A Comparison of COVID-19 Outcomes Between Reservation-Area American Indian and U.S. National Students.

Introduction: This study presents data from 2 population-based surveys of youth (reservation-area American Indian adolescents and U.S. adolescents) on self, family, and friend morbidity and changes in substance use and negative impacts during COVID-19. Methods: Data were obtained in spring 2021 from surveys of American Indian students living on or near reservations (8th grade, n=398; 10th grade, n=367; 12th grade, n=290) and national students from Monitoring the Future (8th grade, n=11,446; 10th grade, n=11,792; 12th grade, n=9,022). The main outcomes were COVID-19 testing, perceived morbidity/mortality, substance-use changes, and emotional changes during COVID-19. Results: The American Indian sample had a greater proportion of testing (e.g., American Indian 8th grade: 58.1% [95% CI=48.6, 68.8]; Monitoring the Future 8th grade: 43.6% [95% CI=39.8, 47.5]) and friend/family hospitalization (e.g., American Indian 8th grade: 36.2% [95% CI=26.2, 47.5]; Monitoring the Future 8th grade: 11.9% [95% CI=10.6, 13.3]). Across grades, greater proportions of the national sample reported increased anxiety, anger, boredom, loneliness, depression, worry, and trouble concentrating, whereas greater proportions of reservation-area American Indians reported decreased anxiety, loneliness, and depression. Conclusions: Findings indicate that reservation-area American Indian youth experienced unique health consequences 1 year into the COVID-19 pandemic compared with national students, illustrating the need for American Indian-specific COVID-19 public health monitoring and response.

Self-reported Illness Experiences and Psychosocial Outcomes for Reservation-Area American Indian Youth During COVID-19.

Importance: Impacts of COVID-19 on reservation-area American Indian youth are unknown and may be substantial owing to the significant COVID-19 morbidity and mortality experienced by American Indian populations. Objective: To measure self-reported illness experiences and changes in psychosocial factors during the COVID-19 pandemic among reservation-area American Indian youth. Design, Setting, and Participants: This cross-sectional study included a random sample of US schools on or near US Indian reservations during Spring 2021, stratified by region, with students in grades 6 to 12 completing cross-sectional online surveys. All enrolled self-identifying American Indian students in grades 6 to 12 attending the 20 participating schools were eligible to be surveyed; participants represented 60.4% of eligible students in these schools. Data were analyzed from January 5 to July 15, 2022. Exposures: Onset of the COVID-19 pandemic. Main Outcomes and Measures: Outcomes of interest were COVID-19 self-reported illness outcomes for self and family and close friends; perceived changes in family and friend relationships, school engagement, social isolation, and other psychological factors since the COVID-19 pandemic began; and worry over COVID-19-related health outcomes. Results: A total of 2559 American Indian students (1201 [46.9%] male; 1284 [50.2%] female; 70 [2.7%] another gender; mean [SD] 14.7 [8.9] years) were included in the analysis. Approximately 14% of the sample reported having had a test result positive for SARS-CoV-2 infection (14.3% [95% CI, 11.4%-17.6%]), a higher rate than for all cases nationally at the time of the survey. Regarding prevalence of COVID-19 among family and close friends, 75.4% (95% CI, 68.8%-80.9%) of participants reported having at least 1 family member or friend who had contracted COVID-19, while 27.9% (95% CI, 18.8%-39.3%) of participants reported that at least 1 family member or close friend had died of COVID-19. Regarding psychosocial impacts, COVID-19 was associated with strained friend relationships (eg, 34.0% [95% CI, 28.4%-40.0%] of students reported worry over losing friends), lower school engagement, and less social connectedness (eg, 62.2% [95% CI, 56.7%-67.4%] of students reported feeling less socially connected to people), although more than 60% of students also reported feeling no change or a decrease in negative emotions. Males were less likely to report perceived negative impacts, especially for negative emotions such as sadness (29.2% [95% CI, 23.3%-35.9%] of males vs 46.1% [95% CI, 43.9%-48.3%] of females reported feeling more sad) and anxiety (21.8% [95% CI, 18.2%-25.8%] of males vs 39.2% [95% CI, 34.1%-44.6%] of females reported feeling more anxious). Conclusions and Relevance: This cross-sectional study provides novel insight into the perceived experiences of reservation-area American Indian youth, a population at uniquely elevated risk of poor health status and health care access, during the COVID-19 pandemic. Although mortality and morbidity rates from COVID-19 were high on American Indian reservations, student reports of psychosocial impacts were complex and suggest many students were resilient in the face of the pandemic. These findings could be used to understand and address the challenges facing American Indian youth due to the pandemic and to guide future research that examines the factors and processes associated with the reported outcomes.

