Impact of Anti-CMV IgG Titers and CD34 Count Prior to Hematopoietic Stem Cell Transplantation from Alternative Donors on CMV reactivation.

Cytomegalovirus (CMV) reactivation remains one of the main infectious complications following hematopoietic stem cell transplantation (HSCT). In this study, we explored the role of anti-CMV antibody titers in HSCT from alternative donors and to compare the risk of CMV reactivation between posttransplant cyclophosphamide-based haploidentical HSCT and antithymocyte globulin-based unrelated donor (URD) HSCT. We included 98 CMV-positive patients, 30 undergoing haploidentical HSCT and 68 undergoing URD HSCT. The majority of patients had a malignant disease (84%), received a myeloablative conditioning regimen (78%), and received a bone marrow graft (90%). The median pretransplantation anti-CMV IgG level was 109 U/mL. With median follow-up of 2.2 years, a total of 72 CMV reactivations occurred in 50 patients. There was no difference in CMV reactivation pattern between haploidentical HSCT recipients and URD HSCT recipients. In multivariable analysis until the first event, the incidence of CMV reactivation was higher in patients with anti-CMV IgG levels >100 U/mL (hazard ratio [HR], 2.38; P = .005) and in patients diagnosed with grade II-IV acute graft-versus-host disease (GVHD) (HR, 10.8; P = .003) after day +50 and lower in patients who received higher doses of CD34 cells (HR, .44; P = .006). In multivariable analysis for recurring events, the incidence of CMV reactivation was higher in patients receiving reduced-intensity conditioning (HR, 1.69: P = .04) and in patients with acute GVHD (HR, 1.88; P = .02), and lower in those who received higher doses of CD34 cells (HR, .55; P = .01). In summary, we have shown that pretransplantation anti-CMV IgG titers are correlated with CMV reactivation risk. More studies are needed to assess how this information can be incorporated in HSCT. The use of high-dose cellular grafts, a modifiable risk factor, also protects against CMV reactivation.

Haploidentical Transplantation with Post-Transplant Cyclophosphamide versus Unrelated Donor Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis.

Hematopoietic stem cell transplantation (HSCT) is the standard treatment for patients with high-risk hematologic malignancies. Only approximately 25% of siblings are HLA-matched, and thus alternative donors-unrelated or haploidentical-are usually the only options available. This meta-analysis aimed to compare haploidentical HSCT with post-transplantation cyclophosphamide and unrelated donor (URD) HSCT. We searched the PubMed and Cochrane databases for pertinent studies indexed between 2008 and 2018. Twenty observational studies (with a total of 1783 haploidentical HSCT recipients and 6077 URD HSCT recipients) were included. Results for overall survival, graft-versus-host disease (GVHD), nonrelapse mortality (NRM), and relapse incidence were pooled. Measures of association used were hazard ratios and risk differences. The median age was 51 years for haploidentical transplant recipients and 52 years for URD transplant recipients. Peripheral blood stem cell (PBSC) grafts were more frequent in the URD transplant recipients (85%) than in the haploidentical transplant recipients (31%). Overall survival was not different between the 2 groups. NRM was lower for haploidentical transplantation. All forms of GVHD (acute grades II-IV and III-IV and moderate, severe, and extensive chronic) were lower with haploidentical donor HSCT. The risk of chronic GVHD was fairly proportional to the differential use of PBSC grafts across studies, however. All included studies were retrospective, representing the major limitation of this meta-analysis. In conclusion, haploidentical HSCT for hematologic malignancies achieved the same overall survival as URD HSCT, with a lower incidence of GVHD and NRM. The increased frequency of PBSC use in the unrelated donor group could partially explain the higher cGVHD rate. Haploidentical transplantation with post-transplantation cyclophosphamide should strongly be considered as the first option for adult patients with hematologic malignancies who do not have matched sibling donors in experienced centers. This systematic review has been registered at PROSPERO (65790).

Reference Values for Human Posture Measurements Based on Computerized Photogrammetry: A Systematic Review.

OBJECTIVE: The main objective of this study was to review the literature to identify reference values for angles and distances of body segments related to upright posture in healthy adult women with the Postural Assessment Software (PAS/SAPO). METHODS: Electronic databases (BVS, PubMed, SciELO and Scopus) were assessed using the following descriptors: evaluation, posture, photogrammetry, physical therapy, postural alignment, postural assessment, and physiotherapy. Studies that performed postural evaluation in healthy adult women with PAS/SAPO and were published in English, Portuguese and Spanish, between the years 2005 and 2014 were included. RESULTS: Four studies met the inclusion criteria. Data from the included studies were grouped to establish the statistical descriptors (mean, variance, and standard deviation) of the body angles and distances. A total of 29 variables were assessed (10 in the anterior views, 16 in the lateral right and left views, and 3 in the posterior views), and its respective mean and standard deviation were calculated. Reference values for the anterior and posterior views showed no symmetry between the right and left sides of the body in the frontal plane. There were also small differences in the calculated reference values for the lateral view. CONCLUSION: The proposed reference values for quantitative evaluation of the upright posture in healthy adult women estimated in the present study using PAS/SAPO could guide future studies and help clinical practice.

