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ABSTRACTVarious 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

Summary: Background: Bacille Calmette-Guérin (BCG) vaccination has off-target (non-specific) effects that are associated with protection against unrelated infections and decreased all-cause mortality in infants. We aimed to determine whether BCG vaccination prevents febrile and respiratory infections in adults. Methods: This randomised controlled phase 3 trial was done in 36 healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom. Healthcare workers were randomised to receive BCG-Denmark (single 0.1 ml intradermal injection) or no BCG in a 1:1 ratio using a web-based procedure, stratified by stage, site, age, and presence of co-morbidity. The difference in occurrence of febrile or respiratory illness were measured over 12 months (prespecified secondary outcome) using the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020, and April 1, 2021, 6828 healthcare workers were randomised to BCG-Denmark (n = 3417) or control (n = 3411; no intervention or placebo) groups. The 12-month adjusted estimated risk of ≥1 episode of febrile or respiratory illness was 66.8% in the BCG group (95% CI 65.3%–68.2%), compared with 63.4% in the control group (95% CI 61.8%–65.0%), a difference of +3.4 percentage points (95% CI +1.3% to +5.5%; p 0.002). The adjusted estimated risk of a severe episode (defined as being incapacitated for ≥3 consecutive days or hospitalised) was 19.4% in the BCG group (95% CI 18.0%–20.7%), compared with 18.8% in the control group (95% CI 17.4%–20.2%) a difference of +0.6 percentage points (95% CI −1.3% to +2.5%; p 0.6). Both groups had a similar number of episodes of illness, pneumonia, and hospitalisation. There were three deaths, all in the control group. There were no safety concerns following BCG vaccination. Interpretation: In contrast to the beneficial off-target effects reported following neonatal BCG in infants, a small increased risk of symptomatic febrile or respiratory illness was observed in the 12 months following BCG vaccination in adults. There was no evidence of a difference in the risk of severe disease. Funding: Bill & Melinda Gates Foundation, 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 UHG Foundation Pty Ltd, Epworth Healthcare, the National Health and Medical Research Council, the Swiss National Science Foundation and individual donors.

Summary: Background: The COVID-19 pandemic led to the rapid development and deployment of several highly effective vaccines against SARS-CoV-2. Recent studies suggest that these vaccines may also have off-target effects on the immune system. We sought to determine and compare the off-target effects of the adenovirus vector ChAdOx1-S (Oxford-AstraZeneca) and modified mRNA BNT162b2 (Pfizer-BioNTech) vaccines on immune responses to unrelated pathogens. Methods: Prospective sub-study within the BRACE trial. Blood samples were collected from 284 healthcare workers before and 28 days after ChAdOx1-S or BNT162b2 vaccination. SARS-CoV-2-specific antibodies were measured using ELISA, and whole blood cytokine responses to specific (SARS-CoV-2) and unrelated pathogen stimulation were measured by multiplex bead array. Findings: Both vaccines induced robust SARS-CoV-2 specific antibody and cytokine responses. ChAdOx1-S vaccination increased cytokine responses to heat-killed (HK) Candida albicans and HK Staphylococcus aureus and decreased cytokine responses to HK Escherichia coli and BCG. BNT162b2 vaccination decreased cytokine response to HK E. coli and had variable effects on cytokine responses to BCG and resiquimod (R848). After the second vaccine dose, BNT162b2 recipients had greater specific and off-target cytokine responses than ChAdOx1-S recipients. Interpretation: ChAdOx1-S and BNT162b2 vaccines alter cytokine responses to unrelated pathogens, indicative of potential off-target effects. The specific and off-target effects of these vaccines differ in their magnitude and breadth. The clinical relevance of these findings is uncertain and needs further study. Funding: Bill & Melinda Gates Foundation, National Health and Medical Research Council, Swiss National Science Foundation and the Melbourne Children’s. BRACE trial funding is detailed in acknowledgements.

