Development and validation of a machine learning model to predict the use of renal replacement therapy in 14,374 patients with COVID-19.

PURPOSE: To develop a model to predict the use of renal replacement therapy (RRT) in COVID-19 patients. MATERIALS AND METHODS: Retrospective analysis of multicenter cohort of intensive care unit (ICU) admissions of Brazil involving COVID-19 critically adult patients, requiring ventilatory support, admitted to 126 Brazilian ICUs, from February 2020 to December 2021 (development) and January to May 2022 (validation). No interventions were performed. RESULTS: Eight machine learning models' classifications were evaluated. Models were developed using an 80/20 testing/train split ratio and cross-validation. Thirteen candidate predictors were selected using the Recursive Feature Elimination (RFE) algorithm. Discrimination and calibration were assessed. Temporal validation was performed using data from 2022. Of 14,374 COVID-19 patients with initial respiratory support, 1924 (13%) required RRT. RRT patients were older (65 [53-75] vs. 55 [42-68]), had more comorbidities (Charlson's Comorbidity Index 1.0 [0.00-2.00] vs 0.0 [0.00-1.00]), had higher severity (SAPS-3 median: 61 [51-74] vs 48 [41-58]), and had higher in-hospital mortality (71% vs 22%) compared to non-RRT. Risk factors for RRT, such as Creatinine, Glasgow Coma Scale, Urea, Invasive Mechanical Ventilation, Age, Chronic Kidney Disease, Platelets count, Vasopressors, Noninvasive Ventilation, Hypertension, Diabetes, modified frailty index (mFI) and Gender, were identified. The best discrimination and calibration were found in the Random Forest (AUC [95%CI]: 0.78 [0.75-0.81] and Brier's Score: 0.09 [95%CI: 0.08-0.10]). The final model (Random Forest) showed comparable performance in the temporal validation (AUC [95%CI]: 0.79 [0.75-0.84] and Brier's Score, 0.08 [95%CI: 0.08-0.1]). CONCLUSIONS: An early ML model using easily available clinical and laboratory data accurately predicted the use of RRT in critically ill patients with COVID-19. Our study demonstrates that using ML techniques is feasible to provide early prediction of use of RRT in COVID-19 patients.

Serum from patients with asthma potentiates macrophage phagocytosis and human mesenchymal stromal cell therapy in experimental allergic asthma.

BACKGROUND/AIMS: Although several studies have demonstrated that mesenchymal stromal cells (MSCs) exhibit beneficial immunomodulatory properties in preclinical models of allergic asthma, effects on airway remodeling have been controversial. Recent evidence has shown that MSCs modify their in vivo immunomodulatory actions depending on the specific inflammatory environment encountered. Accordingly, we assessed whether the therapeutic properties of human mesenchymal stromal cells (hMSCs) could be potentiated by conditioning these cells with serum (hMSC-serum) obtained from patients with asthma and then transplanted in an experimental model of house dust mite (HDM)-induced allergic asthma. METHODS: hMSC and hMSC-serum were administered intratracheally 24 h after the final HDM challenge. hMSC viability and inflammatory mediator production, lung mechanics and histology, bronchoalveolar lavage fluid (BALF) cellularity and biomarker levels, mitochondrial structure and function as well as macrophage polarization and phagocytic capacity were assessed. RESULTS: Serum preconditioning led to: (i) increased hMSC apoptosis and expression of transforming growth factor-ß, interleukin (IL)-10, tumor necrosis factor-α-stimulated gene 6 protein and indoleamine 2,3-dioxygenase-1; (ii) fission and reduction of the intrinsic respiratory capacity of mitochondria; and (iii) polarization of macrophages to M2 phenotype, which may be associated with a greater percentage of hMSCs phagocytosed by macrophages. Compared with mice receiving hMSCs, administration of hMSC-serum led to further reduction of collagen fiber content, eotaxin levels, total and differential cellularity and increased IL-10 levels in BALF, improving lung mechanics. hMSC-serum promoted greater M2 macrophage polarization as well as macrophage phagocytosis, mainly of apoptotic hMSCs. CONCLUSIONS: Serum from patients with asthma led to a greater percentage of hMSCs phagocytosed by macrophages and triggered immunomodulatory responses, resulting in further reductions in both inflammation and remodeling compared with non-preconditioned hMSCs.

Telemedicine Support for Primary Care Providers versus Usual Care in Patients with Heart Failure: Protocol of a Pragmatic Cluster Randomised Trial within the Brazilian Heart Insufficiency with Telemedicine (BRAHIT) Study.

