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Background: The STRONG-HF trial demonstrated substantial reductions in the composite of mortality and morbidity over 6 months among hospitalized heart failure patients who were randomized to intensive guideline-directed medical therapy (GDMT) optimization compared to usual care. Whether an intensive GDMT optimization program would be cost-effective for patients with heart failure with reduced ejection fraction (HFrEF) is unknown. Methods: Using a 2-state Markov model we evaluated the effect of an intensive GDMT optimization program on hospitalized patients with HFrEF. Two population models were created to simulate this intervention, a "Clinical Trial" model, based off the participants in the STRONG-HF trial and a "Real-World" model, based off the Get With The Guidelines-HF Registry of patients admitted with worsening HF. We then modeled the effect of a 6-month intensive triple therapy GDMT optimization program comprised of cardiologists, clinical pharmacists, and registered nurses. Hazard ratios from the intervention arm of the STRONG-HF trial were applied to both populations models to simulate clinical and financial outcomes of an intensive GDMT optimization program from a United States healthcare sector perspective with a lifetime time horizon. Optimal quadruple GDMT use was also modeled. Results: An intensive GDMT optimization program was extremely cost-effective with incremental cost-effectiveness ratios

Heart failure remains a huge societal concern despite medical advancement, with an annual direct cost of over $30 billion. While guideline-directed medical therapy (GDMT) is proven to reduce morbidity and mortality, many eligible patients with heart failure with reduced ejection fraction (HFrEF) are not receiving one or more of the recommended medications, often due to suboptimal initiation and titration in the outpatient setting. Hospitalization serves as a key point to initiate and titrate GDMT. Four evidence-based therapies have clinical benefit within 30 days of initiation and form a crucial foundation for HFrEF therapy: renin-angiotensin-aldosterone system inhibitors with or without a neprilysin inhibitor, β-blockers, mineralocorticoid-receptor-antagonists, and sodium-glucose cotransporter-2 inhibitors. The authors present a practical guide for the implementation of these four pillars of GDMT during a hospitalization for acute heart failure.

BackgroundHeart failure with reduced ejection fraction (HFrEF) is one of the most costly and deadly chronic disease states. The cost effectiveness of a comprehensive quadruple therapy regimen for HFrEF has not been studied.ObjectivesThe authors sought to determine the cost-effectiveness of quadruple therapy comprised of beta-blockers, mineralocorticoid receptor antagonists, angiotensin receptor-neprilysin inhibitors, and sodium glucose cotransporter-2 inhibitors vs regimens composed of only beta-blockers, angiotensin-converting enzyme inhibitors, and mineralocorticoid receptor antagonists (triple therapy), and angiotensin-converting enzyme inhibitors and beta-blockers (double therapy).MethodsUsing a 2-state Markov model, the authors performed a cost-effectiveness study using simulated populations of 1,000 patients with HFrEF based on the participants in the PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) trial and compared them by treatment strategy (quadruple therapy vs triple and double therapy) from a United States health care system perspective. The authors also performed 10,000 probabilistic simulations.ResultsTreatment with quadruple therapy resulted in an increase of 1.73 and 2.87 life-years compared with triple therapy and double therapy, respectively, and an increase in quality-adjusted life-years of 1.12 and 1.85 years, respectively. The incremental cost-effectiveness ratios of quadruple therapy vs triple therapy and double therapy were $81,000 and $51,081, respectively. In 91.7% and 99.9% of probabilistic simulations quadruple therapy had an incremental cost-effectiveness ratio of

