Exploring Prehospital Data for Pandemic Preparedness: A Western Brazilian Amazon Case Study on COVID-19.

BACKGROUND: The timely management of rapidly evolving epidemiological scenarios caused by disease outbreaks is crucial to prevent devastating consequences. However, delayed laboratory diagnostics can hamper swift health policy and epidemic response, especially in remote regions such as the western Brazilian Amazon. The aim of the article is to analyze the impact of the COVID-19 pandemic on the volume and characteristics of emergency medical services (EMS) in Manaus, focusing on how the pandemic affected sensitive indicators such as response time and the use of advanced life support ambulances. Additionally, the study seeks to understand how changes in prehospital EMS patterns, triggered by the pandemic, could be utilized as health surveillance tools, enabling a more rapid response in epidemic scenarios. METHODS: This retrospective, descriptive study included data from the SAMU (Serviço de Atendimento Móvel de Urgência) medical records between January and June 2020. RESULTS: A total of 45,581 calls resulted in mobile units being dispatched during this period. These patients were predominantly male (28,227, 61.9%), with a median age of 47 years (IQR 30-67). The median response time significantly increased during the pandemic, reaching a median of 45.9 min (IQR 30.6-67.7) (p < 0.001). EMS calls were reduced for trauma patients and increased for other medical emergencies, especially respiratory conditions, concomitantly to an escalation in the number of deaths caused by SARS and COVID-19 (p < 0.001). The employment of advanced life support ambulances was higher during the pandemic phase (p = 0.0007). CONCLUSION: The COVID-19 pandemic resulted in a temporary disorder in the volume and reason for EMS calls in Manaus. Consequently, sensitive indicators like the response time and the employment of advanced life support ambulances were negatively affected. Sudden prehospital EMS pattern changes could play an important role in health surveillance systems, allowing for earlier establishment of countermeasures in epidemics. The impact of the COVID-19 pandemic on prehospital EMS and its role in health surveillance should be further explored.

Unveiling the Impact of Human Herpesviruses-Associated on CNS Infections: An Observational Study.

Human Herpesviruses (HHVs) play a significant role in neurological diseases such as encephalitis and meningitis, adding significant morbidity. This study aims to retrospectively analyze the effect of HHVs on patients with neurological symptoms, focusing on the Herpesviridae family's contributions to central nervous system (CNS) infections. METHODS: This retrospective cohort study included 895 patients suspected of viral CNS infections, utilizing molecular diagnosis via qPCR to identify HHVs in cerebrospinal fluid (CSF) samples. This was conducted at a reference tertiary care hospital for infectious diseases in the western Brazilian Amazon from January 2015 to December 2022, focusing on the Herpesviridae family's clinical repercussions and of Cytomegalovirus in CNS infections. RESULTS: The findings revealed that 7.5% of the analyzed samples tested positive for HHVs, with Human Cytomegalovirus (HCMV) and Epstein-Barr Virus (EBV) being the most prevalent. A significant association was found between HHVs and neurological diseases such as encephalitis and meningitis, especially among people living with HIV/AIDS (PLWHA), highlighting the opportunistic nature of these viruses. The study underscores the critical role of CSF analysis in diagnosing CNS infections and the complexity of managing these infections in HIV patients due to their immunocompromised status. CONCLUSIONS: The results emphasize the need for comprehensive diagnostic approaches and tailored treatment strategies for CNS infections in immunocompromised individuals. The study calls for ongoing research and advancements in clinical practice to improve patient outcomes facing CNS infections, particularly those caused by HHVs.

Assistance time and peripheral oxygen saturation in prehospital emergency data as predictors of COVID19 hospital outcomes.

