Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

The PREDICTS database: a global database of how local terrestrial biodiversity responds to human impacts

Biodiversity continues to decline in the face of increasing anthropogenic pressures such as habitat destruction, exploitation, pollution and introduction of alien species. Existing global databases of species’ threat status or population time series are dominated by charismatic species. The collation of datasets with broad taxonomic and biogeographic extents, and that support computation of a range of biodiversity indicators, is necessary to enable better understanding of historical declines and to project – and avert – future declines. We describe and assess a new database of more than 1.6 million samples from 78 countries representing over 28,000 species, collated from existing spatial comparisons of local-scale biodiversity exposed to different intensities and types of anthropogenic pressures, from terrestrial sites around the world. The database contains measurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35) biodiversity hotspots and 16 (of 17) megadiverse countries. The database contains more than 1% of the total number of all species described, and more than 1% of the described species within many taxonomic groups – including flowering plants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopterans and hymenopterans. The dataset, which is still being added to, is therefore already considerably larger and more representative than those used by previous quantitative models of biodiversity trends and responses. The database is being assembled as part of the PREDICTS project (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems – www.predicts.org.uk). We make site-level summary data available alongside this article. The full database will be publicly available in 2015

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)

Characterization of community-acquired pneumonia in the ICU. A 2-year retrospective study

Objetivo: Conocer las características clínicas y microbiológicas y el manejo de los pacientes con neumonía adquirida en la comunidad (NAC) ingresados en una UCI. Material y métodos: estudio observacional retrospectivo en una UCI polivalente de 14 camas en Alcalá de Henares, Madrid, España. Se revisan los ingresos desde enero 2018 a diciembre de 2019, extrayendo los casos cuyo motivo de ingreso fue NAC. Recogemos datos demográficos, APACHE II, tratamiento al ingreso, aislamiento microbiológico, estancia y mortalidad. Se analizan los datos con el programa SPSS statistics 23. Resultados: se recogieron un total de 41 casos. El principal motivo de ingreso fue la insuficiencia respiratoria aguda (IRA) (87,8%) seguido por inestabilidad hemodinámica asociada a IRA (7,3%). Los pacientes requirieron ventilación mecánica (VM) como soporte inicial en un 14,6% de los casos. El soporte ventilatorio inicial más frecuente fue la ventilación mecánica no invasiva en (48,8%) seguido por gafas nasales de alto flujo (26,8%). Finalmente precisaron VM un 48,8% de pacientes. La antibioterapia inicial empírica fue la combinación de betalactámico y fluoroquinolona o macrólido en un 78%; excluyendo los pacientes clasificados como inmunodeprimidos se dio dicha terapia en un 90,3%. El diagnóstico etiológico se alcanzó en 51%, siendo el patógeno más frecuentemente aislado el S. Pneumoniae seguido por el virus Influenza. La mortalidad global en la UCI fue del 14.6%. Se relacionaron con la mortalidad de forma estadísticamente significativa la inmunodepresión, la necesidad de fármacos vasoactivos, y la necesidad de ventilación mecánica. Conclusión: El principal motivo de ingreso por neumonía de comunidad grave es la insuficiencia respiratoria aguda, precisando el uso de ventilación mecánica invasiva en la mitad de los casos. El soporte respiratorio inicial con OAF o VMNI no presenta diferencias estadísticamente significativas en cuanto a tasa de fracaso. El germen más frecuente aislado en nuestra muestra es el Streptococcus pneumoniae, seguido del virus influenza. La mortalidad en la neumonía de comunidad grave se asocia fundamentalmente a necesidad de ventilación mecánica, fármacos vasoactivos y estado inmunitario del paciente.Purpose: to describe the clinical characteristics and outcomes of patients with community-acquired pneumonia (CAP) admitted to the Intensive Care Unit (ICU), analyzing the patients’ profile, microbiology isolations and treatment received. Matherial and methods: a retrospective observational study was performed. Consecutive critically ill CAP patients receiving treatment a polivalent ICU were reviewed from january 1, 2018 to december 30, 2019. Main clinical characteristics, APACHE II, microbiological isolations, treatment, ICU stay and mortality were collected and analysed with SPSS 23 program. Results: A total of 41 consecutive eligible individuals were reviewed. The main reason for admission was acute respiratoriy failure in 87.8% of patients, followed by shock (need of vasoactive drugs). 14.6% required intubation as an initial respiratory support. Non invasive mechanical ventilation was initiated in 48.8% followed by high flow oxigenation in 26.8%. Finally, 48.8% of pacients required mechanical ventilation (20/41). The initial empiric treatment was a betalactamic and a macrolid or a quinolone in 78% of cases. In 51% there was an identifiable microbiological etiology. The isolation was S. Pneumoniae followed by Influenza virus. Global ICU mortality was 14,6%. Inmunosupression, need for vasoactive drugs and mechanical ventilation were related to higher mortality. Conclusions: The main reason for admission for severe community pneumonia was acute respiratory failure, requiring the use of invasive mechanical ventilation in half of the cases. The initial respiratory support with HFOT or NIMV did not present statistically significant differences of failure rate. The most frequent isolated germ in our sample was Streptococcus pneumoniae, followed by influenza virus. Mortality in severe community pneumonia was associated with the need for mechanical ventilation, vasoactive drugs, and the patient’s immune status

