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OBJECTIVE Little is known about temporal changes in nasal bacteria in granulomatosis with polyangiitis (GPA). This study was undertaken to examine longitudinal changes in the nasal microbiome in association with relapse in GPA patients. METHODS Bacterial 16S ribosomal RNA gene sequencing was performed on nasal swabs from 19 patients with GPA who were followed up longitudinally for a total of 78 visits, including 9 patients who experienced a relapse and 10 patients who remained in remission. Relative abundance of bacteria and ratios between bacteria were examined. Generalized estimating equation models were used to evaluate the association between bacterial composition and 1) disease activity and 2) levels of antineutrophil cytoplasmic antibody (ANCA) with specificity for proteinase 3 (PR3), adjusted for medication. RESULTS Corynebacterium and Staphylococcus were the most abundant bacterial genera across all nasal samples. Patients with quiescent disease maintained a stable ratio of Corynebacterium to Staphylococcus across visits. In contrast, in patients who experienced a relapse, a significantly lower ratio was observed at the visit prior to relapse, followed by a higher ratio at the time of relapse (adjusted P < 0.01). Species-level analysis identified an association between a higher abundance of nasal Corynebacterium tuberculostearicum and 1) relapse (adjusted P = 0.04) and 2) higher PR3-ANCA levels (adjusted P = 0.02). CONCLUSION In GPA, significant changes occur in the nasal microbiome over time and are associated with disease activity. The occurrence of these changes months prior to the onset of relapse supports a pathogenic role of nasal bacteria in GPA. Our results uphold existing hypotheses implicating Staphylococcus as an instigator of disease and have generated a novel finding involving Corynebacterium as a potential mediator of disease in GPA.

Background and Purpose— EG-1962 is a sustained release formulation of nimodipine administered via external ventricular drain in patients with aneurysmal subarachnoid hemorrhage. A randomized, open-label, phase 1/2a, dose-escalation study provided impetus for this study to evaluate efficacy and safety of a single intraventricular 600 mg dose of EG-1962 to patients with aneurysmal subarachnoid hemorrhage, compared with standard of care oral nimodipine. Methods— Subjects were World Federation of Neurological Surgeons grades 2–4, modified Fisher grades 2–4 and had an external ventricular drain inserted as part of standard of care. The primary end point was the proportion of subjects with favorable outcome at day 90 after aneurysmal subarachnoid hemorrhage (extended Glasgow outcome scale 6–8). The proportion of subjects with favorable outcome at day 90 on the Montreal cognitive assessment, as well as the incidence of delayed cerebral ischemia and infarction, use of rescue therapy and safety were evaluated. Results— The study was halted by the independent data monitoring board after planned interim analysis of 210 subjects (289 randomized) with day 90 outcome found the study was unlikely to achieve its primary end point. After day 90 follow-up of all subjects, the proportion with favorable outcome on the extended Glasgow outcome scale was 45% (65/144) in the EG-1962 and 42% (62/145) in the placebo group (risk ratio, 1.01 [95% CI, 0.83–1.22], P =0.95). Consistent with its mechanism of action, EG-1962 significantly reduced vasospasm (50% [69/138] EG-1962 versus 63% [91/144], P =0.025) and hypotension (7% [9/138] versus 10% [14/144]). Analysis of prespecified subject strata suggested potential efficacy in World Federation of Neurological Surgeons 3–4 subjects (46% [32/69] EG-1962 versus 32% [24/75] placebo, odds ratio, 1.22 [95% CI, 0.94–1.58], P =0.13). No safety concerns were identified that halted the study or that preclude further development. Conclusions— There was no significant increase in favorable outcome for EG-1962 compared with standard of care in the overall study population. The safety profile was acceptable. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02790632.

A variety of technologies have been developed to assist decision-making during the management of patients with acute brain injury who require intensive care. A large body of research has been generated describing these various technologies. The Neurocritical Care Society (NCS) in collaboration with the European Society of Intensive Care Medicine (ESICM), the Society for Critical Care Medicine (SCCM), and the Latin America Brain Injury Consortium (LABIC) organized an international, multidisciplinary consensus conference to perform a systematic review of the published literature to help develop evidence-based practice recommendations on bedside physiologic monitoring. This supplement contains a Consensus Summary Statement with recommendations and individual topic reviews on physiologic processes important in the care of acute brain injury. In this article we provide the evidentiary tables for select topics including systemic hemodynamics, intracranial pressure, brain and systemic oxygenation, EEG, brain metabolism, biomarkers, processes of care and monitoring in emerging economies to provide the clinician ready access to evidence that supports recommendations about neuromonitoring.

