Role of Dapagliflozin in Ischemic Preconditioning in Patients with Symptomatic Coronary Artery Disease-DAPA-IP Study Protocol.

Background: Ischemic preconditioning (IP) is a powerful cellular protection mechanism. The cellular pathways underlying IP are extremely complex and involve the participation of cell triggers, intracellular signaling pathways, and end-effectors. Experimental studies have shown that sodium-glucose transport protein 2 (SGLT2) inhibitors promote activation of 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK), the main regulator of adenosine 5'-triphosphate homeostasis and energy metabolism in the body. Despite its cardioprotective profile demonstrated by numerous clinical trials, the results of studies on the action of SGLT2 inhibitors in IP are scarce. This study will investigate the effects of dapagliflozin on IP in patients with coronary artery disease (CAD). Methods: The study will include 50 patients with multivessel CAD, ischemia documented by stress testing, and preserved left ventricular ejection fraction (LVEF). Patients will undergo four exercise tests, the first two with a time interval of 30 min between them after washout of cardiovascular or hypoglycemic medications and the last two after 7 days of dapagliflozin 10 mg once a day, also with a time interval of 30 min between them. Discussion: The role of SGLT2 inhibitors on IP is not clearly established. Several clinical trials have shown that SGLT2 inhibitors reduce the occurrence cardiovascular events, notably heart failure. However, such studies have not shown beneficial metabolic effects of SGLT2 inhibitors, such as reducing myocardial infarction or stroke. On the other hand, experimental studies with animal models have shown the beneficial effects of SGLT2 inhibitors on IP, a mechanism that confers cardiac and vascular protection from subsequent ischemia-reperfusion (IR) injury. This is the first clinical study to evaluate the effects of SGLT2 inhibitors on IP, which could result in an important advance in the treatment of patients with stable CAD.

Efficacy and safety of neuroendoscopy surgery versus craniotomy for supratentorial intracerebral hemorrhage: an updated meta-analysis of randomized controlled trials.

Neuroendoscopy (NE) surgery emerged as a promising technique for the treatment of spontaneous intracerebral hemorrhage (ICH). A previous meta-analysis of randomized controlled trials (RCTs) analyzed the efficacy and safety of NE compared to craniotomy, but NE did not present a significant improvement in functional outcomes. However, a new study provided an opportunity to update the current knowledge. We searched PubMed, Embase, and Cochrane Central Register of Controlled Trials for RCTs reporting NE evacuation of spontaneous supratentorial ICH compared to craniotomy. The efficacy outcomes of interest were favorable functional outcome, functional disability, hematoma evacuation rate, and residual hematoma volume. The safety outcomes of interest were rebleeding, infection, and mortality. Seven RCTs were included containing 879 patients. The NE approach presented a significantly higher rate of favorable functional outcome compared with craniotomy (RR: 1.42; 95% CI 1.17, 1.73; p < 0.001). The evacuation rate was higher in patients who underwent the NE approach (MD: -8.36; 95% CI -12.66, -4.07; p < 0.001). NE did not show a benefit in improving the mortality rate (RR: 0.81, 95% CI 0.54, 1.22; p = 0.32). NE was associated with more favorable functional outcomes and lower rates of functional disabilities compared to craniotomy. Also, NE was superior regarding evacuation rate, while presenting a reduction in residual hematoma volume. NE might be associated with lower infection rates. Mortality was not improved by NE surgery. Larger, higher-quality randomized studies are needed to adequately evaluate the efficacy and safety of NE compared to craniotomy.

Relationship Between Brain Tumors and Intracranial Aneurysms: A Systematic Review.

AIM: To investigate the possible relationship between intracranial aneurysms and brain neoplasms. MATERIAL AND METHODS: A comprehensive literature review involving a search of the databases PubMed and Embase to identify relevant articles was conducted in March 2021. The initial search retrieved 451 articles. After deduplication and screening of abstracts, 56 articles were selected. After reading of the full texts, 19 articles were included in the review. RESULTS: There insufficient evidence to support that people with brain neoplasms have a higher incidence rate of IAs. However, the prevalence of IAs appears to be higher in patients with pituitary tumors than in the general population. The key factors affecting prognosis were tumor type in patients with unruptured aneurysms and progression of subarachnoid hemorrhage in individuals with ruptured aneurysms. Treatment should be individualized according to patient age, tumor pathology, location, and aneurysm rupture risk. CONCLUSION: There is a lack of evidence to affirm that the existence of brain neoplasm plays a role in the formation and rupture of intracranial aneurysms. Additionally, there is insufficient evidence to confirm a greater prevalence of intracranial aneurysms in individuals with brain tumors. The association of these two disorders does not appear to worsen patient outcome. Prognosis depends on tumor pathology for malignant cases and on subarachnoid hemorrhage in patients with ruptured aneurysms.

Application of Machine Learning for Classification of Brain Tumors: A Systematic Review and Meta-Analysis.

