The Role of the Extracellular Matrix in Mediating Muscle Soreness

The goal of this dissertation was to examine the role of the extracellular matrix (ECM) in muscle soreness. Study 1 examined how the disruption of the ECM from a minor surgery (e.g. muscle biopsy) affected muscle soreness. Study 1 showed that soreness levels increased at 24 h post-biopsy compared to baseline and resolved within 96 h. However, the level of muscle soreness at 24 h post-biopsy (20 mm) was lower than that reported for performing a strenuous and naïve exercise (40–80 mm). These results will help review boards at institutions where muscle biopsies are performed understand how a muscle biopsy affects individuals. Additionally, these results will help investigators better articulate the effects of a muscle biopsy to a study volunteer. Study 2 examined the molecular changes of ECM molecules in response to a single and repeated bout of exercise. Muscle biopsies were analyzed from baseline, 24 h post-Bout 1, and 24 h post-Bout 2 using qRT-PCR, western blotting, and zymography techniques. In this study, eight individuals (4 men and 4 women) performed the exercise—descending 10 flights of stairs 15 times—and four individuals (2 men and 2 women) were controls and did not exercise. The exercise and control group both had changes in gene expression and in one protein compared to baseline. However, no differences were found for either group in zymography. These results indicate that gene expression is the prominent alteration ECM molecules in skeletal muscle at 24 h after eccentric exercise. Study 3 used microarray analysis to examine the difference in gene expression between individuals (n=30, men) who presented with high-soreness levels (n=5) compared to low-soreness levels (n=7) after eccentric exercise. Muscle biopsies for microarray analysis were collected from the exercised leg at 3 h post-exercise and the non-exercised leg served as control. The 546 genes differentially regulated were imported into Ingenuity Pathway Analysis, which created networks and allowed for the identification of the top 100 up- and down-regulated genes. Despite finding that the up-regulated genes had more significant correlations and a greater number of genes with significant correlations compared to the down-regulated genes, these up-regulated genes were not more commonly found in one pathway compared to another. These results might suggest that the variability of muscle soreness after eccentric exercise is a consequence of the variability in the repair and adaptation of skeletal muscle after eccentric exercise

Update to the study protocol for an implementation-effectiveness trial comparing two education strategies for improving the uptake of noninvasive ventilation in patients with severe COPD exacerbation

BACKGROUND: There is strong evidence that noninvasive ventilation (NIV) improves the outcomes of patients hospitalized with severe COPD exacerbation, and NIV is recommended as the first-line therapy for these patients. Yet, several studies have demonstrated substantial variation in NIV use across hospitals, leading to preventable morbidity and mortality. In addition, prior studies suggested that efforts to increase NIV use in COPD need to account for the complex and interdisciplinary nature of NIV delivery and the need for team coordination. Therefore, our initial project aimed to compare two educational strategies: online education (OLE) and interprofessional education (IPE), which targets complex team-based care in NIV delivery. Due to the impact of the COVID-19 pandemic on recruitment and planned intervention, we had made several changes in the study design, statistical analysis, and implementation strategies delivery as outlined in the methods. METHODS: We originally proposed a two-arm, pragmatic, cluster, randomized hybrid implementation-effectiveness trial comparing two education strategies to improve NIV uptake in patients with severe COPD exacerbation in 20 hospitals with a low baseline rate of NIV use. Due to logistical constrains and slow recruitment, we changed the study design to an opened cohort stepped-wedge design with three steps which will allow the institutions to enroll when they are ready to participate. Only the IPE strategy will be implemented, and the education will be provided in an online virtual format. Our primary outcome will be the hospital-level risk-standardized NIV proportion for the period post-IPE training, along with the change in rate from the period prior to training. Aim 1 will compare the change over time of NIV use among patients with COPD in the step-wedged design. Aim 2 will explore the mediators\u27 role (respiratory therapist autonomy and team functionality) on the relationship between the implementation strategies and effectiveness. Finally, in Aim 3, through interviews with providers, we will assess the acceptability and feasibility of the educational training. CONCLUSION: The changes in study design will result in several limitation. Most importantly, the hospitals in the three cohorts are not randomized as they enroll based on their readiness. Second, the delivery of the IPE is virtual, and it is not known if remote education is conducive to team building. However, this study will be among the first to test the impact of IPE in the inpatient setting carefully and may generalize to other interventions directed to seriously ill patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT04206735 . Registered on December 20, 2019

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Identifying themes to inform nursing decisions when caring for patients with acute exacerbation of chronic obstructive pulmonary disease on noninvasive ventilation: A qualitative descriptive study

Prior studies analyzing patient experience with noninvasive ventilation (NIV) found the most impactful interaction that patients remembered was with nurses, however a survey of nurses regarding the management of patients treated with NIV has shown that most nurses felt unprepared to care for these sick patients. Our qualitative descriptive study explored the current nursing experience using NIV as a treatment for acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Nine (n = 9) subject matter expert nurses practicing in a variety of clinical settings participated in semi-structured interviews. The COnsolidated criteria for REporting Qualitative research checklist was followed for interview development. Interview transcripts were subsequently analyzed using deductive thematic analysis. Themes identified from the interviews pertained to patient assessment, novice nurses\u27 need for clinical support, team communication, and nursing education. Improving interprofessional team communication and collaboration skills, and implementing guidelines for NIV utilization were specified as essential components of NIV education for nurses. Even though the nursing role in the care of AECOPD NIV patient could be institution dependent, the themes presented in our study are useful in identifying opportunities for NIV nursing education and areas for further research. Patient or Public Contribution: Nurses served as interviewees for this study. Keywords: acute exacerbation of COPD; chronic obstructive pulmonary disease (COPD); noninvasive ventilation (NIV); nurse; rapid response team