Heart failure is a prevalent condition and a frequent cause of hospital readmissions and poor quality of life. Teleconsultation support from cardiologists to primary care physicians managing patients with heart failure may improve care, but the effect on patient-relevant outcomes is unclear. We aim to evaluate whether collaboration through a novel teleconsultation platform in the Brazilian Heart Insufficiency with Telemedicine (BRAHIT) project, tested on a previous feasibility study, can improve patient-relevant outcomes. We will conduct a parallel-group, two-arm, cluster-randomised superiority trial with a 1:1 allocation ratio, with primary care practices from Rio de Janeiro as clusters. Physicians from the intervention group practices will receive teleconsultation support from a cardiologist to assist patients discharged from hospitals after admission for heart failure. In contrast, physicians from the control group practices will perform usual care. We will include 10 patients per each of the 80 enrolled practices (n = 800). The primary outcome will be a composite of mortality and hospital admissions after six months. Secondary outcomes will be adverse events, symptoms frequency, quality of life, and primary care physicians' compliance with treatment guidelines. We hypothesise that teleconsulting support will improve patient outcomes.

Perceptions of plagiarism among PhDs across the sciences, engineering, humanities, and arts: Results from a national survey in Brazil.

Plagiarism allegations are not rare in the history of science, and credit for prior work was and continues to be a source of disputes, involving notions of priority of discovery and of plagiarism. However, consensus over what constitutes plagiarism among scientists from different fields cannot be taken for granted. We conducted a national survey exploring perceptions of plagiarism among PhD holders registered in the database of the Brazilian National Council for Scientific and Technological Development. This survey was sent to 143,405 PhD holders across the fields, in the sciences, engineering, humanities, and arts, with a response rate of about 20%. The results suggest that core principles about plagiarism are shared among this multidisciplinary community, corroborating Robert K. Merton's observations that concerns over plagiarism and priority disputes are not field specific. This study offers insight into the way plagiarism is perceived in this community and sheds light on the problem for international collaborative research networks. The data focus on a particular research system in Latin America, but, given the cultural similarities that bind most Latin American nations, these results may be relevant to other PhD populations in the region and should provide an opportunity for comparison with studies from other emerging, non-Anglophone regions.

Impact of Subsyndromal Delirium Occurrence and Its Trajectory during ICU Stay.

Despite recent advances in the field, the association between subsyndromal delirium (SSD) in the ICU and poor outcomes is not entirely clear. We performed a retrospective multicentric observational study analyzing mental status during the first 72 h of ICU stay. Of the 681 patients included, SSD occurred in 22.7%. Considering the worst cognitive assessment during the first 72 h, 233 (34%) patients had normal mental status, 124 (18%) patients had SSD and 324 (48%) patients had delirium or coma. SSD was not independently associated with an increased risk of death when compared with normal mental status (OR 95%IC 1.0 vs. 1.35 [0.73−1.49], p = 0.340), but was associated with a longer ICU LOS (7.0 (4−12) vs. 4 (3−8) days, p < 0.001). SSD patients who deteriorated to delirium or coma (21%) had a longer ICU LOS in comparison with those who improved or maintained mental status (8 (5−11) vs. 6 (4−8) days, p = 0.025), but did not have an increase in mortality. The main factors associated with the progression from SSD to delirium or coma were the use of mechanical ventilation, the use of intravenous benzodiazepines and a baseline APACHE II score > 23 points. Our findings support the association of SSD with increased ICU LOS, but not with ICU mortality. Monitoring the trajectory of SSD early at ICU admission can help to identify patients with increased risk of conversion from SSD to delirium or coma.

Determinants of losses in the tuberculosis infection cascade of care among children and adolescent contacts of pulmonary tuberculosis cases: A Brazilian multi-centre longitudinal study.

Background: Approximately 10% of the global tuberculosis (TB) burden is in children. Identification, diagnosis, and early treatment of Mycobacterium tuberculosis infection (TBI) is critical to prevent progression to TB in children. The risk of TB, including severe disease, is highest in children <5 years old. We evaluated the cascade of TBI care among child and adolescent TB contacts to identify factors associated with losses in the cascade. Methods: Close contacts ≤ 18 years old of pulmonary TB patients enrolled between 2015 and 2019 in a multi-centre Brazilian cohort were followed for up to 24 months and classified according to age groups: <5 years, 5-9 years, 10-14 years and 15-18 years. Data on clinical investigation, radiographic examination, IGRA testing at baseline and 6 months, initiation and completion of TB preventive treatment (TPT) were collected. Multivariable regression analyses identified factors associated with TBI and losses in the cascade of care in children and adolescents. Findings: Among 1795 TB contacts initially identified, 530 (29·5%) were ≤18 years old. Losses for all steps in the cascade were especially high in children <5 years old (88%) because at this age all contacts are recommended to initiate TPT. As a proportion of all children, completion of TPT was low (between 10% and 13%) in all age-groups. Furthermore, multivariable regression revealed that younger age of contacts and TB index cases who were female, had pulmonary cavities, and persistent cough were independently associated with losses in the cascade of care among persons ≤18 years old. Interpretation: Losses in the TBI cascade were the highest among children <5 years, which was the group at highest risk for TB among the four age groups. The findings highlight the need to improve screening, initiation, and completion of TPT of young children who are close contacts of people with TB in Brazil. Funding: National Institutes of Allergy and Infectious Diseases.