20 años de estudios sobre el Caribe colombiano

El Centro de Estudios Económicos Regionales (CEER) fue el primer esfuerzo del Banco de la República para descentralizar la investigación económica, la cual tenía como único centro de operaciones la oficina principal en Bogotá. Es así como en 1997, se puso en marcha el primer centro regional en la sucursal de Cartagena. Inicialmente fue llamado Centro de Investigaciones Económicas del Caribe y luego, en 2001, se convierte en Centro de Estudios Económicos Regionales (CEER), realizando estudios de todas las regiones del país. En 2017, con motivo de la celebración de los 20 años de existencia del CEER, se decidió adelantar un proyecto en el que participarían un grupo de destacados investigadores y estudiosos de la realidad Caribe. El propósito de tal proyecto era realizar un balance de la evolución y principales investigaciones durante las dos últimas décadas en seis dimensiones en particular: Historiografía, Estudios Económicos y Sociales, Arqueología, Estructuras Políticas, Cultura y algunos de los Carnavales y Festivales más populares en la región

The Neurological Pupil index for outcome prognostication in people with acute brain injury (ORANGE): a prospective, observational, multicentre cohort study

Background Improving the prognostication of acute brain injury is a key element of critical care. Standard assessment includes pupillary light reactivity testing with a hand-held light source, but findings are interpreted subjectively; automated pupillometry might be more precise and reproducible. We aimed to assess the association of the Neurological Pupil index (NPi)-a quantitative measure of pupillary reactivity computed by automated pupillometry- with outcomes of patients with severe non-anoxic acute brain injury.Methods ORANGE is a multicentre, prospective, observational cohort study at 13 hospitals in eight countries in Europe and North America. Patients admitted to the intensive care unit after traumatic brain injury, aneurysmal subarachnoid haemorrhage, or intracerebral haemorrhage were eligible for the study. Patients underwent automated infrared pupillometry assessment every 4 h during the first 7 days after admission to compute NPi, with values ranging from 0 to 5 (with abnormal NPi being <3). The co-primary outcomes of the study were neurological outcome (assessed with the extended Glasgow Outcome Scale [GOSE]) and mortality at 6 months. We used logistic regression to model the association between NPi and poor neurological outcome (GOSE <= 4) at 6 months and Cox regression to model the relation of NPi with 6-month mortality. This study is registered with ClinicalTrials.gov, NCT04490005.Findings Between Nov 1, 2020, and May 3, 2022, 514 patients (224 with traumatic brain injury, 139 with aneurysmal subarachnoid haemorrhage, and 151 with intracerebral haemorrhage) were enrolled. The median age of patients was 61 years (IQR 46-71), and the median Glasgow Coma Scale score on admission was 8 (5-11). 40071 NPi measurements were taken (median 40 per patient [20-50]). The 6-month outcome was assessed in 497 (97%) patients, of whom 160 (32%) patients died, and 241 (47%) patients had at least one recording of abnormal NPi, which was associated with poor neurological outcome (for each 10% increase in the frequency of abnormal NPi, adjusted odds ratio 142 [95% CI 127-164]; p<00001) and in-hospital mortality (adjusted hazard ratio 558 [95% CI 392-795]; p<00001).Interpretation NPi has clinically and statistically significant prognostic value for neurological outcome and mortality after acute brain injury. Simple, automatic, repeat automated pupillometry assessment could improve the continuous monitoring of disease progression and the dynamics of outcome prediction at the bedside

DREAM controls the on/off switch of specific activity-dependent transcription pathways

Changes in nuclear Ca(2+) homeostasis activate specific gene expression programs and are central to the acquisition and storage of information in the brain. DREAM (downstream regulatory element antagonist modulator), also known as calsenilin/KChIP-3 (K(+) channel interacting protein 3), is a Ca(2+)-binding protein that binds DNA and represses transcription in a Ca(2+)-dependent manner. To study the function of DREAM in the brain, we used transgenic mice expressing a Ca(2+)-insensitive/CREB-independent dominant active mutant DREAM (daDREAM). Using genome-wide analysis, we show that DREAM regulates the expression of specific activity-dependent transcription factors in the hippocampus, including Npas4, Nr4a1, Mef2c, JunB, and c-Fos. Furthermore, DREAM regulates its own expression, establishing an autoinhibitory feedback loop to terminate activity-dependent transcription. Ablation of DREAM does not modify activity-dependent transcription because of gene compensation by the other KChIP family members. The expression of daDREAM in the forebrain resulted in a complex phenotype characterized by loss of recurrent inhibition and enhanced long-term potentiation (LTP) in the dentate gyrus and impaired learning and memory. Our results indicate that DREAM is a major master switch transcription factor that regulates the on/off status of specific activity-dependent gene expression programs that control synaptic plasticity, learning, and memory.This work was supported by grants from Spanish Ministry of Health and Science, Madrid Community, La Marató, La Caixa, Reina Sofía and Areces Foundations, the EU 6th Framework Program (NeuroNE, CureFXS), the ERA-NET Program (Neuron and E-Rare), and the Medical Research Council. S.K. has a postdoctoral contract from the Ramón y Cajal Program of the Ministry of Science and Innovation