Summary: Background: Recurrences of herpes simplex virus (HSV) in the orofacial region (herpes labialis or cold sores) impact quality-of-life. We aimed to study whether the bacille Calmette-Guérin (BCG) vaccine can attenuate cold sore recurrences through off-target immunomodulatory effects. Methods: In this nested randomised controlled trial within the multicentre, phase 3 BRACE trial, 6828 healthcare workers were randomised in 36 sites in Australia, the Netherlands, Spain, the United Kingdom and Brazil, to receive BCG-Denmark or no BCG (1:1 ratio using a web-based procedure) and followed for 12 months with 3-monthly questionnaires. Exclusion criteria included contraindication to BCG vaccine or previous vaccination with BCG within the past year, any other live-attenuated vaccine within the last month, or any COVID-specific vaccine. The intervention group received one intradermal dose of 0.1 mL of BCG-Denmark corresponding to 2−8 x 105 colony forming units of Mycobacterium bovis, Danish strain 1331. The primary outcome was the difference in restricted mean survival time (i.e., time to first cold-sore recurrence), in participants with frequent recurrent herpes labialis (≥4 recurrences/year), analysed by intention-to-treat. Secondary outcomes addressed additional questions, including analyses in other sub-populations. Adverse events were monitored closely during the first 3 months and were reported in all participants who received one dose of study drug according to intervention received. The BRACE trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020 and February 18, 2021, 84 individuals with frequent recurrent cold sores were randomly assigned to BCG (n = 38) or control (n = 46). The average time to first cold-sore recurrence was 1.55 months longer in the BCG group (95% CI 0.27–2.82, p = 0.02) than the control group (hazard ratio 0.54, 95% CI 0.32–0.91; intention-to-treat). The beneficial effect of BCG was greater in the as-treated population (difference 1.91 months, 95% CI 0.69–3.12, p = 0.003; hazard ratio 0.45, 95% CI 0.26–0.76). In prespecified subgroup analyses, only sex modified the treatment effect (interaction p = 0.007), with benefit restricted to males. Over 12 months, a greater proportion of participants in the BCG group compared with the control group reported a decrease in duration (61% vs 21%), severity (74% vs 21%), frequency (55% vs 21%), and impact on quality of life (42% vs 15%) of cold sore recurrences. In participants who had ever had a cold sore, there was also a decrease in self-reported burden of recurrences in the BCG group. In participants who had never had a cold sore, there was an increased risk of a first episode in the BCG group (risk difference 1.4%; 95% CI 0.3–2.6%, p = 0.02). There were no safety concerns. Interpretation: BCG-Denmark vaccination had a beneficial effect on herpes labialis, particularly in males with frequent recurrences, but may increase the risk of a first cold sore. 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 UHG Foundation Pty Ltd, Epworth Healthcare, and individual donors.

Abstract Globally, malaria and human immunodeficiency virus (HIV) are both independently associated with a massive burden of disease and death. While their co-infection has been well studied for Plasmodium falciparum, scarce data exist regarding the association of P. vivax and HIV. In this cohort study, we assessed the effect of HIV on the risk of vivax malaria infection and recurrence during a 4-year follow-up period in an endemic area of the Brazilian Amazon. For the purpose of this study, we obtained clinical information from January 2012 to December 2016 from two databases. HIV screening data were acquired from the clinical information system at the tropical hospital Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT-HVD). The National Malaria Surveillance database (SIVEP malaria) was utilized to identify malaria infections during a 4-year follow-up period after diagnosis of HIV. Both datasets were combined via data linkage. Between 2012 and 2016, a total of 42,121 people were screened for HIV, with 1569 testing positive (3.7%). Out of all the patients diagnosed with HIV, 198 had at least one episode of P. vivax malaria in the follow-up. In the HIV-negative group, 711 participants had at least one P. vivax malaria episode. When comparing both groups, HIV patients had a 6.48 [(5.37–7.83); P

Abstract Background Pre-Exposure Prophylaxis (PrEP) has demonstrated efficacy in the reduction of sexually transmitted HIV infections. The prolonged use of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) co-formulation (TDF/FTC), however, may result in augmented risk of renal toxicity. We aimed to evaluate changes in the estimated Glomerular Filtration Rate (eGFR) in a real-world population setting of participants enrolled in PrEP Brazil, a 48-week prospective, open-label, demonstration study to assess the feasibility of daily oral TDF/FTC used by men who have sex with men and transgender women at high-risk of HIV infection, all over 18 years old. Methods Kidney function was assessed by serial measurement of serum creatinine and eGFR with the Modification of Diet in Renal Disease Study (MDRD) formula on weeks 4, 12, 24, 36 and 48. Adherence to PrEP was assessed by dosing TDF concentration in dried blood spots at weeks 4 and 48, measured by liquid chromatography-mass spectrometry or mass spectrometry. Results Of 392 participants completing the 48-week follow-up protocol with TDF blood detectable levels and eGFR measures, 43.1% were young adults, of Caucasian ethnic background (57.9%), with BMI below 30 kg/m2, without arterial hypertension. At screening, median eGFR was 93.0 mL/min/1.73 m2. At week 4 follow-up, 90 (23% of the study population) participants presented reductions in eGFR greater than 10 mL/min/1.73 m2 as compared to baseline eGFR, some as large as 59 mL/min/1.73 m2, but with no clinical outcomes (adverse events and renal adverse events) severe enough to demand TDF/FTC discontinuation. A negative relationship was observed between TDF blood levels and eGFR at weeks 4 (r = − 0.005; p