BACKGROUND: Classifying brain tumors accurately is crucial for treatment and prognosis. Machine learning (ML) shows great promise in improving tumor classification accuracy. This study evaluates ML algorithms for differentiating various brain tumor types. METHODS: A systematic review and meta-analysis were conducted, searching PubMed, Embase, and Web of Science up to March 14, 2023. Studies that only investigated image segmentation accuracy or brain tumor detection instead of classification were excluded. We extracted binary diagnostic accuracy data, constructing contingency tables to derive sensitivity and specificity. RESULTS: Fifty-one studies were included. The pooled area under the curve for glioblastoma versus lymphoma and low-grade versus high-grade gliomas were 0.99 (95% confidence interval [CI]: 0.98-1.00) and 0.89, respectively. The pooled sensitivity and specificity for benign versus malignant tumors were 0.90 (95% CI: 0.85-0.93) and 0.93 (95% CI: 0.90-0.95), respectively. The pooled sensitivity and specificity for low-grade versus high-grade gliomas were 0.99 (95% CI: 0.97-1.00) and 0.94, (95% CI: 0.79-0.99), respectively. Primary versus metastatic tumor identification yields sensitivity and specificity of 0.89, (95% CI: 0.83-0.93) and 0.87 (95% CI: 0.82-0.91), correspondingly. The differentiation of gliomas from pituitary tumors yielded the highest results among primary brain tumor classifications: sensitivity of 0.99 (95% CI: 0.99-1.00) and specificity of 0.99 (95% CI: 0.98-1.00). CONCLUSIONS: ML demonstrated excellent performance in classifying brain tumor images, with near-maximum area under the curves, sensitivity, and specificity.

Sepsis death risk factor score based on systemic inflammatory response syndrome, quick sequential organ failure assessment, and comorbidities.

OBJECTIVE: In this study, we aimed to evaluate the death risk factors of patients included in the sepsis protocol bundle, using clinical data from qSOFA, SIRS, and comorbidities, as well as development of a mortality risk score. DESIGN: This retrospective cohort study was conducted between 2016 and 2021. SETTING: Two university hospitals in Brazil. PARTICIPANTS: Patients with sepsis. INTERVENTIONS: Several clinical and laboratory data were collected focused on SIRS, qSOFA, and comorbidities. MAIN VARIABLE OF INTEREST: In-hospital mortality was the primary outcome variable. A mortality risk score was developed after logistic regression analysis. RESULTS: A total of 1,808 patients were included with a death rate of 36%. Ten variables remained independent factors related to death in multivariate analysis: temperature ≥38 °C (odds ratio [OR] = 0.65), previous sepsis (OR = 1.42), qSOFA ≥ 2 (OR = 1.43), leukocytes >12,000 or <4,000 cells/mm3 (OR = 1.61), encephalic vascular accident (OR = 1.88), age >60 years (OR = 1.93), cancer (OR = 2.2), length of hospital stay before sepsis >7 days (OR = 2.22,), dialysis (OR = 2.51), and cirrhosis (OR = 3.97). Considering the equation of the binary regression logistic analysis, the score presented an area under curve of 0.668, is not a potential model for death prediction. CONCLUSIONS: Several risk factors are independently associated with mortality, allowing the development of a prediction score based on qSOFA, SIRS, and comorbidities data, however, the performance of this score is low.

Myocardial tissue expression of mRNA and preoperative neutrophil-lymphocyte ratio in children undergoing congenital heart surgery.

Background: The neutrophil-lymphocyte ratio (NLR) is an easily accessible and inexpensive biomarker that has been shown to predict morbidity and mortality in congenital cardiac surgery. However, its regulatory mechanism remains unclear. This study aims to compare and correlate the tumor necrosis factor alpha (TNF-α), interleukin (IL)-1ß, IL-6, and IL-10 messenger RNAs (mRNAs) with the NLR in patients with tetralogy of Fallot (ToF) and ventricular septal defect (VSD). Methods: A prospective translational study was conducted on 10 children with ToF and 10 with VSD, aged between 1 and 24 months. The NLR was calculated from the blood count taken 24 hours before surgery. The expression of these mRNAs was analyzed in the myocardial tissue of the right atrium prior to cardiopulmonary bypass. Results: Patients with ToF exhibited a higher NLR [ToF 0.46 (interquartile range; IQR) 0.90; VSD 0.28 (IQR 0.17); P=0.02], longer mechanical ventilation time [ToF 24 h (IQR 93); VSD 5.5 h (IQR 8); P<0.001], increased use of vasoactive drugs [ToF 2 days (IQR 1.75); VSD 0 (IQR 1); P=0.01], and longer ICU [ToF 5.5 (IQR 1); VSD 2 (IQR 0.75); P=0.02] and hospital length of stays [ToF 18 days (IQR 17.5); VSD 8.5 days (IQR 2.5); P<0.001]. A negative correlation was found between NLR and oxygen saturation (SaO2) (r=-0.44; P=0.002). In terms of mRNA expression, the ToF group showed a lower expression of IL-10 mRNA (P=0.03). A positive correlation was observed between IL-10-mRNA and SaO2 (r=0.40; P=0.07), and a negative correlation with NLR (r=-0.27; P=0.14). Conclusions: Patients with ToF demonstrated a higher preoperative NLR and lower IL-10 mRNA expression by what appears to be a pro-inflammatory phenotype of cyanotic patients.

Homocysteine serum levels in patients with ruptured and unruptured intracranial aneurysms: a case-control study / Homocisteína sérica em pacientes com aneurismas rotos e não rotos: um estudo caso-controle

