Hospital das Clínicas da Universidade Federal de Minas Gerais

BACKGROUND: Invasive fungal infections are an important cause of morbidity and mortality after allogeneic hematopoietic stem-cell transplantation. METHODS: In an international, randomized, double-blind trial, we compared oral posaconazole with oral fluconazole for prophylaxis against invasive fungal infections in patients with graft-versus-host disease (GVHD) who were receiving immunosuppressive therapy. The primary end point was the incidence of proven or probable invasive fungal infections from randomization to day 112 of the fixed treatment period of the study. RESULTS: Of a total of 600 patients, 301 were assigned to posaconazole and 299 to fluconazole. At the end of the fixed 112-day treatment period, posaconazole was found to be as effective as fluconazole in preventing all invasive fungal infections (incidence, 5.3% and 9.0%, respectively; odds ratio, 0.56; 95 percent confidence interval [CI], 0.30 to 1.07; P=0.07) and was superior to fluconazole in preventing proven or probable invasive aspergillosis (2.3% vs. 7.0%; odds ratio, 0.31; 95% CI, 0.13 to 0.75; P=0.006). While patients were receiving study medications (exposure period), in the posaconazole group, as compared with the fluconazole group, there were fewer breakthrough invasive fungal infections (2.4% vs. 7.6%, P=0.004), particularly invasive aspergillosis (1.0% vs. 5.9%, P=0.001). Overall mortality was similar in the two groups, but the number of deaths from invasive fungal infections was lower in the posaconazole group (1%, vs. 4% in the fluconazole group; P=0.046). The incidence of treatment-related adverse events was similar in the two groups (36% in the posaconazole group and 38% in the fluconazole group), and the rates of treatment-related serious adverse events were 13% and 10%, respectively. CONCLUSIONS: Posaconazole was similar to fluconazole for prophylaxis against fungal infections among patients with GVHD. It was superior in preventing invasive aspergillosis and reducing the rate of deaths related to fungal infections. (ClinicalTrials.gov number, NCT00034645 [ClinicalTrials.gov].).

The role of automatic electrocardiogram (ECG) analysis in clinical practice is limited by the accuracy of existing models. Deep Neural Networks (DNNs) are models composed of stacked transformations that learn tasks by examples. This technology has recently achieved striking success in a variety of task and there are great expectations on how it might improve clinical practice. Here we present a DNN model trained in a dataset with more than 2 million labeled exams analyzed by the Telehealth Network of Minas Gerais and collected under the scope of the CODE (Clinical Outcomes in Digital Electrocardiology) study. The DNN outperform cardiology resident medical doctors in recognizing 6 types of abnormalities in 12-lead ECG recordings, with F1 scores above 80% and specificity over 99%. These results indicate ECG analysis based on DNNs, previously studied in a single-lead setup, generalizes well to 12-lead exams, taking the technology closer to the standard clinical practice.

BACKGROUND: In an attempt to decrease the toxic effects of fluorouracil, doxorubicin, and methotrexate (FAMTX) by reducing the dose of methotrexate from 1500 mg/m2, according to the original regimen, to 1000 mg/m2, the authors designed the modified FAMTX treatment that was evaluated in a prospective Phase II-III randomized trial. METHODS: Patients with advanced gastric cancer were randomized to receive modified FAMTX treatment or supportive measures only (control group). In the middle of the study, the randomization was interrupted because of strong evidence of benefit in terms of tumor reduction and projected survival in the treatment arm receiving chemotherapy. By the end of the study, 30 assessable patients had received chemotherapy and 10 had received supportive treatment. RESULTS: The overall response rate was 50% (15 patients); 12 patients (40%) had partial responses and 3 (10%) had complete responses (CR). One patient with extensive peritoneal carcinomatosis attained a CR pathologically documented by laparoscopic examination and peritoneal biopsy. The median overall survival time of the treated group was 9 months, whereas that of the control group was only 3 months (P = 0.001). The median overall survival time of the responders was 16 months, and their median remission duration was 8 months. The regimen was well tolerated, with a very acceptable toxicity profile. There was one toxic death resulting from neutropenia and sepsis in a patient who did not receive adequate leucovorin rescue. CONCLUSIONS: This regimen appears to prolong survival in patients with advanced gastric cancer, and the reduction of the methotrexate dose does not seem to compromise its efficacy.

