Regular Use of Ivermectin as Prophylaxis for COVID-19 Led Up to a 92% Reduction in COVID-19 Mortality Rate in a Dose-Response Manner: Results of a Prospective Observational Study of a Strictly Controlled Population of 88,012 Subjects.

Background We have previously demonstrated that ivermectin used as prophylaxis for coronavirus disease 2019 (COVID-19), irrespective of the regularity, in a strictly controlled citywide program in Southern Brazil (Itajaí, Brazil), was associated with reductions in COVID-19 infection, hospitalization, and mortality rates. In this study, our objective was to determine if the regular use of ivermectin impacted the level of protection from COVID-19 and related outcomes, reinforcing the efficacy of ivermectin through the demonstration of a dose-response effect. Methods This exploratory analysis of a prospective observational study involved a program that used ivermectin at a dose of 0.2 mg/kg/day for two consecutive days, every 15 days, for 150 days. Regularity definitions were as follows: regular users had 180 mg or more of ivermectin and irregular users had up to 60 mg, in total, throughout the program. Comparisons were made between non-users (subjects who did not use ivermectin), and regular and irregular users after multivariate adjustments. The full city database was used to calculate and compare COVID-19 infection and the risk of dying from COVID-19. The COVID-19 database was used and propensity score matching (PSM) was employed for hospitalization and mortality rates. Results Among 223,128 subjects from the city of Itajaí, 159,560 were 18 years old or up and were not infected by COVID-19 until July 7, 2020, from which 45,716 (28.7%) did not use and 113,844 (71.3%) used ivermectin. Among ivermectin users, 33,971 (29.8%) used irregularly (up to 60 mg) and 8,325 (7.3%) used regularly (more than 180 mg). The remaining 71,548 participants were not included in the analysis. COVID-19 infection rate was 49% lower for regular users (3.40%) than non-users (6.64%) (risk rate (RR): 0.51; 95% CI: 0.45-0.58; p < 0.0001), and 25% lower than irregular users (4.54%) (RR: 0.75; 95% CI: 0.66-0.85; p < 0.0001). The infection rate was 32% lower for irregular users than non-users (RR: 0.68; 95% CI: 0.64-0.73; p < 0.0001). Among COVID-19 participants, regularusers were older and had a higher prevalence of type 2 diabetes and hypertension than irregular and non-users. After PSM, the matched analysis contained 283 subjects in each group of non-users and regular users, between regular users and irregular users, and 1,542 subjects between non-users and irregular users. The hospitalization rate was reduced by 100% in regular users compared to both irregular users and non-users (p < 0.0001), and by 29% among irregular users compared to non-users (RR: 0.781; 95% CI: 0.49-1.05; p = 0.099). Mortality rate was 92% lower in regular users than non-users (RR: 0.08; 95% CI: 0.02-0.35; p = 0.0008) and 84% lower than irregular users (RR: 0.16; 95% CI: 0.04-0.71; p = 0.016), while irregular users had a 37% lower mortality rate reduction than non-users (RR: 0.67; 95% CI: 0.40-0.99; p = 0.049). Risk of dying from COVID-19 was 86% lower among regular users than non-users (RR: 0.14; 95% CI: 0.03-0.57; p = 0.006), and 72% lower than irregular users (RR: 0.28; 95% CI: 0.07-1.18; p = 0.083), while irregular users had a 51% reduction compared to non-users (RR: 0.49; 95% CI: 0.32-0.76; p = 0.001). Conclusion Non-use of ivermectin was associated with a 12.5-fold increase in mortality rate and a seven-fold increased risk of dying from COVID-19 compared to the regular use of ivermectin. This dose-response efficacy reinforces the prophylactic effects of ivermectin against COVID-19.

Catecholamines Are the Key Trigger of COVID-19 mRNA Vaccine-Induced Myocarditis: A Compelling Hypothesis Supported by Epidemiological, Anatomopathological, Molecular, and Physiological Findings.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine-induced myocarditis is a rare but well-documented complication in young males. The increased incidence of sudden death among athletes following vaccination has been reported and requires further investigation. Whether the risk of myocarditis, a known major cause of sudden death in young male athletes, also increases after coronavirus disease 2019 (COVID-19) infection is unknown. The severity and implications of these critical adverse effects require a thorough analysis to elucidate their key triggering mechanisms. The present review aimed to evaluate whether there is a justification to hypothesize that catecholamines in a "hypercatecholaminergic" state are the key trigger of SARS-CoV-2 mRNA vaccine-induced myocarditis and related outcomes and whether similar risks are also present following COVID-19 infection. A thorough, structured scoping review of the literature was performed to build the hypothesis through three pillars: detection of myocarditis risk, potential alterations and abnormalities identified after SARS-CoV-2 mRNA vaccination or COVID-19 infection and consequent events, and physiological characteristics of the most affected population. The following terms were searched in indexed and non-indexed peer review articles and recent preprints (<12 months): agent, "SARS-CoV-2" or "COVID-19"; event, "myocarditis" or "sudden death(s)" or "myocarditis+sudden death(s)" or "cardiac event(s)"; underlying cause, "mRNA" or "spike protein" or "infection" or "vaccine"; proposed trigger, "catecholamine(s)" or "adrenaline" or "epinephrine" or "noradrenaline" or "norepinephrine" or "testosterone"; and affected population, "young male(s)" or "athlete(s)." The rationale and data that supported the hypothesis were as follows: SARS-CoV-2 mRNA vaccine-induced myocarditis primarily affected young males, while the risk was not observed following COVID-19 infection; independent autopsies or biopsies of patients who presented post-SARS-CoV-2 mRNA vaccine myocarditis in different geographical regions enabled the conclusion that a primary hypercatecholaminergic state was the key trigger of these events; SARS-CoV-2 mRNA was densely present, and SARS-CoV-2 spike protein was progressively produced in adrenal medulla chromaffin cells, which are responsible for catecholamine production; the dihydroxyphenylalanine decarboxylase enzyme that converts dopamine into noradrenaline was overexpressed in the presence of SARS-CoV-2 mRNA, leading to enhanced noradrenaline activity; catecholamine responses were physiologically higher in young adults and males than in other populations; catecholamine responses and resting catecholamine production were higher in male athletes than in non-athletes; catecholamine responses to stress and its sensitivity were enhanced in the presence of androgens; and catecholamine expressions in young male athletes were already high at baseline, were higher following vaccination, and were higher than those in non-vaccinated athletes. The epidemiological, autopsy, molecular, and physiological findings unanimously and strongly suggest that a hypercatecholaminergic state is the critical trigger of the rare cases of myocarditis due to components from SARS-CoV-2, potentially increasing sudden deaths among elite male athletes.

