Combining heart rate and systolic blood pressure to improve risk stratification in older patients with heart failure: Findings from the RICA Registry

Objectives: Heart rate (HR) and systolic blood pressure (SBP) are independent prognostic variables in patients with heart failure (HF). We evaluated if combining HR and SBP could improve prognostic assessment in older patients. Methods: Variables associated with all-cause mortality and readmission for HF during 9 months of follow-up were analyzed from the Spanish Heart Failure Registry (RICA). HR and SBP values were stratified in three combined groups. Results: We evaluated 1551 patients, 82 years and 56% women. Using HR strata of < 70 and ≥ 70 bpm we found mortality rates of 9.8 and 13.6%, respectively (hazard ratio 1.0 and 1.35). For SBP ≥ 140, 120–140 and < 120 mm Hg, mortality rates were 8.2, 10.4 and 20.3%. respectively (hazard ratio 1.0, 1.34 and 2.76). Using combined strata of HR < 70 bpm and SBP ≥ 140 mm Hg (n = 176; low-risk), HR < 70 and SBP < 140 + HR ≥ 70 and SBP < 120 (n = 1089; moderate-risk) and HR ≥ 70 and SBP < 120 (n = 286; high-risk) we found mortality rates of 4.5%, 11.0% and 24.0%, respectively. Multivariate Cox regression for all-cause mortality shows for low-, middle- and high-risk groups was 1 (reference), 1.93 (95% CI: 0.93–3.99, p = 0.077) and 4.32 (95% CI: 2.04–9.14, p < 0.001). BMI, NYHA, MDRD, hypertension and sodium were also independent prognostic factors. Conclusions: The combination provides better risk discrimination than use of HR and SBP alone and may provide a simple and reliable tool for risk assessment for older HF patients in clinical practice

A blood microRNA classifier for the prediction of ICU mortality in COVID-19 patients: a multicenter validation study

Background: The identification of critically ill COVID-19 patients at risk of fatal outcomes remains a challenge. Here, we first validated candidate microRNAs (miRNAs) as biomarkers for clinical decision-making in critically ill patients. Second, we constructed a blood miRNA classifier for the early prediction of adverse outcomes in the ICU. Methods: This was a multicenter, observational and retrospective/prospective study including 503 critically ill patients admitted to the ICU from 19 hospitals. qPCR assays were performed in plasma samples collected within the first 48 h upon admission. A 16-miRNA panel was designed based on recently published data from our group. Results: Nine miRNAs were validated as biomarkers of all-cause in-ICU mortality in the independent cohort of critically ill patients (FDR < 0.05). Cox regression analysis revealed that low expression levels of eight miRNAs were associated with a higher risk of death (HR from 1.56 to 2.61). LASSO regression for variable selection was used to construct a miRNA classifier. A 4-blood miRNA signature composed of miR-16-5p, miR-192-5p, miR-323a-3p and miR-451a predicts the risk of all-cause in-ICU mortality (HR 2.5). Kaplan‒Meier analysis confirmed these findings. The miRNA signature provides a significant increase in the prognostic capacity of conventional scores, APACHE-II (C-index 0.71, DeLong test p-value 0.055) and SOFA (C-index 0.67, DeLong test p-value 0.001), and a risk model based on clinical predictors (C-index 0.74, DeLong test-p-value 0.035). For 28-day and 90-day mortality, the classifier also improved the prognostic value of APACHE-II, SOFA and the clinical model. The association between the classifier and mortality persisted even after multivariable adjustment. The functional analysis reported biological pathways involved in SARS-CoV infection and inflammatory, fibrotic and transcriptional pathways. Conclusions: A blood miRNA classifier improves the early prediction of fatal outcomes in critically ill COVID-19 patients.11 página

The microbiota-gut-brain axis

The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within and on our bodies) as one of the key regulators of gut-brain function and has led to the appreciation of the importance of a distinct microbiota-gut-brain axis. This axis is gaining ever more traction in fields investigating the biological and physiological basis of psychiatric, neurodevelopmental, age-related, and neurodegenerative disorders. The microbiota and the brain communicate with each other via various routes including the immune system, tryptophan metabolism, the vagus nerve and the enteric nervous system, involving microbial metabolites such as short-chain fatty acids, branched chain amino acids, and peptidoglycans. Many factors can influence microbiota composition in early life, including infection, mode of birth delivery, use of antibiotic medications, the nature of nutritional provision, environmental stressors, and host genetics. At the other extreme of life, microbial diversity diminishes with aging. Stress, in particular, can significantly impact the microbiota-gut-brain axis at all stages of life. Much recent work has implicated the gut microbiota in many conditions including autism, anxiety, obesity, schizophrenia, Parkinson's disease, and Alzheimer's disease. Animal models have been paramount in linking the regulation of fundamental neural processes, such as neurogenesis and myelination, to microbiome activation of microglia. Moreover, translational human studies are ongoing and will greatly enhance the field. Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders

Combining heart rate and systolic blood pressure to improve risk stratification in older patients with heart failure: Findings from the RICA Registry

Objectives: Heart rate (HR) and systolic blood pressure (SBP) are independent prognostic variables in patients with heart failure (HF). We evaluated if combining HR and SBP could improve prognostic assessment in older patients. Methods: Variables associated with all-cause mortality and readmission for HF during 9 months of follow-up were analyzed from the Spanish Heart Failure Registry (RICA). HR and SBP values were stratified in three combined groups. Results: We evaluated 1551 patients, 82 years and 56% women. Using HR strata of <70 and ≥70 bpm we found mortality rates of 9.8 and 13.6%, respectively (hazard ratio 1.0 and 1.35). For SBP ≥ 140, 120-140 and <120 mm Hg, mortality rates were 8.2, 10.4 and 20.3%. respectively (hazard ratio 1.0, 1.34 and 2.76). Using combined strata of HR < 70 bpm and SBP ≥ 140 mm Hg (n = 176; low-risk), HR < 70 and SBP < 140 + HR ≥ 70 and SBP < 120 (n = 1089; moderate-risk) and HR ≥ 70 and SBP < 120 (n = 286; high-risk) we found mortality rates of 4.5%, 11.0% and 24.0%, respectively. Multivariate Cox regression for all-cause mortality shows for low-, middle- and high-risk groups was 1 (reference), 1.93 (95% CI: 0.93-3.99, p = 0.077) and 4.32 (95% CI: 2.04-9.14, p < 0.001). BMI, NYHA, MDRD, hypertension and sodium were also independent prognostic factors. Conclusions: The combination provides better risk discrimination than use of HR and SBP alone and may provide a simple and reliable tool for risk assessment for older HF patients in clinical practice

Combining heart rate and systolic blood pressure to improve risk stratification in older patients with heart failure: Findings from the RICA Registry

Objectives: Heart rate (HR) and systolic blood pressure (SBP) are independent prognostic variables in patients with heart failure (HF). We evaluated if combining HR and SBP could improve prognostic assessment in older patients. Methods: Variables associated with all-cause mortality and readmission for HF during 9 months of follow-up were analyzed from the Spanish Heart Failure Registry (RICA). HR and SBP values were stratified in three combined groups. Results: We evaluated 1551 patients, 82 years and 56% women. Using HR strata of <70 and ≥70 bpm we found mortality rates of 9.8 and 13.6%, respectively (hazard ratio 1.0 and 1.35). For SBP ≥ 140, 120-140 and <120 mm Hg, mortality rates were 8.2, 10.4 and 20.3%. respectively (hazard ratio 1.0, 1.34 and 2.76). Using combined strata of HR < 70 bpm and SBP ≥ 140 mm Hg (n = 176; low-risk), HR < 70 and SBP < 140 + HR ≥ 70 and SBP < 120 (n = 1089; moderate-risk) and HR ≥ 70 and SBP < 120 (n = 286; high-risk) we found mortality rates of 4.5%, 11.0% and 24.0%, respectively. Multivariate Cox regression for all-cause mortality shows for low-, middle- and high-risk groups was 1 (reference), 1.93 (95% CI: 0.93-3.99, p = 0.077) and 4.32 (95% CI: 2.04-9.14, p < 0.001). BMI, NYHA, MDRD, hypertension and sodium were also independent prognostic factors. Conclusions: The combination provides better risk discrimination than use of HR and SBP alone and may provide a simple and reliable tool for risk assessment for older HF patients in clinical practice

Astrocytic VMAT2 in the developing prefrontal cortex is required for normal grooming behavior in mice