# Annotated 12 lead ECG dataset Contain 827 ECG tracings from different patients, annotated by several cardiologists, residents and medical students. It is used as test set on the paper: "Automatic Diagnosis of the Short-Duration12-Lead ECG using a Deep Neural Network". It contain annotations about 6 different ECGs abnormalities: - 1st degree AV block (1dAVb); - right bundle branch block (RBBB); - left bundle branch block (LBBB); - sinus bradycardia (SB); - atrial fibrillation (AF); and, - sinus tachycardia (ST). ## Folder content: - `ecg_tracings.hdf5`: HDF5 file containing a single dataset named `tracings`. This dataset is a `(827, 4096, 12)` tensor. The first dimension correspond to the 827 different exams from different patients; the second dimension correspond to the 4096 signal samples; the third dimension to the 12 different leads of the ECG exam. The signals are sampled at 400 Hz. Some signals originally have a duration of 10 seconds (10 * 400 = 4000 samples) and others of 7 seconds (7 * 400 = 2800 samples). In order to make them all have the same size (4096 samples) we fill them with zeros on both sizes. For instance, for a 7 seconds ECG signal with 2800 samples we include 648 samples at the beginning and 648 samples at the end, yielding 4096 samples that are them saved in the hdf5 dataset. All signal are represented as floating point numbers at the scale 1e-4V: so it should be multiplied by 1000 in order to obtain the signals in V. In python, one can read this file using the following sequence: ```python import h5py with h5py.File(args.tracings, "r") as f: x = np.array(f['tracings']) ``` - The file `attributes.csv` contain basic patient attributes: sex (M or F) and age. It contain 827 lines (plus the header). The i-th tracing in `ecg_tracings.hdf5` correspond to the i-th line. - `annotations/`: folder containing annotations csv format. Each csv file contain 827 lines (plus the header). The i-th line correspond to the i-th tracing in `ecg_tracings.hdf5` correspond to the in all csv files. The csv files all have 6 columns `1dAVb, RBBB, LBBB, SB, AF, ST` corresponding to weather the annotator have detect the abnormality in the ECG (`=1`) or not (`=0`). 1. `cardiologist[1,2].csv` contain annotations from two different cardiologist. 2. `gold_standard.csv` gold standard annotation for this test dataset. When the cardiologist 1 and cardiologist 2 agree, the common diagnosis was considered as gold standard. In cases where there was any disagreement, a third senior specialist, aware of the annotations from the other two, decided the diagnosis. 3. `dnn.csv` prediction from the deep neural network described in "Automatic Diagnosis of the Short-Duration 12-Lead ECG using a Deep Neural Network". The threshold is set in such way it maximizes the F1 score. 4. `cardiology_residents.csv` annotations from two 4th year cardiology residents (each annotated half of the dataset). 5. `emergency_residents.csv` annotations from two 3rd year emergency residents (each annotated half of the dataset). 6. `medical_students.csv` annotations from two 5th year medical students (each annotated half of the dataset).

BACKGROUND: The onset of puberty is first detected as an increase in pulsatile secretion of gonadotropin-releasing hormone (GnRH). Early activation of the hypothalamic-pituitary-gonadal axis results in central precocious puberty. The timing of pubertal development is driven in part by genetic factors, but only a few, rare molecular defects associated with central precocious puberty have been identified. METHODS: We performed whole-exome sequencing in 40 members of 15 families with central precocious puberty. Candidate variants were confirmed with Sanger sequencing. We also performed quantitative real-time polymerase-chain-reaction assays to determine levels of messenger RNA (mRNA) in the hypothalami of mice at different ages. RESULTS: We identified four novel heterozygous mutations in MKRN3, the gene encoding makorin RING-finger protein 3, in 5 of the 15 families; both sexes were affected. The mutations included three frameshift mutations, predicted to encode truncated proteins, and one missense mutation, predicted to disrupt protein function. MKRN3 is a paternally expressed, imprinted gene located in the Prader-Willi syndrome critical region (chromosome 15q11-q13). All affected persons inherited the mutations from their fathers, a finding that indicates perfect segregation with the mode of inheritance expected for an imprinted gene. Levels of Mkrn3 mRNA were high in the arcuate nucleus of prepubertal mice, decreased immediately before puberty, and remained low after puberty. CONCLUSIONS: Deficiency of MKRN3 causes central precocious puberty in humans. (Funded by the National Institutes of Health and others.).