Nonpharmacological Interventions for the Management of Testosterone and Sperm Parameters: A Scoping Review.

PURPOSE: Testosterone replacement and associated pharmacologic agents are effective strategies to treat male hypogonadism; however, nutraceutical agents and lifestyle modification approaches have gained medical interest. The purpose of this scoping review is to highlight the evidence (or lack thereof) of nutraceuticals and lifestyle modification approaches in the management of testosterone levels and sperm parameters. METHODS: A scoping review of nonpharmacologic interventions (supplements, herbal medicines, diets, sleep, and exercise) with the potential to improve male health was undertaken to elucidate changes in testosterone levels and sperm parameters in men with hypogonadism or infertility compared with healthy patients. FINDINGS: A multitude of nutraceuticals and functional nutrients are purported to stimulate testosterone production; however, only a select few have had promising results, such as zinc, vitamin D (in case of hypovitaminosis D), l-arginine, mucuna, and ashwagandha, based on well-controlled randomized clinical trials of men with low testosterone levels and related problems. Except for l-arginine, these natural agents, as well as tribulus and ω3 fatty acids, can improve some degree of sperm parameters in infertile men. Before implementing these nutraceutical agents, adequate sleep, exercise, and weight loss in patients with obesity are imperative. The effects of nonpharmacologic interventions on testosterone levels are modest and hence do not directly translate into clinical benefits. Correspondingly, androgen receptor content, but not endogenous androgens, has been regarded as the principal factor in muscle hypertrophy. IMPLICATIONS: A limited number of supplements and herbal medicines can be considered as adjunctive approaches in the management of testosterone levels and sperm parameters, primarily in men with low testosterone levels and infertility, whereas most nonpharmacologic supplements appear to lack evidence. Although proper physical exercise, sleep, and diet are indisputable approaches because of the general benefits to health, the use of nutraceuticals, if considered, must be personalized by physicians and/or registered dietitians.

Correction: Ivermectin Prophylaxis Used for COVID-19: A Citywide, Prospective, Observational Study of 223,128 Subjects Using Propensity Score Matching.

[This corrects the article DOI: 10.7759/cureus.21272.].

Ivermectin Prophylaxis Used for COVID-19: A Citywide, Prospective, Observational Study of 223,128 Subjects Using Propensity Score Matching.