To verify if data obtained in the prehospital evaluation of patients with severe acute respiratory syndrome (SARS) during the initial response to the COVID-19 pandemic is associated with clinical outcomes: mechanical ventilation, hospital discharge, and death. This is a retrospective analysis involving secondary data from the Emergency Medical Service (EMS) records and the Health Surveillance Information System of patients assisted by the EMS in Manaus, from January to June 2020, the period of the first peak of COVID-19 cases. The combination of the two databases yielded a total of 1.190 patients, who received a first EMS response and were later admitted to hospital with SARS and had data on clinical outcomes of interest available. Patients were predominantly male (754, 63.4%), with a median age of 66 (IQR: 54.0-78.0) years. SARS illness before medical assistance was associated to need for invasive mechanical ventilation (IMV, p < 0.001). Lower pre-hospital SpO2 was associated to death (p = 0.025). Death was more common among patients with respiratory support needs, especially in the invasive ventilation group (262/287; 91.3%) (p < 0.001). In addition, IMV was more common among elderly individuals (p < 0.001). Patients admitted to ICU had a greater chance of dying when compared to non-ICU admitted patients (p < 0.001), and closely related to IMV (p < 0.001). Patients in ICU were also older (p = 0.003) and had longer hospital stay (p < 0.001). Mortality was associated with mechanical ventilation (p < 0.001), ICU admission (p < 0.001), and older age (p < 0.001). Patients who died had a shorter length of both ICU and total hospital stay (p < 0.001). Prehospital EMS may provide feasible and early recognition of critical patients with SARS in strained healthcare systems, such as in low-resource settings and pandemics.

A spatially resolved single-cell lung atlas integrated with clinical and blood signatures distinguishes COVID-19 disease trajectories.

COVID-19 is characterized by a broad range of symptoms and disease trajectories. Understanding the correlation between clinical biomarkers and lung pathology during acute COVID-19 is necessary to understand its diverse pathogenesis and inform more effective treatments. Here, we present an integrated analysis of longitudinal clinical parameters, peripheral blood markers, and lung pathology in 142 Brazilian patients hospitalized with COVID-19. We identified core clinical and peripheral blood signatures differentiating disease progression between patients who recovered from severe disease compared with those who succumbed to the disease. Signatures were heterogeneous among fatal cases yet clustered into two patient groups: "early death" (<15 days until death) and "late death" (>15 days). Progression to early death was characterized systemically and in lung histopathological samples by rapid endothelial and myeloid activation and the presence of thrombi associated with SARS-CoV-2+ macrophages. In contrast, progression to late death was associated with fibrosis, apoptosis, and SARS-CoV-2+ epithelial cells in postmortem lung tissue. In late death cases, cytotoxicity, interferon, and T helper 17 (TH17) signatures were only detectable in the peripheral blood after 2 weeks of hospitalization. Progression to recovery was associated with higher lymphocyte counts, TH2 responses, and anti-inflammatory-mediated responses. By integrating antemortem longitudinal blood signatures and spatial single-cell lung signatures from postmortem lung samples, we defined clinical parameters that could be used to help predict COVID-19 outcomes.

Antecedent and persistent symptoms in COVID-19 and other respiratory illnesses: Insights from prospectively collected data in the BRACE trial.

BACKGROUND: Some individuals have a persistence of symptoms following both COVID-19 (post-acute COVID-19 syndrome; PACS) and other viral infections. This study used prospectively collected data from an international trial to compare symptoms following COVID-19 and non-COVID-19 respiratory illness, to identify factors associated with the risk of PACS, and to explore symptom patterns before and after COVID-19 and non-COVID-19 respiratory illnesses. METHODS: Data from a multicentre randomised controlled trial (BRACE trial) involving healthcare workers across four countries were analysed. Symptom data were prospectively collected over 12 months, allowing detailed characterisation of symptom patterns. Participants with COVID-19 and non-COVID-19 respiratory illness episodes were compared, focussing on symptom severity, duration (including PACS using NICE and WHO definitions), and pre-existing symptoms. FINDINGS: Compared to those with a non-COVID-19 illness, participants with COVID-19 had significantly more severe illness (OR 7·4, 95%CI 5·6-9·7). Symptom duration meeting PACS definitions occurred in a higher proportion of COVID-19 cases than non-COVID-19 respiratory controls using both the NICE definition (2·5% vs 0·5%, OR 6·6, 95%CI 2·4-18·3) and the WHO definition (8·8% vs 3·7%, OR 2·5, 95%CI 1·4-4·3). When considering only participants with COVID-19, age 40-59 years (aOR 2·8, 95%CI 1·3-6·2), chronic respiratory disease (aOR 5·5, 95%CI 1·3-23·1), and pre-existing symptoms (aOR 3·0, 95%CI 1·4-6·3) were associated with an increased risk of developing PACS. Symptoms associated with PACS were also reported by participants in the months preceding their COVID-19 or non-COVID-19 respiratory illnesses (32% fatigue and muscle ache, 11% intermittent cough and shortness of breath). INTERPRETATION: Healthcare workers with COVID-19 were more likely to have severe and longer-lasting symptoms than those with a non-COVID-19 respiratory illness, with a higher proportion meeting the WHO or NICE definitions of PACS. Age, chronic respiratory disease, and pre-existing symptoms increased the risk of developing PACS following COVID-19.