Nitazoxanide in Patients Hospitalized With COVID-19 Pneumonia: A Multicentre, Randomized, Double-Blind, Placebo-Controlled Trial.

Background: Nitazoxanide exerts antiviral activity in vitro and in vivo and anti-inflammatory effects, but its impact on patients hospitalized with COVID-19 pneumonia is uncertain. Methods: A multicentre, randomized, double-blind, placebo-controlled trial was conducted in 19 hospitals in Brazil. Hospitalized adult patients requiring supplemental oxygen, with COVID-19 symptoms and a chest computed tomography scan suggestive of viral pneumonia or positive RT-PCR test for COVID-19 were enrolled. Patients were randomized 1:1 to receive nitazoxanide (500 mg) or placebo, 3 times daily, for 5 days, and were followed for 14 days. The primary outcome was intensive care unit admission due to the need for invasive mechanical ventilation. Secondary outcomes included clinical improvement, hospital discharge, oxygen requirements, death, and adverse events within 14 days. Results: Of the 498 patients, 405 (202 in the nitazoxanide group and 203 in the placebo group) were included in the analyses. Admission to the intensive care unit did not differ between the groups (hazard ratio [95% confidence interval], 0.68 [0.38-1.20], p = 0.179); death rates also did not differ. Nitazoxanide improved the clinical outcome (2.75 [2.21-3.43], p < 0.0001), time to hospital discharge (1.37 [1.11-1.71], p = 0.005), and reduced oxygen requirements (0.77 [0.64-0.94], p = 0.011). C-reactive protein, D-dimer, and ferritin levels were lower in the nitazoxanide group than the placebo group on day 7. No serious adverse events were observed. Conclusions: Nitazoxanide, compared with placebo, did not prevent admission to the intensive care unit for patients hospitalized with COVID-19 pneumonia. Clinical Trial Registration: Brazilian Registry of Clinical Trials (REBEC) RBR88bs9x; ClinicalTrials.gov, NCT04561219.

Recurrent WWTR1 S89W mutations and Hippo pathway deregulation in clear cell carcinomas of the cervix.

Clear cell carcinoma (CCC) of the cervix (cCCC) is a rare and aggressive type of human papillomavirus (HPV)-negative cervical cancer with limited effective treatment options for recurrent or metastatic disease. Historically, CCCs of the lower genital tract were associated with in utero diethylstilbestrol exposure; however, the genetic landscape of sporadic cCCCs remains unknown. Here we sought to define the molecular underpinning of cCCCs. Using a combination of whole-exome, targeted capture, and RNA-sequencing, we identified pathogenic genetic alterations in the Hippo signaling pathway in 50% (10/20) of cCCCs, including recurrent WWTR1 S89W somatic mutations in 40% (4/10) of the cases harboring mutations in the Hippo pathway. Irrespective of the presence or absence of Hippo pathway genetic alterations, however, all primary cCCCs analyzed in this study (n = 20) harbored features of Hippo pathway deregulation at the transcriptomic and protein levels. In vitro functional analysis revealed that expression of the WWTR1 S89W mutation leads to reduced binding of TAZ to 14-3-3, promoting constitutive nuclear translocation of TAZ and Hippo pathway repression. WWTR1 S89W expression was found to lead to acquisition of oncogenic behavior, including increased proliferation, migration, and colony formation in vitro as well as increased tumorigenesis in vivo, which could be reversed by targeted inhibition of the TAZ/YAP1 complex with verteporfin. Finally, xenografts expressing WWTR1 S89W displayed a shift in tumor phenotype, becoming more infiltrative as well as less differentiated, and were found to be composed of cells with conspicuous cytoplasmic clearing as compared to controls. Our results demonstrate that Hippo pathway alterations are likely drivers of cCCCs and likely contribute to the clear cell phenotype. Therapies targeting this pathway may constitute a new class of treatment for these rare, aggressive tumors. © 2022 The Pathological Society of Great Britain and Ireland.

The Effect of Diabetes and Prediabetes on Antituberculosis Treatment Outcomes: A Multicenter Prospective Cohort Study.