Inflammation in the tumour microenvironment mediated by interleukin 1β is hypothesised to have a major role in cancer invasiveness, progression, and metastases. We did an additional analysis in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), a randomised trial of the role of interleukin-1β inhibition in atherosclerosis, with the aim of establishing whether inhibition of a major product of the Nod-like receptor protein 3 (NLRP3) inflammasome with canakinumab might alter cancer incidence.We did a randomised, double-blind, placebo-controlled trial of canakinumab in 10 061 patients with atherosclerosis who had had a myocardial infarction, were free of previously diagnosed cancer, and had concentrations of high-sensitivity C-reactive protein (hsCRP) of 2 mg/L or greater. To assess dose-response effects, patients were randomly assigned by computer-generated codes to three canakinumab doses (50 mg, 150 mg, and 300 mg, subcutaneously every 3 months) or placebo. Participants were followed up for incident cancer diagnoses, which were adjudicated by an oncology endpoint committee masked to drug or dose allocation. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, NCT01327846. The trial is closed (the last patient visit was in June, 2017).Baseline concentrations of hsCRP (median 6·0 mg/L vs 4·2 mg/L; p0·0001) and interleukin 6 (3·2 vs 2·6 ng/L; p0·0001) were significantly higher among participants subsequently diagnosed with lung cancer than among those not diagnosed with cancer. During median follow-up of 3·7 years, compared with placebo, canakinumab was associated with dose-dependent reductions in concentrations of hsCRP of 26-41% and of interleukin 6 of 25-43% (p0·0001 for all comparisons). Total cancer mortality (n=196) was significantly lower in the pooled canakinumab group than in the placebo group (p=0·0007 for trend across groups), but was significantly lower than placebo only in the 300 mg group individually (hazard ratio [HR] 0·49 [95% CI 0·31-0·75]; p=0·0009). Incident lung cancer (n=129) was significantly less frequent in the 150 mg (HR 0·61 [95% CI 0·39-0·97]; p=0·034) and 300 mg groups (HR 0·33 [95% CI 0·18-0·59]; p0·0001; p0·0001 for trend across groups). Lung cancer mortality was significantly less common in the canakinumab 300 mg group than in the placebo group (HR 0·23 [95% CI 0·10-0·54]; p=0·0002) and in the pooled canakinumab population than in the placebo group (p=0·0002 for trend across groups). Fatal infections or sepsis were significantly more common in the canakinumab groups than in the placebo group. All-cause mortality did not differ significantly between the canakinumab and placebo groups (HR 0·94 [95% CI 0·83-1·06]; p=0·31).Our hypothesis-generating data suggest the possibility that anti-inflammatory therapy with canakinumab targeting the interleukin-1β innate immunity pathway could significantly reduce incident lung cancer and lung cancer mortality. Replication of these data in formal settings of cancer screening and treatment is required.Novartis Pharmaceuticals.

There is growing evidence supporting the role of inflammation in early brain injury and cerebral vasospasm following subarachnoid hemorrhage (SAH). Matrix metalloproteinases (MMPs) are released by inflammatory cells and can mediate early brain injury via disruption of the extracellular matrix and mediate vasospasm by cleaving endothelin-1 into vasoactive fragments. We hypothesize that inflammation marked by neutrophil elevation and MMP-9 release in human SAH is associated with vasospasm and with poor clinical outcome. We enrolled consecutive SAH subjects (N = 55), banked serial blood and cerebrospinal fluid (CSF) samples, and evaluated their 3-month modified Rankin scores (mRS). Vasospasm was defined as >50% vessel caliber reduction on angiography 6–8 days post-SAH. A poor outcome was defined as mRS > 2. We compared blood leukocyte and neutrophil counts during post-SAH days 0–14 with respect to vasospasm and 3-month outcome. In a subset of SAH subjects (N = 35), we compared blood and CSF MMP-9 by enzyme-linked immunosorbent assay (ELISA) on post-SAH days 0–1, 2–3, 4–5, 6–8, and 10–14 with respect to vasospasm and to 3-month outcome. Persistent elevation of blood leukocyte (p = 0.0003) and neutrophil (p = 0.0002) counts during post-SAH days 0–14 are independently associated with vasospasm after adjustment for major confounders. In the same time period, blood neutrophil count (post-SAH days 2–3, p = 0.018), blood MMP-9 (post-SAH days 4–5, p = 0.045), and CSF MMP-9 (post-SAH days 2–3, p = 0.05) are associated with poor 3-month SAH clinical outcome. Neutrophil count correlates with blood MMP-9 (post-SAH days 6–8, R = 0.39; p = 0.055; post-SAH days 10–14, R = 0.79; p