BCG vaccination of healthcare workers for protection against COVID-19: 12-month outcomes from an international randomised controlled trial.

OBJECTIVES: Bacille Calmette-Guérin (BCG) vaccine has immunomodulatory effects that may provide protection against unrelated infectious diseases. We aimed to determine whether BCG vaccination protects adults against COVID-19. DESIGN: Phase III double-blind randomised controlled trial. SETTING: Healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom during the COVID-19 pandemic. PARTICIPANTS: 3988 healthcare workers with no prior COVID-19 and no contraindication to BCG. INTERVENTION: Randomised 1:1 using a web-based procedure to receive a single 0.1 mL intradermal dose of BCG-Denmark (BCG group, n = 1999) or saline (placebo group, n = 1989). MAIN OUTCOME MEASURES: Difference in incidence of (i) symptomatic and (ii) severe COVID-19 during the 12 months following randomisation in the modified intention to treat (mITT) population (confirmed SARS-CoV-2 naïve at inclusion). RESULTS: Of the 3988 participants randomised, 3386 had a negative baseline SARS-CoV-2 test and were included in the mITT population. The 12-month adjusted estimated risk of symptomatic COVID-19 was higher in the BCG group (22.6%; 95% confidence interval [CI] 20.6 to 24.5%) compared with the placebo group (19.6%; 95% CI 17.6 to 21.5%); adjusted difference +3.0% points (95% CI 0.2 to 5.8%; p = 0.04). The 12-month adjusted estimated risk of severe COVID-19 (mainly comprising those reporting being unable to work for ≥3 consecutive days) was 11.0% in the BCG group (95% CI 9.5 to 12.4%) compared with 9.6% in the placebo group (95% CI 8.3 to 11.1%); adjusted difference +1.3% points (95% CI -0.7 to 3.3%, p = 0.2). Breakthrough COVID-19 (post COVID-19 vaccination) and asymptomatic SARS-CoV-2 infections were similar in the two groups. There were 18 hospitalisations due to COVID-19 (11 in BCG group, 7 in placebo group; adjusted hazard ratio 1.56, 95% CI 0.60 to 4.02, p = 0.4) and two deaths due to COVID-19, both in the placebo group. CONCLUSIONS: Compared to placebo, vaccination with BCG-Denmark increased the risk of symptomatic COVID-19 over 12 months among healthcare workers and did not decrease the risk of severe COVID-19 or post-vaccination breakthrough COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov NCT04327206.

Amazon tropical fishes of commercial interest show human-cell contamination but no SARS-CoV-2 in a real-life scenario.

BACKGROUND: Amazonas was one of the most impacted Brazilian states by the COVID-19 pandemic. Mortality rates were high, and the health systems collapsed. It is important to identify possible intermediate reservoirs to avoid animal-to-human contamination. Several tropical fish are of commercial interest and are sold in large open-air markets in the region, representing a large economic and dietary importance. OBJECTIVES: This study aimed to verify if fish species of commercial importance, aerosols, and fish wastewater in local open-air markets, at a major capital city in the western Brazilian Amazon, are contaminated by SARS-CoV-2. METHODS: 488 fish, 50 aerosol, and 45 wastewater samples were analyzed for the presence of SARS-CoV-2. The samples were subjected to extraction using the BIOGENE Viral DNA/RNA Extraction kit, and the molecular diagnosis was tested for SARS-CoV-2 using the Bio-Manguinhos SARS-CoV-2 (EDx) Molecular Kit. RESULTS: It was not possible to detect the virus (Ct≤40, for Gene E) in these samples, however, in 181 samples of fish it was possible to detect the human RP gene (Ct≤35, for the RP Gene), indicating human contact. There was a high number of COVID-19 diagnoses in all city districts in which the samples were collected, showing that SARS-CoV-2 was circulating. CONCLUSION: This study indicates that fish of local commercial importance do not carry SARS-CoV-2 viral particles, despite circulation of SARS-CoV-2, and are not an important source of animal-to-human contamination. Despite these results, the human RP gene was found detectable in fish, air, and fish wastewater, showing that such places may carry human pathogens.