NOD2 and CCDC122-LACC1 genes are associated with leprosy susceptibility in Brazilians.

Leprosy is a complex disease with phenotypes strongly influenced by genetic variation. A Chinese genome-wide association study (GWAS) depicted novel genes and pathways associated with leprosy susceptibility, only partially replicated by independent studies in different ethnicities. Here, we describe the results of a validation and replication study of the Chinese GWAS in Brazilians, using a stepwise strategy that involved two family-based and three independent case-control samples, resulting in 3,614 individuals enrolled. First, we genotyped a family-based sample for 36 tag single-nucleotide polymorphisms (SNPs) of five genes located in four different candidate loci: CCDC122-LACC1, NOD2, TNFSF15 and RIPK2. Association between leprosy and tag SNPs at NOD2 (rs8057431) and CCDC122-LACC1 (rs4942254) was then replicated in three additional, independent samples (combined OR(AA) = 0.49, P = 1.39e-06; OR(CC) = 0.72, P = 0.003, respectively). These results clearly implicate the NOD2 pathway in the regulation of leprosy susceptibility across diverse populations.

The effectiveness of COVID-19 vaccines against severe cases and deaths in Brazil from 2021 to 2022: a registry-based study.

Background: Brazil started the COVID-19 mass vaccination in January 2021 with CoronaVac and ChAdOx1, followed by BNT162b2 and Ad26.COV2.S vaccines. By the end of 2021, more than 317 million vaccine doses were administered in the adult population. This study aimed at estimating the effectiveness of the primary series of COVID-19 vaccination and booster shots in protecting against severe cases and deaths in Brazil during the first year of vaccination. Methods: A cohort dataset of over 158 million vaccination and severe cases records linked from official national registries was analyzed via a mixed-effects Poisson model, adjusted for age, state of residence, time after immunization, and calendar time to estimate the absolute vaccine effectiveness of the primary series of vaccination and the relative effectiveness of the booster. The method permitted analysis of effectiveness against hospitalizations and deaths, including in the periods of variant dominance. Findings: Vaccine effectiveness against severe cases and deaths remained over 25% and 50%, respectively, after 19 weeks from primary vaccination of BNT162b2, ChAdOx1, or CoronaVac vaccines. The boosters conferred greater protection than the primary series of vaccination, with heterologous boosters providing marginally greater protection than homologous. The effectiveness against hospitalization during the Omicron dominance in the 60+ years old population started at 61.7% (95% CI, 26.1-86.2) for ChAdOx1, 95.6% (95% CI, 82.4-99.9) for CoronaVac, and 72.3% (95% CI, 51.4-87.4) for the BNT162b2 vaccine. Interpretation: This study provides real-world evidence of the effectiveness of COVID-19 vaccination in Brazil, including during the Omicron wave, demonstrating protection even after waning effectiveness. Comparisons of the effectiveness among different vaccines require caution due to potential bias effects related to age groups, periods in the pandemic, and eventual behavioural changes. Funding: Fundação Oswaldo Cruz (FIOCRUZ), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ), Pan American Health Organization (PAHO), Departamento de Ciência e Tecnologia da Secretaria de Ciência, Tecnologia, Inovação e Insumos Estratégicos em Saúde do Ministério da Saúde do Brasil (DECIT/SCTIE/MS).

Proteomic profiling of skeletal muscle in an animal model of overtraining.

Excessive training (i.e. overtraining, OT) may result in underperformance, which can be characterized by the time needed to re-establish performance (i.e. functional overreaching (FOR), nonfunctional overreaching, OT syndrome). The present study is an initial screening for proteins presenting altered abundance in the red (RG) and white (WG) portions of the gastrocnemius muscle from rats submitted to an OT protocol that induced FOR. In the RG, compared to the nontrained control, FOR demonstrated an increased abundance of proteins normally related to adaptation to endurance training (e.g. proteins of oxidative phosphorylation complexes, proteins related to lipid metabolism, antioxidants, and chaperones). In the WG, spots identified as mitochondrial aconitase and a component of the succinate dehydrogenase complex were downregulated in FOR, as were proteins related to myofibril stabilization; these latter were upregulated in the RG. This initial study shows that skeletal muscles with different fiber-type compositions respond differently to an OT period. Also, it is likely that actin-interacting proteins have an important role in muscle adaptation to endurance exercise.

Assessing the underreporting of deaths among people living with HIV in Rio de Janeiro, Brazil, from 2014 to 2019.