Profiles of Ecosystemic Resilience and Risk: American Indian Adolescent Substance Use during the First Year of the COVID-19 Crisis.

The COVID-19 pandemic has caused an unprecedented disruption to the lives of American Indian (AI) adolescents. While reservation-area AI youth already have a higher risk of substance use (SU) compared to their non-AI peers, COVID-19 stressors likely exacerbated this risk. However, COVID-19-specific and general resilience factors may have buffered against increased SU over the course of the pandemic. Using a person-centered, ecosystemic framework of resilience, we used latent profile analysis to identify ecosystemic resilience profiles indicated by general and COVID-19-specific risk and resilience factors, then examined inter-profile changes in alcohol and cannabis use after the onset of the COVID-19 pandemic from the spring of 2020 to the spring of 2021. The sample was 2218 reservation-area AI adolescents (7-12th grade; schools = 20; Mage = 15, SD = 1.7; 52% female). Four profiles emerged: Average Risk and Resilience, High Resilience, Low Resilience, and High Risk. Adolescents with a High-Risk profile demonstrated increases in alcohol and cannabis use, while High Resilience youth demonstrated decreases. These findings support the hypothesized COVID-19-specific ecosystemic resilience profiles and the application of a person-centered ecosystemic framework to identify which AI adolescents are most likely to experience substance use changes during a life-altering crisis like COVID-19.

A case of disseminated histoplasmosis in a patient with sarcoidosis

Introduction/Objective: Sarcoidosis is a syndrome of unknown cause that may manifest with clinical, radiographic and pathological findings similar to those seen with histoplasmosis. We present a case of disseminated histoplasmosis in an immunocompetent patient previously diagnosed with sarcoidosis. Methods/Case Report: A 69-year-old obese male with a history of hypertension, diabetes mellitus and long-standing sarcoidosis was admitted to the hospital for several months of intermittent fevers and pancytopenia. His sarcoidosis was diagnosed 21 years prior, initially involving the lungs and eventually showing cardiac involvement, requiring a pacemaker. He had been treated with methotrexate and prednisone. His recent medical history was also significant for COVID-19 infection, diagnosed 3 months before admission. His fevers were initially attributed to sarcoidosis and his pancytopenia to methotrexate. However, his symptoms continued despite discontinuation of his medications, and further workup was initiated. Computed tomography showed hepatomegaly, splenomegaly, and lymphadenopathy, concerning for a lymphoproliferative disorder. The patient underwent a bone marrow biopsy that showed noncaseating granulomas and microorganisms consistent with histoplasmosis on fungal stain. Bone marrow cultures were not possible as the marrow was inaspirable. The patient subsequently underwent a lymph node biopsy with both morphology and culture identifying histoplasmosis. Urine and serum histoplasma antigen also returned positive. The patient's overall clinical picture was consistent with disseminated histoplasmosis and he was administered intravenous Amphotericin B for 3 weeks followed by oral itraconazole for 1 year. One month follow-up after discharge showed significant improvement in the patient's condition. Results (if a Case Study enter NA): N/A Conclusion: Sarcoidosis reduces T-cell activity, and treatment with steroids causes further immunosuppression and vulnerability for development of a disseminated infection. COVID-19 also presumably increases the predisposition to acquire bacterial or fungal co-infections. Clinicians and pathologists should be aware of the overlap in clinical, radiologic and pathological presentations of sarcoidosis and histoplasmosis to make the correct diagnosis and administer the appropriate treatment.

Cardiac PET and SPECT During the COVID-19 Pandemic.

The severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) spread rapidly around the world in the early months of 2020 before the COVID-19 outbreak was officially declared a pandemic in March 2020. Worldwide volumes of non-emergent testing, such as cardiac PET and SPECT, decreased dramatically at the beginning of the lockdown as health systems attempted to limit the spread of the COVID-19 virus. Published reports of increasing cardiovascular mortality compared to months prior to the pandemic raised concerns that lack of access to appropriate cardiovascular testing was adversely affecting patient outcomes. Medical societies published guidance for the best practices of cardiovascular nuclear medicine laboratories to address this emerging cardiovascular epidemic. These nuclear cardiology expert consensus recommendations were remarkably consistent with those from other health organizations and heavily emphasized patient triage, screening of symptoms, strict PPE usage, and limiting patient dwell time in the nuclear medicine lab by favoring shorter testing protocols. Survey responses indicated that nuclear medicine labs took heed of these recommendations and adjusted practices to meet the cardiovascular needs of their population while minimizing transmission risk.

Effect of Treatment With Sacubitril/Valsartan in Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial.

Importance: The use of sacubitril/valsartan is not endorsed by practice guidelines for use in patients with New York Heart Association class IV heart failure with a reduced ejection fraction because of limited clinical experience in this population. Objective: To compare treatment with sacubitril/valsartan treatment with valsartan in patients with advanced heart failure and a reduced ejection fraction and recent New York Heart Association class IV symptoms. Design, Setting, and Participants: A double-blind randomized clinical trial was conducted; a total of 335 patients with advanced heart failure were included. The trial began on March 2, 2017, and was stopped early on March 23, 2020, owing to COVID-19 risk. Intervention: Patients were randomized to receive sacubitril/valsartan (target dose, 200 mg twice daily) or valsartan (target dose, 160 mg twice daily) in addition to recommended therapy. Main Outcomes and Measures: The area under the curve (AUC) for the ratio of N-terminal pro-brain natriuretic peptide (NT-proBNP) compared with baseline measured through 24 weeks of therapy. Results: Of the 335 patients included in the analysis, 245 were men (73%); mean (SD) age was 59.4 (13.5) years. Seventy-two eligible patients (18%) were not able to tolerate sacubitril/valsartan, 100 mg/d, during the short run-in period, and 49 patients (29%) discontinued sacubitril/valsartan during the 24 weeks of the trial. The median NT-proBNP AUC for the valsartan treatment arm (n = 168) was 1.19 (IQR, 0.91-1.64), whereas the AUC for the sacubitril/valsartan treatment arm (n = 167) was 1.08 (IQR, 0.75-1.60). The estimated ratio of change in the NT-proBNP AUC was 0.95 (95% CI 0.84-1.08; P = .45). Compared with valsartan, treatment with sacubitril/valsartan did not improve the clinical composite of number of days alive, out of hospital, and free from heart failure events. Aside from a statistically significant increase in non-life-threatening hyperkalemia in the sacubitril/valsartan arm (28 [17%] vs 15 [9%]; P = .04), there were no observed safety concerns. Conclusions and Relevance: The findings of this trial showed that, in patients with chronic advanced heart failure with a reduced ejection fraction, there was no statistically significant difference between sacubitril/valsartan and valsartan with respect to reducing NT-proBNP levels. Trial Registration: ClinicalTrials.gov Identifier: NCT02816736.

Targeting Future Pandemics, a Case for De Novo Purine Synthesis and Basic Research.

We are currently experiencing a deadly novel viral pandemic with no efficacious, readily available anti-viral therapies to SARS-CoV-2. Viruses will hijack host cellular machinery, including metabolic processes. Here, I provide theory and evidence for targeting the host de novo purine synthetic pathway for broad spectrum anti-viral drug development as well as the pursuit of basic science to mitigate the risks of future novel viral outbreaks.

ACE2, the Counter-Regulatory Renin-Angiotensin System Axis and COVID-19 Severity.