Objective: Background: Case Report: Conclusions: Rare coexistence of disease or pathology Cardiac allograft vasculopathy (CAV) is a post-orthotopic heart transplant (OHT) complication driven by inti-mal smooth muscle proliferation and immune hyperactivity to donor heart tissue. Accelerated CAV leads to al-lograft failure within 1 year after receiving a normal angiogram result. Viruses can contribute to CAV develop-ment, but CAV after SARS-CoV-2 infection has not been reported to date. A 48-year-old man, 5 years after OHT for non-ischemic cardiomyopathy, was admitted to the Cardiac Care Unit with 3 days of abdominal pain, dyspnea, and palpitations. His medical history included hyperlipidemia and in-sulin-dependent diabetes. He was compliant with all medications. Two months prior, he had a mild COVID-19 case. An echocardiogram and coronary angiogram 6 and 9 months prior, respectively, were unremarkable. Right and left heart catheterization demonstrated increased filling pressures, a cardiac index of 1.7 L/ml/m2, and diffuse vasculopathy most severe in the LAD artery. Flow could not be restored despite repeated balloon-ing and intra-catheter adenosine. Empiric ionotropic support, daily high-dose methylprednisolone, and plas-mapheresis were started. A few days later, the patient had cardiac arrest requiring venoarterial extracorporeal membranous oxygenation. Given CAV’s irreversibility, re-transplantation was considered, but the patient had an episode of large-volume hemoptysis and remained clinically unstable for transplant. The patient died while on palliative care. Our patient developed accelerated CAV 2 months after having COVID-19. While CAV has known associations with certain viruses, its incidence after SARS-CoV-2 infection is unknown. Further research is needed to deter-mine if prior SARS-CoV-2 infection is a risk factor for development of CAV in OHT recipients.

Understanding disease burden and transmission dynamics in resource-limited, low-income countries like Nepal are often challenging due to inadequate surveillance systems. These issues are exacerbated by limited access to diagnostic and research facilities throughout the country. Nepal has one of the highest COVID-19 case rates (915 cases per 100,000 people) in South Asia, with densely-populated Kathmandu experiencing the highest number of cases. Swiftly identifying case clusters (hotspots) and introducing effective intervention programs is crucial to mounting an effective containment strategy. The rapid identification of circulating SARS-CoV-2 variants can also provide important information on viral evolution and epidemiology. Genomic-based environmental surveillance can help in the early detection of outbreaks before clinical cases are recognized and identify viral micro-diversity that can be used for designing real-time risk-based interventions. This research aimed to develop a genomic-based environmental surveillance system by detecting and characterizing SARS-CoV-2 in sewage samples of Kathmandu using portable next-generation DNA sequencing devices. Out of 22 sites in the Kathmandu Valley from June to August 2020, sewage samples from 16 (80%) sites had detectable SARS-CoV-2. A heatmap was created to visualize the presence of SARS-CoV-2 infection in the community based on viral load intensity and corresponding geospatial data. Further, 47 mutations were observed in the SARS-CoV-2 genome. Some detected mutations (n = 9, 22%) were novel at the time of data analysis and yet to be reported in the global database, with one indicating a frameshift deletion in the spike gene. SNP analysis revealed possibility of assessing circulating major/minor variant diversity on environmental samples based on key mutations. Our study demonstrated the feasibility of rapidly obtaining vital information on community transmission and disease dynamics of SARS-CoV-2 using genomic-based environmental surveillance.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are a recent addition to the pillars of medical therapy for heart failure (HF) with reduced ejection fraction, all of which improve quality of life, morbidity, and mortality. These benefits are evident within the first 30 days of initiation. This review discusses the rationale for SGLT2i initiation in simultaneous or in rapid sequence with other guideline-directed medical therapy (GDMT). We also discuss SGLT2i use and early benefits in HF patients with an ejection fraction greater than 40%.

Atherosclerotic cardiovascular disease is a growing threat among cancer patients. Not surprisingly, cancer-targeting therapies have been linked to metabolic dysregulation including changes in local and systemic lipid metabolism. Thus, tumor development and cancer therapeutics are intimately linked to cholesterol metabolism and may be a driver of increased cardiovascular morbidity and mortality in this population. Chemotherapeutic agents affect lipid metabolism through diverse mechanisms. In this review, we highlight the mechanistic and clinical evidence linking commonly used cytotoxic therapies with cholesterol metabolism and potential opportunities to limit atherosclerotic risk in this patient population. Better understanding of the link between atherosclerosis, cancer therapy, and cholesterol metabolism may inform optimal lipid therapy for cancer patients and mitigate cardiovascular disease burden.

Heart failure remains a huge societal concern despite medical advancement, with an annual direct cost of over $30 billion. While guideline-directed medical therapy (GDMT) is proven to reduce morbidity and mortality, many eligible patients with heart failure with reduced ejection fraction (HFrEF) are not receiving one or more of the recommended medications, often due to suboptimal initiation and titration in the outpatient setting. Hospitalization serves as a key point to initiate and titrate GDMT. Four evidence-based therapies have clinical benefit within 30 days of initiation and form a crucial foundation for HFrEF therapy: renin-angiotensin-aldosterone system inhibitors with or without a neprilysin inhibitor, β-blockers, mineralocorticoid-receptor-antagonists, and sodium-glucose cotransporter-2 inhibitors. The authors present a practical guide for the implementation of these four pillars of GDMT during a hospitalization for acute heart failure.

