Effectiveness of the fourth dose of COVID-19 vaccines against severe COVID-19 among adults 40 years or older in Brazil: a population-based cohort study.

Background: The emergence of COVID-19 variants with immune scape and the waning of primary vaccine schemes effectiveness have prompted many countries to indicate first and second booster COVID-19 vaccine doses to prevent severe COVID-19. However, current available evidence on second booster dose effectiveness are mostly limited to high-income countries, older adults, and mRNA-based vaccination schemes scenarios. We aimed to investigate the relative vaccine effectiveness (rVE) of the fourth dose compared to three doses for severe COVID-19 outcomes in Brazil; and compare the rVE of a fourth dose with an mRNA vaccine compared to adenovirus-based product in the same settings. Methods: We performed a target emulated trial using a population-based cohort of individuals aged 40 years or older who have received a homologous primary scheme of CoronaVac, ChAdOx1, or BNT162b2, and any third dose product and were eligible for the fourth dose in Brazil. The primary outcome was COVID-19 associated hospitalization or death. We built Cohort A matching individuals vaccinated with a fourth dose to individuals who received three doses to estimate the rVE of the fourth dose. We built Cohort B, a subset of Cohort A, matching mRNA-based (mRNA) to adenovirus-based fourth dose vaccinated individuals to compare their relative hazards for severe COVID-19. Findings: 46,693,484 individuals were included in Cohort A and 6,763,016 in Cohort B. 45% of them were aged between 40 and 60 years old, and 48% between 60 and 79 years old. In Cohort A, the most common previous series was a ChAdOx1 two-dose followed by BNT162b2 (44%), and a CoronaVac two-dose followed by a BNT162b2 (36%). Among those fourth dose vaccinated, 36.9% received ChAdOx1, 32.7% Ad26.COV2.S, 25.8% BNT162b2, and 4.7% CoronaVac. In Cohort B, among those who received an adenovirus fourth dose, 53.7% received ChAdOx1 and 46.3% received Ad26.COV2.S. The estimated rVE for the primary outcome of four doses compared to three doses was 44.1% (95% CI 42.3-46.0), with some waning during follow-up (rVE 7-60 days 46.8% [95% CI 44.4-49.1], rVE after 120 days 33.8% [95% CI 18.0-46.6]). Among fourth dose vaccinated individuals, mRNA-based vaccinated individuals had lower hazards for hospitalization or death compared to adenovirus-vaccinated individuals (HR 0.81, 95% CI 0.75-0.87). After 120 days, no difference in hazards between groups was observed (HR 1.35, 95% CI 0.93-1.97). Similar findings were observed for hospitalization and death separately, except no evidence for differences between fourth dose brands for death in Cohort B. Interpretation: In a heterogeneous scenario of primary and first booster vaccination combinations, a fourth dose provided meaningful and durable protection against severe COVID-19 outcomes. Compared to adenovirus-based booster, a fourth dose wild-type mRNA vaccine was associated with immediate lower hazards of hospitalization or death unsustained after 120 days. Funding: None.

The sural-sparing pattern in clinical variants and electrophysiological subtypes of Guillain-Barré syndrome.

BACKGROUND: Guillain-Barré syndrome (GBS) is the most common cause of acute flaccid paralysis worldwide and can be classified into electrophysiological subtypes and clinical variants. OBJECTIVE: This study aimed to compare the frequency of the sural-sparing pattern (SSP) in subtypes and variants of GBS. METHODS: This retrospective cohort study analyzed clinical and electrophysiological data of 171 patients with GBS hospitalized in public and private hospitals of Natal, Rio Grande do Norte, Brazil, between 1994 and 2018; all cases were followed up by the same neurologist in a reference neurology center. Patients were classified according to electrophysiological subtypes and clinical variants, and the SSP frequency was compared in both categories. The exact Fisher test and Bonferroni correction were used for statistical analysis. RESULTS: The SSP was present in 53% (57 of 107) of the patients with acute inflammatory demyelinating polyradiculoneuropathy (AIDP), 8% (4 of 48) of the patients with axonal subtypes, and 31% (5 of 16) of the equivocal cases. The SSP frequency in the AIDP was significantly higher than in the axonal subtypes (p < 0.0001); the value was kept high after serial electrophysiological examinations. Only the paraparetic subtype did not present SSP. CONCLUSION: The SSP may be present in AIDP and axonal subtypes, including acute motor axonal neuropathy, but it is significantly more present in AIDP. Moreover, the clinical variants reflect a specific pathological process and are correlated to its typical electrophysiological subtype, affecting the SSP frequency.

