The protective roles of coping self-efficacy and social support for posttraumatic stress during the COVID-19 pandemic.

OBJECTIVE: This study examined the roles of social support and coping self-efficacy (CSE) in attenuating posttraumatic stress (PTS) symptoms during the COVID-19 pandemic among a nonclinical university student sample. METHOD: Participants (n = 610; 59% female) completed questionaries assessing psychological distress (Kessler Psychological Distress Scale) at baseline and 6-month follow-up, and social support (Interpersonal Support Evaluation List-12), CSE Scale, and PTS symptoms (Impact of Event Scale-Revised) at 6 months. A path analysis was conducted using SPSS Amos to examine the direct and indirect pathways from psychological distress to PTS symptoms that are accounted for by social support and CSE, controlling for gender. RESULTS: All direct effects in the path analysis were significant except for the relationship between social support and PTS symptoms. Notably, CSE was directly related to PTS symptoms (CSE: ß = -.30, p < .001). There was a significant indirect effect of early psychological distress on PTS symptoms 6 months into the pandemic through social support and CSE (ß = .14, p < .001). CONCLUSIONS: Individuals with higher levels of social support are more likely to have greater confidence in their coping capabilities, which helps to explain PTS symptom severity after controlling for initial levels of psychological distress and gender. These findings suggest that following a potentially traumatic event, CSE may be one factor to screen for to better identify individuals who are at higher risk for significant psychological difficulties and may benefit from interventions that bolster protective factors. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Total artificial heart implantation as a bridge to transplantation in the United States.

OBJECTIVES: Although the SynCardia total artificial heart (SynCardia Systems, LLC) was approved for use as a bridge to transplantation in 2004 in the United States, most centers do not adopt the total artificial heart as a standard bridging strategy for patients with biventricular failure. This study was designed to characterize the current use and outcomes of patients placed on total artificial heart support. METHODS: The United Network of Organ Sharing Standard Transplant Research File was queried to identify total artificial heart implantation in the United States between 2005 and 2018. Multivariable Cox regression models were used for risk prediction. RESULTS: A total of 471 patients (mean age, 49 years; standard deviation, 13 years; 88% were male) underwent total artificial heart implantation. Of 161 transplant centers, 11 centers had cumulative volume of 10 or more implants. The 6-month cumulative incidence of mortality on the total artificial heart was 24.6%. The 6-month cumulative incidence of transplant was 49.0%. The 1-year mortality post-transplantation was 20.0%. Cumulative center volume less than 10 implants was predictive of both mortality on the total artificial heart (hazard ratio, 2.2, 95% confidence interval, 1.5-3.1, P < .001) and post-transplant mortality after a total artificial heart bridge (hazard ratio, 1.5, 95% confidence interval, 1.0-2.2, P = .039). CONCLUSIONS: Total artificial heart use is low, but the total artificial heart can be an option for biventricular bridge to transplant with acceptable bridge to transplant and post-transplant survival, especially in higher-volume centers. The observation of inferior outcomes in lower-volume centers raises questions as to whether targeted training, center certifications, and minimum volume requirements could improve outcomes for patients requiring the total artificial heart.

Late Right Heart Failure After Left Ventricular Assist Device Implantation: Contemporary Insights and Future Perspectives.

Late right heart failure (RHF) is increasingly recognized in patients with long-term left ventricular assist device (LVAD) support and is associated with decreased survival and increased incidence of adverse events such as gastrointestinal bleeding and stroke. Progression of right ventricular (RV) dysfunction to clinical syndrome of late RHF in patients supported with LVAD is dependent on the severity of pre-existing RV dysfunction, persistent or worsening left- or right-sided valvular heart disease, pulmonary hypertension, inadequate or excessive left ventricular unloading, and/or progression of the underlying cardiac disease. RHF likely represents a continuum of risk with early presentation and progression to late RHF. However, de novo RHF develops in a subset of patients leading to increased diuretic requirement, arrhythmias, renal and hepatic dysfunction, and heart failure hospitalizations. The distinction between isolated late RHF and RHF due to left-sided contributions is lacking in registry studies and should be the focus of future registry data collection. Potential management strategies include optimization of RV preload and afterload, neurohormonal blockade, LVAD speed optimization, and treatment of concomitant valvular disease. In this review, the authors discuss definition, pathophysiology, prevention, and management of late RHF.

Single-cell analysis of human nasal mucosal IgE antibody secreting cells reveals a newly minted phenotype.