BACKGROUND: Ivermectin has demonstrated different mechanisms of action that potentially protect from both coronavirus disease 2019 (COVID-19) infection and COVID-19-related comorbidities. Based on the studies suggesting efficacy in prophylaxis combined with the known safety profile of ivermectin, a citywide prevention program using ivermectin for COVID-19 was implemented in Itajaí, a southern city in Brazil in the state of Santa Catarina. The objective of this study was to evaluate the impact of regular ivermectin use on subsequent COVID-19 infection and mortality rates. MATERIALS AND METHODS: We analyzed data from a prospective, observational study of the citywide COVID-19 prevention with ivermectin program, which was conducted between July 2020 and December 2020 in Itajaí, Brazil. Study design, institutional review board approval, and analysis of registry data occurred after completion of the program. The program consisted of inviting the entire population of Itajaí to a medical visit to enroll in the program and to compile baseline, personal, demographic, and medical information. In the absence of contraindications, ivermectin was offered as an optional treatment to be taken for two consecutive days every 15 days at a dose of 0.2 mg/kg/day. In cases where a participating citizen of Itajaí became ill with COVID-19, they were recommended not to use ivermectin or any other medication in early outpatient treatment. Clinical outcomes of infection, hospitalization, and death were automatically reported and entered into the registry in real time. Study analysis consisted of comparing ivermectin users with non-users using cohorts of infected patients propensity score-matched by age, sex, and comorbidities. COVID-19 infection and mortality rates were analyzed with and without the use of propensity score matching (PSM). RESULTS: Of the 223,128 citizens of Itajaí considered for the study, a total of 159,561 subjects were included in the analysis: 113,845 (71.3%) regular ivermectin users and 45,716 (23.3%) non-users. Of these, 4,311 ivermectin users were infected, among which 4,197 were from the city of Itajaí (3.7% infection rate), and 3,034 non-users (from Itajaí) were infected (6.6% infection rate), with a 44% reduction in COVID-19 infection rate (risk ratio [RR], 0.56; 95% confidence interval (95% CI), 0.53-0.58; p < 0.0001). Using PSM, two cohorts of 3,034 subjects suffering from COVID-19 infection were compared. The regular use of ivermectin led to a 68% reduction in COVID-19 mortality (25 [0.8%] versus 79 [2.6%] among ivermectin non-users; RR, 0.32; 95% CI, 0.20-0.49; p < 0.0001). When adjusted for residual variables, reduction in mortality rate was 70% (RR, 0.30; 95% CI, 0.19-0.46; p < 0.0001). There was a 56% reduction in hospitalization rate (44 versus 99 hospitalizations among ivermectin users and non-users, respectively; RR, 0.44; 95% CI, 0.31-0.63; p < 0.0001). After adjustment for residual variables, reduction in hospitalization rate was 67% (RR, 0.33; 95% CI, 023-0.66; p < 0.0001). CONCLUSION: In this large PSM study, regular use of ivermectin as a prophylactic agent was associated with significantly reduced COVID-19 infection, hospitalization, and mortality rates.

Effects of Overtraining Status on the Cortisol Awakening Response-Endocrine and Metabolic Responses on Overtraining Syndrome (EROS-CAR).

The cortisol awakening response (CAR) is a distinct component of the circadian cortisol profile and has promise as a biomarker for the monitoring of athlete readiness and training status. Although some studies have suggested the CAR may be affected by the development of overtraining syndrome (OTS), this has yet to be systematically investigated. PURPOSE: To compare the CAR and diurnal cortisol slope between athletes diagnosed with OTS, healthy athletes, and sedentary controls. METHODS: This study was a secondary analysis of data from the Endocrine and Metabolic Responses on Overtraining study. Male participants were recruited to either OTS, healthy athlete, or sedentary control groups. The participants produced saliva samples immediately after waking (S1), 30 minutes after waking (S2), at 16:00 hours, and at 23:00 hours. Salivary cortisol concentration was determined by an electrochemiluminescence assay. Mixed-effects models were used to assess the conditional effect of group (sedentary controls, OTS, and healthy athletes) on the change in cortisol over time. Separate models were fit for the awakening samples (S1 and S2) and for the diurnal slope (linear change across S1, 16:00 h, and 23:00 h). RESULTS: The models demonstrated significant time-by-group interaction for OTS for the 2 cortisol concentrations collected during the awakening period (ß = -9.33, P < .001), but not for the diurnal cortisol slope (ß = 0.02, P = .80). CONCLUSIONS: These results suggest the CAR may be associated with OTS and should be considered within a panel of biomarkers. Further research is necessary to determine whether alterations in the CAR may precede the diagnosis of OTS.

Stay-At-Home Orders Are Associated With Emergence of Novel SARS-CoV-2 Variants.

Background While public health strategies to contain the current coronavirus disease 2019 (COVID-19) pandemic are primarily focused on social distancing and isolation, emerging evidence suggest that in some regions social isolation failed to lead to further decrease in the number of COVID-19 deaths in the long run. This apparent paradox was particularly observed in the northern region of Brazil, in the state of Amazonas. We hypothesized that the emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutations, leading to more transmissible and pathogenic variants, could explain the lack of further reductions in COVID-19 new cases and related deaths in some regions. Our objective is to determine if social isolation is associated with the emergence of new SARS-CoV-2 variants, particularly the P.1 lineage and E484K mutants, in Brazil and in the state of Amazonas. Materials and methods We assessed the prevailing SARS-CoV-2 genomes present in Brazil available on the GISAID (Global Initiative on Sharing All Influenza Data) database collected between June 1, 2020, and January 31, 2021. Data regarding demographics, lineage, and prevalence of P.1 lineage and E484K mutations were obtained. Social isolation was measured using the Social Isolation Index (SII), which quantifies the percentage of individuals that stayed within a distance of 450 meters from their homes on a given day, between February 1, 2020, and January 24, 2021. The number of daily COVID-19 deaths was obtained from the Brazilian Ministry of Health (OpenDataSUS, 2021) between March 12, 2020, and January 10, 2021. SII was correlated with the prevalence P.1 lineage and E484K mutations in the eight following weeks. All univariate associations were estimated using the Spearman Correlation Index. 3D surfaces were employed to reflect the relationship between time, social isolation, and prevalence of genomic variants simultaneously. Results A total of 773 and 77 samples were obtained in Brazil and in the Amazonas state, respectively. In the state of Amazonas, SII on a given week was positively, significantly, and moderately or strongly (r > 0.6) correlated with the prevalence of both P.1 lineage and other E484K variants in the six following weeks after the SII on a given week. Conversely, in overall Brazil, correlations between SII and P.1 lineage and E484K variants were weaker and shorter, or negative, respectively. When SII was below 40%, P.1 lineage or E484K variants were not detected in the following weeks. When SII was above 40%, apparently exponential positive correlations between SII and prevalence of both P.1 lineage and E484K variants were observed. Conclusion The results of this study indicate that SII above 40% is associated with the emergence of SARS-CoV-2 E484K variants and P.1 lineage in the state of Amazonas, which was not observed in overall Brazil.

