Anisotropy in cell sheeting and cardiac differentiation

Treatment for myocardial infarction is largely limited to alleviating symptoms and preventing recurrence rather than directly repairing or replacing the damaged myocardial tissue. Consequently, one of the overarching goals of cardiac tissue engineering is to generate myocardial tissue that could be implanted as a patch over existing cardiac tissue to improve cardiac function. Advancements in pluripotent stem cell (PSC) technology and differentiation have made PSC-derived cardiomyocytes a viable cell source for engineered cardiac tissues. Because native cardiac tissue is directional in nature (i.e., anisotropic), biomaterial systems have been designed to organize PSC-derived cardiomyocytes to recapitulate this structure. The objective of this dissertation is to use aligned electrospun fibers as anisotropic substrates to generate aligned cell sheets and to evaluate how differentiating cardiomyocytes respond to degrees of anisotropy. We demonstrate that aligned electrospun fibers containing poly(N-isopropylacrylamide), a thermo-sensitive polymer commonly used for cell sheeting, and poly(capro lactone), a hydrophobic polymer commonly used in biomaterials, can be used to generate anisotropic cell sheets. Also shown is that the structure and functional behavior of PSCs-derived cardiomyocytes varies in a gradient-based manner on degree of substrate anisotropy at relatively early timepoints. As time progresses, cardiomyocyte alignment can be achieved on substrates that have a minimum threshold anisotropy. These electrospun, aligned fiber systems can be used in tissue engineering to generate viable cell sheets for cardiac tissue engineering or to precisely study cell sensitivity to differences in substrate anisotropy.Biomedical Engineerin

Metabolic Trajectories Following Contrasting Prudent and Western Diets from Food Provisions: Identifying Robust Biomarkers of Short-Term Changes in Habitual Diet

A large body of evidence has linked unhealthy eating with an alarming increase in obesity and chronic disease worldwide. However, existing methods of assessing dietary intake rely on food frequency questionnaires or dietary records that are prone to bias and selective reporting. Herein, metabolic phenotyping was performed on 42 healthy participants from the Diet and Gene Intervention (DIGEST) pilot study, a parallel two-arm randomized clinical trial that provided complete diets to all participants. Matching urine and plasma specimens were collected at baseline and following 2 weeks of provision of either a Prudent or Western diet with a weight-maintaining menu plan designed by a dietician. Targeted and nontargeted metabolite profiling was conducted using three complementary analytical platforms, where 80 serum metabolites and 84 creatinine-normalized urinary metabolites were reliably measured (CV 75%) after implementing a rigorous data workflow for metabolite authentication with stringent quality control. We classified a panel of metabolites with distinctive trajectories following 2 weeks of food provisions when using complementary univariate and multivariate statistical models. Unknown metabolites associated with contrasting dietary patterns were identified with high resolution MS/MS and/or co-elution after spiking with authentic standards. Overall, 3-methylhistidine and proline betaine concentrations increased consistently when participants were assigned a Prudent diet (q ± 0.30, p < 0.05) to changes in average intake of specific nutrients from self-reported diet records reflecting good adherence to food provisions. This study revealed robust biomarkers sensitive to short-term changes in habitual diet that can be used to reliably monitor healthy eating patterns for new advances in nutritional epidemiology, as well as the design of evidence-based public health policies for chronic disease prevention

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

Reintegration interventions for CPTSD: a systematic review

Background Clinical guidelines recommend a phase-based approach to treatment for complex post-traumatic stress disorder (CPTSD), yet little is known about what interventions are being offered and which may be effective in the final ‘reintegration’ phase. Objective To systematically review literature on reintegration interventions for CPTSD, describing the nature and effectiveness of interventions. Method We searched four electronic databases (Medline, PsycINFO, Embase, and PTSDpubs) for interventions aiming to facilitate reintegration for participants with probable CPTSD. We had two aims: firstly, to describe the interventions and secondly, to describe their effectiveness as measured through measures of reintegration, PTSD and/or disturbances in self-organization (DSO), or qualitative data describing changes experienced. Results are presented using narrative synthesis. Results Fifteen studies met our inclusion criteria. Interventions included yoga, exercise, use of service dogs, residential treatment, education, self-defence and patient research involvement. Overall study quality was low, as assessed by critical appraisal tools. Of the six studies including a control group, two reported a statistically significant improvement in the measure of reintegration between the intervention and control group, four studies reported a statistically significant difference in the measure of PTSD symptoms, but none reported any significant differences between intervention and control groups in DSO. Of all eight quantitative studies, three reported a statistically significant difference in the reintegration measure pre- to post-intervention for the intervention group, five a statistically significant improvement in the measure of PTSD symptoms, and three a significant difference in the DSO measure. From eight studies reporting qualitative date we synthesized themes into eight categories, within which facilitation of connection with others was the most commonly reported benefit. Conclusions The interventions outlined may facilitate reintegration, however, research in this area is still in its infancy and quality research is lacking. Further research is needed to establish whether reintegration interventions enhance treatment for CPTSD

Complete Genome Sequences of 18 Paenibacillus larvae Phages from the Western United States

We present here the complete genomes of 18 phages that infect Paenibacillus larvae, the causative agent of American foulbrood in honeybees. The phages were isolated between 2014 and 2016 as part of an undergraduate phage discovery course at Brigham Young University. The phages were isolated primarily from bee debris and lysogens

Exposure Route Influences Disease Severity in the COVID-19 Cynomolgus Macaque Model

The emergence of SARS-CoV-2 and the subsequent pandemic has highlighted the need for animal models that faithfully replicate the salient features of COVID-19 disease in humans. These models are necessary for the rapid selection, testing, and evaluation of potential medical countermeasures. Here, we performed a direct comparison of two distinct routes of SARS-CoV-2 exposure—combined intratracheal/intranasal and small particle aerosol—in two nonhuman primate species, rhesus and cynomolgus macaques. While all four experimental groups displayed very few outward clinical signs, evidence of mild to moderate respiratory disease was present on radiographs and at necropsy. Cynomolgus macaques exposed via the aerosol route also developed the most consistent fever responses and had the most severe respiratory disease and pathology. This study demonstrates that while all four models produced suitable representations of mild COVID-like illness, aerosol exposure of cynomolgus macaques to SARS-CoV-2 produced the most severe disease, which may provide additional clinical endpoints for evaluating therapeutics and vaccines