Long-term disability after cerebral ischemic stroke following a Bothrops atrox snakebite in the Brazilian Amazon.

Bothrops atrox envenomations in the Brazilian Amazon are responsible for a number of local and systemic effects. Among these, stroke presents the worst prognosis for the patient since it may evolve into disabilities and/or premature death. This complication is caused by coagulation disorders and generates hemorrhagic and thrombotic conditions. This study presents a case report of a 54-year-old female patient who presented extensive cerebral ischemia after a B. atrox envenomation that occurred in the state of Amazonas, Brazil. The patient was hospitalized for 102 days, which included a stay in the intensive care unit. Clinical and laboratory findings indicated a thrombogenic coagulopathy. On discharge, the patient had no verbal response, partial motor response, and right hemiplegia. The assessment carried out four years after discharge evidenced incapacitation, global aphasia and bilateral lower and upper limbs showed hypotrophy with a global decrease in strength. Ischemic stroke is a possible complication of B. atrox snakebites even after antivenom treatment, with the potential to cause debilitating long-term consequences.

Prone positioning in awake patients without ventilatory support does not alter major clinical outcomes in severe COVID-19: results from a retrospective observational cohort study, systematic review and meta-analysis.

OBJECTIVES: During the Coronavirus disease (COVID-19) pandemic, clinicians recommended awake-prone positioning (APP) to avoid the worst outcomes. The objectives of this study were to investigate if APP reduces intubation, death rates, and hospital length of stay (HLOS) in acute COVID-19. METHODS: We performed a retrospective cohort with non-mechanically ventilated patients hospitalized in a reference center in Manaus, Brazil, 2020. Participants were stratified into APP and awake-not-prone positioning (ANPP) groups. Also, we conducted a systematic review and performed a meta-analysis to understand if this intervention had different outcomes in resource-limited settings (PROSPERO CRD42023422452). RESULTS: A total of 115 participants were allocated into the groups. There was no statistical difference between both groups regarding time to intubation (HR: 0.861; 95CI: 0.474-1.1562; p=0.622) and time to death (HR: 1.666; 95CI: 0.939-2.951; p=0.081). APP was not significantly associated with reduced HLOS. A total of 86 articles were included in the systematic review, of which 76 (88,3%) show similar findings after APP. Also, low/middle, and high-income countries were similar regarding such outcomes. CONCLUSION: APP in COVID-19 does not present clinical improvement that affects mortality, intubation rate and HLOS. The lack of a prone position protocol, obtained through a controlled study, is necessary. After 3 years, APP benefits are still inconclusive.

Pulmonary Rehabilitation Associated with Noninvasive Ventilation on Physical Capacity and Quality of Life in Post-COVID-19: A Randomized Controlled Double-Blinded Clinical Trial Protocol.

Background: The coronavirus disease-2019 (COVID-19) pulmonary rehabilitation (PR) seems to be a better choice to improve physical and functional capacity after acute infection. However, there is a lack of evidence regarding the effects of different strategies to optimize post-acute phase rehabilitation and reduce long COVID-19 physical deteriorations. Objective: To compare the use of a noninvasive ventilation (NIV) plus aerobic exercise strategy during PR program with to a standard PR (without NIV) on physical capacity and quality of life outcomes in post-COVID-19. Methods: Double-blinded randomized controlled clinical trial. A total of 100 individuals discharged from hospital in a post-acute phase of severe COVID-19 will be randomized into two groups: PR + NIV (Group 1) and PR (Group 2). Inclusion criteria include participants who present symptomatic dyspnea II and III by the modified Medical Research Council, aged 18 years or older. Both groups will receive aerobic and resistance exercise, and inspiratory muscle training. However, group 1 will perform aerobic training with bilevel NIV. Cardiopulmonary exercise test will assess the O2 peak uptake, 6-minute walk test will assess the walking distance and short-form 36 will assess the quality of life before and after 8 weeks (after 24 PR sessions). Moreover, patients will be contacted by telephone every 3 months for one year to record possible adverse events, hospitalizations, and death. All data will be registered in RedCap, and analyses will be performed in the STATA v13 software. Clinical Trial Registration: RBR-3t9pkzt.

Factors influencing adverse events following COVID-19 vaccination.

