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.

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.

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.

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.

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 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.

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.

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.

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.

Endobronchial ultrasound-guided transbronchial needle aspiration versus mediastinoscopy for mediastinal staging of lung cancer: A systematic review of economic evaluation studies.

INTRODUCTION: The emergence of endobronchial ultrasound (EBUS) changed the approach to staging lung cancer. As a new method being incorporated, the use of EBUS may lead to a shift in clinical and costs outcomes. OBJECTIVE: The aim of this systematic review is to gather information to better understand the economic impact of implementing EBUS. METHODS: This review is reported according to the PRISMA statement and registered on PROSPERO (CRD42019107901). Search keywords were elaborated considering descriptors of terms related to the disease (lung cancer / mediastinal staging of lung cancer) and the technologies of interest (EBUS and mediastinoscopy) combined with a specific economic filter. The literature search was performed in MEDLINE, EMBASE, LILACS, Cochrane Library of Trials, Web of Science, Scopus and National Health System Economic Evaluation Database (NHS EED) of the Center for Reviews and Dissemination (CRD). Screening, selection of articles, data extraction and quality assessment were carried out by two reviewers. RESULTS: Seven hundred and seventy publications were identified through the database searches. Eight articles were included in this review. All publications are full economic evaluation studies, one cost-effectiveness, three cost-utility, and four cost-minimization analyses. The costs of strategies using EBUS-TBNA were lower than the ones using mediastinoscopy in all studies analyzed. Two of the best quality scored studies demonstrate that the mediastinoscopy strategy is dominated by the EBUS-TBNA strategy. CONCLUSION: Information gathered in the eight studies of this systematic review suggest that EBUS is cost-effective compared to mediastinoscopy for mediastinal staging of lung cancer.

Oncogenic properties and signaling basis of the PAX8-GLIS3 fusion gene.

Hyalinizing trabecular tumors of the thyroid are rare and mostly benign epithelial neoplasms of follicular cell origin, which have recently been shown to be underpinned by the PAX8-GLIS3 fusion gene. In our study, we sought to investigate the potential oncogenic mechanisms of the PAX8-GLIS3 fusion gene. Forced expression of PAX8-GLIS3 was found to increase proliferation, clonogenic potential and migration of human nonmalignant thyroid (Nthy-ori 3-1) and embryonic kidney (HEK-293) cells. Moreover, in xenografts, Nthy-ori 3-1 PAX8-GLIS3 expressing cells generated significantly larger and more proliferative tumors compared to controls. These oncogenic effects were found to be mediated through activation of the Sonic Hedgehog (SHH) pathway. Targeting of smoothened (SMO), a key protein in the SHH pathway, using the small molecule inhibitor Cyclopamine partially reversed the increased proliferation, colony formation and migration in PAX8-GLIS3 expressing cells. Our data demonstrate that the oncogenic effects of the PAX8-GLIS3 fusion gene are, at least in part, due to an increased activation of the SHH pathway.

Increased Frequency of Memory CD4+ T-Cell Responses in Individuals With Previously Treated Extrapulmonary Tuberculosis.

Extrapulmonary TB (EPTB) occurs with increased frequency in persons with underlying immunodeficiency. Even after recovery from acute illness, differences in immune phenotype and activation persist. Studies defining characteristics of immune responses after recovery from extrapulmonary TB may provide insights into factors that increase TB risk. We performed two case-control studies (in the United States and Brazil) among HIV-seronegative adults with previous EPTB (n = 9; 25), previous pulmonary TB (n = 7; 25), latent M. tuberculosis (Mtb) infection (n = 11; 25), and uninfected TB contacts (n = 10; 25). We assessed the frequency of dual CD4+ interferon-γ and tumor necrosis factor-α responses after stimulation with overlapping Mtb peptides from ESAT-6 or CFP-10, or gamma-irradiated Mtb H37Rv, proliferative responses to Mtb antigens, T-regulatory cell (Treg) frequency and phenotype. In both study populations, individuals with prior EPTB had the highest frequency of intracellular cytokine-producing cells in response to Mtb antigens (p < 0.05; p <.0001). Persons with prior EPTB in Brazil had the highest levels of CD4 proliferation to Mtb antigens (p < 0.0001), and the highest expression of CD39 on Tregs (p < 0.0001). Individuals with treated EPTB maintained high frequencies of Mtb-specific memory responses and active Treg cells, suggesting that susceptibility to EPTB occurs despite the ability to develop and maintain enhanced adaptive immune responses.