BACKGROUND: It is unclear whether diabetes or prediabetes affects unfavorable treatment outcomes and death in people with tuberculosis (PWTB). METHODS: Culture-confirmed, drug-susceptible PWTB, enrolled in the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil cohort between 2015 and 2019 (N = 643) were stratified based on glycemic status according to baseline glycated hemoglobin. Unfavorable tuberculosis (TB) outcome was defined as treatment failure or modification, recurrence, or death; favorable outcome was cure or treatment completion. We corroborated the findings using data from PWTB reported to the Brazilian National System of Diseases Notification (SINAN) during 2015-2019 (N = 20 989). Logistic regression models evaluated associations between glycemic status and outcomes. RESULTS: In both cohorts, in univariate analysis, unfavorable outcomes were more frequently associated with smoking, illicit drug use, and human immunodeficiency virus infection. Diabetes, but not prediabetes, was associated with unfavorable outcomes in the RePORT-Brazil (adjusted relative risk [aRR], 2.45; P < .001) and SINAN (aRR, 1.76; P < .001) cohorts. Furthermore, diabetes was associated with high risk of death (during TB treatment) in both RePORT-Brazil (aRR, 2.16; P = .040) and SINAN (aRR, 1.93; P = .001). CONCLUSIONS: Diabetes was associated with an increased risk of unfavorable outcomes and mortality in Brazilian PWTB. Interventions to improve TB treatment outcomes in persons with diabetes are needed.

The five times sit-to-stand test: safety, validity and reliability with critical care survivors's at ICU discharge.

BACKGROUND: The Five Times Sit-to-Stand Test (FTSST) has been found reliable, safe and valid for measuring healthy adults' lower limb muscle strength and for determining balance control, fall risk, and exercise capacity among older examinees. We believe that the FTSST has the potential to be a straightforward, low cost and valuable tool for identifying muscle disability and functional status following critical illness. The aim of our study was to establish the applicability, safety, and psychometric qualities of FTSST in patients at Intensive Care Unit (ICU) discharge. METHODS: In our study applicability was determined by assessing the percentage of patients who could perform the test at ICU discharge. Safety was assessed by examining data regarding any exacerbated haemodynamic and respiratory responses or adverse events associated with the test. For assessing FTSST reliability, intraclass correlation coefficients (ICCs), standard error of measurement (SEM) and Bland-Altman plot were used. For assessing concurrent validity handgrip strength, ICU length of stay, duration of invasive ventilation, Simplified Acute Physiology Score 3 (SAPS3) and age variables were used. For investigating predictive validity, correlations between the FTSST and measures of hospital length of stay and functional independence were evaluated. RESULTS: Only 30% of ICU survivors (n = 261 out of 817) were eligible to perform the FTSST and 7% of patients who performed the test (n = 10 out of 142) presented adverse events. Both inter (ICC 0.92 CI95% 0.89-0.94) and intra-rater (ICC 0.95 CI95% 0.93-0.96) reliability were excellent and higher scores were associated with lower muscle strength, longer hospital stay and greater functional impairment at hospital discharge in adult survivors of critical diseases. CONCLUSION: Our results suggest that the FTSST may be applicable only to high-functioning critical care survivors. In this specifical population, FTSST is a safe, easy to perform, valid and reliable measure that can be applied to fall risk and functional recovery management.

Determinants of losses in the latent tuberculosis infection cascade of care in Brazil.

INTRODUCTION: Factors associated with losses in the latent tuberculosis infection (LTBI) cascade of care in contacts of patients with tuberculosis (TB) were investigated in a multicentre prospective cohort from highly endemic regions in Brazil. METHODS: Close contacts of 1187 patients with culture-confirmed pulmonary TB were prospectively studied between 2015 and 2019, with follow-up of 6-24 months. Data on TB screening by clinical investigation, radiographic examination and interferon-gamma release assay (IGRA) were collected. Multivariable regressions were used to identify determinants of losses in the LTBI cascade. RESULTS: Among 4145 TB contacts initially identified, 1901 were examined (54% loss). Among those examined, 933 were people living with HIV, ≤5 years old and/or had positive IGRA results, and therefore had a recommendation to start TB preventive treatment (TPT). Of those, 454 (23%) initiated treatment, and 247 (54% of those initiating; 26% of those in whom treatment was recommended) completed TPT. Multivariable regression analysis revealed that living with HIV, illiteracy and black/pardo (brown) race were independently associated with losses in the cascade. CONCLUSION: There were losses at all LTBI cascade stages, but particularly at the initial screening and examination steps. Close contacts of low socioeconomic status and living with HIV were at heightened risk of not completing the LTBI cascade of care in Brazil.

Rapid On-Site Evaluation by Endosonographer of Endoscopic Ultrasound Fine-Needle Aspiration of Solid Pancreatic Lesions: A Randomized Controlled Trial.