ANTECEDENTES: A síndrome de Guillain-Barré (GBS) é a causa mais comum de paralisia flácida aguda em todo o mundo e pode ser classificada em subtipos eletrofisiológicos e variantes clínicas. OBJETIVO: Este estudo teve como objetivo comparar a frequência do padrão de preservação do sural (SSP) em subtipos e variantes de GBS. MéTODOS: É um estudo de coorte retrospectivo que analisou dados clínicos e eletrofisiológicos de 171 pacientes com GBS internados em hospitais públicos e privados de Natal, Rio Grande do Norte, Brasil, entre 1994 e 2018. Todos os casos foram acompanhados pelo mesmo neurologista em centro de referência em neurologia. Os pacientes foram classificados de acordo com os subtipos eletrofisiológicos e variantes clínicas e a frequência do SSP foi comparada em ambas as categorias. O teste exato de Fisher e a correção de Bonferroni foram utilizados para análise estatística. RESULTADOS: O SSP esteve presente em 53% (57 de 107) dos pacientes com polirradiculoneuropatia desmielinizante inflamatória aguda (PDIA), em 8% (4 de 48) dos pacientes com subtipos axonais e em 31% (5 de 16) dos casos não definidos. A frequência do SSP no AIDP foi significativamente maior do que nos subtipos axonais (p < 0,0001); o valor manteve-se elevado após exames eletrofisiológicos seriados. Apenas o subtipo paraparético não apresentou SSP. CONCLUSãO: O SSP pode estar presente na PDIA e nos subtipos axonais, incluindo a neuropatia axonal motora aguda, mas está significativamente mais presente na PDIA. Além disso, as variantes clínicas refletem um processo patológico específico e estão correlacionadas ao seu subtipo eletrofisiológico típico, afetando a frequência do SSP.

Factors influencing adverse events following COVID-19 vaccination.

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

Neuroprotective effects of platinum nanoparticle-based microreactors in bicuculline-induced seizures.

Epilepsy designates a group of chronic brain disorders, characterized by the recurrence of hypersynchronous, repetitive activity, of neuronal clusters. Epileptic seizures are the hallmark of epilepsy. The primary goal of epilepsy treatment is to eliminate seizures with minimal side effects. Nevertheless, approximately 30% of patients do not respond to the available drugs. An imbalance between excitatory/inhibitory neurotransmission, that leads to excitotoxicity, seizures, and cell death, has been proposed as an important mechanism regarding epileptogenesis. Recently, it has been shown that microreactors composed of platinum nanoparticles (Pt-NP) and glutamate dehydrogenase possess in vitro and in vivo activity against excitotoxicity. This study investigates the in vivo effects of these microreactors in an animal model of epilepsy induced by the administration of the GABAergic antagonist bicuculline. Male Wistar rats were administered intracerebroventricularly (i.c.v.) with the microreactors or saline and, five days later, injected with bicuculline or saline. Seizure severity was evaluated in an open field. Thirty min after behavioral measurements, animals were euthanized, and their brains processed for neurodegeneration evaluation and for neurogenesis. Treatment with the microreactors significantly increased the time taken for the onset of seizures and for the first tonic-clonic seizure, when compared to the bicuculline group that did not receive the microreactor. The administration of the microreactors also increased the time spent in total exploration and grooming. Treatment with the microreactors decreased bicuculline-induced neurodegeneration and increased neurogenesis in the dorsal and ventral hippocampus. These observations suggest that treatment with Pt-NP-based microreactors attenuates the behavioral and neurobiological consequences of epileptiform seizure activity.

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

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

Serial Mass Screening for Tuberculosis among Incarcerated Persons in Brazil.