We assessed the proportions and causes of the underreporting of deaths among people living with HIV (PLHIV) in Rio de Janeiro, Brazil, from 2014 to 2019. Demographic variables, mention of tuberculosis (TB), and CD4 cell counts closest to death were used to compare those who had HIV/AIDS mentioned on their death certificate (HMDC) to those who did not. Out of 10,698 deaths, 2,863 (26.8%) had no HMDC, from which 412 (14.4%) had external underlying cause. After excluding deaths from external causes, we found that 24% still had no HMDC. Age ≥ 40 years (OR = 1.75; 95%CI: 1.52-2.01), non-white race/ethnicity (OR = 1.16; 95%CI: 1.02-1.31), the male gender (OR = 1.25; 95%CI: 1.11-1.42), higher CD4 cell counts closest to death (OR = 1.14; 95%CI: 1.12-1.16), absence of TB (OR = 4.86; 95%CI: 3.76-6.29) and not dying within a hospital (OR = 2.61; 95%CI: 2.31-2.95) were associated with increased probabilities of not having HMDC. The proportion of deaths with no HMDC increased from 18.7% to 35.1% between 2014 and 2019. The high proportion of underreported deaths in Rio de Janeiro indicates that HIV/AIDS mortality coefficients in the state may be underestimated. With the changing patterns of mortality of PLHIV, physicians are advised to consider the broader clinical spectrum of HIV infection, and surveillance officers should improve death monitoring.

Identification of priority groups for COVID-19 vaccination in Brazil. / Identificação de grupos prioritários para a vacinação contra COVID-19 no Brasil.

In a context of community transmission and shortage of vaccines, COVID-19 vaccination should focus on directly reducing the morbidity and mortality caused by the disease. It was thus essential to define priority groups for vaccination by the Brazilian National Immunization Program (PNI in Portuguese), based on the risk of hospitalization and death from the disease. We calculated overrisk according to sex, age group, and comorbidities using hospitalization and death records from severe acute respiratory illness with confirmation of COVID-19 (SARI-COVID) in all of Brazil in the first 6 months of the epidemic. Higher overrisk was associated with male sex (hospitalization = 1.1 and death = 1.2), age over 45 years for hospitalization (OvRag ranging from 1.1 to 8.5), and age over 55 year for death (OvRag ranging from 1.5 to 18.3). In the groups with comorbidities, chronic kidney disease, diabetes mellitus, cardiovascular disease, and chronic lung disease were associated with overrisk, while there was no such evidence for asthma. Chronic kidney disease or diabetes and age over 60 showed an even stronger association, reaching overrisk of death 14 and 10 times greater than in the general population, respectively. For all the comorbidities, there was higher overrisk at older ages, with a downward gradient in the oldest age groups. This pattern was reversed when examining overrisk in the general population, for both hospitalization and death. The current study provided evidence of overrisk of hospitalization and death from SARI-COVID, assisting the definition of priority groups for COVID-19 vaccination.

Em um contexto de transmissão comunitária e escassez de vacinas, a vacinação contra a COVID-19 deve focar na redução direta da morbidade e da mortalidade causadas pela doença. Portanto, é fundamental a definição de grupos prioritários para a vacinação pelo Programa Nacional de Imunizações (PNI), baseada no risco de hospitalização e óbito pela doença. Para tal, calculamos o sobrerrisco por sexo, faixa etária e comorbidades por meio dos registros de hospitalização e óbito por síndrome respiratória aguda grave com confirmação de COVID-19 (SRAG-COVID) em todo o Brasil nos primeiros seis meses de epidemia. Apresentaram maior sobrerrisco pessoas do sexo masculino (hospitalização = 1,1 e óbito = 1,2), pessoas acima de 45 anos para hospitalização (SRfe variando de 1,1 a 8,5) e pessoas acima de 55 anos para óbitos (SRfe variando de 1,5 a 18,3). Nos grupos de comorbidades, doença renal crônica, diabetes mellitus, doença cardiovascular e pneumopatia crônica conferiram sobrerrisco, enquanto para asma não houve evidência. Ter doença renal crônica ou diabetes mellitus e 60 anos ou mais mostrou-se um fator ainda mais forte, alcançando sobrerrisco de óbito 14 e 10 vezes maior do que na população geral, respectivamente. Para todas as comorbidades, houve um sobrerrisco mais alto em idades maiores, com um gradiente de diminuição em faixas mais altas. Esse padrão se inverteu quando consideramos o sobrerrisco em relação à população geral, tanto para hospitalização quanto para óbito. O presente estudo forneceu evidências a respeito do sobrerrisco de hospitalização e óbito por SRAG-COVID, auxiliando na definição de grupos prioritários para a vacinação contra a COVID-19.

En un contexto de transmisión comunitaria y escasez de vacunas, la vacunación contra la COVID-19 debe enfocarse en la reducción directa de la morbilidad y de la mortalidad causadas por la enfermedad. Por lo tanto, es fundamental la definición de grupos prioritarios para la vacunación por el Programa Nacional de Inmunizaciones (PNI), basada en el riesgo de hospitalización y óbito por la enfermedad. Para tal fin, calculamos el sobrerriesgo por sexo, franja de edad y comorbilidades mediante los registros de hospitalización y óbito por síndrome respiratorio agudo grave con confirmación de COVID-19 (SRAG-COVID) en todo Brasil, durante los primeros seis meses de epidemia. Presentaron mayor sobrerriesgo personas del sexo masculino (hospitalización = 1,1 y óbito = 1,2), personas por encima de 45 años para hospitalización (SRfe variando de 1,1 a 8,5) y personas por encima de 55 años para óbitos (SRfe variando de 1,5 a 18,3). En los grupos de comorbilidades, enfermedad renal crónica, diabetes mellitus, enfermedad cardiovascular y neumopatía crónica ofrecieron sobrerriesgo, mientras que para el asma no hubo evidencia. Sufrir una enfermedad renal crónica o diabetes mellitus y tener 60 años o más mostró un factor todavía más fuerte, alcanzando sobrerriesgo de enfermedad 14 y 10 veces mayor que en la población general, respectivamente. Para todas las comorbilidades, hubo un sobrerriesgo más alto en edades mayores, con un gradiente de disminución en franjas más altas. Este patrón se invirtió cuando consideramos el sobrerriesgo en relación con la población general, tanto para hospitalización como para óbito. El presente estudio proporcionó evidencias respecto al sobrerriesgo de hospitalización y óbito por SRAG-COVID, ayudando en la definición de grupos prioritarios para la vacunación contra la COVID-19.

