Impact of the first year of COVID-19 vaccination strategy in Brazil: an ecological study.

OBJECTIVES: No consensus exists about the best COVID-19 vaccination strategy to be adopted by low-income and middle-income countries. Brazil adopted an age-based calendar strategy to reduce mortality and the burden on the healthcare system. This study evaluates the impact of the vaccination campaign in Brazil on the progression of the reported COVID-19 deaths. METHODS: This ecological study analyses the dynamic of vaccination coverage and COVID-19 deaths in hospitalised adults (≥20 years) during the first year of the COVID-19 vaccination roll-out (January to December 2021) using nationwide data (DATASUS). We stratified the adult population into 20-49, 50-59, 60-69 and 70+ years. The dynamic effect of the vaccination campaign on mortality rates was estimated by applying a negative binomial regression. The prevented and possible preventable deaths (observed deaths higher than expected) and potential years of life lost (PYLL) for each age group were obtained in a counterfactual analysis. RESULTS: During the first year of COVID-19 vaccination, 266 153 517 doses were administered, achieving 91% first-dose coverage. A total of 380 594 deaths were reported, 154 091 (40%) in 70+ years and 136 804 (36%) from 50-59 or 20-49 years. The mortality rates of 70+ decreased by 52% (rate ratio [95% CI]: 0.48 [0.43-0.53]) in 6 months, whereas rates for 20-49 were still increasing due to low coverage (52%). The vaccination roll-out strategy prevented 59 618 deaths, 53 088 (89%) from those aged 70+ years. However, the strategy did not prevent 54 797 deaths, 85% from those under 60 years, being 26 344 (45%) only in 20-49, corresponding to 1 589 271 PYLL, being 1 080 104 PYLL (68%) from those aged 20-49 years. CONCLUSION: The adopted aged-based calendar vaccination strategy initially reduced mortality in the oldest but did not prevent the deaths of the youngest as effectively as compared with the older age group. Countries with a high burden, limited vaccine supply and young populations should consider other factors beyond the age to prioritise who should be vaccinated first.

Association of Lack of Fear of Dying With New Organ Failure: Results of a Multicenter Prospective Cohort Study.

BACKGROUND: Patients' anxiety on intensive care unit (ICU) admission is associated with subsequent deterioration. OBJECTIVE: To assess whether patients' fears/anxiety are predictive of new organ failure within 7 days of ICU admission. METHODS: In a prospective 3-center cohort study of non-comatose patients without delirium or invasive mechanical ventilation, 9 specific fears were evaluated through yes/no questions. Illness severity was assessed using the Simplified Acute Physiology Score II (SAPS II) and the Sequential Organ Failure Assessment (SOFA). Intensity of acute and chronic anxiety was assessed with the state and trait components of the State-Trait Anxiety Inventory (STAI). Patients were followed up for 7 days. RESULTS: From April 2014 to December 2017, 373 patients (median [IQR] age, 63 [48-74] years; 152 [40.8%] women; median (IQR) SAPS II, 27 [19-37]) were included. Feelings of vulnerability and fear of dying were reported by 203 (54.4%) and 172 (46.1%) patients, respectively. The STAI-State score was 40 or greater in 192 patients (51.5%). Ninety-four patients (25.2%) had new organ failure. Feelings of vulnerability (odds ratio, 1.96 [95% CI, 1.12-3.43]; P=.02) and absence of fear of dying (odds ratio, 2.38 [95% CI, 1.37-4.17]; P=.002) were associated with new organ failure after adjustment for STAI-State score (≥40), SAPS II, and SOFA score. CONCLUSION: Absence of fear of dying is associated with new organ failure within the first 7 days after ICU admission. Fear of dying may protect against subsequent deterioration by mobilizing patients' homeostatic resources. ClinicalTrials.gov Identifier: NCT02355626.

Comparing causal random forest and linear regression to estimate the independent association of organisational factors with ICU efficiency.