Abstract SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19), is responsible for the largest pandemic facing humanity since the Spanish flu pandemic in the early twentieth century. Since there is no specific antiviral treatment, optimized support is the most relevant factor in the patient's prognosis. In the hospital setting, the identification of high-risk patients for clinical deterioration is essential to ensure access to intensive treatment of severe conditions in a timely manner. The initial management of hypoxemia includes conventional oxygen therapy, high-flow nasal canula oxygen, and non-invasive ventilation. For patients requiring invasive mechanical ventilation, lung-protective ventilation with low tidal volumes and plateau pressure is recommended. Cardiovascular complications are frequent and include myocardial injury, thrombotic events, myocarditis, and cardiogenic shock. Acute renal failure is a common complication and is a marker of poor prognosis, with significant impact in costs and resources allocation. Regarding promising therapies for COVID-19, the most promising drugs until now are remdesivir and corticosteroids although further studies may be needed to confirm their effectiveness. Other therapies such as, tocilizumab, anakinra, other anti-cytokine drugs, and heparin are being tested in clinical trials. Thousands of physicians are living a scenario that none of us have ever seen: demand for hospital exceed capacity in most countries. Until now, the certainty we have is that we should try to decrease the number of infected patients and that an optimized critical care support is the best strategy to improve patient’s survival.

Abstract Background Malaria and HIV are two important public health issues. However, evidence on HIV-Plasmodium vivax co-infection (HIV/PvCo) is scarce, with most of the available information related to Plasmodium falciparum on the African continent. It is unclear whether HIV can change the clinical course of vivax malaria and increase the risk of complications. In this study, a systematic review of HIV/PvCo studies was performed, and recent cases from the Brazilian Amazon were included. Methods Medical records from a tertiary care centre in the Western Brazilian Amazon (2009–2018) were reviewed to identify HIV/PvCo hospitalized patients. Demographic, clinical and laboratory characteristics and outcomes are reported. Also, a systematic review of published studies on HIV/PvCo was conducted. Metadata, number of HIV/PvCo cases, demographic, clinical, and outcome data were extracted. Results A total of 1,048 vivax malaria patients were hospitalized in the 10-year period; 21 (2.0%) were HIV/PvCo cases, of which 9 (42.9%) had AIDS-defining illnesses. This was the first malaria episode in 11 (52.4%) patients. Seven (33.3%) patients were unaware of their HIV status and were diagnosed on hospitalization. Severe malaria was diagnosed in 5 (23.8%) patients. One patient died. The systematic review search provided 17 articles (12 cross-sectional or longitudinal studies and 5 case report studies). A higher prevalence of studies involved cases in African and Asian countries (35.3 and 29.4%, respectively), and the prevalence of reported co-infections ranged from 0.1 to 60%. Conclusion Reports of HIV/PvCo are scarce in the literature, with only a few studies describing clinical and laboratory outcomes. Systematic screening for both co-infections is not routinely performed, and therefore the real prevalence of HIV/PvCo is unknown. This study showed a low prevalence of HIV/PvCo despite the high prevalence of malaria and HIV locally. Even though relatively small, this is the largest case series to describe HIV/PvCo.

BackgroundEvidence on the optimal time to initiate antiretroviral therapy (ART) in the presence of toxoplasmic encephalitis (TE) is scarce. We compared the impact of early vs. delayed ART initiation on mortality and neurologic complications at discharge in a Brazilian population co-infected with HIV and TE.MethodsWe retrospectively evaluated data from 9 years of hospitalizations at a referral center in Manaus, Amazonas. All ART-naïve hospitalized patients were divided into early initiation treatment (EIT) (0-4 weeks) and delayed initiation treatment (DIT) (>4 weeks). The groups were compared using chi-square test and mortality at 16 weeks.ResultsFour hundred sixty nine patients were included, of whom 357 (76.1%) belonged to the EIT group. The median CD4+ lymphocyte count and CD4+/CD8+ ratio were 53 cells/mm3 and 0.09, respectively. Mortality rate and presence of sequelae were 4.9% (n = 23) and 41.6% (n = 195), respectively. Mortality was similar between groups (p = 0.18), although the EIT group had the highest prevalence of sequelae at discharge (p = 0.04). The hazard ratio for death at 16 weeks with DIT was 2.3 (p = 0.18). The necessity for intensive care unit admission, mechanical ventilation, and cardiopulmonary resuscitation were similar between groups.ConclusionIn patients with AIDS and TE, early ART initiation might have a detrimental influence on the occurrence of sequelae.