BACKGROUND: Active search for tuberculosis cases through mass screening is widely described as a tool to improve case detection in hyperendemic settings. However, its effectiveness in high-risk populations, such as incarcerated people, is debated. METHODS: Between 2017 and 2021, three rounds of mass screening were carried out in three Brazilian prisons. Social and health questionnaires, chest X-rays and Xpert MTB/RIF were performed. RESULTS: Over 80% of the prison population was screened. Overall, 684 cases of pulmonary tuberculosis were diagnosed. Prevalence across screening rounds was not statistically different. Among incarcerated persons with symptoms, the overall prevalence of tuberculosis per 100,000 persons was 8,497 (95% CI, 7,346-9,811), 11,115 (95% CI, 9,471-13,082), and 7,957 (95% CI, 6,380-9,882) in screening rounds one, two and three, respectively. Similar to our overall results, there were no statistical differences between screening rounds and within individual prisons. We found no statistical differences in CAD4TB scores across screening rounds among people with tuberculosis - the median scores in rounds 1, 2, and 3 were 82 (IQR, 63-97), 77 (IQR, 60-94), and 81 (IQR, 67-92), respectively. CONCLUSIONS: In this environment with hyperendemic rates of tuberculosis, three rounds of mass screening did not reduce the overall tuberculosis burden. In prisons, where a substantial amount of TB is undiagnosed annually, a range of complementary interventions and more frequent TB screening may be required.

MRI is a Reliable Method for Measurement of Critical Shoulder Angle and Acromial Index.

Objective The objectives of this study are to compare absolute values of acromial index (AI) and critical shoulder angle (CSA) obtained in both radiographs and magnetic resonance image (MRI) of the shoulder; and to compare the interobserver and intra-observer agreement for AI and CSA values measured in these image modalities. Methods Patients who had medical indication of investigating shoulders conditions through radiographs and MRI were included. Images were taken to two fellowship-trained shoulder surgeons, which conducted measurements of AI and CSA in radiographs and in MRI. Twelve weeks after the first evaluation, a second evaluation was conducted. Inter- and intra-observer reliability was presented as an Intraclass Correlation Coefficient (ICC) and agreement was classified according to Landis & Koch criteria. The differences between two measurements were evaluated using Bland-Altman plots. Results 134 shoulders in 124 subjects were included. Mean intra-observer ICC for CSA in X-rays and in MRI were 0.936 and 0.940, respectively; for AI, 0.908 and 0.022. Mean inter-observer ICC for CSA were 0.892 and 0.752 in X-rays and MRI respectively; for AI, ICC values were 0.849 and 0.685. All individual analysis reached statistical power ( p < 0.001). Mean difference for AI values measured in X-rays and in MRI was 0.01 and 0.03 for observers 1 and 2, respectively. Mean difference for CSA values obtained in X-rays and MRI was 0.16 and 0.58 for observers 1 and 2, respectively. Conclusion Both MRI and X-rays provided high intra- and interobserver agreement for measurement of AI and CSA. Absolute values found for AI and CSA were highly correlated in both image modalities. These findings suggest that MRI is a suitable method to measure AI and CSA. Level of Evidence II , Diagnostic Study.

Bacillus Calmette-Guérin vaccination for protection against recurrent herpes labialis: a nested randomised controlled trial.

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.

MRI is a Reliable Method for Measurement of Critical Shoulder Angle and Acromial Index / A ressonância magnética é um método confiável para medida do ângulo crítico do ombro e do índice acromial

Abstract Objective The objectives of this study are to compare absolute values of acromial index (AI) and critical shoulder angle (CSA) obtained in both radiographs and magnetic resonance image (MRI) of the shoulder; and to compare the interobserver and intra-observer agreement for AI and CSA values measured in these image modalities. Methods Patients who had medical indication of investigating shoulders conditions through radiographs and MRI were included. Images were taken to two fellowship-trained shoulder surgeons, which conducted measurements of AI and CSA in radiographs and in MRI. Twelve weeks after the first evaluation, a second evaluation was conducted. Inter- and intra-observer reliability was presented as an Intraclass Correlation Coefficient (ICC) and agreement was classified according to Landis & Koch criteria. The differences between two measurements were evaluated using Bland-Altman plots. Results 134 shoulders in 124 subjects were included. Mean intra-observer ICC for CSA in X-rays and in MRI were 0.936 and 0.940, respectively; for AI, 0.908 and 0.022. Mean inter-observer ICC for CSA were 0.892 and 0.752 in X-rays and MRI respectively; for AI, ICC values were 0.849 and 0.685. All individual analysis reached statistical power (p< 0.001). Mean difference for AI values measured in X-rays and in MRI was 0.01 and 0.03 for observers 1 and 2, respectively. Mean difference for CSA values obtained in X-rays and MRI was 0.16 and 0.58 for observers 1 and 2, respectively. Conclusion Both MRI and X-rays provided high intra- and interobserver agreement for measurement of AI and CSA. Absolute values found for AI and CSA were highly correlated in both image modalities. These findings suggest that MRI is a suitable method to measure AI and CSA. Level of Evidence II, Diagnostic Study.