Abstract Background There is very few data regarding homocysteine's influence on the formation and rupture of intracranial aneurysms. Objective To compare homocysteine levels between patients with ruptured and unruptured intracranial aneurysms, and to evaluate possible influences of this molecule on vasospasm and functional outcomes. Methods This is a retrospective, case-control study. We evaluated homocysteinemia differences between patients with ruptured and unruptured aneurysms; and the association of homocysteine levels with vasospasm and functional outcomes. Logistic regressions were performed. Results A total of 348 participants were included: 114 (32.8%) with previous aneurysm rupture and 234 (67.2%) with unruptured aneurysms. Median homocysteine was 10.75μmol/L (IQR = 4.59) in patients with ruptured aneurysms and 11.5μmol/L (IQR = 5.84) in patients with unruptured aneurysms. No significant association was detected between homocysteine levels and rupture status (OR = 0.99, 95% CI = 0.96-1.04). Neither mild (>15μmol/L; OR = 1.25, 95% CI 0.32-4.12) nor moderate (>30μmol/L; OR = 1.0, 95% CI = 0.54-1.81) hyperhomocysteinemia demonstrated significant correlations with ruptured aneurysms. Neither univariate (OR = 0.86; 95% CI 0.71-1.0) nor multivariable age-adjusted (OR = 0.91; 95% CI = 0.75-1.05) models evidenced an association between homocysteine levels and vasospasm. Homocysteinemia did not influence excellent functional outcomes at 6 months (mRS≤1) (OR = 1.04; 95% CI = 0.94-1.16). Conclusion There were no differences regarding homocysteinemia between patients with ruptured and unruptured intracranial aneurysms. In patients with ruptured aneurysms, homocysteinemia was not associated with vasospasm or functional outcomes.

RESUMO Antecedentes Existem poucos dados sobre a influência da homocisteína na formação e rotura de aneurismas intracranianos (AI). Objetivo Comparar os níveis de homocisteína entre pacientes com AI rotos e não rotos e influências no vasoespasmo e resultados funcionais. Métodos Estudo caso-controle, que avaliou as diferenças de homocisteinemia entre pacientes com aneurismas rotos e não rotos, além da associação entre níveis de homocisteína, vasoespasmo e estado funcional. Regressões logísticas foram realizadas. Resultados Um total de 348 participantes foram incluídos: 114 (32,8%) com aneurismas rotos e 234 (67,2%) não rotos. A homocisteína mediana foi de 10,75μmol/L (IQR = 4,59) nos rotos e 11,5μmol/L (IQR = 5,84) nos não rotos. Não houve associação significativa entre os níveis de homocisteína e o status de ruptura (OR = 0,99, 95% CI = 0,96-1,04). Nem a hiperhomocisteinemia leve (>15μmol/L; OR = 1,25, 95% CI = 0,32-4,12) nem a moderada (>30μmol/L; OR = 1,0, 95% CI = 0,54-1,81) mostraram correlações significativas com aneurismas rotos. Modelos univariados (OR = 0,86; 95% CI = 0,71-1,0) e multivariados ajustados por idade (OR = 0,91; 95% CI = 0,75-1,05) não evidenciaram associação entre homocisteína e vasoespasmo. A homocisteinemia não influenciou resultados funcionais excelentes em seis meses (mRS ≤ 1) (OR = 1,04; 95% CI = 0,94-1,16). Conclusão Não houve diferenças em relação à homocisteinemia entre pacientes com aneurismas intracranianos rotos e não rotos. Em pacientes com aneurismas rotos, a homocisteinemia não foi associada ao vasoespasmo ou resultados funcionais.

Repercussions of the Emergency neurological life support on scientific literature: a bibliometric study / Repercussões do Emergency neurological life support na literatura científica: um estudo bibliométrico

Abstract Background In 2012, the Neurocritical Care Society launched a compilation of protocols regarding the core issues that should be addressed within the first hours of neurological emergencies - the Emergency neurological life support (ENLS). Objective We aim to evaluate this repercussion through a bibliometric analysis. Methods We searched Scopus on October 2022 for articles mentioning ENLS. The following variables were obtained: number of citations; number of citations per year; number of publications per year; year of publication; research type; research subtype; country of corresponding author and its income category and world region; journal of publication and its 5-year impact factor (IF); and section where ENLS appeared. Results After applying eligibility criteria, we retrieved 421 articles, published from 2012 to 2022. The mean number of citations per article was 17.46 (95% Confidence Interval (CI) = 8.20-26.72), while the mean number of citations per year per article was 4.05 (95% CI = 2.50-5.61). The mean destiny journal 5-year IF was 5.141 (95% CI = 4.189-6.093). The majority of articles were secondary research (57.48%; n= 242/421) of which most were narrative reviews (71.90%; n= 174/242). High-Income countries were the most prominent (80.05%; n= 337/421 articles). There were no papers from low-income countries. There were no trials or systematic reviews from middle-income countries. Conclusion Although still low, the number of publications mentioning ENLS is increasing. Articles were mainly published in journals of intensive care medicine, neurology, neurosurgery, and emergency medicine. Most articles were published by authors from high-income countries. The majority of papers were secondary research, with narrative review as the most frequent subtype.

Resumo Antecedentes Em 2012, a Neurocritical Care Society lançou uma compilação de protocolos sobre as questões centrais que devem ser abordadas nas primeiras horas de emergências neurológicas - Emergency neurological life support (ENLS). Objetivo Avaliar a repercussão do ENLS por meio de uma análise bibliométrica. Métodos A base de dados Scopus foi utilizada em outubro de 2022 para a busca por artigos mencionando o ENLS. As seguintes variáveis foram obtidas: número de citações; número de citações por ano; número de publicações por ano; ano de publicação; tipo de pesquisa; país do autor correspondente e sua categoria de renda; revista de publicação e seu fator de impacto de 5 anos (IF); e seção onde o ENLS apareceu. Resultados Os 421 artigos incluídos foram publicados de 2012 a 2022. A média de citações por artigo foi de 17.46 (intervalo de confiança (IC) 95% = 8.20-26.72), enquanto a de citações por ano por artigo foi de 4.05 (IC95% = 2.50-5.61). O IF médio por revista foi de 5.14 (IC95% = 4.19-6.09). A maioria dos artigos era de pesquisa secundária (57.48%; n= 242/421), dos quais a maioria eram revisões narrativas (71.90%; n= 174/242). Os países de alta renda foram os mais prolíficos (80.05%; n= 337/421 artigos). Não houve publicações de países de baixa ou média renda. Conclusão Embora ainda baixo, o número de publicações mencionando o ENLS vem aumentando recentemente. A maioria dos artigos foram publicados em revistas de medicina intensiva, neurologia, neurocirurgia e medicina de emergência. Artigos de pesquisa secundária foram os mais comuns, com revisões narrativas sendo o subtipo mais frequente.