OBJECTIVES: Rapid on-site evaluation (ROSE) by cytopathologists during endoscopic ultrasound-fine-needle aspiration (EUS-FNA) of solid pancreatic lesions (SPLs) improves adequacy and diagnostic accuracy while reducing the number of needle passes. We evaluated the usefulness of ROSE performed by the endosonographer. METHODS: Patients with an SPL were randomly assigned to EUS-FNA with ROSE or non-ROSE. Procedure duration, number of needle passes, specimen adequacy, and adverse event rates were compared. RESULTS: Sixty-five patients were enrolled (33 in the ROSE vs 32 in the non-ROSE group). Both groups were similar in terms of age, sex, size, and location of the lesion. Specimen adequacy rates were high and similar between groups. Mean (standard deviation) procedure duration was shorter in the ROSE versus non-ROSE group (30.0 [11.3] vs 37.0 [7.2] minutes, P < 0.005), as well as the mean (standard deviation) number of needle passes (2.6 [0.8] vs 3.5 [0.8], P < 0.005). Accuracy parameters as sensitivity and accuracy of ROSE by the endosonographer for malignancy were 93% and 88%, respectively. CONCLUSIONS: After specific training, the endosonographer can accurately evaluate samples during EUS-FNA of SPL, allowing for a shorter procedure duration and a lower number of needle passes.

Pre-Treatment Neutrophil Count as a Predictor of Antituberculosis Therapy Outcomes: A Multicenter Prospective Cohort Study.

Background: Neutrophils have been associated with lung tissue damage in many diseases, including tuberculosis (TB). Whether neutrophil count can serve as a predictor of adverse treatment outcomes is unknown. Methods: We prospectively assessed 936 patients (172 HIV-seropositive) with culture-confirmed pulmonary TB, enrolled in a multicenter prospective cohort study from different regions in Brazil, from June 2015 to June 2019, and were followed up to two years. TB patients had a baseline visit before treatment (month 0) and visits at month 2 and 6 (or at the end of TB treatment). Smear microscopy, and culture for Mycobacterium tuberculosis (MTB) were performed at TB diagnosis and during follow-up. Complete blood counts were measured at baseline. Treatment outcome was defined as either unfavorable (death, treatment failure or TB recurrence) or favorable (cure or treatment completion). We performed multivariable logistic regression, with propensity score regression adjustment, to estimate the association between neutrophil count with MTB culture result at month 2 and unfavorable treatment outcome. We used a propensity score adjustment instead of a fully adjusted regression model due to the relatively low number of outcomes. Results: Among 682 patients who had MTB culture results at month 2, 40 (5.9%) had a positive result. After regression with propensity score adjustment, no significant association between baseline neutrophil count (103/mm3) and positive MTB culture at month 2 was found among either HIV-seronegative (OR = 1.06, 95% CI = [0.95;1.19] or HIV-seropositive patients (OR = 0.77, 95% CI = [0.51; 1.20]). Of 691 TB patients followed up for at least 18 months and up to 24 months, 635 (91.9%) were either cured or completed treatment, and 56 (8.1%) had an unfavorable treatment outcome. A multivariable regression with propensity score adjustment found an association between higher neutrophil count (103/mm3) at baseline and unfavorable outcome among HIV-seronegative patients [OR= 1.17 (95% CI= [1.06;1.30]). In addition, adjusted Cox regression found that higher baseline neutrophil count (103/mm3) was associated with unfavorable treatment outcomes overall and among HIV-seronegative patients (HR= 1.16 (95% CI = [1.05;1.27]). Conclusion: Increased neutrophil count prior to anti-TB treatment initiation was associated with unfavorable treatment outcomes, particularly among HIV-seronegative patients. Further prospective studies evaluating neutrophil count in response to drug treatment and association with TB treatment outcomes are warranted.

Mesenchymal Stromal Cells From Emphysematous Donors and Their Extracellular Vesicles Are Unable to Reverse Cardiorespiratory Dysfunction in Experimental Severe Emphysema.