Early Antiandrogen Therapy With Dutasteride Reduces Viral Shedding, Inflammatory Responses, and Time-to-Remission in Males With COVID-19: A Randomized, Double-Blind, Placebo-Controlled Interventional Trial (EAT-DUTA AndroCoV Trial - Biochemical).

Background and objective Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry and subsequent infectivity are mediated by androgens and the androgen receptors through the regulation of transmembrane protease, serine 2 (TMPRSS2). Androgenetic alopecia (AGA) predisposes males to severe coronavirus disease 2019 (COVID-19) disease, while the use of 5-alpha-reductase inhibitors (5ARis) and androgen receptor antagonists reduce COVID-19 disease severity. In this study, we aimed to determine the potential benefit of dutasteride, a commonly used broad and potent 5ARi, as a treatment for COVID-19. Design, setting, and participants The study was conducted at outpatient clinics. Subjects presented to the clinics with a positive reverse transcription-polymerase chain reaction (RT-PCR) test taken within 24 hours of recruitment. All subjects presented with mild to moderate symptoms. Interventions Subjects were given either dutasteride 0.5 mg/day or placebo for 30 days or until full COVID-19 remission. All subjects received standard therapy with nitazoxanide 500 mg twice a day for six days and azithromycin 500 mg/day for five days. Main outcome(s) and measure(s) The main outcome(s) and measure(s) were as follows: time to remission, oxygen saturation (%), positivity rates of RT-PCR-SARS-CoV-2, and biochemical analysis [ultrasensitive C-reactive protein (usCRP), D-dimer, lactate, lactate dehydrogenase (LDH), erythrocyte sedimentation rate (ESR), ultrasensitive troponin, and ferritin]. Results Subjects taking dutasteride (n=43) demonstrated reduced fatigue, anosmia, and overall disease duration compared to subjects taking a placebo (n=44) (p<.0001 for all). Compared to the placebo group, on Day seven, subjects taking dutasteride had a higher virologic remission rate (64.3% versus 11.8%; p=.0094), higher clinical recovery rate (84.7% versus 57.5%; p=.03), higher mean [standard deviation: SD] oxygen saturation (97.0% [1.4%] versus 95.7% [2.0%]; p=.02), lower median [Interquartile range: IQR] usCRP (0.34 mg/L [0.23 mg/L-0.66 mg/L] versus 1.47 mg/L [0.70 mg/L-3.37 mg/L]; p<.0001), lower median [IQR] lactate (2.01 mmol/L [1.12 mmol/L-2.43 mmol/L] versus 2.66 mmol/L [2.05 mmol/L-3.55 mmol/L]; p=.0049), lower median [IQR] ESR (5.0 mm/1h [3.0 mm/1h-11.0 mm/1h] versus 14.0 mm/1h [7.25 mm/1h-18.5 mm/1h]; p=.0007), lower median [IQR] LDH (165 U/L [144 U/L-198 U/L] versus 210 U/L [179 U/L-249 U/L]; p=.0013) and lower median [IQR] troponin levels (0.005 ng/mL [0.003 ng/mL-0.009 ng/mL] versus 0.007 ng/mL [0.006 ng/mL-0.010 ng/mL]; p=.048). Conclusions and relevance The findings from this study suggest that in males with mild COVID-19 symptoms undergoing early therapy with nitazoxanide and azithromycin, treatment with dutasteride reduces viral shedding and inflammatory markers compared to males treated with a placebo.

Proxalutamide Significantly Accelerates Viral Clearance and Reduces Time to Clinical Remission in Patients with Mild to Moderate COVID-19: Results from a Randomized, Double-Blinded, Placebo-Controlled Trial.

Background The entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into type II pneumocytes is dependent on a modification of viral spike proteins by transmembrane protease serine 2 (TMPRSS2) expressed on the surface of human cells. TMPRSS2 is regulated by the androgen receptor, hence, SARS-CoV-2 infectivity is indirectly dependent on androgenic status and phenotype. Previously, we have reported that men affected by androgenetic alopecia (AGA) are overrepresented in severe coronavirus disease 2019 (COVID-19). Additionally, we have reported that men taking antiandrogenic drugs, e.g., 5-alpha-reductase inhibitors (5ARis), are less likely to have severe COVID-19. Here we aimed to test whether the androgen receptor antagonist, Proxalutamide, would be a beneficial treatment for subjects with SARS-CoV-2 infection. Methods Male and female subjects were recruited to a double-blinded, randomized, prospective, investigational study of Proxalutamide for the treatment of COVID-19. Mild to moderate, non-hospitalized subjects, who were confirmed positive for SARS-CoV-2, were treated with either Proxalutamide 200 mg/day or placebo. Endpoints for the study were remission time (days) and the percentage of subjects confirmed negative for SARS-CoV-2 on Day 7 after treatment. A negative SARS-CoV-2 test was defined by concentration-time (Ct)>40 determined by real-time reverse transcription-polymerase chain reaction (rtPCR). Results Two-hundred thirty-six (2360 subjects were included in the study (108 female, 128 male); 171 were randomized to the Proxalutamide arm and 65 were in the placebo group. On Day 7, SARS-CoV-2 became non-detectable with rtPCR (cT>40) in 82% of the subjects in the Proxalutamide group versus 31% in the placebo group (p < 0.001). The average clinical remission time for patients treated with Proxalutamide was 4.2 ±5.4 days versus 21.8 ±13.0 days in the placebo arm (p < 0.001). Conclusion Proxalutamide significantly accelerated viral clearance on Day 7 in mild to moderate COVID-19 patients versus placebo. Further, the time to clinical remission was significantly reduced in patients treated with Proxalutamide versus placebo.