Resumo Objetivo Os objetivos deste estudo foram comparar os valores absolutos do índice acromial (IA) e do ângulo crítico do ombro (ACO) obtidos em radiografias e ressonâncias magnéticas (RM) do ombro e comparar a concordância interobservador e intraobservador dos valores de IA e ACO medidos nessas modalidades de imagem. Métodos Pacientes com indicação médica de investigação de doenças dos ombros por meio de radiografias e RM foram incluídos no estudo. As imagens foram levadas para dois cirurgiões de ombro treinados que realizaram medidas de IA e ACO em radiografias e RM. Doze semanas após a primeira avaliação, uma segunda avaliação foi realizada. A confiabilidade inter e intraobservador foi apresentada como coeficiente de correlação intraclasse (CCI) e a concordância foi classificada segundo os critérios de Landis e Koch. As diferenças entre duas medidas foram avaliadas por meio de gráficos de Bland-Altman. Resultados Cento e trinta e quatro ombros de 124 indivíduos foram incluídos no estudo. O CCI intraobservador médio para ACO em radiografias e RM foi 0,936 e 0,940, respectivamente; para IA, foi 0,908 e 0,022. O CCI interobservador médio para ACO foi 0,892 e 0,752 em radiografias e RM, respectivamente; para IA, os valores de CCI foram 0,849 e 0,685. Todas as análises individuais apresentaram poder estatístico (p < 0,001). A diferença média dos valores de IA em radiografias e RM foi 0,01 e 0,03 para os observadores 1 e 2, respectivamente. A diferença média dos valores de ACO em radiografias e RM foi 0,16 e 0,58 para os observadores 1 e 2, respectivamente. Conclusão Tanto a RM quanto as radiografias tiveram alta concordância intra e interobservador para medida de IA e ACO. Os valores absolutos de IA e ACO foram altamente correlacionados em ambas as modalidades de imagem. Esses achados sugerem que a RM é um método adequado para determinação de IA e ACO. Nível de Evidência II, Estudo Diagnóstico.

Rabies outbreak in Brazil: first case series in children from an indigenous village.

BACKGROUND: Human rabies outbreak transmitted by bats continues to be a relevant public health problem not only in the Amazon region. The disease has affected one of the areas with the greatest poverty in southeastern Brazil, a region inhabited by the Maxakali indigenous people. CASE PRESENTATION: We describe four cases of rabies among indigenous children that occurred in the indigenous village of Pradinho, municipality of Bertópolis, Minas Gerais, Brazil. Cases were notified between April and May 2022, all of whom died on average eight days after the first symptoms. All cases were observed in rural residents under 12 years of age. The probable form of exposure was through bat bites. The predominant symptoms were prostration, fever, dyspnea, sialorrhea, tachycardia, and altered level of consciousness. Half of the cases underwent late and/or incomplete post-exposure rabies prophylaxis, however, the other half underwent pre-exposure rabies prophylaxis, with only one case completing the scheme and another undergoing the adapted Milwaukee Protocol (Recife Protocol). All cases ended in death. CONCLUSIONS: This was the first rabies outbreak among indigenous people in Brazil. Among the manifested clinical forms in the series, there was a disease atypical presentation in at least one case. We suggest active surveillance and an intercultural educational campaign to prevent new cases.

Delay in the diagnosis and treatment of tuberculosis in prisons in Mato Grosso do Sul, Brazil.