Anxiety and stress-related disorders are severe psychiatric conditions that affect performance in daily tasks and represent a high cost to public health. The initial observation of Charles Darwin that animals and human beings share similar characteristics in the expression of emotion raise the possibility of studying the mechanisms of psychiatric disorders in other mammals (mainly rodents). The development of animal models of anxiety and stress has helped to identify the pharmacological mechanisms and potential clinical effects of several drugs. Animal models of anxiety are based on conflict situations that can generate opposite motivational states induced by approach-avoidance situations. The present review revisited the main rodent models of anxiety and stress responses used worldwide. Here we defined as "ethological" the tests that assess unlearned/unpunished responses (such as the elevated plus maze, light-dark box, and open field), whereas models that involve learned/punished responses are referred to as "conditioned operant conflict tests" (such as the Vogel conflict test). We also discussed models that involve mainly classical conditioning tests (fear conditioning). Finally, we addressed the main protocols used to induce stress responses in rodents, including psychosocial (social defeat and neonatal isolation stress), physical (restraint stress), and chronic unpredictable stress.

BACKGROUND: Political, economic, and epidemiological changes in Brazil have affected health and the health system. We used the Global Burden of Disease Study 2016 (GBD 2016) results to understand changing health patterns and inform policy responses. METHODS: We analysed GBD 2016 estimates for life expectancy at birth (LE), healthy life expectancy (HALE), all-cause and cause-specific mortality, years of life lost (YLLs), years lived with disability (YLDs), disability-adjusted life-years (DALYs), and risk factors for Brazil, its 26 states, and the Federal District from 1990 to 2016, and compared these with national estimates for ten comparator countries. FINDINGS: Nationally, LE increased from 68·4 years (95% uncertainty interval [UI] 68·0-68·9) in 1990 to 75·2 years (74·7-75·7) in 2016, and HALE increased from 59·8 years (57·1-62·1) to 65·5 years (62·5-68·0). All-cause age-standardised mortality rates decreased by 34·0% (33·4-34·5), while all-cause age-standardised DALY rates decreased by 30·2% (27·7-32·8); the magnitude of declines varied among states. In 2016, ischaemic heart disease was the leading cause of age-standardised YLLs, followed by interpersonal violence. Low back and neck pain, sense organ diseases, and skin diseases were the main causes of YLDs in 1990 and 2016. Leading risk factors contributing to DALYs in 2016 were alcohol and drug use, high blood pressure, and high body-mass index. INTERPRETATION: Health improved from 1990 to 2016, but improvements and disease burden varied between states. An epidemiological transition towards non-communicable diseases and related risks occurred nationally, but later in some states, while interpersonal violence grew as a health concern. Policy makers can use these results to address health disparities. FUNDING: Bill & Melinda Gates Foundation and the Brazilian Ministry of Health.

As tabelas de classes de recomendação e níveis de evidência desta atualização foram realizadas conforme a padronização a seguir: Classes (graus) de recomendação Classe I Condições para as quais há evidências conclusivas, ou, na sua falta, consenso geral de que o procedimento é seguro, e útil/eficaz Classe IIa Condições para as quais há evidências conflitantes e/ou divergência de opinião sobre segurança, e utilidade/eficácia do procedimento.Peso ou evidência/opinião a favor do procedimento.A maioria dos estudos/especialistas aprova Classe IIb Condições para as quais há evidências conflitantes e/ou divergência de opinião sobre segurança, e utilidade/eficácia do procedimento.Segurança e utilidade/eficácia menos bem estabelecida, não havendo predomínio de opiniões a favor Classe III Condições para as quais há evidências e/ou consenso de que o procedimento não é útil/eficaz e, em alguns casos, pode ser prejudicial Níveis de evidência Nível A Dados obtidos a partir de múltiplos estudos randomizados de bom porte, concordantes e/ou de meta-análise robusta de estudos clínicos randomizados Nível B Dados obtidos a partir de meta-análise menos robusta, a partir de um único estudo randomizado ou de estudos não randomizados (observacionais) Nível C Dados obtidos de opiniões consensuais de especialistas