Putative pathogen-selected polymorphisms in the PKLR gene are associated with mycobacterial susceptibility in Brazilian and African populations.

Pyruvate kinase (PK), encoded by the PKLR gene, is a key player in glycolysis controlling the integrity of erythrocytes. Due to Plasmodium selection, mutations for PK deficiency, which leads to hemolytic anemia, are associated with resistance to malaria in sub-Saharan Africa and with susceptibility to intracellular pathogens in experimental models. In this case-control study, we enrolled 4,555 individuals and investigated whether PKLR single nucleotide polymorphisms (SNPs) putatively selected for malaria resistance are associated with susceptibility to leprosy across Brazil (Manaus-North; Salvador-Northeast; Rondonópolis-Midwest and Rio de Janeiro-Southeast) and with tuberculosis in Mozambique. Haplotype T/G/G (rs1052176/rs4971072/rs11264359) was associated with leprosy susceptibility in Rio de Janeiro (OR = 2.46, p = 0.00001) and Salvador (OR = 1.57, p = 0.04), and with tuberculosis in Mozambique (OR = 1.52, p = 0.07). This haplotype downregulates PKLR expression in nerve and skin, accordingly to GTEx, and might subtly modulate ferritin and haptoglobin levels in serum. Furthermore, we observed genetic signatures of positive selection in the HCN3 gene (xpEHH>2 -recent selection) in Europe but not in Africa, involving 6 SNPs which are PKLR/HCN3 eQTLs. However, this evidence was not corroborated by the other tests (FST, Tajima's D and iHS). Altogether, we provide evidence that a common PKLR locus in Africans contribute to mycobacterial susceptibility in African descent populations and also highlight, for first, PKLR as a susceptibility gene for leprosy and TB.

Description and comparison of demographic characteristics and comorbidities in SARI from COVID-19, SARI from influenza, and the Brazilian general population. / SRAG por COVID-19 no Brasil: descrição e comparação de características demográficas e comorbidades com SRAG por influenza e com a população geral.

The study aims to describe patients hospitalized for severe acute respiratory illness (SARI) due to COVID-19 (SARI-COVID) in Brazil according to demographic characteristics and comorbidities up to the 21st Epidemiological Week of 2020. The study aimed to compare these characteristics with those of patients hospitalized for SARI due to influenza in 2019/2020 (SARI-FLU) and with the Brazilian general population. The proportions of demographic characteristics, comorbidities, and pregnant and postpartum women among patients hospitalized for SARI-COVID and SARI-FLU were obtained from the SIVEP-Gripe database, and the estimates for the Brazilian population were obtained from the population projections performed by Brazilian Institute of Geography and Statistics, Information System on Live Birth data, and nationwide surveys. Compared to the Brazilian population, patients hospitalized for SARI-COVID showed a higher proportion of males, elderly individuals and those aged 40 to 59 years, comorbidities (diabetes mellitus, cardiovascular disease, chronic kidney disease, and chronic lung diseases), and pregnant/postpartum women. Compared to the general population, Brazilians hospitalized for SARI-FLU showed higher prevalence rates of ages 0 to 4 years or over 60 years, white race/color, comorbidities (diabetes, chronic kidney disease, asthma, and other chronic lung diseases), and pregnant/postpartum women. The data suggest that these groups are evolving to more serious forms of the disease, so that longitudinal studies are extremely relevant for investigating this hypothesis and supporting appropriate public health policies.

Mortality profiles among people living with HIV/AIDS: comparison between Rio de Janeiro and other federative units between 1999 and 2015. / Perfis de mortalidade em pessoas vivendo com HIV/aids: comparação entre o Rio de Janeiro e as demais unidades da federação entre 1999 e 2015.