Introduction BCG vaccination modulates immune responses to unrelated pathogens. This off-target effect could reduce the impact of emerging pathogens. As a readily available, inexpensive intervention that has a well-established safety profile, BCG is a good candidate for protecting healthcare workers (HCWs) and other vulnerable groups against COVID-19.Methods and analysis This international multicentre phase III randomised controlled trial aims to determine if BCG vaccination reduces the incidence of symptomatic and severe COVID-19 at 6 months (co-primary outcomes) compared with no BCG vaccination. We plan to randomise 10 078 HCWs from Australia, The Netherlands, Spain, the UK and Brazil in a 1:1 ratio to BCG vaccination or no BCG (control group). The participants will be followed for 1 year with questionnaires and collection of blood samples. For any episode of illness, clinical details will be collected daily, and the participant will be tested for SARS-CoV-2 infection. The secondary objectives are to determine if BCG vaccination reduces the rate, incidence, and severity of any febrile or respiratory illness (including SARS-CoV-2), as well as work absenteeism. The safety of BCG vaccination in HCWs will also be evaluated. Immunological analyses will assess changes in the immune system following vaccination, and identify factors associated with susceptibility to or protection against SARS-CoV-2 and other infections.Ethics and dissemination Ethical and governance approval will be obtained from participating sites. Results will be published in peer-reviewed open-access journals. The final cleaned and locked database will be deposited in a data sharing repository archiving system.Trial registration ClinicalTrials.gov NCT04327206

In the Brazilian Amazon, long distances, low healthcare coverage, common use of ineffective or deleterious self-care practices, and resistance to seeking medical assistance have an impact on access to antivenom treatment. This study aimed to estimate snakebite underreporting, and analyze barriers that prevent victims from obtaining healthcare in communities located in 15 municipalities on the banks of the Solimões, Juruá and Purus Rivers, in the remote Western Brazilian Amazon. Information on the participants' demographics, previous snakebites, access to healthcare, time taken to reach medical assistance, use of self-care practices, and the reason for not accessing healthcare were collected through semi-structured interviews. In the case of deaths, information was collected by interviewing parents, relatives or acquaintances. A total of 172 participants who reported having suffered snakebites during their lifetime were interviewed. A total of 73 different treatment procedures was reported by 65.1% of the participants. Participants living in different river basins share few self-care procedures that use traditional medicine, and 91 (52.9%) participants reported that they had access to healthcare. Living in communities along the Juruá River [OR = 12.6 (95% CI = 3.2-49.7; p

Background: Non-lactational infectious mastitis (NLIM) is an inflammatory breast disease with broad clinical presentation. Inadequate treatment can lead to chronic infections that cause breast deformities. NLIM information is limited, especially in the Americas. A systematic review and meta-analysis have been conducted here.Methods: Literature search was conducted in three databases (Lilacs, PubMed, and Scielo) on NLIM cases in the Americas. Demographic, epidemiological, clinical, radiological, and laboratory data were extracted. The main characteristics and results were also compared according to the country's gross national income.Results: A total of 47 articles were included, resulting in 93 cases. The etiological agent was described in 86 (92.5%) patients. Bacteria were the most prevalent etiology (73; 84.8%). Amongst bacterial diagnoses, more frequent cases were Mycobacterium tuberculosis (28; 38.4%); Corynebacterium spp. (15; 20.5%); non-tuberculous mycobacteria (13; 17.8%). The cases were reported in eight different countries, with the USA being the country with the highest number of cases (35; 37.6%). Patients from high-income countries group presented a shorter diagnostic time when compared to low, low-middle, and upper-middle-income countries. A greater number of radiographic studies with pathological findings were described in high-income countries.Conclusion: Non-lactational infectious mastitis is a complex public health problem with diagnostic and treatment challenges. Hence, multi-professional approach-based additional studies are recommended on its epidemiology, diagnosis, treatment, and control.

Abstract INTRODUCTION: Cardiovascular diseases (CDVs) have become increasingly important for progressively older people living with HIV (PLHIV). Identification of gaps requiring improvement in the care cascade for hypertension, a primary risk factor for CVDs, is of utmost importance. This study analyzed the prevalence of hypertensive status and described the care cascade for hypertension screening, diagnosis, treatment, treatment adherence, and management in PLHIV. METHODS: This cross-sectional study included 298 PLHIV (age >40 years) who visited a referral center in the western Brazilian Amazon. Data were collected through a structured questionnaire interview and medical examinations. Thus, information regarding sociodemographic and clinical aspects, blood pressure, weight, height, body mass index, and laboratory profile was obtained. Descriptive and analytical statistics were performed, and results were considered significant ifp

Bothrops atrox snakes are mostly endemic of the Amazon rainforest and is certainly the South American pit viper responsible for most of the snakebites in the region. The composition of B. atrox venom is significantly known and has been used to trace the relevance of the venom phenotype for snake biology and for the impacts in the clinics of human patients involved in accidents by B. atrox. However, in spite of the wide distribution and the great medical relevance of B. atrox snakes, B. atrox taxonomy is not fully resolved and the impacts of the lack of taxonomic resolution on the studies focused on venom or envenoming are currently unknown. B. atrox venom presents different degrees of compositional variability and is generally coagulotoxic, inducing systemic hematological disturbances and local tissue damage in snakebite patients. Antivenoms are the effective therapy for attenuating the clinical signs. This review brings a comprehensive discussion of the literature concerning B. atrox snakes encompassing from snake taxonomy, diet and venom composition, towards clinical aspects of snakebite patients and efficacy of the antivenoms. This discussion is highly supported by the contributions that venomics and antivenomics added for the advancement of knowledge of B. atrox snakes, their venoms and the treatment of accidents they evoke.