Novel Markers of Recovery From Overtraining Syndrome: The EROS-LONGITUDINAL Study.

PURPOSES: Overtraining syndrome (OTS) is an unexplained underperformance syndrome triggered by excessive training, insufficient caloric intake, inadequate sleep, and excessive cognitive and social demands. Investigation of the recovery process from OTS has not been reported to date. The objective was to unveil novel markers and biochemical and clinical behaviors during the restoration process of OTS. METHODS: This was a 12-week interventional protocol in 12 athletes affected by OTS, including increase of caloric intake, transitory interruption of training, improvement of sleep quality, and management of stress, followed by the assessment of 50 parameters including basal and hormonal responses to an insulin tolerance test and nonhormonal biochemical markers, and body metabolism and composition. RESULTS: Early cortisol (P = .023), late ACTH (adrenocorticotrophic hormone) (P = .024), and early and late growth hormone (P = .005 and P = .038, respectively) responses, basal testosterone (P = .038), testosterone:estradiol ratio (P = .0005), insulinlike growth factor 1 (P = .004), cortisol awakening response (P = .001), and free thyronine (P = .069) increased, while basal estradiol (P = .033), nocturnal urinary catecholamines (P = .038), and creatine kinase (P = .071) reduced. Conversely, markers of body metabolism and composition had slight nonsignificant improvements. CONCLUSION: After a 12-week intervention, athletes affected by actual OTS disclosed a mix of non-, partial, and full recovery processes, demonstrating that remission of OTS is as complex as its occurrence.

The AndroCoV Clinical Scoring for COVID-19 Diagnosis: A Prompt, Feasible, Costless, and Highly Sensitive Diagnostic Tool for COVID-19 Based on a 1757-Patient Cohort.

Introduction A major barrier for successful therapeutic approaches for COVID-19 is the inability to diagnose COVID-19 during the viral replication stage, when drugs with potential antiviral activity could demonstrate efficacy and preclude progression to more severe stages. Reasons that hamper an earlier diagnosis of COVID-19 include the unspecific and mild symptoms during the first stage, the delay in the diagnosis and specific management caused by the requirement of a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) for SARS-CoV-2 for the diagnosis of COVID-19, and the insufficient sensitivity of the RT-PCR-SARS-CoV-2, converse to what is recommended for a screening test during an outbreak. More sensitive and earlier diagnostic tools for COVID-19 should be unraveled as a key strategy for a breakthrough change in the disease course and response to specific therapies, particularly those that target the blockage of viral shedding. We aimed to create an accurate, sensitive, easy-to-perform, and intuitive clinical scoring for the diagnosis of COVID-19 without the need for an RT-PCR-SARS-CoV-2 (termed The AndroCoV Clinical Scoring for COVID-19 Diagnosis), resulting from a 1,757 population cohort, to eventually encourage the management of patients with a high pre-clinical likelihood of presenting COVID-19, independent of an RT-PCR-SARS-COV-2 test, to avoid delays and loss of appropriate timing for potential therapies. Methods This is a post-hoc analysis of clinical data prospectively collected of the Pre-AndroCoV and AndroCov Trials, which resulted in scorings for the clinical diagnosis of COVID-19 based on the likelihood of presenting with actual COVID-19 according to the number of symptoms, presence of anosmia, and known positive household contact. Sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and accuracy were calculated for subjects screened in two different periods and both periods together, for females, males, and both, in a total of nine different scenarios, according to combinations of one, two, or three or more symptoms or the presence of anosmia in subjects without known positive household contacts, and no symptoms, one, two, or three or more symptoms, or presence of anosmia or ageusia in subjects with known positive household contacts. Scorings that yielded the highest pre-test probability, sensitivity, and accuracy were selected. Results Of the 1,757 patients screened, 1,284 were diagnosed with COVID-19. The scoring that required: (1) two or more symptoms, or anosmia or ageusia alone, for subjects without known contact; or (2) one or more symptoms, including anosmia or ageusia alone, when with known positive contacts presented the highest accuracy (80.4%) among all combinations attempted, and higher sensitivity (85.7%) than RT-PCR-SARS-CoV-2 commercially available kit tests. Conclusion The AndroCoV clinical scoring for COVID-19 diagnosis was demonstrated to be a feasible, easy, costless, and sensitive diagnostic tool for the clinical diagnosis of COVID-19. Because the clinical diagnosis of COVID-19 avoids delays in specific treatments, particularly for high-risk populations, prevents false-negative diagnosis, and reduces diagnostic costs, this diagnostic tool should be considered as an option for COVID-19 diagnosis, at least while SARS-CoV-2 is the prevailing circulating virus and vaccination rate is below the required for herd immunity.