PURPOSE: Parametric regression models have been the main statistical method for identifying average treatment effects. Causal machine learning models showed promising results in estimating heterogeneous treatment effects in causal inference. Here we aimed to compare the application of causal random forest (CRF) and linear regression modelling (LRM) to estimate the effects of organisational factors on ICU efficiency. METHODS: A retrospective analysis of 277,459 patients admitted to 128 Brazilian and Uruguayan ICUs over three years. ICU efficiency was assessed using the average standardised efficiency ratio (ASER), measured as the average of the standardised mortality ratio (SMR) and the standardised resource use (SRU) according to the SAPS-3 score. Using a causal inference framework, we estimated and compared the conditional average treatment effect (CATE) of seven common structural and organisational factors on ICU efficiency using LRM with interaction terms and CRF. RESULTS: The hospital mortality was 14 %; median ICU and hospital lengths of stay were 2 and 7 days, respectively. Overall median SMR was 0.97 [IQR: 0.76,1.21], median SRU was 1.06 [IQR: 0.79,1.30] and median ASER was 0.99 [IQR: 0.82,1.21]. Both CRF and LRM showed that the average number of nurses per ten beds was independently associated with ICU efficiency (CATE [95 %CI]: -0.13 [-0.24, -0.01] and -0.09 [-0.17,-0.01], respectively). Finally, CRF identified some specific ICUs with a significant CATE in exposures that did not present a significant average effect. CONCLUSION: In general, both methods were comparable to identify organisational factors significantly associated with CATE on ICU efficiency. CRF however identified specific ICUs with significant effects, even when the average effect was nonsignificant. This can assist healthcare managers in further in-dept evaluation of process interventions to improve ICU efficiency.

Data challenges for international health emergencies: lessons learned from ten international COVID-19 driver projects.

The COVID-19 pandemic highlighted the importance of international data sharing and access to improve health outcomes for all. The International COVID-19 Data Alliance (ICODA) programme enabled 12 exemplar or driver projects to use existing health-related data to address major research questions relating to the pandemic, and developed data science approaches that helped each research team to overcome challenges, accelerate the data research cycle, and produce rapid insights and outputs. These approaches also sought to address inequity in data access and use, test approaches to ethical health data use, and make summary datasets and outputs accessible to a wider group of researchers. This Health Policy paper focuses on the challenges and lessons learned from ten of the ICODA driver projects, involving researchers from 19 countries and a range of health-related datasets. The ICODA programme reviewed the time taken for each project to complete stages of the health data research cycle and identified common challenges in areas such as data sharing agreements and data curation. Solutions included provision of standard data sharing templates, additional data curation expertise at an early stage, and a trusted research environment that facilitated data sharing across national boundaries and reduced risk. These approaches enabled the driver projects to rapidly produce research outputs, including publications, shared code, dashboards, and innovative resources, which can all be accessed and used by other research teams to address global health challenges.

Prevalence, risk factors, and impact of long COVID in a socially vulnerable community in Brazil: a prospective cohort study.

Background: Long COVID is an emerging global public health issue. Socially vulnerable communities in low- and-middle-income countries were severely impacted by the pandemic and are underrepresented in research. This prospective study aimed to determine the prevalence of long COVID, its impact on health, and associated risk factors in one such community in Rio de Janeiro, Brazil. Methods: A total of 710 individuals aged 18 and older, with confirmed SARS-CoV-2 infection at least three months prior, were enrolled between November 25, 2021, and May 5, 2022. Participants were assessed via telephone or in person using a standardized questionnaire to evaluate their perception of recovery, symptoms, quality of life, and functional status. Findings: Twenty percent of participants did not feel fully recovered, 22% experienced new or persistent symptoms, 26% had worsened functional status, 18% had increased dyspnoea, and 32% reported a worse quality of life. Persistent symptoms included headache, cough, fatigue, muscle pain, and shortness of breath. Dyspnoea during the acute phase was the strongest independent predictor of worsening outcomes. Females and individuals with comorbidities were more likely to report worse recovery, functioning, dyspnoea, and quality of life. Interpretation: Our findings reveal a high burden of severe and persistent physical and mental health sequelae in a socially vulnerable community following COVID-19. Funding: UK Foreign, Commonwealth and Development Office and Wellcome Trust Grant (222048/Z/20/Z), Fundação Oswaldo Cruz (FIOCRUZ), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), and the Centers for Disease Control and Prevention (CDC).

Changes in neuroinflammatory biomarkers correlate with disease severity and neuroimaging alterations in patients with COVID-19 neurological complications.