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.

Abstract Background Splenomegaly is one of the most common features of malaria. However, spontaneous splenic rupture, although unusual, represents a severe complication often leading to death. It is mostly seen in acute infection and primary attack, and it is most commonly associated with Plasmodium vivax. Here, a case of spontaneous splenic rupture diagnosed with a portable ultrasound apparatus shortly after starting treatment and with recurrent parasitaemia after splenectomy, is reported. Case description In November 2015, a 45-year-old Brazilian man presented to the hospital in Manaus with fever, headache and myalgia. He was diagnosed with P. vivax malaria and, after a normal G6PD test, he started treatment with chloroquine and primaquine and was discharged. Two days later, he went back to the hospital with abdominal pain, dyspnea, dry cough, pallor, oliguria and fever. Using a portable ultrasound, he was diagnosed of rupture of the spleen, which was removed by emergency surgery. After this episode, he suffered two more malaria episodes with high parasitaemia at approximately 2-month intervals. DNA from different portions of the spleen was extracted and a qualitative PCR was performed to detect P. vivax. Conclusions The splenic rupture suffered by this patient occurred 2 days after starting the treatment. Having a portable ultrasound apparatus may have saved the patient’s life, as it revealed a haemorrhage needing an urgent surgery. Parasites were detected by PCR in the extracted spleen. This patient suffered two more vivax malaria diagnosed episodes in spite of receiving and completing treatment with chloroquine and primaquine for each clinical attack. Splenic rupture during acute malaria is uncommon, but it is likely underdiagnosed and underreported, because the lack of means and equipment hinders diagnostic confirmation, especially in endemic areas.

Abstract Background Respiratory complications are uncommon, but often life-threatening features of Plasmodium vivax malaria. This study aimed to estimate the prevalence and lethality associated with such complications among P. vivax malaria patients in a tertiary hospital in the Western Brazilian Amazon, and to identify variables associated with severe respiratory complications, intensive care need and death. Medical records from 2009 to 2016 were reviewed aiming to identify all patients diagnosed with P. vivax malaria and respiratory complications. Prevalence, lethality and risk factors associated with WHO defined respiratory complications, intensive care need and death were assessed. Results A total of 587 vivax malaria patients were hospitalized during the study period. Thirty (5.1%) developed respiratory complications. Thirteen (43.3%) developed severe respiratory complications, intensive care was required for 12 (40%) patients and 5 (16.6%) died. On admission, anaemia and thrombocytopaenia were common findings, whereas fever was unusual. Patients presented different classes of parasitaemia and six were aparasitaemic on admission. Time to respiratory complications occurred after anti-malarials administration in 18 (60%) patients and progressed very rapidly. Seventeen patients (56.7%) had comorbidities and/or concomitant conditions, which were significantly associated to higher odds of developing severe respiratory complications, need for intensive care and death (p

Snakebites are more frequent in the Brazilian Amazon than in other parts of Brazil, representing a high cost for the health system since antivenoms are only available through medical prescription from central municipal hospitals in most cases. The need for a cold chain and physicians usually restricts access to the only effective treatment of a snakebite, the antivenom. The complex topography of the rivers contributes to delays in treatment, and consequently increases the risk of severe complications, chronic sequelae and death. Thus, decentralization of antivenom treatment to primary healthcare facilities in the interior would increase access by indigenous population groups to proper healthcare. To standardize and evaluate the decentralization to low complexity indigenous healthcare units, we suggest the (i) development and validation of standardized operational procedures, (ii) training of professionals in the validated protocol in a referral health unit, (iii) implementation of the protocol in an indigenous healthcare unit, (iv) assessment of perceptions towards and acceptability of the protocol, and (v) estimation of the impact of the protocol’s implementation. We expect that antivenom decentralization would shorten the time between diagnosis and treatment and, as such, improve the prognosis of snakebites. As health cosmology among indigenous populations has an important role in maintaining their way of life, the introduction of a new therapeutic strategy to their customs must take into account the beliefs of these peoples. Thus, antivenom administration would be inserted as a crucial therapeutic tool in a world of diverse social, natural and supernatural representations. The information presented here also serves as a basis to advocate for support and promotion of health policy initiatives focused on evidence-based care in snakebite management.