Although bone marrow-derived mesenchymal stromal cells (BM-MSCs) from patients with chronic obstructive pulmonary disease (COPD) appear to be phenotypically and functionally similar to BM-MSCs from healthy sources in vitro, the impact of COPD on MSC metabolism and mitochondrial function has not been evaluated. In this study, we aimed to comparatively characterize MSCs from healthy and emphysematous donors (H-MSCs and E-MSCs) in vitro and to assess the therapeutic potential of these MSCs and their extracellular vesicles (H-EVs and E-EVs) in an in vivo model of severe emphysema. For this purpose, C57BL/6 mice received intratracheal porcine pancreatic elastase once weekly for 4 weeks to induce emphysema; control animals received saline under the same protocol. Twenty-four hours after the last instillation, animals received saline, H-MSCs, E-MSCs, H-EVs, or E-EVs intravenously. In vitro characterization demonstrated that E-MSCs present downregulation of anti-inflammatory (TSG-6, VEGF, TGF-ß, and HGF) and anti-oxidant (CAT, SOD, Nrf2, and GSH) genes, and their EVs had larger median diameter and lower average concentration. Compared with H-MSC, E-MSC mitochondria also exhibited a higher respiration rate, were morphologically elongated, expressed less dynamin-related protein-1, and produced more superoxide. When co-cultured with alveolar macrophages, both H-MSCs and E-MSCs induced an increase in iNOS and arginase-1 levels, but only H-MSCs and their EVs were able to enhance IL-10 levels. In vivo, emphysematous mice treated with E-MSCs or E-EVs demonstrated no amelioration in cardiorespiratory dysfunction. On the other hand, H-EVs, but not H-MSCs, were able to reduce the neutrophil count, the mean linear intercept, and IL-1ß and TGF-ß levels in lung tissue, as well as reduce pulmonary arterial hypertension and increase the right ventricular area in a murine model of elastase-induced severe emphysema. In conclusion, E-MSCs and E-EVs were unable to reverse cardiorespiratory dysfunction, whereas H-EVs administration was associated with a reduction in cardiovascular and respiratory damage in experimental severe emphysema.

The Effect of Diabetes and Prediabetes on Mycobacterium tuberculosis Transmission to Close Contacts.

BACKGROUND: It is unknown whether dysglycemia is associated with Mycobacterium tuberculosis transmission. METHODS: We assessed epidemiological and clinical characteristics of patients with culture-confirmed pulmonary tuberculosis and their close contacts, enrolled in a multicenter prospective cohort in Brazil. Contacts were investigated at baseline and 6 months after enrollment. QuantiFERON positivity at baseline and conversion (from negative to positive at month 6) were compared between subgroups of contacts according to glycemic status of persons with tuberculosis (PWTB) as diabetes mellitus (DM) or prediabetes. Multivariable mixed-effects logistic regression models were performed to test independent associations with baseline QuantiFERON positive and QuantiFERON conversion. RESULTS: There were 592 PWTB (153 DM, 141 prediabetes, 211 normoglycemic) and 1784 contacts, of whom 658 were QuantiFERON-positive at baseline and 106 converters. Multivariable analyses demonstrated that tuberculosis-prediabetes cases, acid-fast bacilli-positive, pulmonary cavities, and living with someone who smoked were independently associated with QuantiFERON positive in contacts at baseline. DM, persistent cough, acid-fast bacilli-positive, and pulmonary cavities in tuberculosis source cases were associated with QuantiFERON conversion. CONCLUSIONS: Contacts of persons with pulmonary tuberculosis and dysglycemia were at increased risk of being QuantiFERON positive at baseline or month 6. Increased focus on such close contacts could improve tuberculosis control.

Safety and effectiveness of bronchial thermoplasty after 10 years in patients with persistent asthma (BT10+): a follow-up of three randomised controlled trials.