Development and adaptations of the Graded Prognostic Assessment (GPA) scale: a systematic review.

The Graded Prognostic Assessment (GPA) score has the best accuracy among prognostic scales for patients with brain metastases (BM). A wide range of GPA-derived scales have been established to different types of primary tumor BM. However, there is a high variability between them, and their characteristics have not been described altogether yet. We aim to summarize the features of the existent GPA-derived scales and to compare their predictor factors and their uses in clinical setting. Medline was searched from inception until January 2023 to identify studies related to the development, update, or validation of GPA. The initial search yielded 1,083 results. 16 original studies and 16 validation studies were included, comprising a total of 33,348 patients. 13 different scales were assessed, including: GPA, Diagnosis-Specific GPA, Extracranial Score, Lung-molGPA, Updated Renal GPA, Updated Gastrointestinal GPA, Modified Breast GPA, Integrated Melanoma GPA, Melanoma Mol GPA, Sarcoma GPA, Hepatocellular Carcinoma GPA, Colorectal Cancer GPA, and Uterine Cancer GPA. The most prevalent prognostic predictors were age, Karnofsky Performance Status, number of BM, and presence or absence of extracranial metastases. Treatment modalities consisted of whole brain radiation therapy, stereotactic radiosurgery, surgery, cranial radiotherapy, gamma knife radiosurgery, and BRAF inhibitor therapy. Median survival rates with no treatment and with a specific treatment ranged from 6.1 weeks to 33 months and from 3.1 to 21 months, respectively. Original GPA and GPA-derived scales are valid prognostic tools, but with heterogeneous survival results when compared to each other. More studies are needed to improve scientific evidence of these scales.

Modifiable risk factors for glioblastoma: a systematic review and meta-analysis.

Glioblastoma (GBM) is the most common and aggressive glioma histological subtype, associated with high disability and poor survival. The etiology of this condition is still mostly unknown, and evidence about risk factors is elusive. The aim of this study is to identify modifiable risk factors for GBM. Electronic search was performed by two reviewers independently using the keywords and MeSH terms 'glioblastoma' OR 'glioma' OR 'brain tumor' AND 'risk factor'. The inclusion criteria were (1) observational studies or experimental studies on humans, (2) studies assessing the association between glioblastoma and exposure to modifiable conditions, and (3) studies published in English or Portuguese. Studies on the pediatric population or about exposure to ionizing radiation were excluded. A total of 12 studies were included. Seven were case-control studies, and five were cohort studies. The risk factors assessed included body mass index, alcohol consumption, exposure to magnetic fields, diabetes mellitus type 2 (DM2), and use of non-steroidal anti-inflammatory drugs (NSAID). No significant link was found between GBM incidence and DM2 or magnetic field exposure. On the other hand, higher BMI, alcohol consumption, and NSAID use demonstrated a protective effect on GMB risk. However, given the limited number of studies, it is not possible to obtain a behavioral recommendation; instead, these findings are relevant to guide future basic scientific studies on GBM oncogenesis.

Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios and prognosis after aneurysmal subarachnoid hemorrhage: a cohort study / Razão neutrófilos-linfócitos e razão plaquetas-linfócitos e o prognóstico de hemorragia subaracnóidea aneurismática: um estudo de coorte

Abstract Background Subarachnoid hemorrhage (SAH) prognosis remains poor. Vasospasm mechanism might be associated with inflammation. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been studied as inflammation markers and prognostic predictors. Objective We aimed to investigate NLR and PLR in admission as predictors of angiographic vasospasm and functional outcome at 6 months. Methods This cohort study included consecutive aneurysmal SAH patients admitted to a tertiary center. Complete blood count was recorded at admission before treatment. White blood cell count, neutrophil count, lymphocyte count, platelet count, NLR, and PLR were collected as independent variables. Vasospasm occurrence-modified Rankin scale (mRS), Glasgow outcome scale (GOS), and Hunt-Hess score at admission and at 6 months were recorded as dependent variables. Multivariable logistic regression models were used to adjust for potential confounding and to assess the independent prognostic value of NLR and PLR at admission. Results A total of 74.1% of the patients were female, with mean age of 55.6 ± 12.4 years. At admission, the median Hunt-Hess score was 2 (interquartile range [IQR] 1), and the median mFisher was 3 (IQR 1). Microsurgical clipping was the treatment for 66.2% of the patients. Angiographic vasospasm incidence was 16.5%. At 6 months, the median GOS was 4 (IQR 0.75), and the median mRS was 3 (IQR 1.5). Twenty-one patients (15.1%) died. Neutrophil-to-lymphocyte ratio and PLR levels did not differ between favorable and unfavorable (mRS > 2 or GOS < 4) functional outcomes. No variables were significantly associated with angiographic vasospasm. Conclusion Admission NLR and PLR presented no value for prediction of functional outcome or angiographic vasospasm risk. Further research is needed in this field.

