Investigating the Role of Extracellular Matrix Proteins in Ovarian Folliculogenesis and Ovarian Cancer

The extracellular matrix (ECM) is a highly organized, dynamic structure that maintains tissue integrity and regulates biological processes involved in organ development and function. To explore the role of ECM proteins in ovarian physiology and pathology, my thesis characterizes ECM proteins aberrantly overexpressed in the Estrogen Receptor (ER)β-null (βERKO) mouse ovary and epithelial ovarian cancer (EOC). The ECM undergoes extensive physical changes, and influences numerous cell functions, throughout folliculogenesis. This study identifies a role for ERβ in ovarian development earlier than previously believed. Nidogen 2 and Collagen 11a1 are aberrantly overexpressed in βERKO ovaries as early as postnatal day 13, and this dysregulation continues into adulthood, as determined by qPCR and immunofluorescence. Collagen IV, Nidogen 1 and Laminin are also more highly expressed in the βERKO ovary than in the wildtype ovary, suggesting that the repression of several ECM proteins in the ovary is ERβ-dependent. The molecular mechanisms that initiate gene repression by ERβ are not well understood; therefore a potential mechanism by which ERβ may act as a transcriptional repressor in the ovary is investigated. I characterized a novel ERβ transcriptional corepressor – transcription factor 21 (TCF21). In transient transfection and reporter assays, TCF21 represses ERβ transactivation of synthetic and natural estrogen-responsive promoters in various cell lines. As in the βERKO ovary, when the mechanisms regulating ECM dynamics during normal organ function are disrupted, the ECM becomes disorganized. This disorganization is associated with various pathologies, including cancers. The ECM protein, Spondin 1 (SPON1), is overexpressed in ovarian cancers and has been identified as a promising ovarian cancer marker, particularly for high-grade serous carcinomas; yet, its cellular functions and related mechanisms in EOC progression remain unknown. This study shows that SPON1 is expressed and secreted by immortalized EOC cell lines and human primary ascites-derived EOC cells. Treatment with exogenous SPON1 reduces EOC cell adhesion, viability and proliferation but not migration. Experiments utilizing a non-adherent culture surface suggest SPON1 does not effect EOC spheroid formation but is involved in spheroid anchoring and cell dispersion. These findings support an important role for ECM proteins in ovarian development and progression of ovarian carcinomas

Towards a framework for comparing functionalities of multimorbidity clinical decision support: A literature-based feature set and benchmark cases.

Multimorbidity, the coexistence of two or more health conditions, has become more prevalent as mortality rates in many countries have declined and their populations have aged. Multimorbidity presents significant difficulties for Clinical Decision Support Systems (CDSS), particularly in cases where recommendations from relevant clinical guidelines offer conflicting advice. A number of research groups are developing computer-interpretable guideline (CIG) modeling formalisms that integrate recommendations from multiple Clinical Practice Guidelines (CPGs) for knowledge-based multimorbidity decision support. In this paper we describe work towards the development of a framework for comparing the different approaches to multimorbidity CIG-based clinical decision support (MGCDS). We present (1) a set of features for MGCDS, which were derived using a literature review and evaluated by physicians using a survey, and (2) a set of benchmarking case studies, which illustrate the clinical application of these features. This work represents the first necessary step in a broader research program aimed at the development of a benchmark framework that allows for standardized and comparable MGCDS evaluations, which will facilitate the assessment of functionalities of MGCDS, as well as highlight important gaps in the state-of-the-art. We also outline our future work on developing the framework, specifically, (3) a standard for reporting MGCDS solutions for the benchmark case studies, and (4) criteria for evaluating these MGCDS solutions. We plan to conduct a large-scale comparison study of existing MGCDS based on the comparative framework

Heart Rate and Energy Expenditure Concurrent Validity of Identical Garmin Wrist Watches During Moderately Heavy Resistance Training

