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Guilherme Peixoto Tinoco Arêas,1,2 Cássia da Luz Goulart,3 Thaís Sant’Anna,4 Tiótrefis Gomes Fernandes,4 Rafael de Oliveira Alvim,1 Fernanda Facioli dos Reis Borges,1 Camila Miriam Suemi Sato Barros do Amaral,3 Suzy Cristina França Rodrigues,1 Jefferson Valente,3 João Marcos Bemfica Barbosa Ferreira,5 Anna Gabriela Rezende,1,3 Edival Ferreira de Oliveira Júnior,6 Marcus Vinícius Guimarães de Lacerda,3,7,8 Fernando Fonseca de Almeida-Val1– 4 1Department of Physiological Sciences, Exercise Physiology Laboratory, Federal University of Amazonas, Manaus, AM, Brasil; 2Cardiopulmonary Laboratory, Getúlio Vargas University Hospital, UFAM, Manaus, AM, Brasil; 3Dr Heitor Vieira Dourado Tropical Medicine Foundation, Manaus, AM, Brasil; 4Faculty of Physical Education and Physiotherapy, Respiratory and Cardiovascular Physiotherapy Laboratory, Federal University of Amazonas, Manaus, AM, Brasil; 5Higher School of Health Sciences, Faculty of Medicine, State University of Amazonas, Manaus, AM, Brasil; 6Francisca Mendes University Hospital, Manaus, AM, Brasil; 7Leônidas and Maria Deane Institute, Fiocruz Amazonas, Manaus, AM, Brasil; 8University of Texas Medical Branch at Galveston, Galveston, TX, USACorrespondence: Guilherme Peixoto Tinoco Arêas, Departamento de Ciências Fisiológicas, Universidade Federal Do Amazonas, Avenida Rodrigo Otávio, 6200, Manaus, AM, 69080-900, Brasil, Email guilhermepta@ufam.edu.brBackground: 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.Keywords: COVID-19, noninvasive ventilation, pulmonary rehabilitation