INTRODUCTION: The trend toward stabilization regarding the AIDS epidemic in Brazil over the past decade hides a very complex scenario, where two-thirds of the Brazilian federative units exhibit AIDS standardized mortality rates (ASMR) significantly above the national average and/or in upward tendency. ASMR in Rio de Janeiro State remains virtually unchanged over the years; the state currently occupies the second position in the national ranking of this indicator. OBJECTIVE: To assess temporal trends in causes of death searching for differential profiles that could be useful for understanding mortality among patients with HIV in the state. METHODOLOGY: Causes of death were analyzed in any field of the death certificates from the Mortality Information System between 1999 and 2015 for individuals ≥ 15 years of age. Cardiovascular diseases, non-AIDS-related cancers, external causes, diabetes mellitus, and tuberculosis were established by the mention or not of their codes according to the 10th edition of International Statistical Classification of Diseases and Related Health Problems (ICD-10) in death certificates. Generalized linear mixed-effects models were used to describe odds ratios in relation to 1999 and adjusted mean annual variations. RESULTS: The results point to the emerging role of external causes and genitourinary diseases and the persistent role played by tuberculosis, differentially affecting AIDS mortality in the state, in a scenario of high mortality due to infectious diseases. CONCLUSION: These data suggest that tuberculosis remains a major cause of death among people living with HIV/AIDS (PLWHA) in Rio de Janeiro, highlighting the need for studies that identify individual-level factors impacting their survival, thus improving local HIV/AIDS control measures.

INTRODUÇÃO: A aparente estabilidade da mortalidade por aids no país na última década encobre uma gama de cenários, com dois terços dos estados apresentando taxa padronizada de mortalidade por aids (TPMA) significativamente acima da média nacional e/ou em tendência ascendente. No Rio de Janeiro, a TPMA vem mantendo-se alta e estável ao longo dos anos; atualmente o estado ocupa a segunda posição no ranking nacional desse indicador. OBJETIVO: Examinar tendências temporais em causas de óbito na busca de padrões diferenciais que contribuam para o entendimento da mortalidade por aids no estado. METODOLOGIA: Foram analisadas causas de óbito em qualquer campo das declarações de óbito constantes do Sistema de Informação sobre Mortalidade (SIM) entre 1999 e 2015 para indivíduos ≥ 15 anos. Doenças cardiovasculares, malignidades não relacionadas à aids, causas externas, diabetes melito e tuberculose foram estabelecidas pela menção ou não de seus códigos conforme a Classificação Estatística Internacional de Doenças e Problemas Relacionados com a Saúde (CID-10) nas declarações de óbito. Modelos lineares generalizados com efeitos mistos foram usados para descrever odds ratios relativas a 1999 e variações anuais médias ajustadas. RESULTADOS: Verificaram-se o aumento proporcional em causas externas e doenças geniturinárias e, sobretudo, o persistente papel desempenhado pela tuberculose, impactando diferencialmente a mortalidade por aids no estado, em um cenário de alta mortalidade por doenças infecciosas. CONCLUSÃO: Os achados reforçam a manutenção da tuberculose na mortalidade de pessoas vivendo com HIV/aids (PVHA) no Rio de Janeiro e chamam a atenção para a necessidade de avaliar determinantes individuais atuando na redução da sobrevida desses pacientes, de forma a aprimorar o programa de controle do HIV/aids no estado.

Influence of Angiotensin-converting Enzyme Insertion/Deletion Gene Polymorphism in Progression of Chagas Heart Disease.

INTRODUCTION: Chagas disease (CD) is a neglected disease caused by the parasite Trypanosoma cruzi. One-third of infected patients will develop the cardiac form, which may progress to heart failure (HF). However, the factors that determine disease progression remain unclear. Increased angiotensin II activity is a key player in the pathophysiology of HF. A functional polymorphism of the angiotensin-converting enzyme (ACE) gene is associated with plasma enzyme activity. In CD, ACE inhibitors have beneficial effects supporting the use of this treatment in chagasic cardiomyopathy. METHODS: We evaluated the association of ACE I/D polymorphism with HF, performing a case-control study encompassing 343 patients with positive serology for CD staged as non-cardiomyopathy (stage A; 100), mild (stage B1; 144), and severe (stage C; 99) forms of Chagas heart disease. For ACE I/D genotyping by PCR, groups were compared using unconditional logistic regression analysis and adjusted for nongenetic covariates: age, sex, and trypanocidal treatment. RESULTS: A marginal, but not significant (p=0.06) higher prevalence of ACE I/D polymorphism was observed in patients in stage C compared with patients in stage A. Patients in stage C (CD with HF), were compared with patients in stages A and B1 combined into one group (CD without HF); DD genotype/D carriers were prevalent in the HF patients (OR = 2; CI = 1.013.96; p = 0.04). CONCLUSIONS: Our results of this cohort study, comprising a population from the Northeast region of Brazil, suggest that ACE I/D polymorphism is more prevalent in the cardiac form of Chagas disease with HF.

Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial.