Final Results of a Randomized, Placebo-Controlled, Two-Arm, Parallel Clinical Trial of Proxalutamide for Hospitalized COVID-19 Patients: A Multiregional, Joint Analysis of the Proxa-Rescue AndroCoV Trial.

Background The role of androgens on COVID-19 is well established. Proxalutamide is a second-generation, non-steroidal antiandrogen (NSAA) with the highest antiandrogen potency among NSAAs and concurrent regulation of angiotensin-converting enzyme 2 (ACE2) expression and inflammatory response. Proxalutamide has been demonstrated to be effective to prevent hospitalizations in early COVID-19 in randomized clinical trials (RCTs). Conversely, in hospitalized COVID-19 patients, preliminary results from two different arms of an RCT (The Proxa-Rescue AndroCoV Trial) also demonstrated a reduction in all-cause mortality. This study aims to report the final, joint results of the two arms (North arm and South arm) of the Proxa-Rescue AndroCoV trial of the two arms (North and South arms) combined, and to evaluate whether COVID-19 response to proxalutamide was consistent across different regions (Northern Brazil and Southern Brazil). Materials and methods Upon randomization, hospitalized COVID-19 patients received either proxalutamide 300mg/day or placebo for 14 days, in addition to usual care, in a proxalutamide:placebo ratio of 1:1 in the North arm and 4:1 in the South arm (ratio was modified due to preliminary report of high drug efficacy). Datasets of the South and North arms were combined, and statistical analysis was performed for the overall study population. Proxalutamide was compared to placebo group for 14-day and 28-day recovery (discharge alive from the hospital) and mortality rates, and overall and post-randomization hospitalization stay. Results of proxalutamide and placebo groups were also compared between the North and South arms. Analysis was also performed stratified by sex and baseline WHO COVID Ordinary Score. Results A total of 778 subjects were included (645 from the North, 317 from the proxalutamide group and 328 from the placebo group; 133 from the South arm, 106 from the proxalutamide group and 27 from the placebo group). Recovery rate was 121% higher in proxalutamide than placebo group at day 14 [81.1% vs 36.6%; Recovery ratio (RecR) 2.21; 95% confidence interval (95% CI), 1.92-2.56; p<0.0001], and 81% higher at day 28 (98.1% vs 47.6%; RecR, 1.81; 95% CI, 1.61-2.03; p<0.0001). All-cause mortality rate was 80% lower in proxalutamide than placebo group at Day 14 [8.0% vs 39.2%; Risk ratio (RR), 0.20; 95% CI, 0.14-0.29; p<0.0001], and 78% lower at Day 28 (10.6% vs 48.2%; RR, 0.22; 95% CI 0.16-0.30). Post-randomization time-to-discharge was shorter in proxalutamide [median, 5 days; interquartile range (IQR), 3-8] than placebo group (median, 9 days; IQR, 6-14) (p<0.0001). Results were statistically similar between North and South arms for all measured outcomes. Males and females presented similar results in all outcomes. Patients that did not require oxygen use (scores 3 and 4) did not present statistically significant improvement in recovery and mortality rates, whereas scores 5 and 6 presented significant improvements in all outcomes (p<0.0001 for all). Conclusion Proxalutamide increased recovery rate, reduced mortality rate and shortened hospital stay in hospitalized COVID-19 patients. Results were similar between the two different arms, providing further consistency for the efficacy of proxalutamide when used in late-stage COVID-19.

Repurposing existing drugs for COVID-19: an endocrinology perspective.

BACKGROUND: Coronavirus Disease 2019 (COVID-19) is a multi-systemic infection caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), that has become a pandemic. Although its prevailing symptoms include anosmia, ageusia, dry couch, fever, shortness of brief, arthralgia, myalgia, and fatigue, regional and methodological assessments vary, leading to heterogeneous clinical descriptions of COVID-19. Aging, uncontrolled diabetes, hypertension, obesity, and exposure to androgens have been correlated with worse prognosis in COVID-19. Abnormalities in the renin-angiotensin-aldosterone system (RAAS), angiotensin-converting enzyme-2 (ACE2) and the androgen-driven transmembrane serine protease 2 (TMPRSS2) have been elicited as key modulators of SARS-CoV-2. MAIN TEXT: While safe and effective therapies for COVID-19 lack, the current moment of pandemic urges for therapeutic options. Existing drugs should be preferred over novel ones for clinical testing due to four inherent characteristics: 1. Well-established long-term safety profile, known risks and contraindications; 2. More accurate predictions of clinical effects; 3. Familiarity of clinical management; and 4. Affordable costs for public health systems. In the context of the key modulators of SARS-CoV-2 infectivity, endocrine targets have become central as candidates for COVID-19. The only endocrine or endocrine-related drug class with already existing emerging evidence for COVID-19 is the glucocorticoids, particularly for the use of dexamethasone for severely affected patients. Other drugs that are more likely to present clinical effects despite the lack of specific evidence for COVID-19 include anti-androgens (spironolactone, eplerenone, finasteride and dutasteride), statins, N-acetyl cysteine (NAC), ACE inhibitors (ACEi), angiotensin receptor blockers (ARB), and direct TMPRSS-2 inhibitors (nafamostat and camostat). Several other candidates show less consistent plausibility. In common, except for dexamethasone, all candidates have no evidence for COVID-19, and clinical trials are needed. CONCLUSION: While dexamethasone may reduce mortality in severely ill patients with COVID-19, in the absence of evidence of any specific drug for mild-to-moderate COVID-19, researchers should consider testing existing drugs due to their favorable safety, familiarity, and cost profile. However, except for dexamethasone in severe COVID-19, drug treatments for COVID-19 patients must be restricted to clinical research studies until efficacy has been extensively proven, with favorable outcomes in terms of reduction in hospitalization, mechanical ventilation, and death.