COVID-19 induces acute and persistent neurological symptoms in mild and severe cases. Proposed concomitant mechanisms include direct viral infection and strain, coagulopathy, hypoxia, and neuroinflammation. However, underlying molecular alterations associated with multiple neurological outcomes in both mild and severe cases are majorly unexplored. To illuminate possible mechanisms leading to COVID-19 neurological disease, we retrospectively investigated in detail a cohort of 35 COVID-19 mild and severe hospitalized patients presenting neurological alterations subject to clinically indicated cerebrospinal fluid (CSF) sampling. Clinical and neurological investigation, brain imaging, viral sequencing, and cerebrospinal CSF analyses were carried out. We found that COVID-19 patients presented heterogeneous neurological symptoms dissociated from lung burden. Nasal swab viral sequencing revealed a dominant strain at the time of the study, and we could not detect traces of SARS-CoV-2's spike protein in patients' CSF by multiple reaction monitoring analysis. Patients presented ubiquitous systemic hyper-inflammation and broad alterations in CSF proteomics related to inflammation, innate immunity, and hemostasis, irrespective of COVID-19 severity or neuroimaging alterations. Elevated CSF interleukin-6 (IL6) correlated with disease severity (sex-, age-, and comorbidity-adjusted mean Severe 24.5 pg/ml, 95% confidence interval (CI) 9.62-62.23 vs. Mild 3.91 pg/mL CI 1.5-10.3 patients, p = 0.019). CSF tumor necrosis factor-alpha (TNFα) and IL6 levels were higher in patients presenting pronounced neuroimaging alterations compared to those who did not (sex-, age-, and comorbidity-adjusted mean TNFα Pronounced 3.4, CI 2.4-4.4 vs. Non-Pronounced 2.0, CI 1.4-2.5, p = 0.022; IL6 Pronounced 33.11, CI 8.89-123.31 vs Non-Pronounced 6.22, CI 2.9-13.34, p = 0.046). Collectively, our findings put neuroinflammation as a possible driver of COVID-19 acute neurological disease in mild and severe cases.

Prevention of lipid droplet accumulation by DGAT1 inhibition ameliorates sepsis-induced liver injury and inflammation.

Background & Aims: Lipid droplet (LD) accumulation in cells and tissues is understood to be an evolutionarily conserved tissue tolerance mechanism to prevent lipotoxicity caused by excess lipids; however, the presence of excess LDs has been associated with numerous diseases. Sepsis triggers the reprogramming of lipid metabolism and LD accumulation in cells and tissues, including the liver. The functions and consequences of sepsis-triggered liver LD accumulation are not well known. Methods: Experimental sepsis was induced by CLP (caecal ligation and puncture) in mice. Markers of hepatic steatosis, liver injury, hepatic oxidative stress, and inflammation were analysed using a combination of functional, imaging, lipidomic, protein expression and immune-enzymatic assays. To prevent LD formation, mice were treated orally with A922500, a pharmacological inhibitor of DGAT1. Results: We identified that liver LD overload correlates with liver injury and sepsis severity. Moreover, the progression of steatosis from 24 h to 48 h post-CLP occurs in parallel with increased cytokine expression, inflammatory cell recruitment and oxidative stress. Lipidomic analysis of purified LDs demonstrated that sepsis leads LDs to harbour increased amounts of unsaturated fatty acids, mostly 18:1 and 18:2. An increased content of lipoperoxides within LDs was also observed. Conversely, the impairment of LD formation by inhibition of the DGAT1 enzyme reduces levels of hepatic inflammation and lipid peroxidation markers and ameliorates sepsis-induced liver injury. Conclusions: Our results indicate that sepsis triggers lipid metabolism alterations that culminate in increased liver LD accumulation. Increased LDs are associated with disease severity and liver injury. Moreover, inhibition of LD accumulation decreased the production of inflammatory mediators and lipid peroxidation while improving tissue function, suggesting that LDs contribute to the pathogenesis of liver injury triggered by sepsis. Impact and Implications: Sepsis is a complex life-threatening syndrome caused by dysregulated inflammatory and metabolic host responses to infection. The observation that lipid droplets may contribute to sepsis-associated organ injury by amplifying lipid peroxidation and inflammation provides a rationale for therapeutically targeting lipid droplets and lipid metabolism in sepsis.

Subprodutos do metabolismo da hemoglobina se associam com resposta inflamatória em pacientes com acidente vascular cerebral hemorrágico / Hemoglobin metabolism by-products are associated with an inflammatory response in patients with hemorrhagic stroke