Importance: There is no specific antiviral therapy recommended for coronavirus disease 2019 (COVID-19). In vitro studies indicate that the antiviral effect of chloroquine diphosphate (CQ) requires a high concentration of the drug. Objective: To evaluate the safety and efficacy of 2 CQ dosages in patients with severe COVID-19. Design, Setting, and Participants: This parallel, double-masked, randomized, phase IIb clinical trial with 81 adult patients who were hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was conducted from March 23 to April 5, 2020, at a tertiary care facility in Manaus, Brazilian Amazon. Interventions: Patients were allocated to receive high-dosage CQ (ie, 600 mg CQ twice daily for 10 days) or low-dosage CQ (ie, 450 mg twice daily on day 1 and once daily for 4 days). Main Outcomes and Measures: Primary outcome was reduction in lethality by at least 50% in the high-dosage group compared with the low-dosage group. Data presented here refer primarily to safety and lethality outcomes during treatment on day 13. Secondary end points included participant clinical status, laboratory examinations, and electrocardiogram results. Outcomes will be presented to day 28. Viral respiratory secretion RNA detection was performed on days 0 and 4. Results: Out of a predefined sample size of 440 patients, 81 were enrolled (41 [50.6%] to high-dosage group and 40 [49.4%] to low-dosage group). Enrolled patients had a mean (SD) age of 51.1 (13.9) years, and most (60 [75.3%]) were men. Older age (mean [SD] age, 54.7 [13.7] years vs 47.4 [13.3] years) and more heart disease (5 of 28 [17.9%] vs 0) were seen in the high-dose group. Viral RNA was detected in 31 of 40 (77.5%) and 31 of 41 (75.6%) patients in the low-dosage and high-dosage groups, respectively. Lethality until day 13 was 39.0% in the high-dosage group (16 of 41) and 15.0% in the low-dosage group (6 of 40). The high-dosage group presented more instance of QTc interval greater than 500 milliseconds (7 of 37 [18.9%]) compared with the low-dosage group (4 of 36 [11.1%]). Respiratory secretion at day 4 was negative in only 6 of 27 patients (22.2%). Conclusions and Relevance: The preliminary findings of this study suggest that the higher CQ dosage should not be recommended for critically ill patients with COVID-19 because of its potential safety hazards, especially when taken concurrently with azithromycin and oseltamivir. These findings cannot be extrapolated to patients with nonsevere COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04323527.

IFNG +874T/A, IL10 -1082G/A and TNF -308G/A polymorphisms in association with tuberculosis susceptibility: a meta-analysis study.

Susceptibility to infectious diseases is influenced by genetic background and efficient cellular immune activation is responsible for protection. In tuberculosis (TB), interferon-gamma (IFNgamma) is crucial to control intracellular growth of Mycobacterium tuberculosis while interleukin-10 (IL-10) has an antagonistic role. Tumor necrosis factor (TNF) is a central mediator of granuloma formation and control of bacilli spread synergizing with IFNgamma to hamper M. tuberculosis infection. Single nucleotide polymorphisms (SNPs) located at these genes could influence cytokine levels and regulate resistance and susceptibility to TB. The aim of this study was to determine the association of the interferon-gamma gene (IFNG) +874T/A, interleukin-10 gene (IL10) -1082G/A and tumor necrosis factor gene (TNF) -308G/A SNPs with TB in several populations using meta-analysis. We searched for association studies correlating these polymorphisms and TB using pre-established keywords in Medline. Meta-analysis was conducted with random effects models to account for heterogeneity between studies. Eleven studies were included in the IFNG +874T/A meta-analysis, while eight were used for the IL10 -1082G/A, and 10 were employed for TNF -308G/A. Data were analyzed in respect to associations between alleles, genotypes and minor allele carriers. Statistically significant results were found only for IFNG. The +874T allele of IFNG showed a protective significant association (OR = 0.75; 95% CI, 0.634-0.887; P = 0.0008). Though not significant, IL10 presented a trend towards protection when only studies with pulmonary TB patients were considered. This data reinforces the critical importance of IFNG +874T/A as a genetic marker for TB resistance and this information can be used for better design of a TB vaccine.

A comparison of accuracy and computational feasibility of two record linkage algorithms in retrieving vital status information from HIV/AIDS patients registered in Brazilian public databases.

BACKGROUND AND OBJECTIVE: While cross-referencing information from people living with HIV/AIDS (PLWHA) to the official mortality database is a critical step in monitoring the HIV/AIDS epidemic in Brazil, the accuracy of the linkage routine may compromise the validity of the final database, yielding to biased epidemiological estimates. We compared the accuracy and the total runtime of two linkage algorithms applied to retrieve vital status information from PLWHA in Brazilian public databases. METHODS: Nominally identified records from PLWHA were obtained from three distinct government databases. Linkage routines included an algorithm in Python language (PLA) and Reclink software (RlS), a probabilistic software largely utilized in Brazil. Records from PLWHA1 known to be alive were added to those from patients reported as deceased. Data were then searched into the mortality system. Scenarios where 5% and 50% of patients actually dead were simulated, considering both complete cases and 20% missing maternal names. RESULTS: When complete information was available both algorithms had comparable accuracies. In the scenario of 20% missing maternal names, PLA2 and RlS3 had sensitivities of 94.5% and 94.6% (p > 0.5), respectively; after manual reviewing, PLA sensitivity increased to 98.4% (96.6-100.0) exceeding that for RlS (p < 0.01). PLA had higher positive predictive value in 5% death proportion. Manual reviewing was intrinsically required by RlS in up to 14% register for people actually dead, whereas the corresponding proportion ranged from 1.5% to 2% for PLA. The lack of manual inspection did not alter PLA sensitivity when complete information was available. When incomplete data was available PLA sensitivity increased from 94.5% to 98.4%, thus exceeding that presented by RlS (94.6%, p < 0.05). RlS spanned considerably less processing time compared to PLA. CONCLUSION: Both linkage algorithms presented interchangeable accuracies in retrieving vital status data from PLWHA. RlS had a considerably lesser runtime but intrinsically required manually reviewing a fastidious proportion of the matched registries. On the other hand, PLA spent quite more runtime but spared manual reviewing at no expense of accuracy.