Spironolactone may provide protection from SARS-CoV-2: Targeting androgens, angiotensin converting enzyme 2 (ACE2), and renin-angiotensin-aldosterone system (RAAS).

In coronavirus disease-19 (COVID-19), four major factors have been correlated with worse prognosis: aging, hypertension, obesity, and exposure to androgen hormones. Angiotensin-converting enzyme-2 (ACE2) receptor, regulation of the renin-angiotensin-aldosterone system (RAAS), and transmembrane serine protease 2 (TMPRSS2) action are critical for the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) cell entry and infectivity. ACE2 expression and RAAS are abnormal in hypertension and obesity, while TMPRSS2 is overexpressed when exposed to androgens, which may justify why these factors are overrepresented in COVID-19. Among therapeutic targets for SARS-CoV-2, we hypothesized that spironolactone, a long used and safe mineralocorticoid and androgen receptors antagonist, with effective anti-hypertensive, cardioprotective, nephroprotective, and anti-androgenic properties may offer pleiotropic actions in different sites to protect from COVID-19. Current data shows that spironolactone may concurrently mitigate abnormal ACE2 expression, correct the balances membrane-attached and free circulating ACE2 and between angiotensin II and Angiotensin-(1-7) (Ang-(1-7)), suppress androgen-mediated TMPRSS2 activity, and inhibit obesity-related RAAS dysfunctions, with consequent decrease of viral priming. Hence, spironolactone may provide protection from SARS-CoV-2, and has sufficient plausibility to be clinically tested, particularly in the early stages of COVID-19.

Eating, Sleep, and Social Patterns as Independent Predictors of Clinical, Metabolic, and Biochemical Behaviors Among Elite Male Athletes: The EROS-PREDICTORS Study.

Objectives: Physiological hormonal adaptions in athletes and pathological changes that occur in overtraining syndrome among athletes are unclear. The Endocrine and Metabolic Responses on Overtraining Syndrome (EROS) study evaluated 117 markers and unveiled novel hormonal and metabolic beneficial adaptive processes in athletes. The objective of the present study was to uncover which modifiable factors predict the behaviors of clinical and biochemical parameters and to understand their mechanisms and outcomes using the parameters evaluated in the EROS study. Methods: We used multivariate linear regression with 39 participants to analyze five independent variables-the modifiable parameters (caloric, carbohydrate, and protein intake, and sleep quality and duration of concurrent cognitive activity) on 37 dependent variables-that were elected among the parameters evaluated in the EROS study. Results: Carbohydrate intake predicted quick hormonal responses to stress and improved explosive responses during exercise. Protein intake predicted improved body composition and metabolism and caloric intake, regardless of the proportion of macronutrients, predicted muscle recovery, and alertness in the morning. Sleep quality predicted improved mood and excessive concurrent cognitive effort in athletes under intense training predicted impaired metabolism and libido. Conclusions: The results support the premise that eating, sleep, and social patterns modulate metabolic and hormonal function, clinical behaviors, and performance status of male athletes, and should be monitored continuously and actively to avoid dysfunctions.

Enhancement of hypothalamic-pituitary activity in male athletes: evidence of a novel hormonal mechanism of physical conditioning.

BACKGROUND: Exercise is known to induce multiple beneficial conditioning processes. Conversely, although exercise may generate several hormonal effects, an intrinsic hormonal conditioning process has not been reported. In the Endocrine and Metabolic Responses on Overtraining Syndrome (EROS) study, we observed inherent and independent conditioning processes of the hypothalamic-pituitary axes in athletes. Our objective is to describe the theory of the novel hormonal conditioning mechanism using the findings from the EROS study. METHODS: In this cross-sectional study, we selected 25 healthy athletes (ATL) and 12 non-physically active healthy controls (NPAC), 18-50 years old, males, with BMI 20-30 kg/m2, with similar baseline characteristics, who underwent gold-standard exercise-independent tests: cosyntropin stimulation test (CST) and insulin tolerance test (ITT), to evaluate cortisol response to CST, and ACTH, cortisol, GH, and prolactin responses to an ITT. RESULTS: Responses to ITT were significantly earlier and higher in ATL than NPAC for cortisol [Mean ± SD: 21.7 ± 3.1 vs 16.9 ± 4.1 µg/dL; p < 0.001], GH [Median (95% CI): 12.73 (1.1-38.1) vs 4.80 (0.33-27.36) µg/L; p = 0.015], and prolactin [24.3 (10.5-67.45) vs 10.50 (6.21-43.44) ng/mL; p = 0.002]. Cortisol response to CST was similar between ATL and NPAC. During ITT, cortisol, GH, and ACTH mean increase in ATL were 52.2, 265.2, and 18.6% higher than NPAC, respectively. Prolactin response was absent in NPAC, while present in ATL. CONCLUSIONS: We found sufficient evidence to propose the existence of a diffuse enhancement of the hypothalamic-pituitary activity in athletes, not restricted to any axis, showing an intrinsic and independent process of "hormonal conditioning" in athletes, similar to those observed in the cardiovascular and neuromuscular systems. This novel conditioning process may be the missing link for understanding the improved responses observed in athletes to harmful situations, traumas, infections, inflammations, and psychiatric conditions.