SARS-CoV-2 infection is associated with significant lung and cardiac morbidity but there is a limited understanding of the endocrine manifestations of coronavirus disease 2019 (COVID-19). Although thyrotoxicosis due to subacute thyroiditis has been reported in COVID-19, it is unknown whether SARS-CoV-2 infection can also lead to decompensated hypothyroidism. We present the first case of myxedema coma (MC) in COVID-19 and we discuss how SARS-CoV-2 may have precipitated multiorgan damage and sudden cardiac arrest in our patient. A 69-year-old woman with a history of small cell lung cancer presented with hypothermia, hypotension, decreased respiratory rate, and a Glasgow Coma Scale score of 5. The patient was intubated and administered vasopressors. Laboratory investigation showed elevated thyrotropin, very low free thyroxine, elevated thyroid peroxidase antibody, and markedly elevated inflammatory markers. SARS-CoV-2 test was positive. Computed tomography showed pulmonary embolism and peripheral ground-glass opacities in the lungs. The patient was diagnosed with myxedema coma with concomitant COVID-19. While treatment with intravenous hydrocortisone and levothyroxine were begun the patient developed a junctional escape rhythm. Eight minutes later, the patient became pulseless and was eventually resuscitated. Echocardiogram following the arrest showed evidence of right heart dysfunction. She died 2 days later of multiorgan failure. This is the first report of SARS-CoV-2 infection with MC. Sudden cardiac arrest likely resulted from the presence of viral pneumonia, cardiac arrhythmia, pulmonary emboli, and MC-all of which were associated with the patient's SARS-CoV-2 infection.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

Posttranslational modification with ubiquitin chains controls cell fate in all eukaryotes. Depending on the connectivity between subunits, different ubiquitin chain types trigger distinct outputs, as seen with K48- and K63-linked conjugates that drive protein degradation or complex assembly, respectively. Recent biochemical analyses also suggested roles for mixed or branched ubiquitin chains, yet without a method to monitor endogenous conjugates, the physiological significance of heterotypic polymers remained poorly understood. Here, we engineered a bispecific antibody to detect K11/K48-linked chains and identified mitotic regulators, misfolded nascent polypeptides, and pathological Huntingtin variants as their endogenous substrates. We show that K11/K48-linked chains are synthesized and processed by essential ubiquitin ligases and effectors that are mutated across neurodegenerative diseases; accordingly, these conjugates promote rapid proteasomal clearance of aggregation-prone proteins. By revealing key roles of K11/K48-linked chains in cell-cycle and quality control, we establish heterotypic ubiquitin conjugates as important carriers of biological information.

Background: For preclinical evaluations of radiopharmaceuticals, most studies are carried out on mice. Electron specific absorbed fractions (SAF) values have had vital role in the assessment of absorbed dose. In past studies, electron SAFs were given for limited source target pairs using older reports of human organ compositions. Objective: Electron specific absorbed fraction values for monoenergetic electrons of energies 15, 50, 100, 500, 1000 & 4000 keV were evaluated for the Digimouse voxel phantom incorporated in Monte Carlo code FLUKA. From the latest report (International Commission on Radiological Protection ICRP) 110, organ compositions and densities were adopted. Material and Methods: We have used the Digimouse voxel phantom which was incorporated in Monte Carlo code FLUKA. Simulation studies were performed using FLUKA. The organ sources considered in this study were lungs, skeleton, heart, bladder, testis, stomach, spleen, pancreas, liver, kidney, adrenal, eye and brain. The considered target organs were lungs, skeleton, heart, bladder, testis, stomach, spleen, pancreas, liver, kidney, adrenal and brain. Eye and brain were considered as target organs only for eye and brain as source organs. Results: The electron SAF values for self-irradiation decreases with increasing electron energy. The electron SAF values for cross-irradiation are also found to be dependent on the electron energy and the geometries of source and target. Organ masses and electron SAF values are presented in tabular form. Conclusion: The results of this study will be useful in evaluating the absorbed dose to various organs of mice similar in size to the present study