digital hardware and a measure of lifetime called a "pseudophasor" that we could compute quickly enough to permit sorting by lifetime in flow. We used these abilities to sort mixtures of cells expressing TFP and the short-lifetime TFP variant into subpopulations that were respectively 97% and 94% pure. This work demonstrates the feasibility of using information about fluorescence lifetime to help quantify cell signaling in living cells at the high throughput provided by flow cytometry. Moreover, it demonstrates the feasibility of isolating and recovering subpopulations of cells with different XFP lifetimes for subsequent experimentation