Novel causes and consequences of overtraining syndrome: the EROS-DISRUPTORS study.

BACKGROUND: Hormonal physiology in athletes, dysfunctional paths leading to overtraining syndrome (OTS), and clinical and biochemical behaviors that are independently modified by the presence of OTS remain unclear. Although multiple markers of OTS have recently been identified, the independent influence of OTS on hormones and metabolism have not been assessed. Hence, the objective of the present study was to uncover the previously unrecognized independent predictors of OTS and understand how OTS independently modifies the behaviors of clinical and biochemical parameters. METHODS: In a total of 39 athletes (OTS-affected athletes (OTS) = 14 and healthy athletes (ATL) = 25), we performed two clusters of statistical analyses using the full data of the Endocrine and Metabolic Responses on Overtraining Syndrome (EROS) study, in a total of 117 markers. We first used logistic regression to analyze five modifiable parameters (carbohydrate, protein, and overall caloric intake, sleep quality, and concurrent cognitive effort) as potential additional independent risk factors for OTS, and OTS as the outcome. We then used multivariate linear regression to analyze OTS as the independent variable and 38 dependent variables. Training patterns were found to be similar between OTS and ATL, and therefore excessive training was not a risk, and consequently not a predictor, for OTS. RESULTS: Each of the three dietary patterns (daily carbohydrate, daily protein, and daily overall calorie intake) were found to be the independent triggers of OTS, while sleeping, social, and training characteristics depended on other factors to induce OTS. Once triggered, OTS independently induced multiple changes, including reductions of cortisol, late growth hormone and adrenocorticotropic hormone responses to stimulations, testosterone-to-estradiol ratio, neutrophils, neutrophil-to-lymphocyte ratio, vigor levels, hydration status, and muscle mass, while increase of tension levels and visceral fat. CONCLUSIONS: OTS can be independently triggered by eating patterns, regardless of training patterns, while the occurrence of OTS reduced late hormonal responses and the testosterone-to-estradiol ratio, worsened mood, and affected the immunology panel. These novel findings may explain underperformance, which is the key characteristic of OTS.

Basal Hormones and Biochemical Markers as Predictors of Overtraining Syndrome in Male Athletes: The EROS-BASAL Study.

CONTEXT: Overtraining syndrome (OTS) and related conditions cause decreased training performance and fatigue through an imbalance among training volume, nutrition, and recovery time. No definitive biochemical markers of OTS currently exist. OBJECTIVE: To compare muscular, hormonal, and inflammatory parameters among OTS-affected athletes, healthy athletes, and sedentary controls. DESIGN: Cross-sectional study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: Fifty-one men aged 18 to 50 years (14 OTS-affected athletes [OTS group], 25 healthy athletes [ATL group], and 12 healthy sedentary participants [NCS group]), with a body mass index of 20 to 30.0 kg/m2 (sedentary) or 20 to 33.0 kg/m2 (athletes), recruited through social media. All 39 athletes performed both endurance and resistance sports. MAIN OUTCOME MEASURE(S): We measured total testosterone, estradiol, insulin-like growth factor 1, thyroid-stimulating hormone, free thyronine, total and fractioned catecholamines and metanephrines, lactate, ferritin, creatinine, creatine kinase, erythrocyte sedimentation rate, C-reactive protein, lipid profile, hemogram, and testosterone : estradiol, testosterone : cortisol, neutrophil : lymphocyte, platelet: lymphocyte, and catecholamine : metanephrine ratios. Each parameter was statistically analyzed through 3-group comparisons, and whenever P < .05, pairwise comparisons were performed (OTS × ATL, OTS × NCS, and ATL × NCS). RESULTS: Neutrophils and testosterone were lower in the OTS group than in the ATL group but similar between the OTS and NCS groups. Creatine kinase, lactate, estradiol, total catecholamines, and dopamine were higher in the OTS group than in the ATL and NCS groups, whereas the testosterone : estradiol ratio was lower, even after adjusting for all variables. Lymphocytes were lower in the ATL group than in the OTS and NCS groups. The ATL and OTS groups trained with the same intensity, frequency, and types of exercise. CONCLUSIONS: At least in males, OTS was typified by increased estradiol, decreased testosterone, overreaction of muscle tissue to physical exertion, and immune system changes, with deconditioning effects of the adaptive changes observed in healthy athletes.