Tissue plasminogen activator (tPA) is the only FDA-approved medical therapy for acute ischemic stroke. But as a serine peptidase, intravenous tPA can affect the expression of other proteases that may be implicated in blood-brain barrier breakdown. Such parallel cascades of cell signaling may be involved in intracranial hemorrhage, the major side effect of tPA. Here, we describe an initial attempt in proteomic substrate profiling, i.e., degradomics in human plasma within the context of acute stroke. Plasma from acute stroke patients were analyzed pre- and post-intravenous tPA using tandem mass spectrometry and protein array profiling to identify substrates and proteases of interest. In non-tPA-treated stroke plasma, degradomic patterns indicated a rapid induction of protease activity within 3 h of stroke onset that mostly stabilized by 24 h. But in tPA-treated patients, pre- and post-tPA samples from the same patient demonstrated distinct degradomic patterns that persisted even up to 3-5 days after stroke onset. Matching control patients without strokes had little change in degradomic profiles over time. Our findings demonstrate that tPA treatment changes the plasma degradomic profiles in acute stroke patients. These composite proteolytic profiles may provide a glimpse of the pleiotropic effects of tPA on cellular signaling cascades at the bedside. This study supports the feasibility of performing pharmaco-proteomics at the bedside, which may ultimately allow us to dissect mechanisms of thrombolysis-related therapeutic efficacy in stroke.

Careful patient monitoring using a variety of techniques including clinical and laboratory evaluation, bedside physiological monitoring with continuous or non-continuous techniques and imaging is fundamental to the care of patients who require neurocritical care. How best to perform and use bedside monitoring is still being elucidated. To create a basic platform for care and a foundation for further research the Neurocritical Care Society in collaboration with the European Society of Intensive Care Medicine, the Society for Critical Care Medicine and the Latin America Brain Injury Consortium organized an international, multidisciplinary consensus conference to develop recommendations about physiologic bedside monitoring. This supplement contains a Consensus Summary Statement with recommendations and individual topic reviews as a background to the recommendations. In this article, we highlight the recommendations and provide additional conclusions as an aid to the reader and to facilitate bedside care.

Background and Purpose— Cerebral autoregulation may be impaired in the early days after subarachnoid hemorrhage (SAH). The purpose of this study was to examine the relationship between cerebral autoregulation and angiographic vasospasm (aVSP) and radiographic delayed cerebral ischemia (DCI) in patients with SAH. Methods— Sixty-eight patients (54±13 years) with a diagnosis of nontraumatic SAH were studied. Dynamic cerebral autoregulation was assessed using transfer function analysis (phase and gain) of the spontaneous blood pressure and blood flow velocity oscillations on days 2 to 4 post-SAH. aVSP was diagnosed using a 4-vessel conventional angiogram. DCI was diagnosed from CT. Decision tree models were used to identify optimal cut-off points for clinical and physiological predictors of aVSP and DCI. Multivariate logistic regression models were used to develop and validate a risk scoring tool for each outcome. Results— Sixty-two percent of patients developed aVSP, and 19% developed DCI. Patients with aVSP had higher transfer function gain (1.06±0.33 versus 0.89±0.30; P =0.04) and patients with DCI had lower transfer function phase (17.5±39.6 versus 38.3±18.2; P =0.03) compared with those who did not develop either. Multivariable scoring tools using transfer function gain >0.98 and phase Conclusions— Dynamic cerebral autoregulation is impaired in the early days after SAH. Including autoregulation as part of the initial clinical and radiographic assessment may enhance our ability to identify patients at a high risk for developing secondary complications after SAH.

Purpose Typically, apolipoproteins are individually measured in blood by immunoassay. In this report, we describe the development of a multiplexed selected reaction monitoring (SRM) based assay for a panel of apolipoproteins and its application to a clinical cohort of samples derived from acute stroke patients. Experimental Design An SRM assay for a panel of nine apolipoproteins was developed on a triple quadrupole mass spectrometer. Quantitative data for each apolipoprotein were analyzed to determine expression ratio and receiver operating characteristic (ROC) values for ischemic versus hemorrhagic stroke. Results The optimized SRM assay was used to interrogate a small cohort of well-characterized plasma samples obtained from patients with acute ischemic and hemorrhagic strokes. The ROC analyses demonstrated good classification power for several single apolipoproteins, most notably apoC-III and apoC-I. When a novel multi-marker ROC algorithm was applied, the ischemic versus hemorrhagic groups were best differentiated by a combination of apoC-III and apoA-I with an area under the curve (AUC) value of 0.92. Conclusions and clinical relevance This proof-of-concept study provides interesting and provocative data for distinguishing ischemic versus hemorrhage within first week of symptom onset. However, the observations are based on one cohort of patient samples and further confirmation will be required.