Immunoglobulin (Ig) E is central to the pathogenesis of allergic conditions, including allergic fungal rhinosinusitis. However, little is known about IgE antibody secreting cells (ASCs). We performed single-cell RNA sequencing from cluster of differentiation (CD)19+ and CD19- ASCs of nasal polyps from patients with allergic fungal rhinosinusitis (n = 3). Nasal polyps were highly enriched in CD19+ ASCs. Class-switched IgG and IgA ASCs were dominant (95.8%), whereas IgE ASCs were rare (2%) and found only in the CD19+ compartment. Through Ig gene repertoire analysis, IgE ASCs shared clones with IgD-CD27- "double-negative" B cells, IgD+CD27+ unswitched memory B cells, and IgD-CD27+ switched memory B cells, suggesting ontogeny from both IgD+ and memory B cells. Transcriptionally, mucosal IgE ASCs upregulate pathways related to antigen presentation, chemotaxis, B cell receptor stimulation, and survival compared with non-IgE ASCs. Additionally, IgE ASCs have a higher expression of genes encoding lysosomal-associated protein transmembrane 5 (LAPTM5) and CD23, as well as upregulation of CD74 (receptor for macrophage inhibitory factor), store-operated Calcium entry-associated regulatory factor (SARAF), and B cell activating factor receptor (BAFFR), which resemble an early minted ASC phenotype. Overall, these findings reinforce the paradigm that human ex vivo mucosal IgE ASCs have a more immature plasma cell phenotype than other class-switched mucosal ASCs and suggest unique functional roles for mucosal IgE ASCs in concert with Ig secretion.

Reduced hepatocyte mitophagy is an early feature of NAFLD pathogenesis and hastens the onset of steatosis, inflammation and fibrosis.

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of pathologies that includes steatosis, steatohepatitis (NASH) and fibrosis and is strongly associated with insulin resistance and type 2 diabetes. Changes in mitochondrial function are implicated in the pathogenesis of NAFLD, particularly in the transition from steatosis to NASH. Mitophagy is a mitochondrial quality control mechanism that allows for the selective removal of damaged mitochondria from the cell via the autophagy pathway. While past work demonstrated a negative association between liver fat content and rates of mitophagy, when changes in mitophagy occur during the pathogenesis of NAFLD and whether such changes contribute to the primary endpoints associated with the disease are currently poorly defined. We therefore undertook the studies described here to establish when alterations in mitophagy occur during the pathogenesis of NAFLD, as well as to determine the effects of genetic inhibition of mitophagy via conditional deletion of a key mitophagy regulator, PARKIN, on the development of steatosis, insulin resistance, inflammation and fibrosis. We find that loss of mitophagy occurs early in the pathogenesis of NAFLD and that loss of PARKIN hastens the onset but not severity of key NAFLD disease features. These observations suggest that loss of mitochondrial quality control in response to nutritional stress may contribute to mitochondrial dysfunction and the pathogenesis of NAFLD.

Psychological distress of college students during the COVID-19 pandemic.

Objectives To assess levels of psychological distress among a group of US undergraduate college students during the initial phases of the novel coronavirus (SARS-CoV-2) pandemic. Methods: All undergraduates at Kent State University were surveyed in three randomly selected cohorts on March 18, March 25, and April 1, yielding 3924 valid responses for the weighted dataset (73.8% female, 88.9% White). Distress was assessed using the Kessler Psychological Distress Scale (K6). Data were weighted using known population counts. Results: K6 scores averaged 8.19 ± 5.9, with 44.3% in the moderately elevated range and 23.8% above the cutoff for severe psychological distress.Conclusions: A high proportion of undergraduate university students reported elevated psychological distress as the COVID-19 pandemic unfolded. K6 scores appeared higher than averages from comparison samples. Targeted surveillance can inform public health in mitigating threats to mental health conferred by pandemics. Colleges and universities should anticipate sharply elevated psychological distress during and after the COVID-19 pandemic.

Reflecting on the advancements of HFrEF therapies over the last two decades and predicting what is yet to come.