Various novel platform technologies have been used for the development of COVID-19 vaccines. In this nested cohort study among healthcare workers in Australia and Brazil who received three different COVID-19-specific vaccines, we (a) evaluated the incidence of adverse events following immunization (AEFI); (b) compared AEFI by vaccine type, dose and country; (c) identified factors influencing the incidence of AEFI; and (d) assessed the association between reactogenicity and vaccine anti-spike IgG antibody responses. Of 1302 participants who received homologous 2-dose regimens of ChAdOx1-S (Oxford-AstraZeneca), BNT162b2 (Pfizer-BioNTech) or CoronaVac (Sinovac), 1219 (94%) completed vaccine reaction questionnaires. Following the first vaccine dose, the incidence of any systemic reaction was higher in ChAdOx1-S recipients (374/806, 46%) compared with BNT162b2 (55/151, 36%; p = 0.02) or CoronaVac (26/262, 10%; p < 0.001) recipients. After the second vaccine dose, the incidence of any systemic reaction was higher in BNT162b2 recipients (66/151, 44%) compared with ChAdOx1-S (164/806, 20%; p < 0.001) or CoronaVac (23/262, 9%; p < 0.001) recipients. AEFI risk was higher in younger participants, females, participants in Australia, and varied by vaccine type and dose. Prior COVID-19 did not impact the risk of AEFI. Participants in Australia compared with Brazil reported a higher incidence of any local reaction (170/231, 74% vs 222/726, 31%, p < 0.001) and any systemic reaction (171/231, 74% vs 328/726, 45%, p < 0.001), regardless of vaccine type. Following a primary course of ChAdOx1-S or CoronaVac vaccination, participants who did not report AEFI seroconverted at a similar rate to those who reported local or systemic reactions. In conclusion, we found that the incidence of AEFI was influenced by participant age and COVID-19 vaccine type, and differed between participants in Australia and Brazil.

Effect of BCG vaccination against Mycobacterium tuberculosis infection in adult Brazilian health-care workers: a nested clinical trial.

BACKGROUND: The effectiveness of BCG vaccine for adult pulmonary tuberculosis remains uncertain. In this study, we aimed to evaluate the effect of vaccination with BCG-Denmark to prevent initial and sustained interferon-γ release assay conversion in Brazilian health-care workers. METHODS: This substudy is a nested randomised controlled trial embedded within the BRACE trial (NCT04327206). Specifically, this substudy enrolled Brazilian health-care workers (aged ≥18 years) from three sites in Brazil (Manaus, Campo Grande, and Rio de Janeiro) irrespective of previously receiving BCG vaccination. Participants were excluded if they had contraindications to BCG vaccination, more than 1 month of treatment with specific tuberculosis treatment drugs, previous adverse reactions to BCG, recent BCG vaccination, or non-compliance with assigned interventions. Those eligible were randomly assigned (1:1) to either the BCG group (0·1 mL intradermal injection of BCG-Denmark [Danish strain 1331; AJ Vaccines, Copenhagen]) or the placebo group (intradermal injection of 0·9% saline) using a web-based randomisation process in variable-length blocks (2, 4, or 6), and were stratified based on the study site, age (<40, ≥40 to <60, ≥60 years), and comorbidity presence (diabetes, chronic respiratory disease, cardiac condition, hypertension). Sealed syringes were used to prevent inadvertent disclosure of group assignments. The QuantiFERON-TB Gold (QFT) Plus test (Qiagen; Hilden, Germany) was used for baseline and 12-month tuberculosis infection assessments. The primary efficacy outcome was QFT Plus conversion (≥0·35 IU/mL) by 12 months following vaccination in participants who had a negative baseline result (<0·35 IU/mL). FINDINGS: Between Oct 7, 2020, and April 12, 2021, 1985 (77·3%) of 2568 participants were eligible for QFT Plus assessment at 12 months and were included in this substudy; 996 (50·2%) of 1985 were in the BCG group and 989 (49·8%) were in the placebo group. Overall, 1475 (74·3%) of 1985 participants were women and 510 (25·7%) were men, and the median age was 39 years (IQR 32-47). During the first 12 months, QFT Plus conversion occurred in 66 (3·3%) of 1985 participants, with no significant differences by study site (p=0·897). Specifically, 34 (3·4%) of 996 participants had initial QFT conversion in the BCG group compared with 32 (3·2%) of 989 in the placebo group (risk ratio 1·09 [95% CI 0·67-1·77]; p=0·791). INTERPRETATION: BCG-Denmark vaccination did not reduce initial QFT Plus conversion risk in Brazilian health-care workers. This finding underscores the need to better understand tuberculosis prevention in populations at high risk. FUNDING: Bill & Melinda Gates Foundation, the Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the United Health Group Foundation, Epworth Healthcare, and individual donors. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.