BACKGROUND: Bronchial thermoplasty is an endoscopic treatment for uncontrolled asthma. Previous randomised clinical trials have shown that bronchial thermoplasty reduces severe exacerbations in people with asthma. However, the long-term efficacy and safety of bronchial thermoplasty beyond 5 years is unknown. The BT10+ study aimed to investigate the efficacy and safety of bronchial thermoplasty after 10 or more years of follow-up. METHODS: BT10+ was an international, multicentre, follow-up study of participants who were previously enrolled in the AIR, RISA, and AIR2 trials and who had 10 or more years of follow-up since bronchial thermoplasty treatment. Data on patient demographics, quality of life, lung function, CT scans (AIR2 participants only), severe exacerbations, and health-care use during the previous year were collected at the BT10+ 10-year outcomes study visit. The primary effectiveness endpoint was durability of the thermoplasty treatment effect, determined by comparing the proportion of participants who had severe exacerbations during the first and fifth years after bronchial thermoplasty treatment with the proportion of participants who had severe exacerbations during the 12-month period before the BT10+ visit. The primary safety endpoint was the absence of clinically significant post-treatment respiratory image changes after bronchial thermoplasty, defined as bronchiectasis or bronchial stenosis as confirmed by pulmonary volumetric high-resolution CT scan at the BT10+ visit (AIR2 participants only). All analyses were done on an intention-to-treat basis. The trial is registered with ClinicalTrials.gov, NCT03243292. The last patient was enrolled on Dec 11, 2018. The last patient completed follow-up on Jan 10, 2019. FINDINGS: The BT10+ study enrolled 192 (45%) of the 429 participants who were enrolled in the AIR, RISA, and AIR2 trials. The BT10+ participants comprised 136 who received bronchial thermoplasty (52% of the 260 participants who received bronchial thermoplasty in the original trials), and 56 sham or control participants (33% of 169 from the original trials). 18 (32%) sham or control participants received bronchial thermoplasty after the previous trials concluded. The participants included in BT10+ were followed for 10·8-15·6 years (median 12·1 years) post-treatment. Baseline characteristics were similar between participants enrolled in BT10+ and those not enrolled. Participants treated with bronchial thermoplasty had similar proportions of severe exacerbations at the BT10+ visit (34 [25%] of 136 participants) compared with 1 year (33 [24%] of 135 participants; difference 0·6%, 95% CI -9·7 to 10·8) and 5 years (28 [22%] of 130 participants; difference 3·5%, -6·7% to 13·6) after treatment. Quality of life measurements and spirometry were similar between year 1, year 5, and the BT10+ visit. At the BT10+ study visit, pulmonary high-resolution CT scans from AIR2 participants treated with bronchial thermoplasty showed that 13 (13%) of 97 participants had bronchiectasis. When compared with baseline high-resolution CT scans, six (7%) of 89 participants treated with bronchial thermoplasty who did not have bronchiectasis at baseline had developed bronchiectasis after treatment (5 classified as mild, 1 classified as moderate). Participants treated with bronchial thermoplasty after the original study and participants in the sham or control group also had reductions in severe exacerbations at the BT10+ visit compared with baseline. INTERPRETATION: Our findings suggest that efficacy of bronchial thermoplasty is sustained for 10 years or more, with an acceptable safety profile. Therefore, bronchial thermoplasty is a long-acting therapeutic option for patients with asthma that remains uncontrolled despite optimised medical treatment. FUNDING: Boston Scientific.

Early use of nitazoxanide in mild COVID-19 disease: randomised, placebo-controlled trial.

BACKGROUND: Nitazoxanide is widely available and exerts broad-spectrum antiviral activity in vitro. However, there is no evidence of its impact on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: In a multicentre, randomised, double-blind, placebo-controlled trial, adult patients presenting up to 3 days after onset of coronavirus disease 2019 (COVID-19) symptoms (dry cough, fever and/or fatigue) were enrolled. After confirmation of SARS-CoV-2 infection using reverse transcriptase PCR on a nasopharyngeal swab, patients were randomised 1:1 to receive either nitazoxanide (500 mg) or placebo, three times daily, for 5 days. The primary outcome was complete resolution of symptoms. Secondary outcomes were viral load, laboratory tests, serum biomarkers of inflammation and hospitalisation rate. Adverse events were also assessed. RESULTS: From June 8 to August 20, 2020, 1575 patients were screened. Of these, 392 (198 placebo, 194 nitazoxanide) were analysed. Median (interquartile range) time from symptom onset to first dose of study drug was 5 (4-5) days. At the 5-day study visit, symptom resolution did not differ between the nitazoxanide and placebo arms. Swabs collected were negative for SARS-CoV-2 in 29.9% of patients in the nitazoxanide arm versus 18.2% in the placebo arm (p=0.009). Viral load was reduced after nitazoxanide compared to placebo (p=0.006). The percentage viral load reduction from onset to end of therapy was higher with nitazoxanide (55%) than placebo (45%) (p=0.013). Other secondary outcomes were not significantly different. No serious adverse events were observed. CONCLUSIONS: In patients with mild COVID-19, symptom resolution did not differ between nitazoxanide and placebo groups after 5 days of therapy. However, early nitazoxanide therapy was safe and reduced viral load significantly.

Prevalence and Clinical Profiling of Dysglycemia and HIV Infection in Persons With Pulmonary Tuberculosis in Brazil.