BACKGROUND:Chloroquine (CQ) is the main anti-schizontocidal drug used in the treatment of uncomplicated malaria caused by Plasmodium vivax. Chloroquine resistant P. vivax (PvCR) malaria in the Western Pacific region, Asia and in the Americas indicates a need for biomarkers of resistance to improve therapy and enhance understanding of the mechanisms associated with PvCR. In this study, we compared plasma metabolic profiles of P. vivax malaria patients with PvCR and chloroquine sensitive parasites before treatment to identify potential molecular markers of chloroquine resistance. METHODS:An untargeted high-resolution metabolomics analysis was performed on plasma samples collected in a malaria clinic in Manaus, Brazil. Male and female patients with Plasmodium vivax were included (n = 46); samples were collected before CQ treatment and followed for 28 days to determine PvCR, defined as the recurrence of parasitemia with detectable plasma concentrations of CQ ≥100 ng/dL. Differentially expressed metabolic features between CQ-Resistant (CQ-R) and CQ-Sensitive (CQ-S) patients were identified using partial least squares discriminant analysis and linear regression after adjusting for covariates and multiple testing correction. Pathway enrichment analysis was performed using Mummichog. RESULTS:Linear regression and PLS-DA methods yielded 69 discriminatory features between CQ-R and CQ-S groups, with 10-fold cross-validation classification accuracy of 89.6% using a SVM classifier. Pathway enrichment analysis showed significant enrichment (p

Abstract Background The World Health Organization (WHO) declared the end of the COVID-19 (SARS-CoV-2) global public health emergency on May 5, 2023, but its long-term consequences have still been haunting the global population. Post-acute sequelae of COVID-19 (PASC) and long-term COVID-19 are serious concerns and present with various symptoms. Intranasal chlorpheniramine (iCPM) has been shown to decrease the viral burden of SARS-COV-2. iCPM uses decreased COVID-19 disease progression and severity in Accelerating COVID-19 Clinical Recovery in an Outpatient Setting (ACROSS)-I & III randomized control trials (RCT). Methods This prospective survey study included 259 participants in ACROSS I and III RCTs. We compared the effect of iCPM versus placebo on the reduction of PASC symptoms. A PASC questionnaire containing 17 questions regarding the most common PASC symptoms was used in this study. T-test and Pearson chi-square statistics were performed according to continuous and categorical data using STATA 17.0 Basic Edition software. Findings The iCPM cohort had a lower proportion of patients with fatigue or tiredness vs. placebo (0 Vs 17, 21, p

Analizamos un aspecto de la obra de la autora que ha sido menos tenido en cuenta, su cultivo del artículo y del ensayo, sobre todo en dos libros de 1973 y 2002, ahora reeditados, significativamente ampliados, imprescindible para com prender sus ideas literarias, y cómo la creación siempre estuvo acompañada a lo largo de toda su trayectoria como escritora de un análisis y una reflexión crítica, pero también de las especulaciones propias del ensayo.

The development of effective HIV cure strategies is crucial. However, most research in this area has been concentrated in high-income countries, underscoring the need to expand efforts to regions like Latin America and the Caribbean (LAC), which face distinct biomedical, social, political, and economic challenges. Data on LAC’s participation in HIV cure research, along with stakeholder perceptions, reveal that the work being done in the region is scarce, fragmented, scattered, and characterized by limited resources and infrastructure. Establishing a regional consortium of basic researchers, clinicians, social scientists, and community members in LAC could be a key step in integrating the region into the global HIV cure landscape. We have already begun laying the groundwork for its creation and propose to name it ‘LAC-Cura’—short for ‘Latin America and the Caribbean HIV Cure Consortium’.

Abstract The diverse applications of light-matter interactions in science and technology stem from the qualitatively distinct ways these interactions manifest, prompting the development of physical platforms that can interchange between regimes on demand. Bosonic cQED employs the light field of high-Q superconducting cavities coupled to nonlinear circuit elements, harnessing the rich dynamics of their interaction for quantum information processing. However, implementing fast switching of the interaction regime without deteriorating the cavity coherence is a significant challenge. We present an experiment that achieves this feat, combining nanosecond-scale frequency tunability of a transmon coupled to a cavity with lifetime of hundreds of microseconds. Our implementation affords a range of useful capabilities for quantum information processing; from fast creation of cavity Fock states using resonant interaction and interchanging tomography techniques at qualitatively distinct interaction regimes on the fly, to the suppression of unwanted cavity-transmon dynamics during idle evolution. By bringing flux tunability into the bosonic cQED toolkit, our work opens up the possibility to probe the full range of light-matter interaction dynamics within a single platform and provides valuable pathways towards robust and versatile quantum information processing.