Endobronchial ultrasound-guided transbronchial needle aspiration versus mediastinoscopy for mediastinal staging of lung cancer: A protocol for a systematic review of economic evaluation studies.

BACKGROUND: Lung cancer is a major health problem, with estimates of 1.6 million tumor-related deaths annually worldwide. The emergence of endobronchial ultrasound (EBUS), a minimally invasive procedure capable of providing valuable information for primary tumor diagnosis and mediastinal staging, significantly changed the approach of pulmonary cancer, becoming part of the routine mediastinal evaluation of lung cancer in developed countries. Some economic evaluation studies published in the last 10 years have already analyzed the incorporation of the EBUS technique in different health systems. The aim of this systematic review is to synthesize the relevant information brought by these studies to better understand the economic effect of the implementation of this staging tool. METHODS: The systematic review will be reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines. Eletronic databases (Medline, Lilacs, Embase, Cochrane Library of Trials, Web of Science, Scopus, National Health System Economic Evaluation Database) will be searched for full economic analyses regarding the use of EBUS-guided transbronchial needle aspiration (EBUS-TBNA) compared to the surgical technique of mediastinoscopy for the mediastinal staging of lung cancer. Two authors will perform the selection of studies, data extraction, and the assessment of risk of bias. Occasionally, a senior reviewer will participate, if necessary, on study selection or data extraction. RESULTS: Results will be published in a peer-reviewed journal. CONCLUSION: This review may influence a more cost-effective mediastinal staging approach for patients with lung cancer around the world and help health decision makers decide whether the EBUS-TBNA technique should be incorporated into their health systems and how to do it efficiently. PROTOCOL REGISTRY: PROSPERO 42019107901.

Genetic Diversity and Molecular Epidemiology of Mycobacterium tuberculosis in Roraima State, Brazil.

National border areas are special places for the spread of Mycobacterium tuberculosis (MTB). These regions concentrate vulnerable populations and constant population movements. Understanding the dynamics of the transmission of MTB is fundamental to propose control measures and to monitor drug resistance. We conducted a population-based prospective study of tuberculosis (TB) to evaluate molecular characteristics of MTB isolates circulating in Roraima, a state on the border of Venezuela and Guyana. Eighty isolates were genotyped by IS6110-RFLP (restriction fragment length polymorphism), spoligotyping, and 24-locus mycobacterial interspersed repetitive unit-variable number of repeats tandem (MIRU-VNTR). Drug susceptibility tests were performed by using the proportion method and GeneXpert® MTB/RIF (Cepheid, Sunnyvale, CA). Isolates showing a phenotypic resistance profile were submitted to polymerase chain reaction (PCR) and sequencing. Spoligotyping showed 40 distinct patterns with a high prevalence of Latin-American and Mediterranean (LAM), Haarlem (H), and the "ill-defined" T clades. Mycobacterial interspersed repetitive unit -VNTR and IS6110-RFLP showed clustering rates of 21.3% and 30%, respectively. Drug resistance was detected in 11 (15.1%) isolates, and all were found to have primary resistance; among these, six (8.2%) isolates were streptomycin mono-resistant, four (5.4%) isoniazid mono-resistant, and one (1.3%) multidrug resistant. This is the first study on the molecular epidemiology and drug resistance profile of MTB from Roraima. Herein, we describe high diversity of genetic profiles circulating in this region that may be driven by the introduction of new strain types because of large population flow in this region. In summary, our results showed that analyses of these circulating strains can contribute to a better understanding of TB epidemiology in the northern Brazilian border and be useful to establish public health policies on TB prevention.

Patterns of C-reactive protein ratio response to antibiotics in pediatric sepsis: A prospective cohort study.