Consistent with previous years, ACSM has found that wearable technology and resistance training (RT) are two of the top 5 fitness trends in 2023. Our lab recently found that wrist-worn devices, such as Garmin Instinct, are neither valid nor reliable at measuring average or maximal heart rate (HR) or estimating energy expenditure (EE) following light intensity circuit RT. We postulated that the errors may have been due to the device’s algorithms assuming higher intensity during RT. PURPOSE: The purpose of this study was to determine the concurrent validity of identical Garmin Instinct wrist-watches to record valid measures of average and maximal HR as well as estimated EE following moderately heavy RT. METHODS: Twenty-one adult participants completed this study (n=10 female, n=11 male). Two Garmin Instinct wrist-watches were evaluated, along with the Polar H10 chest strap and Cosmed K5 portable metabolic unit as the criterion devices for average/maximal HR and EE, respectively. Participants completed 8 supersets of the reverse lunge and shoulder press exercises using dumbbells at a light (4 sets) and moderately heavy (4 sets) intensity with 1 superset of 6 repetitions per exercise (12 repetitions per superset) and 1 min rest between supersets. Data were analyzed for validity (Mean Absolute Percent Error [MAPE] and Lin’s Concordance Coefficient [CCC]), with predetermined thresholds of MAPE\u3c10% and CCC\u3e0.70. A one-way repeated measures ANOVA with Sidak post-hoc test was used to determine differences (p\u3c0.05). RESULTS: The identical Garmin Instinct devices were not considered valid for average HR (MAPE range: 36.5-81.6%; CCC range: 0.07-0.18), maximal HR (MAPE range: 18.6-18.8%; CCC range: 0.15-0.31), or estimated EE (MAPE range: 14.0-16.4%; CCC range: 0.08-0.32) compared to the criterion references. The devices were significantly different than each other for average HR (p=0.005), maximal HR (p\u3c0.001), and estimated EE (p\u3c0.0001). CONCLUSION: The wearable wrist-worn devices tested herein should not be utilized for accurate measurements of HR or EE during RT, and there are even differences between identical devices. People who RT while using these devices should do so with caution if wishing to utilize them for physiological measures

Rating of Perceived Exertion, Average Heart Rate, and Energy Expenditure Following Indoor and Outdoor Moderately Heavy Superset Resistance Training

Our lab recently found that light intensity circuit resistance training outdoors had a significantly lower perception of effort (RPE) compared to indoor resistance training, despite no physiological differences in heart rate and energy expenditure. However, no study has examined other intensities or set schemes in differing environmental settings. PURPOSE: To determine how indoor or outdoor environments effect rating of perceived exertion (RPE) following light and moderately heavy intensity superset resistance training in recreationally resistance trained adults. METHODS: Twenty-three adult participants completed this study (n=10 female, n=13 male; age: 26.1±8.8 yrs; height: 172.2±9.5 cm; mass: 73.4±18.7 kg; RT experience: 5.3±4.8 yrs). Participants wore devices to measure heart rate (Polar H10 chest strap) and energy expenditure (Cosmed K5 Portable Metabolic Cart). Randomly in indoor and outdoor settings, participants completed 4 supersets of the reverse lunge and shoulder press exercises using dumbbells at a light (2 sets) and moderately heavy (2 sets) intensity with 1 superset of 6 repetitions per exercise (12 repetitions per superset) and 1 min rest between supersets. The OMNI Rating of Perceived Exertion Scale for Resistance Exercise 0-10 RPE scale was used following each superset. A paired T-test was used to determine differences between environmental setting (pRESULTS: No significant differences were observed between indoor and outdoor environments for average heart rate (129.4±17.2 and 127.8±23.3 bpm, p=0.67), energy expenditure (30.6±11.5 and 28.3±9.9 kcals; p=0.06), as well as RPE during light intensity (2.9±0.9 and 2.9±0.8 arbitrary units/AU’s, p=0.70) and moderately heavy intensity (6.5±1.7 and 6.3±1.5 AU’s, p=0.27) supersets. CONCLUSION: In recreationally resistance trained adults, light intensity and moderately heavy intensity superset resistance training in indoor or outdoor settings does not alter heart rate, energy expenditure, or perceived effort

Perceived Fatigue and Physical Activity Enjoyment Following Indoor and Outdoor Moderately Heavy Superset Resistance Training