What was once considered a topic best avoided, managing heart failure with reduced ejection fraction (HFrEF) has become the focus of many drug and device therapies. While the four pillars of guideline-directed medical therapies have successfully reduced heart failure hospitalizations, and some have even impacted cardiovascular mortality in randomized controlled trials (RCTs), patient-reported outcomes have emerged as important endpoints that merit greater emphasis in future studies. The prospect of an oral inotrope seems more probable now as targets for drug therapies have moved from neurohormonal modulation to intracellular mechanisms and direct cardiac myosin stimulation. While we have come a long way in safely providing durable mechanical circulatory support to patients with advanced HFrEF, several percutaneous device therapies have emerged, and many are under investigation. Biomarkers have shown promise in not only improving our ability to diagnose incident heart failure but also our potential to implicate specific pathophysiological pathways. The once-forgotten concept of discordance between pressure and volume, the forgotten splanchnic venous and lymphatic compartments, have all emerged as promising targets for diagnosing and treating heart failure in the not-so-distant future. The increase in heart failure-related cardiogenic shock (CS) has revived interest in defining optimal perfusion targets and designing RCTs in CS. Rapid developments in remote monitoring, telemedicine, and artificial intelligence promise to change the face of heart failure care. In this state-of-the-art review, we reminisce about the past, highlight the present, and predict what might be the future of HFrEF therapies.

Distress and Prevention Behaviors During the COVID-19 Pandemic Among College Students: the Moderating Role of Resilience.

BACKGROUND: Pandemics can generate considerable distress, which can affect prevention behaviors. Resilience may buffer the negative effects of distress on engagement in relevant prevention behaviors, which may also hold true for COVID-19 prevention behaviors. The objective of the current study was to evaluate whether resilience moderated the relationship between distress and COVID-19 prevention behaviors early in the pandemic. METHODS: Data were collected via surveys in which all students at a large midwestern university were emailed invitations beginning March 18, 2020. Surveys were completed by 5,530 individuals. In addition to demographic questions and items about COVID-19 prevention behaviors, distress was assessed using the K6 Distress Scale and resilience using the Brief Resilience Scale. Data were analyzed using moderator regression analysis. RESULTS: Resilience moderates the effects from distress to prevention behaviors, such that the relationship was stronger for individuals with higher resilience than for individuals with lower resilience. When resilience was one standard deviation below the mean, at the mean value of resilience, and when resilience was one standard deviation above the mean, there was a significant positive relationship between distress and COVID-19 prevention behaviors. However, the relationship was strongest for those with high resilience, and lowest for those with low resilience. CONCLUSIONS: In the current sample, resilience appeared to influence the strength of the relationship between distress and COVID-19 prevention behaviors. Having higher resilience may promote positive adaptation to distress, leading individuals to engage in a greater number of disease-related prevention behaviors. Future research should examine this relationship longitudinally and in relation to differing constructs of resilience.

Evolutionary rate covariation identifies SLC30A9 (ZnT9) as a mitochondrial zinc transporter.

Recent advances in genome sequencing have led to the identification of new ion and metabolite transporters, many of which have not been characterized. Due to the variety of subcellular localizations, cargo and transport mechanisms, such characterization is a daunting task, and predictive approaches focused on the functional context of transporters are very much needed. Here we present a case for identifying a transporter localization using evolutionary rate covariation (ERC), a computational approach based on pairwise correlations of amino acid sequence evolutionary rates across the mammalian phylogeny. As a case study, we find that poorly characterized transporter SLC30A9 (ZnT9) coevolves with several components of the mitochondrial oxidative phosphorylation chain, suggesting mitochondrial localization. We confirmed this computational finding experimentally using recombinant human SLC30A9. SLC30A9 loss caused zinc mishandling in the mitochondria, suggesting that under normal conditions it acts as a zinc exporter. We therefore propose that ERC can be used to predict the functional context of novel transporters and other poorly characterized proteins.

Ileal Derived Organoids From Crohn's Disease Patients Show Unique Transcriptomic and Secretomic Signatures.

BACKGROUND & AIMS: We used patient-derived organoids (PDOs) to study the epithelial-specific transcriptional and secretome signatures of the ileum during Crohn's disease (CD) with varying phenotypes to screen for disease profiles and potential druggable targets. METHODS: RNA sequencing was performed on isolated intestinal crypts and 3-week-old PDOs derived from ileal biopsies of CD patients (n = 8 B1, inflammatory; n = 8 B2, stricturing disease) and non-inflammatory bowel disease (IBD) controls (n = 13). Differentially expressed (DE) genes were identified by comparing CD vs control, B1 vs B2, and inflamed vs non-inflamed. DE genes were used for computational screening to find candidate small molecules that could potentially reverse B1and B2 gene signatures. The secretome of a second cohort (n = 6 non-IBD controls, n = 7 CD, 5 non-inflamed, 2 inflamed) was tested by Luminex using cultured organoid conditioned medium. RESULTS: We found 90% similarity in both the identity and abundance of protein coding genes between PDOs and intestinal crypts (15,554 transcripts of 19,900 genes). DE analysis identified 814 genes among disease group (CD vs non-IBD control), 470 genes different between the CD phenotypes, and 5 false discovery rate correction significant genes between inflamed and non-inflamed CD. The PDOs showed both similarity and diversity in the levels and types of soluble cytokines and growth factors they released. Perturbagen analysis revealed potential candidate compounds to reverse B2 disease phenotype to B1 in PDOs. CONCLUSIONS: PDOs are similar at the transcriptome level with the in vivo epithelium and retain disease-specific gene expression for which we have identified secretome products, druggable targets, and corresponding pharmacologic agents. Targeting the epithelium could reverse a stricturing phenotype and improve outcomes.