Pneumocephalus is a rare complication of craniofacial surgeries.1,2 A 48-year-old man presented with severe left frontal headaches, confusion, and right-sided myoclonic seizures 8 days after mucoperichondrial repair of CSF leak following left nasal polypectomy. Imaging studies demonstrated …

We describe a patient with a history of allogeneic hematopoietic stem cell transplantation complicated by chronic graft-versus-host disease who developed painful meningoradiculitis and myositis due to Lyme borreliosis. To our knowledge, this is the first report of such an infection occurring after allogeneic hematopoietic stem cell transplantation in the United States.

A correcao atmosferica é um dos preprocessamentos importantes na qualificacao de dados de satelite; especialmente quando estes sao obtidoscom datas de passsagens diferentes. Pesquisas realizadas nas ultimas decadas revelam que existem 4 abordagens principais de correcao atmosferica:(1)os modelos de transferencia radiativa, (2)as medidas ""in situ"", (3)a normalizacao de histogramas/retificacao de imagens ou metoso de regressao, e (4)o metodo de subtracao. os modelos de transferencia radiativa necessitam de informacoes sobre as condicoes atmosfericas na ocasiao da passagem de satelite, enquanto que as medidas ""in situ""envolvem trabalho de campo. Por outro lado o metodo de regressao é limitado para analisar as imagens com presencas de alvos especificos nos dados multitemporais. Consequentemente, o metodo de subtracao aperfeicoado, sugerido por Chavez, parece ser uma alternativa de correcao atmosferica para a regiao amazonica. Nste estudo, a aplicabilidade do metodo de Chavez foi avaliada, analisando varias imagens TM-Landsat da regiao. Os resultados demostraram que os modelos de espalhamento relativo, usados por Chavez, nao adequados para estimar as contribuicoes de aerossois,tanto a partir de alvos com tonalidade escura como a partir doshistogram as de imagem. De maneira geral,independenteme do modelo de espalhamenbto escolhido, a aplicacao desta abordagem resultou em super-correcao atmosfericanas bandas espectrais do sensor TM-Landasat., Number of Pages: 20

Orientador: Lee Luan Ling Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Engenharia Eletrica e de Computação Resumo: Neste trabalho foi implementada uma plataforma que permite o cadastramento, consulta e autenticação automática de identidade via rede internet. A identificação pessoal pode ser feita através de diferentes métodos biométricos. Cada um desses métodos biométricos podem ser adicionados à plataforma através de módulos de identificação. Um módulo de identificação consiste em programas CGI que realizam tanto a tarefa de autenticação pessoal quanto a comunicação entre os dados enviados por um usuário através de um browser e um servidor Web. No presente trabalho foi também implementado o módulo de identificação pessoal por imagens de assinaturas. Esse módulo é constituído por um método de verificação automático de assinaturas que se caracteriza por ser um sistema multi-especialista de dois estágios, onde o primeiro estágio trata das falsificações aleatórias e simples, e o segundo estágio de falsificações habilidosas. Esse método de verificação se serve tanto de características globais quanto locais para fazer a descrição da assinatura. As características utilizadas no primeiro estágio do sistema se baseiam na distribuição espacial dos pixels que compõe a assinatura. No segundo estágio, as características escolhidas se servem de técnicas de morfologia matemática para descreverem as inclinações e contornos dos traços que compõe a assinatura. Como parâmetros de desempenho do método de verificação automático, obtivemos os valores de 0,47 % de taxa de erro de falsa rejeição e 2,35 % de taxa de erro de falsa aceitação frente a falsificações aleatórias. No caso de falsificações habilidosas, as taxas de erros foram de 12,75 % e 19,22 % para falsa rejeição e falsa aceitação, respectivamente Abstract: In this work, it was implemented a platform for identity's enrollment, consulting and automatic authentication through Internet. The personal identification could be made using different biometric methods. Each one of those methods could be add into the platform like as an identity module. An identity module is a group of CGI programs that authenticates an identity and deals with the communication between a user using a browser and a web server. Also, it was implemented a personal identity module using signature's images. This module is based on an automatic verification method that is characterized by being a multi-expert system that works in two stages. In the first stage, the system deals with simple and random forgeries and, in the second one, with skilled forgeries. The verification method uses global and local features for describing a signature. The features used in the first stage are based on the pixels' spatial distribution that compose the signature. In the second stage, the chosen features use mathematic morphology techniques for describing the strokes' inclinations and contours of a signature. As a measure of performance, it was obtained 0.47 % of false rejection error rate and 2.35 % of false acceptance error rate working with random forgeries. Working with skilled forgeries, error rates were 12.75 % and 19.22 % for false rejection and false acceptance, respectively Doutorado Doutor em Engenharia Elétrica