PURPOSE: Evaluate sequential C-reactive protein (CRP) measurements and patterns of CRP-ratio response to antibiotic therapy during first 7days in Pediatric Intensive Care Unit (PICU) of septic children. METHODS: Prospective, cohort study of children (1month-12years) admitted at 3 PICUs, with diagnosis of sepsis with <72h course. CRP-ratio was calculated in relation to D0_CRP value. Children were classified according to an individual pattern of CRP-ratio response: fast - CRP_D4 of therapy was <0.4 of D0_CRP; slow - continuous but slow decrease of CRP; non - CRP remained ≥0.8 of D0_CRP; biphasic - initial CRP decrease to levels <0.8 of D0_CRP followed by secondary rise ≥0.8. RESULTS: 103 septic children (age-median: 2yrs; 54% male) were prospectively included (infection focus: 65% respiratory, 12.5% central nervous system). Overall PICU mortality was 11.7%. 102 children could be classified according to a predefined CRP-ratio response pattern. Time-dependent analysis of CRP-ratio and CRP course of the different patterns were significantly different. Besides, PICU mortality rate was significantly different according CRP-ratio response patterns: fast response 4.5%; slow response 5.8%; non-response 29.4%; biphasic response 42.8%. CONCLUSIONS: In pediatric sepsis, CRP-ratio serial evaluation was useful in early identification of patients with poor outcome.

Mesenchymal stromal cell therapy in COPD: from bench to bedside.

COPD is the most frequent chronic respiratory disease and a leading cause of morbidity and mortality. The major risk factor for COPD development is cigarette smoke, and the most efficient treatment for COPD is smoking cessation. However, even after smoking cessation, inflammation, apoptosis, and oxidative stress may persist and continue contributing to disease progression. Although current therapies for COPD (primarily based on anti-inflammatory agents) contribute to the reduction of airway obstruction and minimize COPD exacerbations, none can avoid disease progression or reduce mortality. Within this context, recent advances in mesenchymal stromal cell (MSC) therapy have made this approach a strong candidate for clinical use in the treatment of several pulmonary diseases. MSCs can be readily harvested from diverse tissues and expanded with high efficiency, and have strong immunosuppressive properties. Preclinical studies have demonstrated encouraging outcomes of MSCs therapy for lung disorders, including emphysema. These findings instigated research groups to assess the impact of MSCs in human COPD/emphysema, but clinical results have fallen short of expectations. However, MSCs have demonstrated a good adjuvant role in the clinical scenario. Trials that used MSCs combined with another, primary treatment (eg, endobronchial valves) found that patients derived greater benefit in pulmonary function tests and/or quality of life reports, as well as reductions in systemic markers of inflammation. The present review summarizes and describes the more recent preclinical studies that have been published about MSC therapy for COPD/emphysema and discusses what has already been applied about MSCs treatment in COPD patients in the clinical setting.

Combined Bone Marrow-Derived Mesenchymal Stromal Cell Therapy and One-Way Endobronchial Valve Placement in Patients with Pulmonary Emphysema: A Phase I Clinical Trial.

One-way endobronchial valves (EBV) insertion to reduce pulmonary air trapping has been used as therapy for chronic obstructive pulmonary disease (COPD) patients. However, local inflammation may result and can contribute to worsening of clinical status in these patients. We hypothesized that combined EBV insertion and intrabronchial administration of mesenchymal stromal cells (MSCs) would decrease the inflammatory process, thus mitigating EBV complications in severe COPD patients. This initial study sought to investigate the safety of this approach. For this purpose, a phase I, prospective, patient-blinded, randomized, placebo-controlled design was used. Heterogeneous advanced emphysema (Global Initiative for Chronic Lung Disease [GOLD] III or IV) patients randomly received either allogeneic bone marrow-derived MSCs (108 cells, EBV+MSC) or 0.9% saline solution (EBV) (n = 5 per group), bronchoscopically, just before insertion of one-way EBVs. Patients were evaluated 1, 7, 30, and 90 days after therapy. All patients completed the study protocol and 90-day follow-up. MSC delivery did not result in acute administration-related toxicity, serious adverse events, or death. No significant between-group differences were observed in overall number of adverse events, frequency of COPD exacerbations, or worsening of disease. Additionally, there were no significant differences in blood tests, lung function, or radiological outcomes. However, quality-of-life indicators were higher in EBV + MSC compared with EBV. EBV + MSC patients presented decreased levels of circulating C-reactive protein at 30 and 90 days, as well as BODE (Body mass index, airway Obstruction, Dyspnea, and Exercise index) and MMRC (Modified Medical Research Council) scores. Thus, combined use of EBV and MSCs appears to be safe in patients with severe COPD, providing a basis for subsequent investigations using MSCs as concomitant therapy. Stem Cells Translational Medicine 2017;6:962-969.