Structural and functional cardiac changes in endomyocardial fibrosis treated with endomyocardial resection: Disease progression captured by multimodality imaging.

Eosinophilic myocarditis, a rare and under-recognized disease process, occurs due to cytotoxic inflammation of the endomyocardium that over time may lead to a restrictive cardiomyopathy. We report clinical, multimodality imaging, and pathologic findings in a 45-year-old woman over a 17-month period as she progressed from suspected acute eosinophilic myocarditis to phenotypic endomyocardial fibrosis resulting in recurrent ascites. Interval echocardiograms demonstrate definitive pathologic structural changes that reflect the hemodynamic consequences of the underlying cardiomyopathy. Despite a negative myocardial biopsy, characteristic findings on cardiovascular magnetic resonance imaging clarified the diagnosis which led to successful treatment with endomyocardial resection and valve replacements.

RIP3-dependent necroptosis contributes to the pathogenesis of chronic obstructive pulmonary disease.

Necroptosis has emerged as a potential mechanism in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, we found that markers of necroptosis, including high mobility group box 1 release and phosphorylation of mixed lineage kinase domain-like protein (p-MLKL), were markedly induced in the late stage of cigarette smoking-induced (CS-induced) emphysema in mouse lung tissue as well as in lung epithelial cells and organoids with higher dosage of or more prolonged exposure to cigarette smoking extract (CSE). Apoptotic signals were also detected and maximally induced in the early stage of CS-exposed mice and CSE-treated epithelial cells. Inhibition of apoptosis by Z-VAD, a pan-caspase inhibitor, switched the cellular stress to enhanced necroptosis in lung epithelial cells and organoids treated with CSE. Depletion or inhibition of receptor-interacting protein kinase 3 (RIP3) or MLKL attenuated the CSE-induced cell death, suggesting that necroptosis contributes to CSE-induced cell death. Silencing or inhibition of RIP1 had no protective effect, indicating a RIP1-independent RIP3 activation pathway. CSE-induced necroptosis released more damage-associated molecular patterns and evoked greater engulfment but slower clearance by bone marrow-derived macrophages, leading to enhanced expression of proinflammatory cytokines Tnfα and Il6. Finally, our in vivo data verified that inhibition of necroptosis by RIP3 inhibitor GSK'872 protected mice from CS-induced emphysema and suppressed the lung inflammation. In conclusion, we provide evidence that necroptosis contributes to the pathogenesis of COPD. Targeting RIP3 and its downstream pathway may be an effective therapy for COPD.

Using Ligand-Accelerated Catalysis to Repurpose Fluorogenic Reactions for Platinum or Copper.

The development of a fluorescent probe for a specific metal has required exquisite design, synthesis, and optimization of fluorogenic molecules endowed with chelating moieties with heteroatoms. These probes are generally chelation- or reactivity-based. Catalysis-based fluorescent probes have the potential to be more sensitive; however, catalytic methods with a biocompatible fluorescence turn-on switch are rare. Here, we have exploited ligand-accelerated metal catalysis to repurpose known fluorescent probes for different metals, a new approach in probe development. We used the cleavage of allylic and propargylic ethers as platforms that were previously designed for palladium. After a single experiment that combinatorially examined >800 reactions with two variables (metal and ligand) for each ether, we discovered a platinum- or copper-selective method with the ligand effect of specific phosphines. Both metal-ligand systems were previously unknown and afforded strong signals owing to catalytic turnover. The fluorometric technologies were applied to geological, pharmaceutical, serum, and live cell samples and were used to discover that platinum accumulates in lysosomes in cisplatin-resistant cells in a manner that appears to be independent of copper distribution. The use of ligand-accelerated catalysis may present a new blueprint for engineering metal selectivity in probe development.

A long non-coding RNA GATA6-AS1 adjacent to GATA6 is required for cardiomyocyte differentiation from human pluripotent stem cells.