IntroductionEmerging evidence suggests that psoriasis and periodontitis are linked via systemic inflammation. However, the role of angiogenesis as an additional connecting mechanism between these diseases remains unclear.MethodsThis case control study explored the effect of psoriasis on the gingival crevicular fluid (GCF) levels of vascular endothelial growth factor A (VEGF-A) in patients with different stages of periodontitis. Thirty-one patients with psoriasis (P) and thirty healthy controls (C) underwent physical and intraoral evaluations, with diagnoses confirmed by dermatologists and periodontists. GCF VEGF-A was measured using a multiplex-bead immunoassay. Statistical analyses included Fisher exact tests, Student’s T-tests, linear regression models, and mediation analyses.ResultsPsoriasis patients had significantly lower GCF VEGF-A levels compared to controls (p=0.008). Psoriasis was negatively associated with GCF VEGF-A (p=0.006), while severe periodontitis was positively associated with GCF VEGF-A levels, regardless of tobacco use (p=0.027). Further analyses revealed that severe periodontitis significantly increased GCF VEGF-A levels only in the C group (p=0.038), but not in psoriasis patients (p>0.610). Mediation analyses confirmed a significant direct and total effect of psoriasis on GCF VEGF-A (p>0.002), with no significant indirect effect through periodontitis (p=0.699).DiscussionPsoriasis and severe periodontitis are associated with GCF levels of VEGF-A in opposite and independent ways. In subjects with psoriasis, the impact of the dermatosis is direct with no mediation from periodontitis.

Abstract Population loss in rural areas is rapidly increasing in high‐income countries, raising concerns and debate, given its socio‐economic consequences. Despite the evident environmental dimension of the phenomenon, ecological knowledge has been neglected in the analysis of actions aiming to reverse rural depopulation. Particularly, cultural landscapes reflect memories of ecological processes that have configured current patterns of biodiversity and ecosystem services. Based on ecological principles, we present a conceptual procedure to assess the behaviour of social–ecological systems subjected to depopulation, projecting their expected trajectories through time within a framework defined jointly by demographic and environmental–ecological dimensions (in our case, biodiversity, carbon storage, pollution control, water resources and soil conservation). We applied this procedure to various alternative interventions designed to confront depopulation in Spain: (1) non‐intervention, (2) maintenance of the historical landscape configuration, (3) active conservation, (4) extensive, sustainable land use and (5) intensified land use. We conclude that extensive, sustainable land use better optimizes criteria of demographic consolidation, environmental impact, resilience and implementation of actions confronting depopulation. We highlight the need to incorporate ecological knowledge into the assessment and application of actions confronting rural depopulation. Read the free Plain Language Summary for this article on the Journal blog.

Abstract Background It is internationally known that our population is aging. At the same time, some patients with COVID-19, due to their symptoms, required mechanical ventilation (MV) and subsequent pulmonary rehabilitation (PR). This study aimed to compare the effects of a multimodal PR program “ADULT” versus “OLDER” people with COVID-19 who were on MV. Methods The intervention consisted of an 8-week hybrid PR program (2x week). Forced vital capacity (FVC) was measured at the beginning and end of PR, upper and lower limb strength was obtained through hand grip strength (HGS) and the sit-to-stand test (STST), respectively, and functional exercise capacity was measured with the 6-minute walking test (6MWT). Results The main results were an increase in the FVC in the ADULT and OLDER groups (time effect, P = 0.000; η2 = 0.27), an increase in HGS in the ADULT and OLDER groups (time effect, P = 0.000; η2 = 0.52), in the same way, the number of repetitions on the STST increased in the ADULT and OLDER groups (time effect, P = 0.000; η2 = 0.55). Finally, the distance covered on the 6MWT increased in the ADULT and OLDER groups (time effect, P = 0.000; η2 = 0.65). Conclusions The PR program is an effective strategy to improve FVC, muscle strength, and functional exercise capacity similarly in adults and older people with post severe COVID-19 who required MV.