Astrocytes control synaptic activity by modulating peri-synaptic concentrations of ion and neurotransmitters including dopamine and, as such, can be critically involved in the modulation of some aspect of mammalian behavior. Here we report that genetic mouse model with a reduced medial prefrontal cortex (mPFC) dopamine levels, arising from astrocyte-specific conditional deletion of vesicular monoamine transporter 2 (VMAT2; aVMTA2cKO mice) shows excessive grooming and anxiety-like behaviour. The VMAT2cKO mice also develop a synaptic pathology, expressed through increased relative AMPA vs. NMDA receptor currents in synapses of the dorsal striatum receiving inputs from the mPFC. Importantly, behavioural and synaptic phenotypes are prevented by reexpression of mPFC VMAT2, showing that the deficits are driven by mPFC astrocytes. By analysing human tissue samples, we found that VMAT2 is expressed in human mPFC astrocytes, corroborating the potential translational relevance of our observations in mice. Our study shows that impairments of the astrocytic-control of dopamine in the mPFC has a profound impact on circuit function and behaviours, which resemble symptoms of anxiety disorders and obsessive compulsive disorder (OCD)

The microbiota-gut-brain axis

The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within and on our bodies) as one of the key regulators of gut-brain function and has led to the appreciation of the importance of a distinct microbiota-gut-brain axis. This axis is gaining ever more traction in fields investigating the biological and physiological basis of psychiatric, neurodevelopmental, age-related, and neurodegenerative disorders. The microbiota and the brain communicate with each other via various routes including the immune system, tryptophan metabolism, the vagus nerve and the enteric nervous system, involving microbial metabolites such as short-chain fatty acids, branched chain amino acids, and peptidoglycans. Many factors can influence microbiota composition in early life, including infection, mode of birth delivery, use of antibiotic medications, the nature of nutritional provision, environmental stressors, and host genetics. At the other extreme of life, microbial diversity diminishes with aging. Stress, in particular, can significantly impact the microbiota-gut-brain axis at all stages of life. Much recent work has implicated the gut microbiota in many conditions including autism, anxiety, obesity, schizophrenia, Parkinson\u27s disease, and Alzheimer\u27s disease. Animal models have been paramount in linking the regulation of fundamental neural processes, such as neurogenesis and myelination, to microbiome activation of microglia. Moreover, translational human studies are ongoing and will greatly enhance the field. Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders

Subcutaneous anti-COVID-19 hyperimmune immunoglobulin for prevention of disease in asymptomatic individuals with SARS-CoV-2 infection: a double-blind, placebo-controlled, randomised clinical trialResearch in context

Summary: Background: Anti-COVID-19 hyperimmune immunoglobulin (hIG) can provide standardized and controlled antibody content. Data from controlled clinical trials using hIG for the prevention or treatment of COVID-19 outpatients have not been reported. We assessed the safety and efficacy of subcutaneous anti-COVID-19 hyperimmune immunoglobulin 20% (C19-IG20%) compared to placebo in preventing development of symptomatic COVID-19 in asymptomatic individuals with SARS-CoV-2 infection. Methods: We did a multicentre, randomized, double-blind, placebo-controlled trial, in asymptomatic unvaccinated adults (≥18 years of age) with confirmed SARS-CoV-2 infection within 5 days between April 28 and December 27, 2021. Participants were randomly assigned (1:1:1) to receive a blinded subcutaneous infusion of 10 mL with 1 g or 2 g of C19-IG20%, or an equivalent volume of saline as placebo. The primary endpoint was the proportion of participants who remained asymptomatic through day 14 after infusion. Secondary endpoints included the proportion of individuals who required oxygen supplementation, any medically attended visit, hospitalisation, or ICU, and viral load reduction and viral clearance in nasopharyngeal swabs. Safety was assessed as the proportion of patients with adverse events. The trial was terminated early due to a lack of potential benefit in the target population in a planned interim analysis conducted in December 2021. ClinicalTrials.gov registry: NCT04847141. Findings: 461 individuals (mean age 39.6 years [SD 12.8]) were randomized and received the intervention within a mean of 3.1 (SD 1.27) days from a positive SARS-CoV-2 test. In the prespecified modified intention-to-treat analysis that included only participants who received a subcutaneous infusion, the primary outcome occurred in 59.9% (91/152) of participants receiving 1 g C19-IG20%, 64.7% (99/153) receiving 2 g, and 63.5% (99/156) receiving placebo (difference in proportions 1 g C19-IG20% vs. placebo, −3.6%; 95% CI -14.6% to 7.3%, p = 0.53; 2 g C19-IG20% vs placebo, 1.1%; −9.6% to 11.9%, p = 0.85). None of the secondary clinical efficacy endpoints or virological endpoints were significantly different between study groups. Adverse event rate was similar between groups, and no severe or life-threatening adverse events related to investigational product infusion were reported. Interpretation: Our findings suggested that administration of subcutaneous human hyperimmune immunoglobulin C19-IG20% to asymptomatic individuals with SARS-CoV-2 infection was safe but did not prevent development of symptomatic COVID-19. Funding: Grifols