Long noncoding RNAs (lncRNAs) are crucial in many cellular processes, yet relatively few have been shown to regulate human cardiomyocyte differentiation. Here, we demonstrate an essential role of GATA6 antisense RNA 1 (GATA6-AS1) in cardiomyocyte differentiation from human pluripotent stem cells (hPSCs). GATA6-AS1 is adjacent to cardiac transcription factor GATA6. We found that GATA6-AS1 was nuclear-localized and transiently upregulated along with GATA6 during the early stage of cardiomyocyte differentiation. The knockdown of GATA6-AS1 did not affect undifferentiated cell pluripotency but inhibited cardiomyocyte differentiation, as indicated by no or few beating cardiomyocytes and reduced expression of cardiomyocyte-specific proteins. Upon cardiac induction, the knockdown of GATA6-AS1 decreased GATA6 expression, altered Wnt-signaling gene expression, and reduced mesoderm development. Further characterization of the intergenic region between genomic regions of GATA6-AS1 and GATA6 indicated that the expression of GATA6-AS1 and GATA6 were regulated by a bidirectional promoter within the intergenic region. Consistently, GATA6-AS1 and GATA6 were co-expressed in several human tissues including the heart, similar to the mirror expression pattern of GATA6-AS1 and GATA6 during cardiomyocyte differentiation. Overall, these findings reveal a previously unrecognized and functional role of lncRNA GATA6-AS1 in controlling human cardiomyocyte differentiation.

COVID-19 in recent heart transplant recipients: Clinicopathologic features and early outcomes.

BACKGROUND: The impact of COVID-19 on heart transplant (HTx) recipients remains unclear, particularly in the early post-transplant period. METHODS: We share novel insights from our experience in five HTx patients with COVID-19 (three within 2 months post-transplant) from our institution at the epicenter of the pandemic. RESULTS: All five exhibited moderate (requiring hospitalization, n = 3) or severe (requiring ICU and/or mechanical ventilation, n = 2) illness. Both cases with severe illness were transplanted approximately 6 weeks before presentation and acquired COVID-19 through community spread. All five patients were on immunosuppressive therapy with mycophenolate mofetil (MMF) and tacrolimus, and three that were transplanted within the prior 2 months were additionally on prednisone. The two cases with severe illness had profound lymphopenia with markedly elevated C-reactive protein, procalcitonin, and ferritin. All had bilateral ground-glass opacities on chest imaging. MMF was discontinued in all five, and both severe cases received convalescent plasma. All three recent transplants underwent routine endomyocardial biopsies, revealing mild (n = 1) or no acute cellular rejection (n = 2), and no visible viral particles on electron microscopy. Within 30 days of admission, the two cases with severe illness remain hospitalized but have clinically improved, while the other three have been discharged. CONCLUSIONS: COVID-19 appears to negatively impact outcomes early after heart transplantation.

Targeting HIF-1α in combination with PPARα activation and postnatal factors promotes the metabolic maturation of human induced pluripotent stem cell-derived cardiomyocytes.

Immature phenotypes of cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) limit the utility of these cells in clinical application and basic research. During cardiac development, postnatal cardiomyocytes experience high oxygen tension along with a concomitant downregulation of hypoxia-inducible factor 1α (HIF-1α), leading to increased fatty acid oxidation (FAO). We hypothesized that targeting HIF-1α alone or in combination with other metabolic regulators could promote the metabolic maturation of hiPSC-CMs. We examined the effect of HIF-1α inhibition on the maturation of hiPSC-CMs and investigated a multipronged approach to promote hiPSC-CM maturation by combining HIF-1α inhibition with molecules that target key pathways involved in the energy metabolism. Cardiac spheres of highly-enriched hiPSC-CMs were treated with a HIF-1α inhibitor alone or in combination with an agonist of peroxisome proliferator activated receptor α (PPARα) and three postnatal factors (triiodothyronine hormone T3, insulin-like growth factor-1 and dexamethasone). HIF-1α inhibition significantly increased FAO and basal and maximal respiration of hiPSC-CMs. Combining HIF-1α inhibition with PPARα activation and the postnatal factors further increased FAO and improved mitochondrial maturation in hiPSC-CMs. Compared with mock-treated cultures, the cultures treated with the five factors had increased mitochondrial content and contained more cells with mitochondrial distribution throughout the cells, which are features of more mature cardiomyocytes. Consistent with these observations, a number of transcriptional regulators of mitochondrial metabolic processes were upregulated in hiPSC-CMs treated with the five factors. Furthermore, these cells had significantly increased Ca2+ transient kinetics and contraction and relaxation velocities, which are functional features for more mature cardiomyocytes. Therefore, targeting HIF-1α in combination with other metabolic regulators significantly improves the metabolic maturation of hiPSC-CMs.