Low handgrip strength is associated with worse functional outcomes in long COVID.

The diagnosis of long COVID is troublesome, even when functional limitations are present. Dynapenia is the loss of muscle strength and power production that is not caused by neurologic or muscular diseases, being mostly associated with changes in neurologic function and/or the intrinsic force-generating properties of skeletal muscle, which altogether, may partially explain the limitations seen in long COVID. This study aimed to identify the distribution and possible associations of dynapenia with functional assessments in patients with long COVID. A total of 113 patients with COVID-19 were evaluated by functional assessment 120 days post-acute severe disease. Body composition, respiratory muscle strength, spirometry, six-minute walk test (6MWT, meters), and hand-grip strength (HGS, Kilogram-force) were assessed. Dynapenia was defined as HGS < 30 Kgf (men), and < 20 Kgf (women). Twenty-five (22%) participants were dynapenic, presenting lower muscle mass (p < 0.001), worse forced expiratory volume in the first second (FEV1) (p = 0.0001), lower forced vital capacity (p < 0.001), and inspiratory (p = 0.007) and expiratory (p = 0.002) peek pressures, as well as worse 6MWT performance (p < 0.001). Dynapenia, independently of age, was associated with worse FEV1, maximal expiratory pressure (MEP), and 6MWT, (p < 0.001) outcomes. Patients with dynapenia had higher intensive care unit (ICU) admission rates (p = 0.01) and need for invasive mechanical ventilation (p = 0.007) during hospitalization. The HGS is a simple, reliable, and low-cost measurement that can be performed in outpatient clinics in low- and middle-income countries. Thus, HGS may be used as a proxy indicator of functional impairment in this population.

Anodal transcranial direct current stimulation associated with aerobic exercise on the functional and physical capacity of patients with heart failure with reduced ejection fraction: ELETRIC study protocol.

BACKGROUND: The hallmark symptom of heart failure (HF) is severe exercise intolerance. Fortunately, accumulated evidence suggests that exercise programs improve physical performance, enhance autonomy in daily activities and quality of life, and reduce cardiovascular and other hospitalizations. Recently, experimental studies have explored the application of non-invasive brain stimulation techniques, especially transcranial direct current stimulation (tDCS), aiming to improve physical performance due to its ability to modulate brain functioning. The primary objective of the present study is to evaluate the effects of anodal tDCS associated with aerobic exercise on the functional capacity of patients with HF with reduced ejection fraction (HFrEF). Secondary objectives are to compare the effects of tDCS associated with aerobic exercise vs. sham-tDCS associated with aerobic exercise on cardiopulmonary exercise capacity; inflammatory cytokines; and quality of life. METHODS: This is a two-arm, prospectively registered, randomized trial with concealed allocation, double-blind, and intention-to-treat analysis. Forty-four patients with HFrEF will be recruited. The experimental group will undertake 25-30 min aerobic exercise training associated with tDCS, for 4 weeks. The control group will undergo the same aerobic exercise training, but with sham-tDCS. The primary outcome will be functional performance by the 6-min walk test. Secondary outcomes will include cardiopulmonary exercise capacity, inflammatory cytokines, and quality of life. Outcomes will be collected by a researcher blinded to group allocation at baseline (T0) and after 4 weeks of intervention (T1). DISCUSSION: Although previous studies have investigated the combined effect of tDCS on T3 area and physical performance and have suggested that tDCS could have reduced ratings of perceived exertion by affecting the activity of the insular cortex, and therefore increase exercise tolerance, this study is the first to evaluate the effects of the addition of anodal tDCS to aerobic exercise training for improving physical and functional performance, decreasing the perceived exertion, altering the quantification of inflammatory cytokines, and improving the subclinical values of the cardiopulmonary test in patients with HFrEF, which could result in an important advance in cardiac rehabilitation for patients with chronic HF. TRIAL REGISTRATION: Brazilian Registry of Clinical Trials (ReBEC) RBR-10w787j6. Registered on 25 April 2023. https://ensaiosclinicos.gov.br/pesquisador.