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., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The trial is financially supported by the Foundations listed in the Funding section. Authors disclose funding support over the past 36 months: National Health and Medical Research Council (NHMRC) Ideas Grant (NM), NHMRC Investigator Grant (NC), Melbourne Children’s Clinician-Scientist Fellowship Grant (KPP). Outside of the submitted work, JCr has received grants or contracts from Sanofi, MSD & CEPI; payment or honoraria for presentations from Pfizer and participates on Latin American data safety monitoring/advisory boards for mRNA-1273 (Modern/Zodiac), RSV maternal vaccine (Pfizer), Qdenga vaccine (Takeda) and Nirmatrelvir/Ritonavir-Paxlovid (Pfizer). KG is a member of the Royal Children’s Hospital (RCH) Human Research Ethics Committee (the primary ethics committee providing approval for the BRACE trial) and Director of Research Operations at RCH; she abstained from all discussion, voting, approval and review related to the BRACE trial. All other authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The 8-aminoquinolines, primaquine and tafenoquine, are the only available drugs for the radical cure of Plasmodium vivax hypnozoites. Previous evidence suggests that there is dose-dependent 8-aminoquinoline induced methaemoglobinaemia and that higher methaemoglobin concentrations are associated with a lower risk of P. vivax recurrence. We undertook a systematic review and individual patient data meta-analysis to examine the utility of methaemoglobin as a population-level surrogate endpoint for 8-aminoquinoline antihypnozoite activity to prevent P. vivax recurrence., Methods and Findings: We conducted a systematic search of Medline, Embase, Web of Science, and the Cochrane Library, from 1 January 2000 to 29 September 2022, inclusive, of prospective clinical efficacy studies of acute, uncomplicated P. vivax malaria mono-infections treated with radical curative doses of primaquine. The day 7 methaemoglobin concentration was the primary surrogate outcome of interest. The primary clinical outcome was the time to first P. vivax recurrence between day 7 and day 120 after enrolment. We used multivariable Cox proportional-hazards regression with site random-effects to characterise the time to first recurrence as a function of the day 7 methaemoglobin percentage (log base 2 transformed), adjusted for the partner schizonticidal drug, the primaquine regimen duration as a proxy for the total primaquine dose (mg base/kg), the daily primaquine dose (mg/kg), and other factors. The systematic review protocol was registered with PROSPERO (CRD42023345956). We identified 219 P. vivax efficacy studies, of which 8 provided relevant individual-level data from patients treated with primaquine; all were randomised, parallel arm clinical trials assessed as having low or moderate risk of bias. In the primary analysis data set, there were 1,747 patients with normal glucose-6-phosphate dehydrogenase (G6PD) activity enrolled from 24 study sites across 8 different countries (Indonesia, Brazil, Vietnam, Thailand, Peru, Colombia, Ethiopia, and India). We observed an increasing dose-response relationship between the daily weight-adjusted primaquine dose and day 7 methaemoglobin level. For a given primaquine dose regimen, an observed doubling in day 7 methaemoglobin percentage was associated with an estimated 30% reduction in the risk of P. vivax recurrence (adjusted hazard ratio = 0.70; 95% confidence interval [CI] [0.57, 0.86]; p = 0.0005). These pooled estimates were largely consistent across the study sites. Using day 7 methaemoglobin as a surrogate endpoint for recurrence would reduce required sample sizes by approximately 40%. Study limitations include the inability to distinguish between recrudescence, reinfection, and relapse in P. vivax recurrences., Conclusions: For a given primaquine regimen, higher methaemoglobin on day 7 was associated with a reduced risk of P. vivax recurrence. Under our proposed causal model, this justifies the use of methaemoglobin as a population-level surrogate endpoint for primaquine antihypnozoite activity in patients with P. vivax malaria who have normal G6PD activity., Competing Interests: JAG and GCKWK are former employees of GSK and hold shares in GSK and AstraZeneca. GCKWK reports travel support from AstraZeneca. JKB reports participation on the US National Institutes of Health data safety monitoring board; and membership of the editorial board of Travel Medicine and Infectious Disease and the guidelines development group for malaria control and elimination, Global Malaria Programme, WHO. RJC, JKB, and RNP report contributions to Up-to-Date. All other authors declare no competing interests., (Copyright: © 2024 Fadilah et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: HIV incidence estimation is critical for monitoring the HIV epidemic dynamics and the effectiveness of public health prevention interventions. We aimed to identify sexual and gender minorities (SGM) with recent HIV infections, factors associated with recent HIV infection, and to estimate annualised HIV incidence rates., Methods: Cross-sectional multicentre study in HIV testing services in Brazil and Peru (15 cities). Inclusion criteria: 18+ years, SGM assigned male at birth, not using pre-/post-exposure prophylaxis. We identified recent HIV infection using the Maxim HIV-1 LAg-Avidity EIA assay as part of a recent infection testing algorithm (RITA). Annualized HIV incidence was calculated using the UNAIDS/WHO incidence estimator tool. Multivariable logistic regression models were used to estimate factors associated with recent HIV infection. Trial registration: NCT05674682., Findings: From 31-Jan-2021 to 29-May-2022, 6899 individuals participated [Brazil: 4586 (66.5%); Peru: 2313 (33.5%)]; 5946 (86.2%) cisgender men, 751 (10.9%) transgender women and 202 (2.9%) non-binary/gender diverse. Median age was 27 (IQR: 23-34) years. HIV prevalence was 11.4% (N = 784/6899); 137 (2.0%) SGM were identified with recent HIV infection. The overall annualized HIV incidence rate was 3.88% (95% CI: 2.86-4.87); Brazil: 2.62% (95% CI: 1.78-3.43); Peru: 6.69% (95% CI: 4.62-8.69). Participants aged 18-24 years had higher odds of recent HIV infection compared to those aged 30+ years in both countries., Interpretation: Our results highlight the significant burden of HIV epidemic among SGM in large urban centres of Brazil and Peru. Public health policies and interventions to increase access to effective HIV prevention methods such as PrEP are urgently needed in Latin America., Funding: Unitaid, WHO (Switzerland), Ministry of Health from Brazil and Peru., Competing Interests: Nothing to declare., (© 2023 The Author(s).)

Background: This study aimed at improving a real-time polymerase-chain-reaction (qPCR) assay for the detection of Histoplasma capsulatum, a fungal pathogen that can cause severe respiratory infections in humans, in clinical and soil samples., Methods: Primer and probes were in-silico designed, in-silico and in-vitro evaluated including clinical biopsy materials and finally subjected to a real-world application with collected soil samples., Results: Applying the qPCR assay with liver and lung biopsies from 71 patients each, including 59 patients infected with human immunodeficiency virus (HIV), as well as with Sabouraud (SAB) agar culture as the diagnostic reference standard, diagnostic accuracy of the qPCR assay of 100% (5/5) sensitivity and 96% (63/66) specificity for liver samples and 100% (4/4) sensitivity and 94% (63/67) specificity for the lung samples was recorded. When applying the assay with soil samples from caves near of Presidente Figueiredo city, Amazonas, Brazil, one sample from the Maroaga cave was confirmed as positive., Conclusions: The improved qPCR assessed in this study was successful in detecting H. capsulatum with high efficiency and accuracy in in-vitro evaluation, including the identification of the target pathogen in both clinical and environmental samples.