Alzheimer's disease (AD) is associated with memory impairment and altered peripheral metabolism. Mounting evidence indicates that abnormal signaling in a brain-periphery metabolic axis plays a role in AD pathophysiology. The activation of pro-inflammatory pathways in the brain, including the interleukin-6 (IL-6) pathway, comprises a potential point of convergence between memory dysfunction and metabolic alterations in AD that remains to be better explored. Using T2-weighted magnetic resonance imaging (MRI), we observed signs of probable inflammation in the hypothalamus and in the hippocampus of AD patients when compared to cognitively healthy control subjects. Pathological examination of post-mortem AD hypothalamus revealed the presence of hyperphosphorylated tau and tangle-like structures, as well as parenchymal and vascular amyloid deposits surrounded by astrocytes. T2 hyperintensities on MRI positively correlated with plasma IL-6, and both correlated inversely with cognitive performance and hypothalamic/hippocampal volumes in AD patients. Increased IL-6 and suppressor of cytokine signaling 3 (SOCS3) were observed in post-mortem AD brains. Moreover, activation of the IL-6 pathway was observed in the hypothalamus and hippocampus of AD mice. Neutralization of IL-6 and inhibition of the signal transducer and activator of transcription 3 (STAT3) signaling in the brains of AD mouse models alleviated memory impairment and peripheral glucose intolerance, and normalized plasma IL-6 levels. Collectively, these results point to IL-6 as a link between cognitive impairment and peripheral metabolic alterations in AD. Targeting pro-inflammatory IL-6 signaling may be a strategy to alleviate memory impairment and metabolic alterations in the disease.

INTRODUCTION: An increase in the incidence and severity of acute osteoarticular infections in children was perceived after the emergence of community-associated methicillin-resistant Staphylococcus aureus (MRSA) in our community. This study was performed to describe changes in the epidemiology and clinical features of acute osteoarticular infections. METHODS: The records of patients discharged from Le Bonheur Children's Medical Center with a diagnosis of acute osteoarticular infection between 2000 and 2004 were reviewed. Data regarding signs and symptoms, diagnostic testing, therapeutics, surgery, and hospital course were collected. RESULTS: There were 158 cases of acute osteoarticular infection. The incidence increased from 2.6 to 6.0 per 1000 admissions between 2000 and 2004. The proportion of infections caused by methicillin-susceptible S. aureus (MSSA) remained constant (10%-13%) and that caused by MRSA rose from 4% to 40%. There was no difference between MRSA and MSSA patients in the duration of fever or pain before diagnosis. Seventy-one percent of patients with MRSA had subperiosteal abscesses compared with 38% with MSSA (P = 0.02). Ninety-one percent of MRSA patients required a surgical procedure compared with 62% of MSSA patients (P < 0.001). Median hospital stay was 7 days for MSSA patients and 10 days for MRSA patients (P = 0.0001). Three patients developed chronic osteomyelitis, 2 with MRSA. There was no association between a delay in institution of appropriate antibiotic therapy and presence of subperiosteal abscess (P = 0.8). CONCLUSIONS: There has been an increase in the incidence and severity of acute osteoarticular infections in Memphis. Patients with community-associated MRSA infections are at higher risk of subperiosteal abscess requiring surgical intervention.

