Challenges and developments in research of the early stages of bipolar disorder

Recently, attention in the field of bipolar disorder (BD) has focused on prevention, including early detection and intervention, as these strategies have the potential to delay, lessen the severity, or even prevent full-blown episodes of BD. Although knowledge of the neurobiology of BD has advanced substantially in the last two decades, most research was conducted with chronic patients. The objective of this paper is to comprehensively review the literature regarding the early stages of BD, to explore recent discoveries on the neurobiology of these stages, and to discuss implications for research and clinical care. The following databases were searched: PubMed, PsycINFO, Cochrane Library, and SciELO. Articles published in English from inception to December 2015 were retrieved. Several research approaches were used, including examination of offspring studies, retrospective studies, prospective studies of clinical high-risk populations, and exploration of the progression after the first manic episode. Investigations with neuroimaging, cognition assessments, and biomarkers provide promising (although not definitive) evidence of alterations in the neural substrate during the at-risk stage. Research on BD should be expanded to encompass at-risk states and aligned with recent methodological progress in neuroscience

Early mobilisation in critically ill COVID-19 patients: a subanalysis of the ESICM-initiated UNITE-COVID observational study

Background Early mobilisation (EM) is an intervention that may improve the outcome of critically ill patients. There is limited data on EM in COVID-19 patients and its use during the first pandemic wave. Methods This is a pre-planned subanalysis of the ESICM UNITE-COVID, an international multicenter observational study involving critically ill COVID-19 patients in the ICU between February 15th and May 15th, 2020. We analysed variables associated with the initiation of EM (within 72 h of ICU admission) and explored the impact of EM on mortality, ICU and hospital length of stay, as well as discharge location. Statistical analyses were done using (generalised) linear mixed-effect models and ANOVAs. Results Mobilisation data from 4190 patients from 280 ICUs in 45 countries were analysed. 1114 (26.6%) of these patients received mobilisation within 72 h after ICU admission; 3076 (73.4%) did not. In our analysis of factors associated with EM, mechanical ventilation at admission (OR 0.29; 95% CI 0.25, 0.35; p = 0.001), higher age (OR 0.99; 95% CI 0.98, 1.00; p ≤ 0.001), pre-existing asthma (OR 0.84; 95% CI 0.73, 0.98; p = 0.028), and pre-existing kidney disease (OR 0.84; 95% CI 0.71, 0.99; p = 0.036) were negatively associated with the initiation of EM. EM was associated with a higher chance of being discharged home (OR 1.31; 95% CI 1.08, 1.58; p = 0.007) but was not associated with length of stay in ICU (adj. difference 0.91 days; 95% CI − 0.47, 1.37, p = 0.34) and hospital (adj. difference 1.4 days; 95% CI − 0.62, 2.35, p = 0.24) or mortality (OR 0.88; 95% CI 0.7, 1.09, p = 0.24) when adjusted for covariates. Conclusions Our findings demonstrate that a quarter of COVID-19 patients received EM. There was no association found between EM in COVID-19 patients' ICU and hospital length of stay or mortality. However, EM in COVID-19 patients was associated with increased odds of being discharged home rather than to a care facility. Trial registration ClinicalTrials.gov: NCT04836065 (retrospectively registered April 8th 2021)