Plasmodium vivax is a public health problem and the most common type of malaria outside sub-Saharan Africa. The capacity of cytoadhesion, rosetting, and liver latent phase development could impact treatment and disease control. Although the ability to P. vivax gametocyte develop rosetting is known, it is not yet clear which role it plays during the infection and transmission process to the mosquito. Here, we used ex vivo approaches for evaluate the rosetting P. vivax gametocytes capacity and we have investigated the effect of this adhesive phenotype on the infection process in the vector Anopheles aquasalis mosquito. Rosette assays were performed in 107 isolates, and we have observed an elevated frequency of cytoadhesive phenomena (77,6%). The isolates with more than 10% of rosettes have presented a higher infection rate in Anopheles aquasalis (p=0.0252). Moreover, we found a positive correlation between the frequency of parasites in rosetting with the infection rate (p=0.0017) and intensity (p=0.0387) in the mosquito. The disruption of P. vivax rosette formation through mechanical rupture assay confirmed the previously findings, since the paired comparison showed that isolates with disrupted rosettes have a lower infection rate (p<0.0001) and intensity (p=0.0003) compared to the control group (no disruption). Herein we have demonstrated for the first time a potential effect of the rosette phenomenon on the infection process in the mosquito vector An. aquasalis , favoring its capacity and intensity of infection, thus allowing the perpetuation of the parasite cycle life., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Salazar Alvarez, Carneiro Barbosa, Vera Lizcano, Baia da Silva, Gonçalves Santana, Fabbri, Paoluci Pimenta, Monteiro, Albrecht, Guimarães de Lacerda, Trindade Maranhão Costa and Costa Pinto Lopes.)

Background: In the clinical course of diseases such as arboviruses, skin rashes may appear, as is often seen in other infectious diseases. The aim of this study was to estimate the prevalence of arboviruses and other infectious causes of skin rash in a tertiary health unit in Manaus, Amazonas state, Western Brazilian Amazon., Methodology/principal Findings: This was a cross-sectional study of patients presenting with rash who sought care at Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT-HVD) from February 2018 to May 2019. Individuals of either gender, aged over 18 years, were invited to participate voluntarily. Infection by Zika virus (ZIKV), dengue virus (DENV), chikungunya virus (CHIKV), Mayaro virus (MAYV), Oropouche virus (OROV) and measles was evaluated using RT-qPCR (real-time polymerase chain reaction). Immunodiagnostic tests for EBV, CMV, HIV, syphilis, rubella and measles were also performed. A total of 340 participants were included, most were female (228, 67.1%) with an average age of 36.5 years (SD ± 12.2 years). The highest prevalence was of ZIKV monoinfections (65.3%, 222/340), followed by DENV (0.9%, 3/340) and CHIKV infection (0.3%, 1/340). No cases of MAYV, OROV or rubella were found. Other causes of skin rash were detected: measles (2.9%, 10/340), parvovirus B19 (0.9% 3/340), HIV (0.3%, 1/340) and syphilis 0.6% (2/340). The co-infections identified were ZIKV+HIV (0.3%, 1/340), ZIKV+measles (0.3%, 1/340), ZIKV+parvovirus B19 (0.3%, 1/340), ZIKV+EBV (0.3%, 1/340), EBV+parvovirus B19 (0.3%, 1/340), CMV+parvovirus B19 (0.6%, 2/340), CMV+syphilis (0.3%, 1/340), ZIKV+EBV+parvovirus B19 (0.3%, 1/340) and CMV+EBV+parvovirus B19 (0.9%, 3/340). Approximately one quarter of patients had no defined cause for their skin rash (25.3%, 86/340)., Conclusions: Despite the benign clinical evolution of most of the diseases diagnosed in this series of cases, syndromic surveillance of diseases such as syphilis and HIV are of utmost importance. Periodic serosurveillance might also aid in evaluating the trends of endemic diseases and eventual outbreaks., Competing Interests: The authors have declared that no competing interests exist.