PURPOSE OF REVIEW: The number of adolescent and adult patients submitting to bariatric surgery is increasing rapidly around the world. This review describes the literature published in the last few years concerning nutritional deficiencies after bariatric surgery as well as their etiology, incidence, treatment and prevention. RECENT FINDINGS: Although bariatric surgery was first introduced in the 1950s, safe and successful surgical management has progressed over the last two decades and longer post-surgical follow-up data are now available. Most of the patients undergoing malabsorptive procedures will develop some nutritional deficiency, justifying mineral and multivitamin supplementation to all postoperatively. Nutrient deficiency is proportional to the length of absorptive area and to the percentage of weight loss. Low levels of iron, vitamin B12, vitamin D and calcium are predominant after Roux-en-Y gastric bypass. Protein and fat-soluble vitamin deficiencies are mainly detected after biliopancreatic diversion. Thiamine deficiency is common in patients with frequent vomiting. As the incidence of these deficiencies progresses with time, the patients should be monitored frequently and regularly to prevent malnutrition. SUMMARY: Nutritional deficiencies can be prevented if a multidisciplinary team regularly assists the patient. Malnutrition is generally reverted with nutrient supplementation, once it is promptly diagnosed. Especial attention should be given to adolescents, mainly girls at reproductive age who have a substantial risk of developing iron deficiency. Future studies are necessary to detect nutrient abnormalities after new procedures and to evaluate the safety of bariatric surgery in younger obese patients.

: Obesity is a highly prevalent condition with important health implications. Face-to-face interventions to treat obesity demand a large number of human resources and time, generating a great burden to individuals and health system. In this context, the internet is an attractive tool for delivering weight loss programs due to anonymity, 24-hour-accessibility, scalability, and reachability associated with Web-based programs. : We aimed to investigate the effectiveness of Web-based digital health interventions, excluding hybrid interventions and non-Web-based technologies such as text messaging, short message service, in comparison to nontechnology active or inactive (wait list) interventions on weight loss and lifestyle habit changes in individuals with overweight and obesity. : We searched PubMed or Medline, SciELO, Lilacs, PsychNet, and Web of Science up to July 2018, as well as references of previous reviews for randomized trials that compared Web-based digital health interventions to offline interventions. Anthropometric changes such as weight, body mass index (BMI), waist, and body fat and lifestyle habit changes in adults with overweight and obesity were the outcomes of interest. Random effects meta-analysis and meta-regression were performed for mean differences (MDs) in weight. We rated the risk of bias for each study and the quality of evidence across studies using the Grades of Recommendation, Assessment, Development, and Evaluation approach. : Among the 4071 articles retrieved, 11 were included. Weight (MD −0.77 kg, 95% CI −2.16 to 0.62; 1497 participants; moderate certainty evidence) and BMI (MD −0.12 kg/m2; 95% CI −0.64 to 0.41; 1244 participants; moderate certainty evidence) changes were not different between Web-based and offline interventions. Compared to offline interventions, digital interventions led to a greater short-term (<6 months follow-up) weight loss (MD −2.13 kg, 95% CI −2.71 to −1.55; 393 participants; high certainty evidence), but not in the long-term (MD −0.17 kg, 95% CI −2.10 to 1.76; 1104 participants; moderate certainty evidence). Meta-analysis was not possible for lifestyle habit changes. High risk of attrition bias was identified in 5 studies. For weight and BMI outcomes, the certainty of evidence was moderate mainly due to high heterogeneity, which was mainly attributable to control group differences across studies (R2=79%). : Web-based digital interventions led to greater short-term but not long-term weight loss than offline interventions in overweight and obese adults. Heterogeneity was high across studies, and high attrition rates suggested that engagement is a major issue in Web-based interventions.