ACSM has again determined that resistance training (RT) and outdoor activities are two of the top ten worldwide fitness trends for 2023. We previously found that RT outdoors had a significantly lower perception of effort (RPE) compared to indoor RT, despite no physiological differences in heart rate (HR) and energy expenditure (EE). However, no study has examined other feelings during RT in indoor or outdoor settings. PURPOSE: To determine how indoor or outdoor environments effect perceptions of fatigue and physical activity enjoyment following RT in recreationally resistance trained adults. METHODS: Twenty-three adult participants (n=10 female, n=13 male) completed this study. The Visual Analog Scale Fatigue (VAS-F) measured perceived fatigue and the Physical Activity Enjoyment Scale – Short Version (PACES-S) measured PA enjoyment, and both were measured at baseline and then immediately following an acute session of indoor or outdoor RT. HR was obtained from a chest strap (Polar H10) and EE from a Portable Metabolic Cart (COSMED K5). Randomly in indoor and outdoor settings, participants completed 4 supersets of the reverse lunge and shoulder press exercises using dumbbells at a light (2 sets) and moderately heavy (2 sets) intensity with 1 superset of 6 repetitions per exercise and 1 min rest between supersets. A paired T-test (for HR & EE comparisons) or one-way repeated measures ANOVA with Sidak post-hoc test (for VAS-F & PACES-S comparisons) were used to determine differences (p\u3c0.05). RESULTS: No significant differences were observed between indoor and outdoor RT for the physiological variables of average HR (129.4±17.2 and 127.75±23.3 bpm, respectively, p=0.66) and EE (30.6±11.5 and 28.3±9.9 kcals, respectively, p=0.06). Perceived fatigue significantly (p\u3c0.0001) increased from baseline (1.13±0.94 arbitrary units, AU’s) following indoor (4.54±1.91 AU’s) and outdoor (3.99±1.54 AU’s) RT, but no environmental differences (p=0.36) were observed. PA enjoyment was not significantly (p range: 0.27-0.93) different between baseline (18.73±1.83 AU’s) and following indoor (18.18±1.99 AU’s) or outdoor (18.36±1.99 AU’s) RT. CONCLUSION: In recreationally resistance trained adults, moderately heavy superset RT in indoor or outdoor settings does not alter perceived fatigue or physical activity enjoyment

Design and validation of a 63K genome-wide SNP-genotyping platform for caribou/reindeer (Rangifer tarandus)

Background Development of large single nucleotide polymorphism (SNP) arrays can make genomic data promptly available for conservation problematic. Medium and high-density panels can be designed with sufficient coverage to offer a genome-wide perspective and the generated genotypes can be used to assess different genetic metrics related to population structure, relatedness, or inbreeding. SNP genotyping could also permit sexing samples with unknown associated metadata as it is often the case when using non-invasive sampling methods favored for endangered species. Genome sequencing of wild species provides the necessary information to design such SNP arrays. We report here the development of a SNP-array for endangered Rangifer tarandus using a multi-platform sequencing approach from animals found in diverse populations representing the entire circumpolar distribution of the species. Results From a very large comprehensive catalog of SNPs detected over the entire sample set (N = 894), a total of 63,336 SNPs were selected. SNP selection accounted for SNPs evenly distributed across the entire genome (~ every 50Kb) with known minor alleles across populations world-wide. In addition, a subset of SNPs was selected to represent rare and local alleles found in Eastern Canada which could be used for ecotype and population assignments - information urgently needed for conservation planning. In addition, heterozygosity from SNPs located in the X-chromosome and genotyping call-rate of SNPs located into the SRY gene of the Y-chromosome yielded an accurate and robust sexing assessment. All SNPs were validated using a high-throughput SNP-genotyping chip. Conclusion This design is now integrated into the first genome-wide commercially available genotyping platform for Rangifer tarandus. This platform would pave the way to future genomic investigation of populations for this endangered species, including estimation of genetic diversity parameters, population assignments, as well as animal sexing from genetic SNP data for non-invasive samples

Validation of the Body Concealment Scale for Scleroderma (BCSS): Replication in the Scleroderma Patient-centered Intervention Network (SPIN) Cohort

© 2016 Elsevier Ltd Body concealment is an important component of appearance distress for individuals with disfiguring conditions, including scleroderma. The objective was to replicate the validation study of the Body Concealment Scale for Scleroderma (BCSS) among 897 scleroderma patients. The factor structure of the BCSS was evaluated using confirmatory factor analysis and the Multiple-Indicator Multiple-Cause model examined differential item functioning of SWAP items for sex and age. Internal consistency reliability was assessed via Cronbach's alpha. Construct validity was assessed by comparing the BCSS with a measure of body image distress and measures of mental health and pain intensity. Results replicated the original validation study, where a bifactor model provided the best fit. The BCSS demonstrated strong internal consistency reliability and construct validity. Findings further support the BCSS as a valid measure of body concealment in scleroderma and provide new evidence that scores can be compared and combined across sexes and ages

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570