RESUMO Objetivo: Avaliar o relacionamento entre os níveis cerebrais de ferro e heme e a resposta inflamatória sistêmica e no sistema nervoso central, assim como o papel dos sistemas de defesa contra a toxicidade do ferro e do heme, no sistema nervoso central. Métodos: Avaliamos uma coorte prospectiva de pacientes com quadro de hemorragia intracraniana e subaracnóidea. Realizamos ensaios em amostras de plasma e líquido cefalorraquidiano quanto à presença de ferro, heme, hemopexina, haptoglobina, enolase, S100-β e citocinas nos primeiros 3 dias após um acidente vascular cerebral hemorrágico. Analisamos também as alterações dinâmicas em todos os componentes de ambos os líquidos e seu relacionamento com as taxas de mortalidade precoce. Resultados: As concentrações de hemopexina e haptoglobina foram quase desprezíveis no cérebro após hemorragia intracraniana e subaracnóidea. As concentrações de ferro e heme no líquido cefalorraquidiano se correlacionaram com resposta pró-inflamatória no sistema nervoso central, e os perfis inflamatórios no líquido cefalorraquidiano no terceiro dia após acidente vascular cerebral hemorrágico se correlacionaram com as taxas de mortalidade precoce. Identificamos que os níveis de interleucina 4 no líquido cefalorraquidiano durante as primeiras 24 horas após acidente vascular cerebral hemorrágico foram mais altos nos sobreviventes do que nos que não sobreviveram. Conclusão: Os níveis de ferro e heme se associaram com resposta pró-inflamatória no sistema nervoso central após acidente vascular cerebral hemorrágico, e o cérebro humano não tem proteção contra hemoglobina e heme. Os perfis inflamatórios dos pacientes se associaram com prognósticos piores, e as respostas inflamatórias locais pareceram ter um papel protetor.

ABSTRACT Objective: To evaluate the relationships of brain iron and heme with the inflammatory response of the systemic and central nervous systems and to investigate the role of defensive systems against the toxicity of iron and heme in the central nervous system. Methods: We assessed a prospective cohort of patients presenting with intracerebral and subarachnoid hemorrhage. We assayed plasma and cerebrospinal fluid samples for the presence of iron, heme, hemopexin, haptoglobin, enolase, S100-β and cytokines for the first three days following hemorrhagic stroke. We also analyzed the dynamic changes in these components within both fluids and their relationship with early mortality rates. Results: Hemopexin and haptoglobin concentrations were nearly negligible in the brain after intracerebral and subarachnoid hemorrhage. Cerebrospinal fluid iron and heme concentrations correlated with a pro-inflammatory response in the central nervous system, and plasmatic and cerebrospinal fluid inflammatory profiles on the third day after hemorrhagic stroke were related to early mortality rates. Interleukin 4 levels within the cerebrospinal fluid during the first 24 hours after hemorrhagic stroke were found to be higher in survivors than in non-survivors. Conclusion: Iron and heme are associated with a pro-inflammatory response in the central nervous system following hemorrhagic stroke, and protections against hemoglobin and heme are lacking within the human brain. Patient inflammatory profiles were associated with a poorer prognosis, and local anti-inflammatory responses appeared to have a protective role.

Oseltamivir-resistant influenza A(H1N1)pdm2009 strains found in Brazil are endowed with permissive mutations, which compensate the loss of fitness imposed by antiviral resistance

The 2009 pandemic influenza A virus outbreak led to the systematic use of the neuraminidase (NA) inhibitor oseltamivir (OST). Consequently, OST-resistant strains, carrying the mutation H275Y, emerged in the years after the pandemics, with a prevalence of 1-2%. Currently, OST-resistant strains have been found in community settings, in untreated individuals. To spread in community settings, H275Y mutants must contain additional mutations, collectively called permissive mutations. We display the permissive mutations in NA of OST-resistant A(H1N1)pdm09 virus found in Brazilian community settings. The NAs from 2013 are phylogenetically distinct from those of 2012, indicating a tendency of positive selection of NAs with better fitness. Some previously predicted permissive mutations, such as V241I and N369K, found in different countries, were also detected in Brazil. Importantly, the change D344N, also predicted to compensate loss of fitness imposed by H275Y mutation, was found in Brazil, but not in other countries in 2013. Our results reinforce the notion that OST-resistant A(H1N1)pdm09 strains with compensatory mutations may arise in an independent fashion, with samples being identified in different states of Brazil and in different countries. Systematic circulation of these viral strains may jeopardise the use of the first line of anti-influenza drugs in the future. (AU)

Chest computed tomography findings in severe influenza pneumonia occurring in neutropenic cancer patients

OBJECTIVE: To describe the chest computed tomography findings for severe influenza H1N1 infection in a series of hospitalized neutropenic cancer patients. METHODS: We performed a retrospective systematic analysis of chest computed tomography scans for eight hospitalized patients with fever, neutropenia, and confirmed diagnoses of influenza H1N1. The clinical data had been prospectively collected. RESULTS: Six of eight patients (75%) developed respiratory failure and required intensive care. Prolonged H1N1 shedding was observed in the three mechanically ventilated patients, and overall hospital mortality in our series was 25%. The most frequent computed tomography findings were ground-glass opacity (all patients), consolidation (7/8 cases), and airspace nodules (6/8 cases) that were frequently moderate or severe. Other parenchymal findings were not common. Five patients had features of pneumonia, two had computed tomography findings compatible with bronchitis and/or bronchiolitis, and one had tomographic signs of chronicity. CONCLUSION: In this series of neutropenic patients with severe influenza H1N1 infection, chest computed tomography demonstrated mainly moderate or severe parenchymatous disease, but bronchiolitis was not a common feature. These findings associated with febrile neutropenia should elicit a diagnosis of severe viral infection.