Resumo Antecedentes O prognóstico da hemorragia subaracnoidea (HSA) permanece ruim. Vasoespasmo pode estar associado à inflamação. Razões neutrófilo-linfócito (NLR) e plaqueta-linfócito (PLR) têm sido estudadas como marcadores de inflamação e prognóstico. Objetivo Investigar NLR e PLR na admissão como preditores de vasoespasmo angiográfico e desfecho aos 6 meses. Métodos Este estudo de coorte incluiu pacientes consecutivos com HSA aneurismática de um centro terciário. Contagem de leucócitos, neutrófilos, linfócitos e plaquetas, proporção de neutrófilos para linfócitos e de plaquetas para linfócitos foram coletados como variáveis independentes. Ocorrência de vasoespasmo, escala de Rankin modificada, escala de desfecho de Glasgow e o escore de Hunt-Hess na admissão e 6 meses após a mesma foram registradas como variáveis dependentes. Modelos de regressão logística multivariável foram usados para ajustar potenciais fatores de confusão e avaliar valor prognóstico independente de NLR e PLR. Resultados Um total de 74,1% pacientes eram do sexo feminino, com idade média de 55,6 ± 12,4 anos. Na admissão, a pontuação média de Hunt-Hess foi de 2 (IQR 1) e a mediana de mFisher foi de 3 (IQR 1). Clipagem microcirúrgica foi o tratamento escolhido para 66,2% dos pacientes. A incidência de vasoespasmo angiográfico foi de 16,5%. Aos 6 meses, a escala de desfecho de Glasgow mediana era 4 (IQR 0,75) e a escala de Rankin modificada mediana era 3 (IQR 1,5). Vinte e um pacientes (15,1%) morreram. Os níveis de NLR e PLR não diferiram entre resultados funcionais favoráveis e desfavoráveis (mRS > 2 ou GOS < 4). Nenhuma variável foi significativamente associada ao vasoespasmo angiográfico. Conclusão Razão neutrófilo-linfócito e a PLR não apresentaram valor preditivo de desfecho funcional ou risco de vasoespasmo angiográfico. Mais pesquisas são necessárias neste campo.

Failure to predict amikacin elimination in critically ill patients with cancer based on the estimated glomerular filtration rate: applying PBPK approach in a therapeutic drug monitoring study.

PURPOSE: The aim of this work was to integrate the Therapeutic Drug Monitoring (TDM) with the model-informed precision dosing (MIPD) approach, using Physiologically-based Pharmacokinetic/Pharmacodynamic (PBPK/PD) modelling and simulation, to explore the relationship between amikacin exposure and estimated glomerular filtration rate (GFR) in critically ill patients with cancer. METHODS: In the TDM study, samples from 51 critically-ill patients with cancer treated with amikacin were analysed. Patients were stratified according to renal function based on GFR status. A full-body PBPK model with 12 organs model was developed using Simcyp V. 21, including steady-state volume of distribution of 0.21 L/kg and renal clearance of 6.9 L/h in healthy adults. PK parameters evaluated were within the 2-fold error range. RESULTS: During the validation step, predicted vs observed amikacin clearance values after single infusion dose in patients with normal renal function, mild and moderate renal impairment were 7.6 vs 8.1 L/h (7.5 mg/kg dose); 3.8 vs 4.5 L/h (1500 mg dose) and 2.2 vs 3.1 L/h (25 mg/kg dose), respectively. However, predicted vs observed amikacin clearance after a single dose infusion of 1400 mg in critically-ill patients with cancer were 1.46 vs 1.63 (P = 0.6406) L/h (severe), 2.83 vs 1.08 (P < 0.05) L/h (moderate), 4.23 vs 2.49 (P = 0.0625) L/h (mild) and 7.41 vs 3.36 (P < 0.05) L/h (normal renal function). CONCLUSION: This study demonstrated that estimated GFR did not predict amikacin elimination in critically-ill patients with cancer. Further studies are necessary to find amikacin PK covariates to optimize the pharmacotherapy in this population. Therefore, TDM of amikacin is imperative in cancer patients.

Dual orexin receptor antagonists for the treatment of insomnia: systematic review and network meta-analysis / Antagonistas duais do receptor de orexina para o tratamento da insônia: revisão sistemática e metanálise em rede

Abstract Background Several randomized clinical trials (RCTs) have shown that dual orexin receptor antagonists (DORAs) are effective in the treatment of chronic insomnia. However, the superiority of one particular DORA over the others remains unclear. Objective To perform a network meta-analysis to evaluate the efficacy of different DORAs in patients with chronic insomnia. Methods The Medline, Embase, and Cochrane Central databases were searched for RCTs that compared DORA with placebo in patients ≥ 18 years of age with a diagnosis of insomnia disorder. We pooled outcomes for wake time after sleep onset (WASO), latency to persistent sleep (LPS), total sleep time (TST), and adverse events (AEs). Results We included 10 RCTs with 7,806 patients, 4,849 of whom received DORAs as the intervention. Overall, we found that DORAs were associated with the improvement of all analyzed efficacy outcomes. Concerning TST, an apparent dose-dependent pattern was noticed, with higherdoses relating to a longerTST. Lemborexant 10mg provided the largest reduction in WASO (at month 1) in minutes (standardized mean difference [SMD] = −25.40; 95% confidence interval [95%CI] = −40.02- −10.78), followed by suvorexant 20/15mg (SMD = −25.29; 95%CI = −36.42- −14.15), which also appeared to provide the largest decrease in long-term WASO (SMD = −23.70; 95%CI = −35.89- −11.51). The most frequent AEs were somnolence, nasopharyngitis, and headache, with rates of up to 14.8%. Conclusion Our results suggest that DORAs are associated with greater efficacy when compared with placebo in the treatment of insomnia, a complex 24-hour sleep disorder. Additionally, dosing might play an important role in the management of chronic insomnia.