BACKGROUND: The clinical utility of serum procalcitonin levels in guiding antibiotic treatment decisions in patients with sepsis remains unclear. This patient-level meta-analysis based on 11 randomized trials investigates the impact of procalcitonin-guided antibiotic therapy on mortality in intensive care unit (ICU) patients with infection, both overall and stratified according to sepsis definition, severity, and type of infection. METHODS: For this meta-analysis focusing on procalcitonin-guided antibiotic management in critically ill patients with sepsis of any type, in February 2018 we updated the database of a previous individual patient data meta-analysis which was limited to patients with respiratory infections only. We used individual patient data from 11 trials that randomly assigned patients to receive antibiotics based on procalcitonin levels (the "procalcitonin-guided" group) or the current standard of care (the "controls"). The primary endpoint was mortality within 30 days. Secondary endpoints were duration of antibiotic treatment and length of stay. RESULTS: Mortality in the 2252 procalcitonin-guided patients was significantly lower compared with the 2230 control group patients (21.1% vs 23.7%; adjusted odds ratio 0.89, 95% confidence interval (CI) 0.8 to 0.99; p = 0.03). These effects on mortality persisted in a subgroup of patients meeting the sepsis 3 definition and based on the severity of sepsis (assessed on the basis of the Sequential Organ Failure Assessment (SOFA) score, occurrence of septic shock or renal failure, and need for vasopressor or ventilatory support) and on the type of infection (respiratory, urinary tract, abdominal, skin, or central nervous system), with interaction for each analysis being > 0.05. Procalcitonin guidance also facilitated earlier discontinuation of antibiotics, with a reduction in treatment duration (9.3 vs 10.4 days; adjusted coefficient -1.19 days, 95% CI -1.73 to -0.66; p < 0.001). CONCLUSION: Procalcitonin-guided antibiotic treatment in ICU patients with infection and sepsis patients results in improved survival and lower antibiotic treatment duration.

Chagas disease is a neglected chronic condition that presents high morbidity and mortality burden, with considerable psychological, social, and economic impact. The disease represents a significant public health issue in Brazil, with different regional patterns. This document presents the evidence that resulted in the Brazilian Consensus on Chagas Disease. The objective was to review and standardize strategies for diagnosis, treatment, prevention, and control of Chagas disease in the country, based on the available scientific evidence. The consensus is based on collaboration and contribution of renowned Brazilian experts with vast knowledge and experience on various aspects of the disease. It is the result of close collaboration between the Brazilian Society of Tropical Medicine and the Ministry of Health. This document shall strengthen the development of integrated control measures against Chagas disease in the country, focusing on epidemiology, management, comprehensive care (including families and communities), communication, information, education, and research.

Sobre estas estatísticas Esta é a edição de 2021 da Estatística Cardiovascular – Brasil , um esforço multi-institucional para fornecer periodicamente informação atualizada sobre a epidemiologia das DCV e AVC no Brasil. Este relatório incorpora estatísticas oficiais fornecidas pelo Ministério da Saúde brasileiro e outros órgãos governamentais, pelo projeto GBD liderado pelo IHME da Universidade de Washington, além de dados gerados por outras fontes e estudos científicos, como coortes e registros, sobre as DCV e seus fatores de risco. Este [...]

Cardiac thromboembolism attributed to atrial fibrillation (AF) is responsible for up to one-third of ischemic strokes. Stroke may be the first manifestation of previously undetected AF. Given the efficacy of oral anticoagulants in preventing AF-related ischemic strokes, strategies of searching for AF after a stroke using ECG monitoring followed by oral anticoagulation (OAC) treatment have been proposed to prevent recurrent cardioembolic strokes. This white paper by experts from the AF-SCREEN International Collaboration summarizes existing evidence and knowledge gaps on searching for AF after a stroke by using ECG monitoring. New AF can be detected by routine plus intensive ECG monitoring in approximately one-quarter of patients with ischemic stroke. It may be causal, a bystander, or neurogenically induced by the stroke. AF after a stroke is a risk factor for thromboembolism and a strong marker for atrial myopathy. After acute ischemic stroke, patients should undergo 72 hours of electrocardiographic monitoring to detect AF. The diagnosis requires an ECG of sufficient quality for confirmation by a health professional with ECG rhythm expertise. AF detection rate is a function of monitoring duration and quality of analysis, AF episode definition, interval from stroke to monitoring commencement, and patient characteristics including old age, certain ECG alterations, and stroke type. Markers of atrial myopathy (eg, imaging, atrial ectopy, natriuretic peptides) may increase AF yield from monitoring and could be used to guide patient selection for more intensive/prolonged poststroke ECG monitoring. Atrial myopathy without detected AF is not currently sufficient to initiate OAC. The concept of embolic stroke of unknown source is not proven to identify patients who have had a stroke benefitting from empiric OAC treatment. However, some embolic stroke of unknown source subgroups (eg, advanced age, atrial enlargement) might benefit more from non-vitamin K-dependent OAC therapy than aspirin. Fulfilling embolic stroke of unknown source criteria is an indication neither for empiric non-vitamin K-dependent OAC treatment nor for withholding prolonged ECG monitoring for AF. Clinically diagnosed AF after a stroke or a transient ischemic attack is associated with significantly increased risk of recurrent stroke or systemic embolism, in particular, with additional stroke risk factors, and requires OAC rather than antiplatelet therapy. The minimum subclinical AF duration required on ECG monitoring poststroke/transient ischemic attack to recommend OAC therapy is debated.