Revisiting steroid treatment for septic shock: molecular actions and clinical effects - a review

Corticosteroids are widely used to treat a diversity of pathological conditions including allergic, autoimmune and some infectious diseases. These drugs have complex mechanisms of action involving both genomic and non-genomic mechanisms and interfere with different signal transduction pathways in the cell. The use of corticosteroids to treat critically ill patients with acute respiratory distress syndrome and severe infections, such as sepsis and pneumonia, is still a matter of intense debate in the scientific and medical community with evidence both for and against its use in these patients. Here, we review the basic molecular mechanisms important for corticosteroid action as well as current evidence for their use, or not, in septic patients. We also present an analysis of the reasons why this is still such a controversial point in the literature.

Beyond sepsis pathophysiology with cytokines: what is their value as biomarkers for disease severity?

Sepsis is a major challenge in medicine. It is a common and frequently fatal infectious condition. The incidence continues to increase, with unacceptably high mortality rates, despite the use of specific antibiotics, aggressive operative intervention, nutritional support, and anti-inflammatory therapies. Typically, septic patients exhibit a high degree of heterogeneity due to variables such as age, weight, gender, the presence of secondary disease, the state of the immune system, and the severity of the infection. We are at urgent need for biomarkers and reliable measurements that can be applied to risk stratification of septic patients and that would easily identify those patients at the highest risk of a poor outcome. Such markers would be of fundamental importance to decision making for early intervention therapy or for the design of septic clinical trials. In the present work, we will review current biomarkers for sepsis severity and especially the use of cytokines as biomarkers with important pathophysiological role.

Cutaneous periumbilical purpura in disseminated strongyloidiasis in cancer patients: a pathognomonic feature of potentially lethal disease?

Cutaneous manifestations in disseminated strongyloidiasis are infrequent but should raise the suspicion for its diagnosis. We retrospectively evaluated the charts of six patients with cancer and a proven diagnosis of disseminated strongyloidiasis. All patients had received prophylaxis with albendazole before starting antineoplastic therapy, which included high-dose steroids. They presented with septic shock, acute respiratory failure and characteristic purpuric periumbilical skin lesions. Strongyloides larvae were identified in tracheal aspirates (n=5), gastric aspirates (n=4), lung (n=2) and skin biopsies (n=2). All patients died despite antihelminthic therapy and intensive care support.

Controle automático da ventilação mecânica para minimizar a lesão pulmonar induzida pela ventilação / Automatic control of the mechanical ventilation for minimizing the ventilation induced lung injury

O ajuste de parâmetros dos ventiladores mecânicos pulmonares para evitar a reabertura cíclica de unidades alveolares e pequenas vias aéreas, assim como a hiperdistensão dos septos alveolares, tem sido motivo de atenção nos últimos anos. Este trabalho utiliza um modelo de lesão pulmonar aguda (ALI) em suínos para testar um controlador de ventiladores em malha fechada baseado em regras e modelos discutidos na literatura. Utiliza-se um modelo polinomial da cursa pressão-volume do sistema respiratório para o ajuste da pressão positiva ao final da expiração (PEEP), visando evitar a reabertura cíclica de unidades alveolares, e o ajuste do volume corrente, visando evitar a hiperdistensão pulmonar. Um índice de hiperdistensão baseado na identificação de uma elastância não linear para o sistema respiratório permite o uso do controlador com qualquer forma de onda de ventilação constrolada. Os resultados do controlador proposto foram confrontados com resultados obtidos na ventilação de um grupo controle, manualmente ventilados com base nas mesmas premissas. Como resultado, o controlador automático obteve valores de PEEP dentro da faixa de valores obtidos no grupo controle, porém com menor dispersão. O índice de hiperdistensão calculado ficou abaixo do limiar de hiperdistensão em 5 dos 6 animais do grupo ventilado automaticamente, e em 3 dos 6 animais ventilados do grupo controle. O controlador se comportou de forma estável e os resultados recomendam seu uso em ALI.