Resumo Antecedentes Inúmeros ensaios clínicos randomizados (ECRs) têm demonstrado que os antagonistas duais do receptor de orexina (dual orexin receptor antagonists, DORAs, em inglês) são eficazes no tratamento da insônia. Contudo, restam dúvidas quanto à superioridade de um DORA com relação aos outros. Objetivo Realizar uma meta-análise em rede para avaliar a eficácia de diferentes DORAs em pacientes com insônia. Métodos Foram feitas buscas nas bases de dados Medline, Embase e Cochrane Central por ECRs que comparassem DORAs e placebo em pacientes ≥ 18 anos de idade com diagnóstico de insônia. Os seguintes desfechos foram selecionados: tempo desperto após o início do sono (wake time after sleep onset, WASO, em inglês), latência para o sono persistente (latency to persistent sleep, LPS, em inglês), tempo total de sono (total sleep time, TST, em inglês), e efeitos adversos (EAs). Resultados Incluímos 10 ensaios clínicos com 7,806 pacientes, 4,849 dos quais receberam DORAs como intervenção. Os DORAs foram associados à melhoria de todos os desfechos de eficácia analisados. Em relação ao TST, um aparente padrão de dependência da dose foi identificado, com doses maiores se associando a um maior TST. Lemborexant 10 mg proporcionou a maior redução em WASO (no primeiro mês) em minutos (diferença padronizada das médias [standardized mean difference, [SMD], em inglês) = −25.40; intervalo de confiança de 95% [IC95%] = −40.02- −10.78), seguido de suvorexant 20/15mg (SMD = −25.29; IC95% = −36.42- −14.15), o qual também proporcionou a maior diminuição em WASO no longo prazo (SMD = −23.70; IC95% = −35.89- −11.51). Os EAs mais frequentes foram sonolência, nasofaringite e cefaleia, com taxas de até 14.8%. Conclusão Nossos resultados sugerem que os DORAs estão associados a uma maior eficácia quando comparados com placebo no tratamento da insónia, um complexo transtorno do sono de 24 horas. Além disso, a dosagem pode desempenhar um papel importante no manejo da insónia crônica.

Minipterional Approach for Middle Fossa Skull Base Lesions: Technical Note.

Surgical access to the middle fossa can be technically challenging. As neurosurgery evolves to minimally invasive approaches, the objective of this study is to demonstrate the extension of the Minipterional approach to access the middle fossa. We present a new surgical approach to the middle fossa for the treatment of secondary trigeminal neuralgia. Three cases are reported to illustrate the following techniques: a patient with petrotentorial meningioma and trigeminal neuralgia, a patient with an arachnoid cyst compressing the fifth nerve, and a patient with a middle cerebral artery aneurysm and a long history of TN (trigeminal neuralgia) refractory to medical and surgical treatments. All three experienced full symptom controls with no permanent neurological deficits. Therefore, the Minipterional technique might represent a feasible, effective, and safe option to treat refractory secondary TN. It also allows approaching these lesions when the posterior fossa approach is compromised by anatomical distortion and enables the simultaneous treatment of secondary trigeminal neuralgia and other lesions, such as aneurysms and meningiomas.

Predictors of Survival After Stereotactic Radiosurgery for Untreated Single Non-Small Cell Lung Cancer Brain Metastases: 5- and 10-year Results.

BACKGROUND: Stereotactic radiosurgery (SRS) presents as a good treatment option for smaller, deep-seated brain metastases (BMs). This study aims to determine predictors of SRS failure for patients with non-small cell lung cancer BMs. METHODS: This was a retrospective study of single non-small cell lung cancer BMs treated using SRS. We included patients >18 years with a single, previously untreated lesion. Primary outcome was treatment failure, defined as BMs dimension increase above the initial values. Demographic, clinical, and radiological data were collected to study potential predictors of treatment failure. RESULTS: Worse rates of progression-free survival (PFS) were associated with heterogeneous contrast enhancement (18.1 ± 4.1 vs. 41.9 ± 4 months; P < 0.001). Better rates of PFS were associated with volumes <1.06 cm3 (log-rank; P = 0.001). Graded prognostic assessment was significantly associated with survival at 120 months (log-rank; P < 0.001). Karnofsky Performance Scale was evaluated in 3 strata: 90-100, 80, and ≤70. Mean survival rates for these strata were 31.8 ± 3.9, 10.6 ± 2.2, and 9.8 ± 2.3 months, respectively (log-rank; P < 0.001). There were no differences regarding presence of extracranial metastases, age, or lesion location. A multivariable logistic regression found that volume <1.06 cm3 was associated with higher survival rates at 10 years (odds ratio: 3.2, 95% confidence interval: 1.3-8.0). CONCLUSIONS: Contrast-homogeneous metastases and lesions <1.06 cm3 are associated with better rates of PFS. Karnofsky Performance Scale and graded prognostic assessment were associated with more favorable survival rates after 10 years. Volume <1.06 cm3 was the only significant predictor of survival in the multivariable analysis.

Neurocysticercosis: challenges in pediatric neurosurgery practice.