Endobronchial ultrasound in real life: primary diagnosis and mediastinal staging of lung cancer in patients submitted to thoracic surgery.

BACKGROUND: Since the first articles published for over 10 years ago, endobronchial ultrasound (EBUS) has gained a strong scientific backing and has been incorporated into routine medical practice in pulmonology and thoracic surgery centers. How is EBUS performing outside the scientific environment, as a diagnostic and mediastinal staging tool in a subset of patients that undergo thoracic surgery, is an interesting question. METHODS: This study evaluated consecutive patients who, during the period from January 2010 to August 2012, were submitted to EBUS and later to thoracic surgery. The samples obtained by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) were compared to surgical samples. The primary endpoint was the proportion of patients with a final diagnosis of non-small cell lung cancer (NSCLC) by EBUS-TBNA correctly subtyped. The secondary endpoint was the negative predictive value (NPV) of EBUS-TBNA for mediastinal staging of lung cancer. RESULTS: Two hundred eighty seven patients were studied. Considering 84 patients with a final diagnosis of NSCLC by EBUS-TBNA, 79 % (CI 95 % 70.1-87.3) were correctly subclassified. The NPV of EBUS-TBNA for mediastinal staging was 89 % (IC 95 % 84.9-92.7). From a total of 21 false negative cases of mediastinal staging, 16 (76 %) did not undergo positron emission tomography-computed tomography (PET-CT) before the EBUS and in 15 (71 %) the affected lymph node chain was not punctured by EBUS-TBNA. Ten (47 %) patients had only lymph node metastases not directly accessible by the EBUS. CONCLUSIONS: Performed in hospital routine and in patients submitted to thoracic surgery, EBUS-TBNA proved to be a good tool for proper pathological diagnosis of lung cancer. The negative predictive value of 89 % for mediastinal staging of lung cancer is comparable to that reported in previous studies, but the relatively high number of 21 false negative cases points to the need for standardization of routine strategies before, during and after EBUS.

Difficulties in access and estimates of public beds in intensive care units in the state of Rio de Janeiro.

OBJECTIVE: To estimate the required number of public beds for adults in intensive care units in the state of Rio de Janeiro to meet the existing demand and compare results with recommendations by the Brazilian Ministry of Health. METHODS: The study uses a hybrid model combining time series and queuing theory to predict the demand and estimate the number of required beds. Four patient flow scenarios were considered according to bed requests, percentage of abandonments and average length of stay in intensive care unit beds. The results were plotted against Ministry of Health parameters. Data were obtained from the State Regulation Center from 2010 to 2011. RESULTS: There were 33,101 medical requests for 268 regulated intensive care unit beds in Rio de Janeiro. With an average length of stay in regulated ICUs of 11.3 days, there would be a need for 595 active beds to ensure system stability and 628 beds to ensure a maximum waiting time of six hours. Deducting current abandonment rates due to clinical improvement (25.8%), these figures fall to 441 and 417. With an average length of stay of 6.5 days, the number of required beds would be 342 and 366, respectively; deducting abandonment rates, 254 and 275. The Brazilian Ministry of Health establishes a parameter of 118 to 353 beds. Although the number of regulated beds is within the recommended range, an increase in beds of 122.0% is required to guarantee system stability and of 134.0% for a maximum waiting time of six hours. CONCLUSIONS: Adequate bed estimation must consider reasons for limited timely access and patient flow management in a scenario that associates prioritization of requests with the lowest average length of stay.