Malaria patients are at risk of cardiopulmonary complications but diagnosis and management can be difficult in resource-limited settings. B-lines on lung ultrasound (LUS) mark changes in lung density; however, little is known about their role in malaria. We aimed to examine the prevalence of B-lines in adults with malaria at baseline and follow-up compared with controls in the Amazon Basin. We also examined the relationship between B-lines and left ventricular ejection fraction. We performed eight-zone LUS, echocardiography, and blood smears in 94 adults (mean age 40 years, 54% men) with uncomplicated malaria and 449 controls without heart failure, renal insufficiency or lung disease (mean age 41 years, 38% men). Examinations of adults with malaria were repeated after antimalarial treatment, corresponding to a median of 30 days (interquartile range [IQR] 27-39). Adults with malaria suffered from Plasmodium vivax (N = 70, median 2,823 [IQR 598-7,698] parasites/μL) or P. falciparum (N = 24, median 1,148 [IQR 480-3,128] parasites/μL). At baseline, adults with malaria more frequently had ≥ 3 B-lines (summed across eight zones) compared with controls (30% versus 2%, P value < 0.001), indicating higher lung density. When examinations were repeated, only 6% of adults with malaria had ≥ 3 B-lines at follow-up, which was significant lower compared with baseline (median reduction 3 B-line; P value < 0.001). B-lines were not significantly associated with left ventricular ejection fraction in adults with malaria. In conclusion, B-lines detected by LUS were more frequent in adults with uncomplicated malaria compared with controls and decreased after completed antimalarial treatment.

The Amazonas was one of the most heavily affected Brazilian states by the COVID-19 epidemic. Despite a large number of infected people, particularly during the second wave associated with the spread of the Variant of Concern (VOC) Gamma (lineage P.1), SARS-CoV-2 continues to circulate in the Amazonas. To understand how SARS-CoV-2 persisted in a human population with a high immunity barrier, we generated 1,188 SARS-CoV-2 whole-genome sequences from individuals diagnosed in the Amazonas state from 1st January to 6th July 2021, of which 38 were vaccine breakthrough infections. Our study reveals a sharp increase in the relative prevalence of Gamma plus (P.1+) variants, designated Pango Lineages P.1.3 to P.1.6, harboring two types of additional Spike changes: deletions in the N-terminal (NTD) domain (particularly Δ144 or Δ141-144) associated with resistance to anti-NTD neutralizing antibodies or mutations at the S1/S2 junction (N679K or P681H) that probably enhance the binding affinity to the furin cleavage site, as suggested by our molecular dynamics simulations. As lineages P.1.4 (S:N679K) and P.1.6 (S:P681H) expanded (Re > 1) from March to July 2021, the lineage P.1 declined (Re < 1) and the median Ct value of SARS-CoV-2 positive cases in Amazonas significantly decreases. Still, we did not find an increased incidence of P.1+ variants among breakthrough cases of fully vaccinated patients (71%) in comparison to unvaccinated individuals (93%). This evidence supports that the ongoing endemic transmission of SARS-CoV-2 in the Amazonas is driven by the spread of new local Gamma/P.1 sublineages that are more transmissible, although not more efficient to evade vaccine-elicited immunity than the parental VOC. Finally, as SARS-CoV-2 continues to spread in human populations with a declining density of susceptible hosts, the risk of selecting more infectious variants or antibody evasion mutations is expected to increase. IMPORTANCE The continuous evolution of SARS-CoV-2 is an expected phenomenon that will continue to happen due to the high number of cases worldwide. The present study analyzed how a Variant of Concern (VOC) could still circulate in a population hardly affected by two COVID-19 waves and with vaccination in progress. Our results showed that the answer behind that was a new generation of Gamma-like viruses, which emerged locally carrying mutations that made it more transmissible and more capable of spreading, partially evading prior immunity triggered by natural infections or vaccines. With thousands of new cases daily, the current pandemics scenario suggests that SARS-CoV-2 will continue to evolve and efforts to reduce the number of infected subjects, including global equitable access to COVID-19 vaccines, are mandatory. Thus, until the end of pandemics, the SARS-CoV-2 genomic surveillance will be an essential tool to better understand the drivers of the viral evolutionary process.

Background: Plasmodium vivax, the major cause of malaria in Latin America, has a large subtelomeric multigene family called vir. In the P. vivax genome, about 20% of its sequences are vir genes. Vir antigens are grouped in subfamilies according to their sequence similarities and have been shown to have distinct roles and subcellular locations. However, little is known about vir subfamilies, especially when comes to their functions., Objective: To evaluate the diversity, antigenicity, and adhesiveness of Plasmodium vivax VIR-E., Methods: Vir-E genes were amplified from six P. vivax isolates from Manaus, North of Brazil. The presence of naturally acquired antibodies to recombinant PvBrVIR-E and PvAMA-1 was evaluated by ELISA. Binding capacity of recombinant PvBrVIR-E was assessed by adhesion assay to CHO-ICAM1 cells., Findings: Despite vir-E sequence diversity, among those identified sequences, a representative one was chosen to be expressed as recombinant protein. The presence of IgM or IgG antibodies to PvBrVIR-E was detected in 23.75% of the study population while the presence of IgG antibodies to PvAMA-1 antigen was 66.25% in the same population. PvBrVIR-E was adhesive to CHO-ICAM1., Main Conclusions: PvBrVIR-E was antigenic and adhesive to CHO-ICAM1.