Ninjurin 1 asp110ala single nucleotide polymorphism is associated with protection in leprosy nerve damage.

Leprosy is the major cause of non-traumatic neuropathy. Herein, we investigated the role of ninjurin 1, an adhesion molecule involved in nerve regeneration in leprosy. Our results demonstrated that M. leprae stimulates in vitro up-regulation of ninjurin mRNA in cultured Schwann and blood cells as well as in vivo mRNA and protein expression in leprosy nerve biopsies. A polymorphism (asp110ala) was investigated in a case-control study (1123 individuals) and no association was found with leprosy per se or with disseminated forms. Nevertheless, ala110 was associated with functional nerve impairment (OR=2.42; p=0.02 for ala/ala) and with lower mRNA levels. Our data suggests that asp110ala could be a valuable genetic marker of nerve damage in leprosy.

Host genetics and dengue fever.

Dengue is a major worldwide problem in tropical and subtropical areas; it is caused by four different viral serotypes, and it can manifest as asymptomatic, mild, or severe. Many factors interact to determine the severity of the disease, including the genetic profile of the infected patient. However, the mechanisms that lead to severe disease and eventually death have not been determined, and a great challenge is the early identification of patients who are more likely to progress to a worse health condition. Studies performed in regions with cyclic outbreaks such as Cuba, Brazil, and Colombia have demonstrated that African ancestry confers protection against severe dengue. Highlighting the host genetics as an important factor in infectious diseases, a large number of association studies between genetic polymorphisms and dengue outcomes have been published in the last two decades. The most widely used approach involves case-control studies with candidate genes, such as the HLA locus and genes for receptors, cytokines, and other immune mediators. Additionally, a Genome-Wide Association Study (GWAS) identified SNPs associated with African ethnicity that had not previously been identified in case-control studies. Despite the increasing number of publications in America, Africa, and Asia, the results are quite controversial, and a meta-analysis is needed to assess the consensus among the studies. SNPs in the MICB, TNF, CD209, FcγRIIA, TPSAB1, CLEC5A, IL10 and PLCE1 genes are associated with the risk or protection of severe dengue, and the findings have been replicated in different populations. A thorough understanding of the viral, human genetic, and immunological mechanisms of dengue and how they interact is essential for effectively preventing dengue, but also managing and treating patients.

Assessing the underreporting of deaths among people living with HIV in Rio de Janeiro, Brazil, from 2014 to 2019 / Avaliação da subnotificação de óbitos em pessoas vivendo com HIV no Rio de Janeiro, Brasil, entre 2014 e 2019 / Evaluando el subregistro de muertes entre personas que viven con VIH en Río de Janeiro, Brasil, de 2014 a 2019

Abstract: We assessed the proportions and causes of the underreporting of deaths among people living with HIV (PLHIV) in Rio de Janeiro, Brazil, from 2014 to 2019. Demographic variables, mention of tuberculosis (TB), and CD4 cell counts closest to death were used to compare those who had HIV/AIDS mentioned on their death certificate (HMDC) to those who did not. Out of 10,698 deaths, 2,863 (26.8%) had no HMDC, from which 412 (14.4%) had external underlying cause. After excluding deaths from external causes, we found that 24% still had no HMDC. Age ≥ 40 years (OR = 1.75; 95%CI: 1.52-2.01), non-white race/ethnicity (OR = 1.16; 95%CI: 1.02-1.31), the male gender (OR = 1.25; 95%CI: 1.11-1.42), higher CD4 cell counts closest to death (OR = 1.14; 95%CI: 1.12-1.16), absence of TB (OR = 4.86; 95%CI: 3.76-6.29) and not dying within a hospital (OR = 2.61; 95%CI: 2.31-2.95) were associated with increased probabilities of not having HMDC. The proportion of deaths with no HMDC increased from 18.7% to 35.1% between 2014 and 2019. The high proportion of underreported deaths in Rio de Janeiro indicates that HIV/AIDS mortality coefficients in the state may be underestimated. With the changing patterns of mortality of PLHIV, physicians are advised to consider the broader clinical spectrum of HIV infection, and surveillance officers should improve death monitoring.