Peripheral biomarkers in first episode psychosis

INTRODUÇÃO: Transtornos psicóticos são uma experiência extremamente perturbadora para o indivíduo e seus familiares, em que ocorre uma distorção da realidade evidenciada por sintomas como delírios, alucinações e desorganização do comportamento. Estima-se que o principal transtorno psicótico, a esquizofrenia, seja a 11a causa de incapacidade em todo o mundo. O estudo em pacientes em primeiro episódio psicótico (PEP), livres de medicação e de muitas variáveis confundidoras presentes em amostras de pacientes crônicos pode contribuir para o avanço do conhecimento da neurobiologia e etiologia da psicose, além de fatores relacionados à resposta ao tratamento com antipsicóticos. Apesar de nos anos recentes o primeiro episódio psicótico ter sido amplamente estudado, até o presente momento não se conhece exatamente a sua fisiopatologia. Diversos estudos apontam para o envolvimento do sistema imune na etiologia das psicoses. Uma resposta inflamatória aumentada e níveis reduzidos de fator neurotrófico derivado do cérebro (BDNF) foram encontrados já nas fases iniciais dos transtornos psicóticos, o que pode acarretar a efeitos prejudiciais no cérebro, levando a anormalidades duradouras nos circuitos cerebrais. No entanto, há uma variabilidade nos resultados dos biomarcadores inflamatórios na literatura, o que pode ser explicado devido ao uso da medicação, fase ativa dos sintomas ou estadiamento da doença. A maioria dos estudos também utiliza estudos transversais e é restrita a análise de poucos marcadores inflamatórios. OBJETIVOS : Nesta tese foram avaliados biomarcadores relacionados à resposta imune e níveis plasmáticos de BDNF em pacientes no Primeiro Episódio Psicótico virgens de antipsicóticos antes e depois do uso de risperidona. O objetivo é avaliar alterações nos níveis de biomarcadores e possíveis relações com sintomas e com a resposta ao tratamento. MÉTODOS: Foram incluídos 31 pacientes, com diagnóstico realizado pela Entrevista Clínica Estruturada para DSM-IV (SCID-I), e 22 controles saudáveis. A sintomatologia foi avaliada usando a The Positive and Negative Syndrome Scale (PANSS). Amostras de sangue (10 mL) foram coletadas de todos os pacientes na admissão, antes da primeira dose de risperidona, e após 10 semanas de tratamento e de todos os controles saudáveis. RESULTADOS: Os pacientes no PEP mostraram uma resposta inflamatória maior (especialmente fator estimulador de colônias de granulócitos e macrófagos (GM-CSF), interleucina (IL)-6 e IL -12) em comparação com a resposta anti-inflamatória. Marcadores inflamatórios, especialmente IL-6 e IL-8, foram significativamente correlacionados com dimensões dos sintomas negativos, psicóticos, afetivos e de excitação. O tratamento com risperidona suprimiu significativamente os componentes inflamatórios e anti-inflamatórios. Os níveis basais de biomarcadores anti-inflamatórios, especialmente o receptor de fator de necrose tumoral solúvel-1 e IL-10, foram preditores de melhora clínica após o tratamento. Os pacientes em PEP virgens de antipsicóticos também apresentaram níveis diminuídos de BDNF, que foram normalizados após o tratamento com risperidona. Os níveis de BDNF foram inversamente associados à ativação do sistema de resposta inflamatório. Os resultados apoiam a hipótese de que o aumento da inflamação está ligado à uma diminuição do BDNF, que portanto, pode estar envolvida no desenvolvimento de psicose e na progressão da doença. CONCLUSÃO: Os resultados indicam que existe uma resposta inflamatória exacerbada no PEP, e que os pacientes estão propensos aos efeitos prejudiciais das citocinas inflamatórias e dos menores níveis de BDNF nesta fase da doença.INTRODUCTION: Psychotic disorders are an extremely disturbing experience for the individual and his family members, in which there is a distortion of reality evidenced by symptoms such as delusions, hallucinations and disorganization of behavior. The main psychotic disorder, schizophrenia, is estimated to be the 11th cause of disability worldwide. Studying patients with first-episode psychosis (FEP), free of medication and of many confounding variables present in samples of chronic patients, may contribute to the knowledge advance on the neurobiology and etiology of psychosis, in addition to the factors related to the response to antipsychotic treatment. Although in recent years the first psychotic episode has been comprehensively studied, to date its pathophysiology is not exactly known. Several studies point to the involvement of the immune system in the etiology of psychosis. An increased inflammatory response and reduced levels of brainderived neurotrophic factor (BDNF) have been found already in the early stages of psychotic disorders, which can lead to detrimental effects on the brain, leading to longlasting abnormalities in brain circuitry. However, there is variability in the results of inflammatory biomarkers in the literature, which can be explained by the use of medication, active phase of symptoms or disease staging. Most studies also use crosssectional studies and are restricted to the analysis of few inflammatory markers. OBJECTIVES: In this thesis, biomarkers related to the immune response and plasma levels of BDNF in patients in the First Psychotic Episode (FEP) naïve to antipsychotics before and after the use of risperidone were analyzed. The aim is to assess changes in biomarker levels and possible relationships with symptoms and response to treatment. METHODS: Thirty-one patients, diagnosed by the Structured Clinical Interview for DSM-IV (SCID-I), and 22 healthy controls were included. The sintomatology was assessed using The Positive and Negative Syndrome Scale (PANSS). Blood samples (10 mL) were collected from all patients on admission, before the first dose of risperidone, and after 10 weeks of treatment and from all healthy controls. RESULTS: Patients on FEP showed a greater inflammatory response (especially granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-6 and IL12) compared to the anti-inflammatory response. Inflammatory markers, especially IL-6 and IL-8, were significantly correlated with dimensions of negative, psychotic, affective and arousal symptoms. Risperidone treatment significantly suppressed inflammatory and anti-inflammatory components. Baseline levels of anti-inflammatory biomarkers, especially soluble tumor necrosis factor receptor-1 and IL-10, were predictors of clinical improvement after treatment. Patients on antipsychotic-naive FEP also had decreased levels of BDNF, which normalized after treatment with risperidone. BDNF levels were inversely associated with activation of the inflammatory response system. The results support the hypothesis that increased inflammation is linked to a decrease in BDNF, which therefore may be involved in the development of psychosis and disease progression. CONCLUSION: The results indicate that there is an exacerbated inflammatory response in FEP, and that patients are prone to the harmful effects of inflammatory cytokines and lower BDNF levels at this stage of the disease.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES

Co-infection and ICU-acquired infection in COIVD-19 ICU patients: a secondary analysis of the UNITE-COVID data set

Background: The COVID-19 pandemic presented major challenges for critical care facilities worldwide. Infections which develop alongside or subsequent to viral pneumonitis are a challenge under sporadic and pandemic conditions; however, data have suggested that patterns of these differ between COVID-19 and other viral pneumonitides. This secondary analysis aimed to explore patterns of co-infection and intensive care unit-acquired infections (ICU-AI) and the relationship to use of corticosteroids in a large, international cohort of critically ill COVID-19 patients.Methods: This is a multicenter, international, observational study, including adult patients with PCR-confirmed COVID-19 diagnosis admitted to ICUs at the peak of wave one of COVID-19 (February 15th to May 15th, 2020). Data collected included investigator-assessed co-infection at ICU admission, infection acquired in ICU, infection with multi-drug resistant organisms (MDRO) and antibiotic use. Frequencies were compared by Pearson's Chi-squared and continuous variables by Mann-Whitney U test. Propensity score matching for variables associated with ICU-acquired infection was undertaken using R library MatchIT using the "full" matching method.Results: Data were available from 4994 patients. Bacterial co-infection at admission was detected in 716 patients (14%), whilst 85% of patients received antibiotics at that stage. ICU-AI developed in 2715 (54%). The most common ICU-AI was bacterial pneumonia (44% of infections), whilst 9% of patients developed fungal pneumonia; 25% of infections involved MDRO. Patients developing infections in ICU had greater antimicrobial exposure than those without such infections. Incident density (ICU-AI per 1000 ICU days) was in considerable excess of reports from pre-pandemic surveillance. Corticosteroid use was heterogenous between ICUs. In univariate analysis, 58% of patients receiving corticosteroids and 43% of those not receiving steroids developed ICU-AI. Adjusting for potential confounders in the propensity-matched cohort, 71% of patients receiving corticosteroids developed ICU-AI vs 52% of those not receiving corticosteroids. Duration of corticosteroid therapy was also associated with development of ICU-AI and infection with an MDRO.Conclusions: In patients with severe COVID-19 in the first wave, co-infection at admission to ICU was relatively rare but antibiotic use was in substantial excess to that indication. ICU-AI were common and were significantly associated with use of corticosteroids

Clinical and organizational factors associated with mortality during the peak of first COVID-19 wave : the global UNITE-COVID study

Purpose To accommodate the unprecedented number of critically ill patients with pneumonia caused by coronavirus disease 2019 (COVID-19) expansion of the capacity of intensive care unit (ICU) to clinical areas not previously used for critical care was necessary. We describe the global burden of COVID-19 admissions and the clinical and organizational characteristics associated with outcomes in critically ill COVID-19 patients. Methods Multicenter, international, point prevalence study, including adult patients with SARS-CoV-2 infection confirmed by polymerase chain reaction (PCR) and a diagnosis of COVID-19 admitted to ICU between February 15th and May 15th, 2020. Results 4994 patients from 280 ICUs in 46 countries were included. Included ICUs increased their total capacity from 4931 to 7630 beds, deploying personnel from other areas. Overall, 1986 (39.8%) patients were admitted to surge capacity beds. Invasive ventilation at admission was present in 2325 (46.5%) patients and was required during ICU stay in 85.8% of patients. 60-day mortality was 33.9% (IQR across units: 20%-50%) and ICU mortality 32.7%. Older age, invasive mechanical ventilation, and acute kidney injury (AKI) were associated with increased mortality. These associations were also confirmed specifically in mechanically ventilated patients. Admission to surge capacity beds was not associated with mortality, even after controlling for other factors. Conclusions ICUs responded to the increase in COVID-19 patients by increasing bed availability and staff, admitting up to 40% of patients in surge capacity beds. Although mortality in this population was high, admission to a surge capacity bed was not associated with increased mortality. Older age, invasive mechanical ventilation, and AKI were identified as the strongest predictors of mortality