PURPOSE: Neurocysticercosis (NCC) is considered a neglected infectious disease, but the most common parasitic disease of the central nervous system (CNS). Due to oral tendencies in childhood, it is hypothesized that individuals are infected around this age and develop symptoms as lately as during young adulthood. Although it is considered a benign disease, it may cause great impact in the patient's quality of life due to epilepsy, visual symptoms, and hydrocephalus, which eventually requires frequent hospitalizations. The treatment of hydrocephalus is the main challenge for neurosurgeons. METHODS: We performed a concise review on neurocysticercosis in children and the main presentations of NCC in the neurosurgery practice and a systematic review on hydrocephalus secondary to extraparenchymal NCC. RESULTS: Our review showed a rate of complete resolution of hydrocephalus secondary to NCC of around 80% with the first attempt of surgical treatment combined with medication therapy. Endoscopic removal of the intraventricular cysts with third ventriculostomy was the most common treatment modality. Patients previously managed with ventricular shunts are likely to have worse outcomes and complications. CONCLUSION: Endoscopic approach is the gold standard surgical treatment for hydrocephalus secondary to neurocysticercosis.

Cerebral toxoplasmosis with neurological co-infection in people living with AIDS/HIV: results of a prospective cohort in São Paulo, Brazil / Toxoplasmose cerebral com coinfecção neurológica em pessoas que vivem com HIV/AIDS: resultados de uma coorte prospectiva em São Paulo, Brasil

Abstract Background Concomitant neurological diseases in people living with HIV/AIDS (PLWHA) is a challenging subject that has been insufficiently evaluated by prospective clinical studies. The goal of the present study was to identify the clinical characteristics and outcomes of PLWHA with cerebral toxoplasmosis and neurological co-infections. Methods We conducted a prospective observational cohort study at a tertiary teaching center in São Paulo, Brazil, from January to July 2017. Hospitalized PLWHA aged ≥ 18 years with cerebral toxoplasmosis were consecutively enrolled. A standardized neurological examination was performed at admission and weekly until discharge or death. Diagnosis and treatment followed institutional routines; neuroradiology, molecular diagnosis, neurosurgery, and the intensive care unit (ICU) were available. The main outcomes were neurological coinfections and in-hospital death. Results We included 44 (4.3%) cases among 1,032 hospitalized patients. The median age was 44 (interquartile range [IQR]: 35-50) years, and 50% (n = 22) of the patients were male. The median CD4+ T lymphocyte count was of 50 (IQR: 15-94) cells/mm3. Multiple lesions on computed tomography were present in 59% of the cases. Neurological coinfections were diagnosed in 20% (n = 9) of the cases, and cytomegalovirus was the most common etiology (encephalitis: n = 3; polyradiculopathy: n = 2). Longer hospital stays (30 versus 62 days; p= 0.021) and a higher rate of ICU admissions (14% versus 44%; p= 0.045) were observed among PLWHA with neurological coinfections in comparison to those without them. The rate of in-hospital mortality was of 13.6% (n = 6) (coinfection group: 33%; no coinfection group: 8.6%; p= 0.054). Conclusion Neurological c-infections were common among PLWHA with cerebral toxoplasmosis, and cytomegalovirus was the main copathogen. The group of PLWHA with neurological co-infections underwent longer hospital stays and more frequent intensive care unit admissions. Additionally, this group of patients tended to have higher in-hospital mortality rate.

Resumo Antecedentes Coinfecções neurológicas em pessoas que vivem com HIV/AIDS (PVHA) é um tema que não foi suficientemente avaliado em estudos clínicos prospectivos. Nosso objetivo foi identificar as características clínicas e os desfechos de PVHA com toxoplasmose cerebral e coinfecções neurológicas. Métodos Estudo prospectivo de coorte observacional conduzido em um centro de ensino terciário de São Paulo, Brasil, entre janeiro e julho de 2017. Foram incluídos consecutivamente PVHA internadas com ≥ 18 anos e toxoplasmose cerebral. Realizou-se exame neurológico padronizado na admissão e semanalmente até a alta/óbito. Tanto o diagnóstico quanto o tratamento seguiram a rotina institucional; neurorradiologia, diagnóstico molecular, neurocirurgia e Unidade de Terapia Intensiva (UTI) estavam disponíveis. Os principais desfechos foram coinfecções neurológicas e óbitos hospitalares. Resultados Incluímos 44 (4,3%) casos entre 1.032 pacientes internados. A idade mediana foi de 44 (intervalo interquartil [IIQ]: : 35-50) anos, e 50% (n = 22) dos pacientes eram do sexo masculino. A contagem mediana de linfócitos T CD4+ foi de 50 (IIQ:15-94) células/mm3. Múltiplas lesões na tomografia computadorizada foram observadas em 59% dos casos. Coinfecções neurológicas foram diagnosticadas em 20% (n = 9) dos casos, sendo o citomegalovírus a etiologia mais comum (encefalite: n = 3; polirradiculopatia: n = 2). Observou-se maior tempo de internação (26 versus 62 dias; p= 0,021) e uma taxa mais alta de admissão à UTI (14% versus 44%; p= 0,045) em PVHA com coinfecções neurológicas em comparação àquelas sem coinfecção. A mortalidade intra-hospitalar foi de 13,6% (n = 6) (grupo com coinfecções: 33% versus grupo sem coinfecção: 8,6%; p= 0,054). Conclusão Coinfecções neurológicas foram comuns em PVHA com toxoplasmose cerebral, sendo o citomegalovírus o principal copatógeno. O grupo de PVHA com coinfecções neurológicas apresentou maior tempo de internação, maior taxa de internações na UTI, e tendência a maior taxa de mortalidade intra-hospitalar.

Sarcopenia as a Predictor of the Functional Outcome in Patients with Intracranial Aneurysms.