BACKGROUND: The number of tuberculosis (TB) cases in prisons is higher than that in the general population and has been reported as the most common cause of death in prisons. This study evaluated the delay in the diagnosis and treatment of TB in Brazilian prisons. METHODS: A retrospective cohort study was conducted between 2007 and 2015 using data from the five largest male prisons in Mato Grosso do Sul, Brazil. TB case data was collected from the National Database of Notifiable Diseases (SINAN), GAL-LACEN, and prison medical records. The following variables were recorded: prison, year of diagnosis, age, race, education, HIV status, smoking status, comorbidities, number of symptoms, percentage of cures, delay in diagnosis, patient delay, provider delay, laboratory delay, and delay in treatment. Descriptive statistics were used for the variables of interest. RESULTS: A total of 362 pulmonary TB cases were identified. The average time between the first symptom and reporting of data was 94 days. The mean time between symptom onset and laboratory diagnosis was 91 days. The average time from symptom onset to first consultation was 80 days. The time between diagnosis and treatment initiation was 5 days. CONCLUSIONS: Delays were significant between reporting of the first symptoms and diagnosis and significantly smaller from the time between notification and start of treatment. Control strategies should be implemented to diagnose cases through active screening, to avoid delays in diagnosis and treatment, and to reduce TB transmission.

Impact of vaccine platform and BCG vaccination on antibody responses to COVID-19 vaccination.

Multiple factors, including vaccine platform and prior vaccinations, influence vaccine responses. We compared antibody responses to CoronaVac (Sinovac) and ChAdOx1-S (AstraZeneca-Oxford) vaccination in 874 healthcare workers in Brazil. As participants were randomised to BCG vaccination or placebo in the preceding 0-6 months as part of the BCG vaccination to reduce the impact of COVID-19 in healthcare workers (BRACE) trial, we also investigated the influence of recent BCG vaccination on antibody responses to these COVID-19 vaccines. Twenty-eight days after the second dose of each vaccine, ChAdOx1-S induced a stronger anti-spike IgG response than CoronaVac vaccination. Recent BCG vaccination did not impact IgG antibody responses to ChAdOx1-S or CoronaVac.

Randomized Trial of BCG Vaccine to Protect against Covid-19 in Health Care Workers.

BACKGROUND: The bacille Calmette-Guérin (BCG) vaccine has immunomodulatory "off-target" effects that have been hypothesized to protect against coronavirus disease 2019 (Covid-19). METHODS: In this international, double-blind, placebo-controlled trial, we randomly assigned health care workers to receive the BCG-Denmark vaccine or saline placebo and followed them for 12 months. Symptomatic Covid-19 and severe Covid-19, the primary outcomes, were assessed at 6 months; the primary analyses involved the modified intention-to-treat population, which was restricted to participants with a negative test for severe acute respiratory syndrome coronavirus 2 at baseline. RESULTS: A total of 3988 participants underwent randomization; recruitment ceased before the planned sample size was reached owing to the availability of Covid-19 vaccines. The modified intention-to-treat population included 84.9% of the participants who underwent randomization: 1703 in the BCG group and 1683 in the placebo group. The estimated risk of symptomatic Covid-19 by 6 months was 14.7% in the BCG group and 12.3% in the placebo group (risk difference, 2.4 percentage points; 95% confidence interval [CI], -0.7 to 5.5; P = 0.13). The risk of severe Covid-19 by 6 months was 7.6% in the BCG group and 6.5% in the placebo group (risk difference, 1.1 percentage points; 95% CI, -1.2 to 3.5; P = 0.34); the majority of participants who met the trial definition of severe Covid-19 were not hospitalized but were unable to work for at least 3 consecutive days. In supplementary and sensitivity analyses that used less conservative censoring rules, the risk differences were similar but the confidence intervals were narrower. There were five hospitalizations due to Covid-19 in each group (including one death in the placebo group). The hazard ratio for any Covid-19 episode in the BCG group as compared with the placebo group was 1.23 (95% CI, 0.96 to 1.59). No safety concerns were identified. CONCLUSIONS: Vaccination with BCG-Denmark did not result in a lower risk of Covid-19 among health care workers than placebo. (Funded by the Bill and Melinda Gates Foundation and others; BRACE ClinicalTrials.gov number, NCT04327206.).

3D gravity modelling of areas under the aptian lakes in the Jatobá basin and Tucano Norte sub-basin - Negra and Tonã hills.