Analysis of shared cognitive tasks in the application of non-invasive ventilation to patients with COPD exacerbation

Interprofessional teamwork plays a key role in the uptake of evidence-based interventions, such as noninvasive ventilation (NIV) for patients with exacerbated Chronic Obstructive Pulmonary Disease (COPD). We aimed to identify the shared cognitive tasks in interprofessional teams using NIV for patients with COPD exacerbation. We used a cognitive task analysis approach (CTA) to engage nurses, rapid response team members, respiratory therapists, and physicians involved in the use of NIV to treat patients with COPD exacerbation. Clinicians participated in a semi-structured interview (n = 21) that elicited cognitions needed to treat COPD exacerbation. Three shared cognitive tasks were identified: Complete a thorough assessment, Formulate a care plan, and Continuously monitor patient status. Findings attest to the importance of having access to up-to-date information and expertise necessary to make accurate clinical inferences for patient assessment. Shared understanding of the formulated care plan among all members of the care team was important to its execution. Continuous monitoring was crucial; however, this cognitive task relied on patient assessment skills and ongoing collaboration within the clinical care team. Application of NIV for patients with COPD exacerbation may require enhancing collaboration through nontechnical skills and interprofessional training. Keywords: COPD; Noninvasive ventilation; cognitive task analysis

Update to the study protocol for an implementation-effectiveness trial comparing two education strategies for improving the uptake of noninvasive ventilation in patients with severe COPD exacerbation

Background: There is strong evidence that noninvasive ventilation (NIV) improves the outcomes of patients hospitalized with severe COPD exacerbation, and NIV is recommended as the first-line therapy for these patients. Yet, several studies have demonstrated substantial variation in NIV use across hospitals, leading to preventable morbidity and mortality. In addition, prior studies suggested that efforts to increase NIV use in COPD need to account for the complex and interdisciplinary nature of NIV delivery and the need for team coordination. Therefore, our initial project aimed to compare two educational strategies: online education (OLE) and interprofessional education (IPE), which targets complex team-based care in NIV delivery. Due to the impact of the COVID-19 pandemic on recruitment and planned intervention, we had made several changes in the study design, statistical analysis, and implementation strategies delivery as outlined in the methods. Methods: We originally proposed a two-arm, pragmatic, cluster, randomized hybrid implementation-effectiveness trial comparing two education strategies to improve NIV uptake in patients with severe COPD exacerbation in 20 hospitals with a low baseline rate of NIV use. Due to logistical constrains and slow recruitment, we changed the study design to an opened cohort stepped-wedge design with three steps which will allow the institutions to enroll when they are ready to participate. Only the IPE strategy will be implemented, and the education will be provided in an online virtual format. Our primary outcome will be the hospital-level risk-standardized NIV proportion for the period post-IPE training, along with the change in rate from the period prior to training. Aim 1 will compare the change over time of NIV use among patients with COPD in the step-wedged design. Aim 2 will explore the mediators\u27 role (respiratory therapist autonomy and team functionality) on the relationship between the implementation strategies and effectiveness. Finally, in Aim 3, through interviews with providers, we will assess the acceptability and feasibility of the educational training. Conclusion: The changes in study design will result in several limitation. Most importantly, the hospitals in the three cohorts are not randomized as they enroll based on their readiness. Second, the delivery of the IPE is virtual, and it is not known if remote education is conducive to team building. However, this study will be among the first to test the impact of IPE in the inpatient setting carefully and may generalize to other interventions directed to seriously ill patients. Trial registration: ClinicalTrials.gov NCT04206735 . Registered on December 20, 2019

Cucurbitaceae COld Peeling Extracts (CCOPEs) protect plants from root-knot nematode infections through induced resistance and nematicidal effects

With nematicides progressively being banned due to their environmental impact, an urgent need for novel and sustainable control strategies has arisen. Stimulation of plant immunity, a phenomenon referred to as “induced resistance” (IR), is a promising option. In this study, Cucurbitaceae COld Peeling Extracts (CCOPEs) were shown to protect rice (Oryza sativa) and tomato (Solanum lycopersicum) against the root-knot nematodes Meloidogyne graminicola and Meloidogyne incognita, respectively. Focusing on CCOPE derived from peels of melon (Cucumis melo var. cantalupensis; mCOPE), we unveiled that this extract combines an IR-triggering capacity with direct nematicidal effects. Under lab conditions, the observed resistance was comparable to the protection obtained by commercially available IR stimuli or nematicides. Via mRNA sequencing and confirmatory biochemical assays, it was proven that mCOPE-IR in rice is associated with systemic effects on ethylene accumulation, reactive oxygen species (ROS) metabolism and cell wall-related modifications. While no negative trade-offs were detected with respect to plant growth or plant susceptibility to necrotrophic pests or pathogens, additional infection experiments indicated that mCOPE may have a predominant activity toward biotrophs. In summary, the presented data illustrate a propitious potential for these extracts, which can be derived from agro-industrial waste streams