Resumo: Os autores avaliaram as proporções de subnotificação de óbitos e fatores associados em pessoas vivendo com HIV (PVHIV) no Rio de Janeiro, Brasil, entre 2014 e 2019. Variáveis demográficas, menção de tuberculose (TB) e contagem de células CD4 mais próxima ao óbito foram utilizadas para comparar indivíduos que tiveram códigos para HIV/aids mencionados na declaração de óbito (HMDO) àqueles que não apresentaram tal menção. Entre 10.698 certidões de óbito, 2.863 (26.8%) não citaram HIV/aids. Entre estes, 412 (14,4%) apresentaram causas externas como a causa subjacente. Depois de excluir as causas externas, 24% das certidões não mencionaram HIV/aids. Idade acima de 40 anos (OR = 1,75; IC95%: 1,52-2,01), raça/etnicidade não branca (OR = 1,16; IC95%: 1,02-1,31), sexo masculino (OR = 1,25; IC95%: 1,11-1,42), contagem de CD4 mais alta próximo ao óbito (OR = 1,14; IC95%: 1,12-1,16), não ter TB (OR = 4,86; IC95%: 3,76-6,29) e morte extra-hospitalar (OR = 2,61; IC95%: 2,31-2,95) mostraram associação com aumento de probabilidade de não apresentar HMDO. A proporção de certidões de óbito que não citavam HIV/aids aumentou de 18,7% para 35,1% entre 2014 e 2019. A alta proporção de óbitos subnotificados no Rio de Janeiro indica a possível subestimação dos coeficientes de mortalidade por HIV/aids no estado. A mudança nos padrões de mortalidade em PVHIV desafia tanto os médicos, no sentido de considerar o espectro clínico mais amplo na infecção pelo HIV, quanto os especialistas em vigilância, no sentido de aprimorar o monitoramento da mortalidade.

Resumen: Evaluamos los porcentajes y factores asociados con el subregistro de muertes entre personas afectadas por VIH (PLHIV) en Río de Janeiro, Brasil, desde 2014 a 2019. Se utilizaron variables demográficas, mención de tuberculosis (TB) y recuentos de células CD4 más cercanos al fallecimiento, para comparar a quienes tenían VIH/SIDA reflejado en el certificado de defunción (HMDC), con quienes no lo tenían. De las 10.698 muertes, 2.863 (26,8%) no tuvieron HMDC. De entre ellos, 412 (14,4%) tenían causas externas como causa subyacente. Tras excluir las causas externas, un 24% no tuvieron HMDC. Edad ≥ 40 años (OR = 1,75; IC95%: 1,52-2,01), raza no blanca raza/etnicidad (OR = 1,16; IC95%: 1,02-1,31), género masculino (OR = 1,25; IC95%: 1,11-1,42), recuentos de células CD4 más altos más cercanos a la muerte (OR = 1,14; IC95%: 1,12-1,16), que no tenían TB (OR = 4,86; IC95%: 3,76-6,29), y que no murieron en un hospital (OR = 2,61; IC95%: 2,31-2,95), estuvieron asociados con probabilidades crecientes de no tener HMDC. La proporción de muertes que no tenían HMDC aumentó de un 18,7% a un 35,1% entre 2014 y 2019. La alta proporción de muertes subregistradas en Río de Janeiro indican que los coeficientes de mortalidad VIH/SIDA en el estado quizás estaban subestimados. Los patrones cambiantes de mortalidad suponen un desafío para las PLHIV, así como para los médicos, a la hora de considerar infección por VIH dentro de un espectro clínico más amplio, al igual que para los agentes de supervisión, con el fin de mejorar el monitoreo de muertes.

Assessing the underreporting of deaths among people living with HIV in Rio de Janeiro, Brazil, from 2014 to 2019 / Avaliação da subnotificação de óbitos em pessoas vivendo com HIV no Rio de Janeiro, Brasil, entre 2014 e 2019

Os autores avaliaram as proporções de subnotificação de óbitos e fatores associados em pessoas vivendo com HIV (PVHIV) no Rio de Janeiro, Brasil, entre 2014 e 2019. Variáveis demográficas, menção de tuberculose (TB) e contagem de células CD4 mais próxima ao óbito foram utilizadas para comparar indivíduos que tiveram códigos para HIV/aids mencionados na declaração de óbito (HMDO) àqueles que não apresentaram tal menção. Entre 10.698 certidões de óbito, 2.863 (26.8%) não citaram HIV/aids. Entre estes, 412 (14,4%) apresentaram causas externas como a causa subjacente. Depois de excluir as causas externas, 24% das certidões não mencionaram HIV/aids. Idade acima de 40 anos (OR = 1,75; IC95%: 1,52-2,01), raça/etnicidade não branca (OR = 1,16; IC95%: 1,02-1,31), sexo masculino (OR = 1,25; IC95%: 1,11-1,42), contagem de CD4 mais alta próximo ao óbito (OR = 1,14; IC95%: 1,12-1,16), não ter TB (OR = 4,86; IC95%: 3,76-6,29) e morte extra-hospitalar (OR = 2,61; IC95%: 2,31-2,95) mostraram associação com aumento de probabilidade de não apresentar HMDO. A proporção de certidões de óbito que não citavam HIV/aids aumentou de 18,7% para 35,1% entre 2014 e 2019. A alta proporção de óbitos subnotificados no Rio de Janeiro indica a possível subestimação dos coeficientes de mortalidade por HIV/aids no estado. A mudança nos padrões de mortalidade em PVHIV desafia tanto os médicos, no sentido de considerar o espectro clínico mais amplo na infecção pelo HIV, quanto os especialistas em vigilância, no sentido de aprimorar o monitoramento da mortalidade.