Due to structural similarities and the possibility of connection between the two Aptian paleolakes in the Jatobá Basin and the Tucano Norte Sub-basin in North-eastern Brazil, the influence of the architecture of the crystalline basement under these lacustrine sedimentary rocks was analysed using gravimetric data near the faulted edges of the basins where the paleolakes are located. The Negra (Jatobá Basin) and Tonã (Tucano Norte Sub-basin) Hills are mainly sedimentary deposits of Aptian age and are linked to the post-rift I tectonic sequence. Aiming at the study of reservoirs analogous to pre-salt reservoirs, the gravimetric data were processed and interpreted to define the structural framework of the basin regions around these hills. Depth maps and density models were generated that could be analysed from various 3D perspectives, and the behaviour of the crystalline basement below these sedimentary sequences was investigated. In addition to the identification of horsts and semi-grabens that influenced the current relief pattern, the modelling showed that the Aptian paleolake sedimentary rocks of the Negra Hill are in the Ibimirim Low, which is approximately 2,900 m deep, while in the Tonã Hill, the sedimentary rocks are in the Salgado do Melão Low, which is approximately 5,100 m deep.

Evaluation of chest X-ray with automated interpretation algorithms for mass tuberculosis screening in prisons: a cross-sectional study.

Background: The World Health Organization (WHO) recommends systematic tuberculosis (TB) screening in prisons. Evidence is lacking for accurate and scalable screening approaches in this setting. We aimed to assess the accuracy of artificial intelligence-based chest x-ray interpretation algorithms for TB screening in prisons. Methods: We performed prospective TB screening in three male prisons in Brazil from October 2017 to December 2019. We administered a standardized questionnaire, performed a chest x-ray in a mobile unit, and collected sputum for confirmatory testing using Xpert MTB/RIF and culture. We evaluated x-ray images using three algorithms (CAD4TB version 6, Lunit version 3.1.0.0 and qXR version 3) and compared their accuracy. We utilized multivariable logistic regression to assess the effect of demographic and clinical characteristics on algorithm accuracy. Finally, we investigated the relationship between abnormality scores and Xpert semi-quantitative results. Findings: Among 2075 incarcerated individuals, 259 (12.5%) had confirmed TB. All three algorithms performed similarly overall with area under the receiver operating characteristic curve (AUC) of 0.88-0.91. At 90% sensitivity, only LunitTB and qXR met the WHO Target Product Profile requirements for a triage test, with specificity of 84% and 74%, respectively. All algorithms had variable performance by age, prior TB, smoking, and presence of TB symptoms. LunitTB was the most robust to this heterogeneity but nonetheless failed to meet the TPP for individuals with previous TB. Abnormality scores of all three algorithms were significantly correlated with sputum bacillary load. Interpretation: Automated x-ray interpretation algorithms can be an effective triage tool for TB screening in prisons. However, their specificity is insufficient in individuals with previous TB. Funding: This study was supported by the US National Institutes of Health (grant numbers R01 AI130058 and R01 AI149620) and the State Secretary of Health of Mato Grosso do Sul.

Phytogenotoxicity of thymol and semisynthetic thymoxyacetic acid in pre/post emergence of model plants and weeds.

Herbicides are commonly used to control weed. However, some plants are resistant to such products. To identify less harmful herbicides, it is crucial to search for different mechanisms of action. Thymol is an easily acquired allelopathic compound, capable of producing its respective semisynthetic derivative, thymoxyacetic acid. The aim of this study was to determine the effects of thymol and thymoxyacetic acid molecules as bioherbicides in greenhouse at the concentration of 3 mmol L-1 in pre- and postemergence applications in five species: Amaranthus viridis L., Cucumis sativus L., Lactuca sativa L., Eleusine indica L., and Sorghum bicolor L. The initial seedling development and DNA changes were analyzed. These molecules were contrasting with the solvent, in the negative control, and with the glyphosate, in the positive control, promoting phytogenotoxic activities. The toxic effect of thymoxyacetic acid was more effective in preemergence and thymol's in postemergence. We also observed a reduction in the germination speed index and root growth with a negative correlation to the increase in potassium leaching. Damage to the root and shoot of the seedlings was verified at the DNA level, and the phytotoxicity of the plants treated with the herbicide glyphosate was similar to the plants treated with the natural molecules tested. The bioherbicidal effect of thymol and thymoxyacetic acid exacerbates the reduction of the environmental impact caused by the disordered and increased use of residual pesticides.

Anaerobic digestion of vinasse and water treatment plant sludge increases methane production and stability of UASB reactors.

