Alzheimer's Disease and COVID-19 Pathogenic Overlap: Implications for Drug Repurposing.

As COVID-19 continues, a safe, cost-effective treatment strategy demands continued inquiry. Chronic neuroinflammatory disorders may appear to be of little relevance in this regard; often indolent and progressive disorders characterized by neuroinflammation (such as Alzheimer's disease (AD)) are fundamentally dissimilar in etiology and symptomology to COVID-19's rapid infectivity and pathology. However, the two disorders share extensive pathognomonic features, including at membrane, cytoplasmic, and extracellular levels, culminating in analogous immunogenic destruction of their respective organ parenchyma. We hypothesize that these mechanistic similarities may extent to therapeutic targets, namely that it is conceivable an agent against AD's immunopathy may have efficacy against COVID-19 and vice versa. It is notable that while extensively investigated, no agent has yet demonstrated significant therapeutic efficacy against AD's cognitive and memory declines. Yet this very failure has driven the development of numerous agents with strong mechanistic potential and clinical characteristics. Having already approved for clinical trials, these agents may be an expedient starting point in the urgent search for an effective COVID-19 therapy. Herein, we review the overlapping Alzheimer's/ COVID-19 targets and theorize several initial platforms.

Renal Dysfunction After Heart Transplant.

BACKGROUND: Moderate or severe renal dysfunction (MSRD) is a frequent complication after heart transplantation. Strategies to delay progression and improve outcomes, such as renoprotective medications and timely referral to nephrology, remain important in providing care to heart transplant recipients with MSRD. RESEARCH QUESTION: What are chronic renal dysfunction's prevalence, risk factors, and optimal clinical management strategies in heart transplant recipients? DESIGN: This single-center, cross-sectional study examined patients who received a heart transplant from January 1, 2000, to June 30, 2011, and followed until December 31, 2011. Moderate or severe renal dysfunction was defined as a glomerular filtration rate of <60 mL/min/1.73 m2. RESULTS: The prevalence of MSRD among 195 heart transplant recipients was 60%. Variables associated with MSRD were female sex (odds ratio [OR]: 4.82; 95% CI, 1.72-13.54), greater age (OR: 1.10 per year; 95% CI, 1.06-1.14), time since transplant (OR: 1.0004 per year; 95% CI, 1.0001-1.0007), and mTOR inhibitor use (OR: 2.89; 95% CI, 1.24-6.71). Tacrolimus use (OR: 0.19; 95% CI, 0.05-0.71) and cyclosporine use (OR: 0.21; 95% CI, 0.05-0.80) were associated with patients without MSRD. Among patients with MSRD, 19.6% were referred to a nephrologist. Median eGFR remained stable at approximately 60 mL/min/1.73 m2 for 3 years after the study. CONCLUSIONS: Our results suggest that female sex, older age at transplant, and time since transplant are associated with MSRD in heart transplant recipients. Tacrolimus and cyclosporine use seemed renoprotective, but lower usage and increased mTOR inhibitor use may more likely indicate existing treatment patterns for patients with MSRD.

Alzheimer's disease as an autoimmune disorder of innate immunity endogenously modulated by tryptophan metabolites.

Introduction: Alzheimer's disease (AD) is characterized by neurotoxic immuno-inflammation concomitant with cytotoxic oligomerization of amyloid beta (Aß) and tau, culminating in concurrent, interdependent immunopathic and proteopathic pathogeneses. Methods: We performed a comprehensive series of in silico, in vitro, and in vivo studies explicitly evaluating the atomistic-molecular mechanisms of cytokine-mediated and Aß-mediated neurotoxicities in AD.  Next, 471 new chemical entities were designed and synthesized to probe the pathways identified by these molecular mechanism studies and to provide prototypic starting points in the development of small-molecule therapeutics for AD. Results: In response to various stimuli (e.g., infection, trauma, ischemia, air pollution, depression), Aß is released as an early responder immunopeptide triggering an innate immunity cascade in which Aß exhibits both immunomodulatory and antimicrobial properties (whether bacteria are present, or not), resulting in a misdirected attack upon "self" neurons, arising from analogous electronegative surface topologies between neurons and bacteria, and rendering them similarly susceptible to membrane-penetrating attack by antimicrobial peptides (AMPs) such as Aß. After this self-attack, the resulting necrotic (but not apoptotic) neuronal breakdown products diffuse to adjacent neurons eliciting further release of Aß, leading to a chronic self-perpetuating autoimmune cycle.  AD thus emerges as a brain-centric autoimmune disorder of innate immunity. Based upon the hypothesis that autoimmune processes are susceptible to endogenous regulatory processes, a subsequent comprehensive screening program of 1137 small molecules normally present in human brain identified tryptophan metabolism as a regulator of brain innate immunity and a source of potential endogenous anti-AD molecules capable of chemical modification into multi-site therapeutic modulators targeting AD's complex immunopathic-proteopathic pathogenesis. Discussion:  Conceptualizing AD as an autoimmune disease, identifying endogenous regulators of this autoimmunity, and designing small molecule drug-like analogues of these endogenous regulators represents a novel therapeutic approach for AD.

Evaluation of a professional development course on research methods for healthcare professionals.

Healthcare is constantly evolving and thus requires lifelong learning. Evidence-based learning has been shown to lead to better patient outcomes, yet many healthcare professionals report gaps in their research abilities. We sought to evaluate the efficacy of a professional development program in addressing identified gaps.

Small molecule therapeutics for COVID-19: repurposing of inhaled furosemide.

The novel coronavirus SARS-CoV-2 has become a global health concern. The morbidity and mortality of the potentially lethal infection caused by this virus arise from the initial viral infection and the subsequent host inflammatory response. The latter may lead to excessive release of pro-inflammatory cytokines, IL-6 and IL-8, as well as TNF-α ultimately culminating in hypercytokinemia ("cytokine storm"). To address this immuno-inflammatory pathogenesis, multiple clinical trials have been proposed to evaluate anti-inflammatory biologic therapies targeting specific cytokines. However, despite the obvious clinical utility of such biologics, their specific applicability to COVID-19 has multiple drawbacks, including they target only one of the multiple cytokines involved in COVID-19's immunopathy. Therefore, we set out to identify a small molecule with broad-spectrum anti-inflammatory mechanism of action targeting multiple cytokines of innate immunity. In this study, a library of small molecules endogenous to the human body was assembled, subjected to in silico molecular docking simulations and a focused in vitro screen to identify anti-pro-inflammatory activity via interleukin inhibition. This has enabled us to identify the loop diuretic furosemide as a candidate molecule. To pre-clinically evaluate furosemide as a putative COVID-19 therapeutic, we studied its anti-inflammatory activity on RAW264.7, THP-1 and SIM-A9 cell lines stimulated by lipopolysaccharide (LPS). Upon treatment with furosemide, LPS-induced production of pro-inflammatory cytokines was reduced, indicating that furosemide suppresses the M1 polarization, including IL-6 and TNF-α release. In addition, we found that furosemide promotes the production of anti-inflammatory cytokine products (IL-1RA, arginase), indicating M2 polarization. Accordingly, we conclude that furosemide is a reasonably potent inhibitor of IL-6 and TNF-α that is also safe, inexpensive and well-studied. Our pre-clinical data suggest that it may be a candidate for repurposing as an inhaled therapy against COVID-19.