A SEA Swarm (Sensor Equipped Aquatic Swarm) is a sensor "cloud" that drifts with water currents and enables 4D (space and time) monitoring of local underwater events such as contaminants, marine life and intruders. The swarm is escorted at the surface by drifting sonobuoys that collect the data from underwater sensors via acoustic modems and report it in real-time via radio to a monitoring center. The goal of this study is to design an efficient anycast routing algorithm for reliable underwater sensor event reporting to any one of the surface sonobuoys. Major challenges are the ocean current and the limited resources (bandwidth and energy). In this paper, we address these challenges and propose HydroCast, a hydraulic pressure based anycast routing protocol that exploits the measured pressure levels to route data to surface buoys. The paper makes the following contributions: a novel opportunistic routing mechanism to select the subset of forwarders that maximizes greedy progress yet limiting co-channel interference; and an efficient underwater "dead end" recovery method that outperforms recently proposed approaches. The proposed routing protocols are validated via extensive simulations.

The electrocardiogram (ECG) is the most commonly used exam for the evaluation of cardiovascular diseases. Here we propose that the age predicted by artificial intelligence (AI) from the raw ECG (ECG-age) can be a measure of cardiovascular health. A deep neural network is trained to predict a patient's age from the 12-lead ECG in the CODE study cohort (n = 1,558,415 patients). On a 15% hold-out split, patients with ECG-age more than 8 years greater than the chronological age have a higher mortality rate (hazard ratio (HR) 1.79, p < 0.001), whereas those with ECG-age more than 8 years smaller, have a lower mortality rate (HR 0.78, p < 0.001). Similar results are obtained in the external cohorts ELSA-Brasil (n = 14,236) and SaMi-Trop (n = 1,631). Moreover, even for apparent normal ECGs, the predicted ECG-age gap from the chronological age remains a statistically significant risk predictor. These results show that the AI-enabled analysis of the ECG can add prognostic information.

Disruption of the physiologic balance between cell proliferation and cell death is an important step of cancer development. Increased resistance to apoptosis is a key oncogenic mechanism in several hematological malignancies and, in many cases, especially in lymphoid neoplasias, has been attributed to the upregulation of BCL-2. The BCL-2 protein is the founding member of the BCL-2 family of apoptosis regulators and was the first apoptosis modulator to be associated with cancer. The recognition of the important role played by BCL-2 for cancer development and resistance to treatment made it a relevant target for therapy for many diseases, including solid tumors and hematological neoplasias. Among the different strategies that have been developed to inhibit BCL-2, BH3-mimetics have emerged as a novel class of compounds with favorable results in different clinical settings, including chronic lymphocytic leukemia (CLL). In April 2016, the first inhibitor of BCL-2, venetoclax, was approved by the US Food and Drug Administration for the treatment of patients with CLL who have 17p deletion and had received at least one prior therapy. This review focuses on the relevance of BCL-2 for apoptosis modulation at the mitochondrial level, its potential as therapeutic target for hematological malignancies, and the results obtained with selective inhibitors belonging to the BH3-mimetics, especially venetoclax used in monotherapy or in combination with other agents.

Sobre este Documento O Brasil é um país continental de extrema diversidade quanto a clima e condições ambientais, densidade populacional, desenvolvimento econômico e características raciais e culturais. Uma das dez economias mais ricas do mundo, o Brasil é também um dos países mais desiguais: segundo o Banco Mundial, está entre os dez países de maior Índice de Gini, uma medida da desigualdade de distribuição de renda (https://data.worldbank.org/indicator/SI.POV.GINI). O Brasil possui o SUS, um dos maiores sistemas públicos de saúde com [...]