BACKGROUND: There are scarce data on the prevalence and disease presentation of HIV in patients with tuberculosis (TB) and dysglycemia (diabetes [DM] and prediabetes [PDM]), especially in TB-endemic countries. METHODS: We assessed the baseline epidemiological and clinical characteristics of patients with culture-confirmed pulmonary TB, enrolled in a multicenter prospective cohort in Brazil (RePORT-Brazil) during 2015-2019. Dysglycemia was defined by elevated glycated hemoglobin and stratified as PDM or DM. Additionally, we used data from TB cases obtained through the Brazilian National Notifiable Diseases Information System (SINAN), during 2015-2019. In SINAN, diagnosis of diabetes was based on self-report. Logistic regression models were performed to test independent associations between HIV, dysglycemia status, and other baseline characteristics in both cohorts. RESULTS: In the RePORT-Brazil cohort, the prevalence of DM and of PDM was 23.7 and 37.8%, respectively. Furthermore, the prevalence of HIV was 21.4% in the group of persons with TB-dysglycemia and 20.5% in that of patients with TBDM. In the SINAN cohort, the prevalence of DM was 9.2%, and among the TBDM group the prevalence of HIV was 4.1%. Logistic regressions demonstrated that aging was independently associated with PDM or DM in both the RePORT-Brazil and SINAN cohorts. In RePORT-Brazil, illicit drug use was associated with PDM, whereas a higher body mass index (BMI) was associated with DM occurrence. Of note, HIV was not associated with an increased risk of PDM or DM in patients with pulmonary TB in both cohorts. Moreover, in both cohorts, the TBDM-HIV group presented with a lower proportion of positive sputum smear and a higher frequency of tobacco and alcohol users. CONCLUSION: There is a high prevalence of dysglycemia in patients with pulmonary TB in Brazil, regardless of the HIV status. This reinforces the idea that DM should be systematically screened in persons with TB. Presence of HIV does not substantially impact clinical presentation in persons with TBDM, although it is associated with more frequent use of recreational drugs and smear negative sputum samples during TB screening.

Novel stepwise approach to assess representativeness of a large multicenter observational cohort of tuberculosis patients: The example of RePORT Brazil.

BACKGROUND: A major goal of tuberculosis (TB) epidemiological studies is to obtain results that can be generalized to the larger population with TB. The ability to extrapolate findings on the determinants of TB treatment outcomes is also important. METHODS: We compared baseline clinical and demographic characteristics and determinants of anti-TB treatment outcomes between persons enrolled in the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil cohort between June 2015 and June 2019, and the registry of TB cases reported to the Brazilian National TB Program (Information System for Notifiable Diseases [SINAN]) during the same time period. Multivariable regression models adjusted for the study site were performed using second-generation p-values, a novel statistical approach. Associations with unfavorable treatment outcomes were tested for both RePORT-Brazil and SINAN cohorts. FINDINGS: A total of 1,060 culture-confirmed TB patients were enrolled in RePORT-Brazil and 455,873 TB cases were reported to SINAN. Second-generation p-value analyses revealed that the cohorts were strikingly similar with regard to sex, age, use of antiretroviral therapy and positive initial smear sputum microscopy. However, diabetes, HIV infection, and smoking were more frequently documented in RePORT-Brazil. Illicit drug use, the presence of diabetes, and history of prior TB were associated with unfavorable TB treatment outcomes; illicit drug use was associated with such outcomes in both cohorts. CONCLUSIONS: There were important similarities in demographic characteristics and determinants of clinical outcomes between the RePORT-Brazil cohort and the Brazilian National registry of TB cases.

An Uncommon Lung Neoplasm in a Young Patient: Diagnostic Challenges.

BACKGROUND Adenosquamous carcinoma of the lung (ASC) is a rare subtype of non-small-cell lung carcinoma (NSCLC), histologically defined by the presence of both squamous cell carcinoma and adenocarcinoma components. This aggressive malignancy has been rarely described in young female patients. Due to its low incidence and difficult-to-establish preoperative diagnosis, little is known about the complete clinical course for young patients with this specific NSCLC subtype. Moreover, a history of smoking is positively associated with ASC, but evidence for an association with exposure to secondhand smoke is sparse. CASE REPORT We present the case of a previously healthy 29-year-old woman with a long-standing history of secondhand smoke exposure, who was ultimately diagnosed with advanced ASC via fiberoptic bronchoscopy with transbronchial biopsy after a number of different investigations and treatments performed outside our service. She had visited many clinicians in 4 months of symptoms, initially presented as thoracic pain and cough thought to be due to a complicated pneumonia. Symptoms progressed despite empiric treatment and eventually included low back pain, weight loss, and night sweats. The hypothesis of tuberculosis was then investigated and discarded, at which point, 3 months after the onset of symptoms, she had a CT scan of the chest, revealing a pulmonary mass. She was referred to our hospital to further investigate this finding via fiberoptic bronchoscopy with transbronchial biopsy. During the procedure, she experienced an acute exacerbation of the low back pain, which prompted her admission in the Emergency Department, and she was later admitted to our pneumology ward. An extensive treatment plan including chemotherapy and radiotherapy was initially started, but could not be completed due to rapid disease progression, defined by pulmonary and spine metastatic implants, which limited treatment to palliative care. The patient died 6 months after the initial onset of symptoms. CONCLUSIONS This case report shows the clinical course of a difficult and rare diagnosis, and demonstrates the high level of suspicion required for the early diagnosis of lung neoplasms in young patients.