INTRODUCTION: Radiological indicators in head computed tomography (CT) scan have emerged as tools to evaluate sarcopenia using the sectional area and thickness of the temporal muscle. They can be obtained by standardized measurements in preoperative image assessment of patients with brain aneurysms. We aimed to evaluate the association between functional outcomes after interventions for intracranial aneurysms (IAs) and temporal muscle thickness (TMT) and area (TMA), as surrogates of sarcopenia. METHODS: This is a prospective observational cohort study in patients who underwent microsurgery or embolization for ruptured or unruptured IA between January 2018 and December 2019, with a 6-month follow-up. Preoperative CT scans were analyzed to measure TMT and TMA. The functional outcome was assessed by the modified Rankin Scale (mRS). The main outcome was the relationship between sarcopenia and the postoperative functional outcome. RESULTS: A total of 361 patients were included, of whom 199 (55.1%) had ruptured and 162 (44.9%) had unruptured lesions. Larger TMA significantly predicted better functional outcomes at discharge. TMT was associated with functional outcomes at both discharge and 6 months, adjusted for rupture and hypertension. Maximizing the sum sensitivity-specificity, an optimal TMT cutoff of 6.25 mm can predict unfavorable outcomes. Maximizing the positive predictive value × negative predictive value of a product, the cutpoint was 3.55 mm. CONCLUSIONS: Sarcopenia, represented by TMT and TMA, is associated with poorer functional results at discharge and 6-month follow-up in IA surgery. TMT below 6.25 mm was associated with unfavorable functional outcomes. These easily obtainable measurements may improve the decision-making process for patients with IAs.

Role of temporary arterial occlusion in subarachnoid hemorrhage outcomes: a prospective cohort study

Purpose: Temporary arterial occlusion (TAO) is a widespread practice in the surgical treatment of intracranial aneurysms. This study aimed to investigate TAO's role during ruptured aneurysm clipping as an independent prognostic factor on short- and long-term outcomes. Methods: This prospective cohort included 180 patients with ruptured intracranial aneurysms and an indication of microsurgical treatment. Patients who died in the first 12 hours after admission were excluded. Results: TAO was associated with intraoperative rupture (IOR) (odds ratio ­ OR = 10.54; 95% confidence interval ­ 95%CI 4.72­23.55; p < 0.001) and surgical complications (OR = 2.14; 95%CI 1.11­4.07; p = 0.01). The group with TAO and IOR had no significant difference in clinical (p = 0.06) and surgical (p = 0.94) complications compared to the group that had TAO, but no IOR. Among the 111 patients followed six months after treatment, IOR, number of occlusions, and total time of occlusion were not associated with Glasgow Outcome Scale (GOS) in the follow-up (respectively, p = 0.18, p = 0.30, and p = 0.73). Among patients who underwent TAO, IOR was also not associated with GOS in the follow-up (p = 0.29). Conclusions: TAO was associated with IOR and surgical complications, being the latter independent of IOR occurrence. In long-term analysis, neither TAO nor IOR were associated with poor clinical outcomes.

Cross-sectional study for COVID-19-related mortality predictors in a Brazilian state-wide landscape: the role of demographic factors, symptoms and comorbidities.

OBJECTIVE: The Brazilian state of Paraná has suffered from COVID-19 effects, understanding predictors of increased mortality in health system interventions prevent hospitalisation of patients. We selected the best models to evaluate the association of death with demographic characteristics, symptoms and comorbidities based on three levels of clinical severity for COVID-19: non-hospitalised, hospitalised non-ICU ward and ICU ward. DESIGN: Cross-sectional survey using binomial mixed models. SETTING: COVID-19-positive cases diagnosed by reverse transcription-PCR of municipalities located in Paraná State. PATIENTS: Cases of anonymous datasets of electronic medical records from 1 April 2020 to 31 December 2020. PRIMARY AND SECONDARY OUTCOME MEASURES: The best prediction factors were chosen based on criteria after a stepwise analysis using multicollinearity measure, lower Akaike information criterion and goodness-of-fit χ2 tests from univariate to multivariate contexts. RESULTS: Male sex was associated with increased mortality among non-hospitalised patients (OR 1.76, 95% CI 1.47 to 2.11) and non-ICU patients (OR 1.22, 95% CI 1.05 to 1.43) for symptoms and for comorbidities (OR 1.89, 95% CI 1.59 to 2.25, and OR 1.30, 95% CI 1.11 to 1.52, respectively). Higher mortality occurred in patients older than 35 years in non-hospitalised (for symptoms: OR 4.05, 95% CI 1.55 to 10.54; and for comorbidities: OR 3.00, 95% CI 1.24 to 7.27) and in hospitalised over 40 years (for symptoms: OR 2.72, 95% CI 1.08 to 6.87; and for comorbidities: OR 2.66, 95% CI 1.22 to 5.79). Dyspnoea was associated with increased mortality in non-hospitalised (OR 4.14, 95% CI 3.45 to 4.96), non-ICU (OR 2.41, 95% CI 2.04 to 2.84) and ICU (OR 1.38, 95% CI 1.10 to 1.72) patients. Neurological disorders (OR 2.16, 95% CI 1.35 to 3.46), neoplastic (OR 3.22, 95% CI 1.75 to 5.93) and kidney diseases (OR 2.13, 95% CI 1.36 to 3.35) showed the majority of increased mortality for ICU as well in the three levels of severity jointly with heart disease, diabetes and CPOD. CONCLUSIONS: These findings highlight the importance of the predictor's assessment for the implementation of public healthcare policy in response to the COVID-19 pandemic, mainly to understand how non-pharmaceutical measures could mitigate the virus impact over the population.