Studies are still needed to increase the stability and efficiency of methane production from vinasse. Therefore, operations strategies, such as the anaerobic digestion with one or more wastes and adding micronutrients, especially iron, become attractive. The performance of two treatment systems, each one composed of two UASB reactors in series, operated under mesophilic (R1M and R2M) and thermophilic (R1T and R2T) temperature conditions, was evaluated in the anaerobic digestion of vinasse (ADV). First, the reactors were operated with the effluent recirculation and increasing organic loading rate (OLR) up to 20 g CODtotal L-1d-1 in the R1M and R1T. Then, the anaerobic digestion of vinasse and water treatment plant (WTP) sludge (ADVS) was performed in the proportions of 25:75 to 50:50 (% v/v) in both systems. In the ADV, applying the highest OLR, the mesophilic and thermophilic reactors instabilities happened. The ADVS of over 35% of WTP sludge promoted the recovery of the mesophilic and thermophilic UASB reactors with significantly reduced total volatile acids and increased alkalinity and biogas production. The higher average values of the volumetric methane production (VMP) occurred in the ADVS at 50% of WTP; in the R1M and R1T, they were 3.23 and 3.00 L CH4 L-1d-1, respectively. In the ADV, the thermophilic system presented higher VMP concerning the mesophilic for OLR up to 15 g CODtotal L-1d-1. For higher OLR, the mesophilic system showed better carrying capacity and stability. The ADVS with above 35% of WTP sludge promoted similar benefits in the two systems, with no significant differences in CODtotal removal and VMP. Therefore, adding iron by WTP sludge in ADVS improves methane production and increases the stability of UASB reactors under mesophilic and thermophilic conditions.

A geographical study on amyotrophic lateral sclerosis in Rio Grande Do Norte, Brazil, from 2005 to 2018.

OBJECTIVE: amyotrophic lateral sclerosis (ALS) is a rare and fatal neurodegenerative disorder with variable incidence and prevalence worldwide. However, clinical-epidemiological studies on ALS are scarce in Brazil. Thus, this study investigated whether ALS incidence had uniform spatial distribution in population-based cluster analysis in Rio Grande do Norte state (Brazil), from 2005 to 2018. METHODS: new cases of ALS were identified in a database of the ALS multidisciplinary care center of the Onofre Lopes University Hospital in Natal (Rio Grande do Norte, Brazil). Approaches were based on incidence (empirical Bayes estimator and Moran's I analysis) and cluster analyses (Moran scatter plot and spatial correlogram). RESULTS: a total of 177 patients (59% males) participated in the study; the mean age of ALS onset was 57 years. Mean annual incidence of ALS was 0.3769 per 100,000 inhabitants (95% confidence interval of 0.0889), higher in males than in females (0.4516 per 100,000 vs. 0.3044 per 100,000). According to spatial statistics, patients were homogeneously distributed throughout the studied area. CONCLUSION: a low estimate was observed compared with other populations. Results did not indicate areas of increased risk or significant spatial geographic dependence, suggesting a random ALS incidence in Rio Grande do Norte.

Statistical process control of manufacturing tablets for antiretroviral therapy

Abstract In this study, the manufacturing process of lamivudine (3TC) and zidovudine (AZT) tablets (150+300 mg respectively) was evaluated using statistical process control (SPC) tools. These medicines are manufactured by the Fundação para o Remédio Popular "Chopin Tavares de Lima" (FURP) laboratory, and are distributed free of charge to patients infected with HIV by the Ministry of Health DST/AIDS national program. Data of 529 batches manufactured from 2012 to 2015 were collected. The critical quality attributes of weight variation, uniformity of dosage units, and dissolution were evaluated. Process stability was assessed using control charts, and the capability indices Cp, Cpk, Pp, and Ppk (process capability; process capability adjusted for non-centered distribution; potential or global capability of the process; and potential process capability adjusted for non-centered distribution, respectively) were evaluated. 3TC dissolution data from 2013 revealed a non-centered process and lack of consistency compared to the other years, showing Cpk and Ppk lower than 1.0 and the chance of failure of 2,483 in 1,000,000 tablets. Dissolution data from 2015 showed process improvement, revealed by Cpk and Ppk equal to 2.19 and 1.99, respectively. Overall, the control charts and capability indices showed the variability of the process and special causes. Additionally, it was possible to point out the opportunities for process changes, which are fundamental for understanding and supporting a continuous improvement environment.