Angiotensin (ANG)-converting enzyme (ACE2) is an entry receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19). ACE2 also contributes to a deviation of the lung renin-angiotensin system (RAS) towards its counter-regulatory axis, thus transforming harmful ANG II to protective ANG (1-7). Based on this purported ACE2 double function, it has been put forward that the benefit from ACE2 upregulation with renin-angiotensin-aldosterone system inhibitors (RAASi) counterbalances COVID-19 risks due to counter-regulatory RAS axis amplification. In this manuscript we discuss the relationship between ACE2 expression and function in the lungs and other organs and COVID-19 severity. Recent data suggested that the involvement of ACE2 in the lung counter-regulatory RAS axis is limited. In this setting, an augmentation of ACE2 expression and/or a dissociation of ACE2 from the ANG (1-7)/Mas pathways that leaves unopposed the ACE2 function, the SARS-CoV-2 entry receptor, predisposes to more severe disease and it appears to often occur in the relevant risk factors. Further, the effect of RAASi on ACE2 expression and on COVID-19 severity and the overall clinical implications are discussed.

The Counter Regulatory Axis of the Lung Renin-Angiotensin System in Severe COVID-19: Pathophysiology and Clinical Implications.

The severe acute respiratory syndrome coronavirus (SARS-CoV)-2, which is responsible for coronavirus disease 2019 (COVID-19), uses angiotensin (ANG)-converting enzyme 2 (ACE2) as the entrance receptor. Although most COVID-19 cases are mild, some are severe or critical, predominantly due to acute lung injury. It has been widely accepted that a counter regulatory renin-angiotensin system (RAS) axis including the ACE2/ANG [1-7]/Mas protects the lungs from acute lung injury. However, recent evidence suggests that the generation of protective ANG [1-7] in the lungs is predominantly mediated by proinflammatory prolyl oligopeptidase (POP), which has been repeatedly demonstrated to be involved in lung pathology. This review contends that acute lung injury in severe COVID-19 is characterised by a) ACE2 downregulation and malfunction (inflammatory signalling) due to viral occupation, and b) dysregulation of the protective RAS axis, predominantly due to increased activity of proinflammatory POP. It follows that a reasonable treatment strategy in COVID-19-related acute lung injury would be delivering functional recombinant (r) ACE2 forms to trap the virus. Additionally, or alternatively to rACE2 delivery, the potential benefits resulting from lowering POP activity should also be explored. These treatment strategies deserve further investigation.

On Answering the Call to Action for COVID-19: Continuing a Bold Legacy of Health Advocacy.

The indelible impacts on our nation from the Coronavirus pandemic along with high fatality rates that disproportionately burden racial and ethnic minorities necessitate long-term coordinated federal, state and local action to improve critical determinants of population health, specifically important health and public health infrastructures as well as emergency and disaster preparedness systems. While our purview as the new pandemic epicenter should be a sufficient driver, coordinated health professionals bringing thoughtful attention to our historical context may be warranted. Prompting our advocacy should be the reality that our collective ability to rebound from such crises may ultimately hinge on protecting and equipping our most vulnerable racial-ethnic minority groups and any susceptible individuals within those populations. Recent historic firsts on behalf of racial and ethnic minorities taken by U.S. Department of Health and Human Services, through the Health Resources and Services Administration, the Office of Minority Health and the Centers for Disease Control and Prevention in response to COVID-19, if proven effective, should be considered for permanency within policy, practice and funding. In addition, given the complex history of Black Americans in this country and persistent and substantial Black-white disparities on health and economic measures across the board, the ultimate solution for improving the health and status Black Americans may look slightly different. Influenced by the 400th year anniversary of the first documented arrival of unfree Africans in North America in 1619, as well as the introduction of bills S.1080 and H.R.40 into Congress (The Commission to Study and Develop Reparation Proposals for African-Americans Act), some kind of reparations for Black Americans might serve as the logical starting point for further advocacy. Nevertheless, we remain supportive allies of all organizations concerned with communities who suffer the weight of this pandemic and any future world health disasters. What is additionally needed is a thoughtful unification of efforts and a commitment to sustained progress with measurable results for as long as the need exists and certainly for the foreseeable future. Let us as humane clinicians and public health professionals capture this moment of challenge and follow through on this urgent call to action.

Myocarditis and inflammatory cardiomyopathy: current evidence and future directions.