Methylprednisolone therapy induces differential metabolic trajectories in severe COVID-19 patients.

IMPORTANCE: The SARS-CoV-2 virus infection in humans induces significant inflammatory and systemic reactions and complications of which corticosteroids like methylprednisolone have been recommended as treatment. Our understanding of the metabolic and metabolomic pathway dysregulations while using intravenous corticosteroids in COVID-19 is limited. This study will help enlighten the metabolic and metabolomic pathway dysregulations underlying high daily doses of intravenous methylprednisolone in COVID-19 patients compared to those receiving placebo. The information on key metabolites and pathways identified in this study together with the crosstalk with the inflammation and biochemistry components may be used, in the future, to leverage the use of methylprednisolone in any future pandemics from the coronavirus family.

Temporal patterns of cytokine and injury biomarkers in hospitalized COVID-19 patients treated with methylprednisolone.

Background: The novel coronavirus disease 2019 (COVID-19) presents with complex pathophysiological effects in various organ systems. Following the COVID-19, there are shifts in biomarker and cytokine equilibrium associated with altered physiological processes arising from viral damage or aggressive immunological response. We hypothesized that high daily dose methylprednisolone improved the injury biomarkers and serum cytokine profiles in COVID-19 patients. Methods: Injury biomarker and cytokine analysis was performed on 50 SARS-Cov-2 negative controls and 101 hospitalized severe COVID-19 patients: 49 methylprednisolone-treated (MP group) and 52 placebo-treated serum samples. Samples from the treated groups collected on days D1 (pre-treatment) all the groups, D7 (2 days after ending therapy) and D14 were analyzed. Luminex assay quantified the biomarkers HMGB1, FABP3, myoglobin, troponin I and NTproBNP. Immune mediators (CXCL8, CCL2, CXCL9, CXCL10, TNF, IFN-γ, IL-17A, IL-12p70, IL-10, IL-6, IL-4, IL-2, and IL-1ß) were quantified using cytometric bead array. Results: At pretreatment, the two treatment groups were comparable demographically. At pre-treatment (D1), injury biomarkers (HMGB1, TnI, myoglobin and FABP3) were distinctly elevated. At D7, HMGB1 was significantly higher in the MP group (p=0.0448) compared to the placebo group, while HMGB1 in the placebo group diminished significantly by D14 (p=0.0115). Compared to healthy control samples, several immune mediators (IL-17A, IL-6, IL-10, MIG, MCP-1, and IP-10) were considerably elevated at baseline (all p≤0.05). At D7, MIG and IP-10 of the MP-group were significantly lower than in the placebo-group (p=0.0431, p=0.0069, respectively). Longitudinally, IL-2 (MP-group) and IL-17A (placebo-group) had increased significantly by D14. In placebo group, IL-2 and IL-17A continuously increased, as IL-12p70, IL-10 and IP-10 steadily decreased during follow-up. The MP treated group had IL-2, IFN-γ, IL-17A and IL-12p70 progressively increase while IL-1ß and IL-10 gradually decreased towards D14. Moderate to strong positive correlations between chemokines and cytokines were observed on D7 and D14. Conclusion: These findings suggest MP treatment could ameliorate levels of myoglobin and FABP3, but appeared to have no impact on HMGB1, TnI and NTproBNP. In addition, methylprednisolone relieves the COVID-19 induced inflammatory response by diminishing MIG and IP-10 levels. Overall, corticosteroid (methylprednisolone) use in COVID-19 management influences the immunological molecule and injury biomarker profile in COVID-19 patients.

Antigen-Specific Antibody Signature Is Associated with COVID-19 Outcome.

Numerous studies have focused on inflammation-related markers to understand COVID-19. In this study, we performed a comparative analysis of spike (S) and nucleocapsid (N) protein-specific IgA, total IgG and IgG subclass response in COVID-19 patients and compared this to their disease outcome. We observed that the SARS-CoV-2 infection elicits a robust IgA and IgG response against the N-terminal (N1) and C-terminal (N3) region of the N protein, whereas we failed to detect IgA antibodies and observed a weak IgG response against the disordered linker region (N2) in COVID-19 patients. N and S protein-specific IgG1, IgG2 and IgG3 response was significantly elevated in hospitalized patients with severe disease compared to outpatients with non-severe disease. IgA and total IgG antibody reactivity gradually increased after the first week of symptoms. Magnitude of RBD-ACE2 blocking antibodies identified in a competitive assay and neutralizing antibodies detected by PRNT assay correlated with disease severity. Generally, the IgA and total IgG response between the discharged and deceased COVID-19 patients was similar. However, significant differences in the ratio of IgG subclass antibodies were observed between discharged and deceased patients, especially towards the disordered linker region of the N protein. Overall, SARS-CoV-2 infection is linked to an elevated blood antibody response in severe patients compared to non-severe patients. Monitoring of antigen-specific serological response could be an important tool to accompany disease progression and improve outcomes.