Abstract Key message In European mountain forests, the growth of silver fir (Abies alba Mill.), sycamore maple (Acer pseudoplatanus L.), European beech (Fagus sylvatica L.) and Norway spruce (Picea abies (L.) H. Karst.) seedlings is more strongly affected by ungulate browsing than by elevation. But, the constraint exerted by ungulates, in particular the probability for seedlings to be browsed, increases with elevation for most species. Context While concerns about mountain forest regeneration rise due to their high vulnerability to climate change, the increase in wild ungulate populations and the expansion of their range in the last decades exert an additional constraint on the survival and growth of young trees. Understanding how this constraint can vary with elevation is thus a key to assess the consequences of this population increase for the regeneration of mountain forests. Aims In this study, we investigate the effect of elevation on (i) the occurrence of browsing for seedlings and on (ii) the reduction in seedling growth induced by ungulate browsing. Methods We monitored height growth and browsing occurrence on silver fir, sycamore maple, European beech and Norway spruce seedlings across seven elevation gradients (from 400 to 2013 m) located from France to northern Sweden. Results Seedlings of the two most palatable species—fir and maple—were more likely to be browsed at high elevation while the opposite effect was observed for spruce. Browsing strongly reduced seedling growth for all species but Norway spruce, while elevation had no direct effect on seedling growth. This browsing-induced growth reduction was stronger at high elevation for fir seedlings. Conclusions Browsing is overall a stronger constraint on seedling growth than elevation for four dominant species of European mountain forests. Elevation can, however, affect both browsing probability and the effect of browsing on seedling growth. Our results highlight the importance of taking into account ungulate pressure and its interactive effect with elevation when forecasting the regeneration of mountain forests under a changing climate.

Quantum state reconstruction is an essential element in quantum information processing. However, efficient and reliable reconstruction of nontrivial quantum states in the presence of hardware imperfections can be challenging. This task is particularly demanding for high-dimensional states encoded in continuous-variable (CV) systems, where a large number of grid-based measurements are often used to adequately sample relevant regions of phase space. In this work, we introduce an efficient and robust technique of optimized reconstruction with excitation-number sampling (ORENS) based on the idea of the generalized Q function. We use a standard bosonic circuit quantum electrodynamics (cQED) setup to experimentally demonstrate effective state reconstruction using the theoretically minimum number of measurements. Our investigation highlights that ORENS is naturally free of parasitic system dynamics and resilient to decoherence effects in the hardware, enabling it to outperform the conventional reconstruction techniques in cQED such as Wigner tomography. Finally, ORENS relies only on the ability to accurately measure the excitation number of a given CV state, making it a versatile and accessible tool for a wide range of CV platforms and readily scalable to multimode systems. Thus, our work provides a crucial and valuable primitive for practical quantum information processing using bosonic modes.

RNA-binding proteins (RBPs) are cellular factors involved in every step of RNA metabolism. During HIV-1 infection, these proteins are key players in the fine-tuning of viral and host cellular and molecular pathways, including (but not limited to) viral entry, transcription, splicing, RNA modification, translation, decay, assembly, and packaging, as well as the modulation of the antiviral response. Targeted studies have been of paramount importance in identifying and understanding the role of RNA-binding proteins that bind to HIV-1 RNAs. However, novel approaches aimed at identifying all the proteins bound to specific RNAs (RBPome), such as RNA interactome capture, have also contributed to expanding our understanding of the HIV-1 replication cycle, allowing the identification of RBPs with functions not only in viral RNA metabolism but also in cellular metabolism. Strikingly, several of the RBPs found through interactome capture are not canonical RBPs, meaning that they do not have conventional RNA-binding domains and are therefore not readily predicted as being RBPs. Further studies on the different cellular targets of HIV-1, such as subtypes of T cells or myeloid cells, or on the context (active replication versus reactivation from latency) are needed to fully elucidate the host RBPome bound to the viral RNA, which will allow researchers and clinicians to discover new therapeutic targets during active replication and provirus reactivation from latency.

Objective: This study evaluated the effects of advanced footwear technology (AFT) spikes on running performance measures, spatiotemporal variables, and perceptive parameters on different surfaces (track and grass). Methods: Twenty-seven male trained runners were recruited for this study. In Experiment 1, participants performed 12 × 200 m at a self-perceived 3000 m running pace with a recovery of 5 min. Performance (time in each repetition), spatiotemporal, and perceptive parameters were measured. In Experiment 2, participants performed 8 × 5 min at 4.44 m/s while energy cost of running (W/kg), spatiotemporal, and perceptive parameters were measured. In both experiments the surface was randomized and mirror order between spike conditions (Polyether Block Amide (PEBA) and PEBA + Plate) was used. Results: Experiment 1: Runners were faster on the track (p = 0.002) and using PEBA + Plate spike (p = 0.049). Experiment 2: Running on grass increased energy cost (p = 0.03) and heart rate (p < 0.001) regardless of the spike used, while PEBA + Plate spike reduced respiratory exchange ratio (RER) (p = 0.041). Step frequency was different across surfaces (p < 0.001) and spikes (p = 0.002), with increased performance and comfort perceived with PEBA + Plate spikes (p < 0.001; p = 0.049). Conclusions: Running on the track surface with PEBA + Plate spikes enhanced auto-perceived 3000 m running performance, showed lower RER, and improved auto-perceptive comfort and performance. Running on grass surfaces increased energy cost and heart rate without differences between spike conditions.