Inflammatory cardiomyopathy, characterized by inflammatory cell infiltration into the myocardium and a high risk of deteriorating cardiac function, has a heterogeneous aetiology. Inflammatory cardiomyopathy is predominantly mediated by viral infection, but can also be induced by bacterial, protozoal or fungal infections as well as a wide variety of toxic substances and drugs and systemic immune-mediated diseases. Despite extensive research, inflammatory cardiomyopathy complicated by left ventricular dysfunction, heart failure or arrhythmia is associated with a poor prognosis. At present, the reason why some patients recover without residual myocardial injury whereas others develop dilated cardiomyopathy is unclear. The relative roles of the pathogen, host genomics and environmental factors in disease progression and healing are still under discussion, including which viruses are active inducers and which are only bystanders. As a consequence, treatment strategies are not well established. In this Review, we summarize and evaluate the available evidence on the pathogenesis, diagnosis and treatment of myocarditis and inflammatory cardiomyopathy, with a special focus on virus-induced and virus-associated myocarditis. Furthermore, we identify knowledge gaps, appraise the available experimental models and propose future directions for the field. The current knowledge and open questions regarding the cardiovascular effects associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are also discussed. This Review is the result of scientific cooperation of members of the Heart Failure Association of the ESC, the Heart Failure Society of America and the Japanese Heart Failure Society.

Sacubitril/Valsartan in Advanced Heart Failure With Reduced Ejection Fraction: Rationale and Design of the LIFE Trial.

The PARADIGM-HF (Prospective Comparison of Angiotensin II Receptor Blocker Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial reported that sacubitril/valsartan (S/V), an angiotensin receptor-neprilysin inhibitor, significantly reduced mortality and heart failure (HF) hospitalization in HF patients with a reduced ejection fraction (HFrEF). However, fewer than 1% of patients in the PARADIGM-HF study had New York Heart Association (NYHA) functional class IV symptoms. Accordingly, data that informed the use of S/V among patients with advanced HF were limited. The LIFE (LCZ696 in Hospitalized Advanced Heart Failure) study was a 24-week prospective, multicenter, double-blinded, double-dummy, active comparator trial that compared the safety, efficacy, and tolerability of S/V with those of valsartan in patients with advanced HFrEF. The trial planned to randomize 400 patients ≥18 years of age with advanced HF, defined as an EF ≤35%, New York Heart Association functional class IV symptoms, elevated natriuretic peptide concentration (B-type natriuretic peptide [BNP] ≥250 pg/ml or N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥800 pg/ml), and ≥1 objective finding of advanced HF. Following a 3- to 7-day open label run-in period with S/V (24 mg/26 mg twice daily), patients were randomized 1:1 to S/V titrated to 97 mg/103 mg twice daily versus 160 mg of V twice daily. The primary endpoint was the proportional change from baseline in the area under the curve for NT-proBNP levels measured through week 24. Secondary and tertiary endpoints included clinical outcomes and safety and tolerability. Because of the COVID-19 pandemic, enrollment in the LIFE trial was stopped prematurely to ensure patient safety and data integrity. The primary analysis consists of the first 335 randomized patients whose clinical follow-up examination results were not severely impacted by COVID-19. (Entresto [LCZ696] in Advanced Heart Failure [LIFE STUDY] [HFN-LIFE]; NCT02816736).

Renin-angiotensin-system inhibition in the context of corona virus disease-19: experimental evidence, observational studies, and clinical implications.

Coronavirus disease 2019 (COVID-19) is due to severe acute respiratory syndrome coronavirus (SARS-CoV)-2 which binds and enters the host cells through the angiotensin-converting enzyme (ACE)2. While the potential for benefit with the use of renin-angiotensin-aldosterone system inhibitors (RAASi) and the risks from stopping them is more evident, potential harm by RAΑSi may also be caused by the increase in the activity of the ACE2 receptor, the inefficient counter regulatory axis in the lungs in which the proinflammatory prolyloligopeptidase (POP) is the main enzyme responsible for the conversion of deleterious angiotensin (ANG) II to protective ANG [1-7] and the proinflammatory properties of ACE2(+) cells infected with SARS-CoV-2. Acknowledging the proven RAΑSi benefit in patients with several diseases such as hypertension, heart failure, coronary disease, and diabetic kidney disease in the non-COVID-19 era, it is a reasonable strategy in this period of uncertainty to use these agents judiciously with careful consideration and to avoid the use of RAASi in select patients whenever possible, until definitive evidence becomes available.