Componentes ético-clínicos presentes en la indicación de tratamiento en mujeres con cáncer de mama según edad de diagnóstico

Objetivo: Evaluar si existen diferencias basadas en la edad en la aproximación diagnóstica y de tratamiento del cáncer de mama. Se analizan aspectos éticos, como justicia, beneficencia y autonomía, en relación a la toma de decisiones. Material y Método: Estudio descriptivo cuantitativo y corresponde a un análisis retrospectivo de la base de datos del Centro de la Mama de Clínica Alemana de Santiago, en la que se analiza información de las mujeres de 70 años o más en relación a motivo consulta, estadio de la enfermedad al momento del diagnóstico y tratamientos recibidos y se la compara con la obtenida del grupo de mujeres menores de 70 años. Resultados: No hay diferencia en la oportunidad de la consulta, en el acceso al diagnóstico ni en el tipo de cirugía entre los dos grupos. Existen diferencias significativas en relación a la indicación de tratamientos adyuvantes como quimioterapia, radioterapia y hormonoterapia. El grupo de mujeres mayores de 70 años reciben menos terapias que las mujeres de menor edad. No existe información respecto a los motivos que expliquen esta diferencia. Discusión: Actualmente, mujeres mayores se encuentran en buenas condiciones generales, con una expectativa de vida mayor a 75 años. Es importante tratar sus enfermedades sin limitar a priori el acceso a protocolos de tratamiento, evitando la discriminación por edad. Conclusión: Se propone incorporar una evaluación geriátrica protocolizada con el objetivo de mejorar la atención de este grupo etario, preservando de esta manera los principios de justicia, beneficencia y autonomía en pacientes mayores.

Objective: To evalúate if there are differences on the diagnostic approach and breast cancer treatment based on women age. We analyze ethical aspects like justice, beneficence and autonomy in regards of decision making. Material and Method: Descriptiva and quantitative study that correspond and analysis of the Data Base of the Breast Cancer Center in Clínica Alemana de Santiago, in which we gather the information of women 70 years or more in relation to consultation motive, illness stage and treatments received, compare with the obtain in the group of women under 70 years. Results: There are no differences in the opportunity to reach consultation, access to diagnosis neither the type of surgery. There are significant differences in considering adjuvant treatment like chemotherapy, radiotherapy and hormonal therapy. The group of women with 70 years or older, receive less treatments than the younger group. There is no information that explains this differences. Discussion: In current days, women of the third and fourth age are in good general conditions and their life expectancy is over 75 years old. It is important to treat their diseases without limiting access to them only because of their age, avoiding this type of discrimination. Conclusion: it is proposed to incorporate a geriatric evaluation to improve quality of clinical attention in this age group, aiming to preserve justice, beneficence and autonomy principles in older patients.

Validation of a Culturally Relevant Snakebite Envenomation Clinical Practice Guideline in Brazil.

Snakebite envenoming (SBE) is a neglected tropical disease with significant global morbidity and mortality. Even when antivenom is available in low-resource areas, health workers do not receive adequate training to manage SBEs. This study aims to develop and validate a clinical practice guideline (CPG) for SBE management across Brazil. A panel of expert judges with academic and/or technical expertise in SBE management performed content validation. The content validity index (CVI) score was 90% for CPG objectives, 89% for structure and presentation and 92% for relevance and classified the CPG as valid. A semantic validation was performed by analyzing focus group discussions with doctors and nurses from three municipalities of the Brazilian Amazon, after a 5-day meeting during which the CPG was presented. Two central themes emerged: knowledge acquired during the meeting and recommendations for improving the CPG. Based on these results, the CPG was revised into a final version. This study presents the successful development and validation process of a CPG for SBE management, which is targeted to a specific low-resource, high-burden setting. This development and validation process can be adapted to other settings and/or other neglected tropical diseases.