Mortality by cause of death in Colombia : a local analysis using spatial econometrics

Colombia is undergoing major changes in mortality patterns. National- and department-level cause-specific analyses have previously been carried out, but very little is known about municipal-level trends, despite their epidemiological interest. We first analyze standardized mortality rates for seven cause-of-death groups to obtain high and low mortality clusters based on the spatial autocorrelation indicators Global Moran's I and Local Moran's I. The Mann-Whitney nonparametric test is then used to ascertain statistical associations between the high and low mortality clusters and known health determinants. We subsequently apply spatial lag and Durbin (when spatial autocorrelation was present) and OLS models (when not) to explain overall spatial patterns in cause-specific mortality. Age- and sex-specific cause-of-death mortality and population data were obtained from the National Administrative Department of Statistics (DANE). Deaths were corrected for each municipality due to under-registration. Results show that spatial autocorrelation declined over time for all cause-of-death categories, except male circulatory system diseases and perinatal mortality. It is highest in external causes, especially among men, with mortality hotspots moving from the central Andean area to Orinoquia and the Amazon rainforest. Male mortality is also more spatially clustered than female mortality and especially neoplasms, and external-cause mortality is also indirectly affected by the conditions of neighboring municipalities. Municipal surface area, ethnicity and public expenditure on health and education are the most frequent contextual variables explaining territorial differences in mortality. The identification of geographical mortality clusters in Colombia will allow decision makers to prioritize those regions with higher mortality

Serum micrornas as tool to predict early response to benralizumab in severe eosinophilic asthma

Severe eosinophilic asthma poses a serious health and economic problem, so new therapy approaches have been developed to control it, including biological drugs such as benralizumab, which is a monoclonal antibody that binds to IL-5 receptor alpha subunit and depletes peripheral blood eosinophils rapidly. Biomarkers that predict the response to this drug are needed so that microRNAs (miRNAs) can be useful tools. This study was performed with fifteen severe eosinophilic asthmatic patients treated with benralizumab, and serum miRNAs were evaluated before and after treatment by semi-quantitative PCR (qPCR). Patients showed a clinical improvement after benralizumab administration. Additionally, deregulation of miR-1246, miR-5100 and miR-338-3p was observed in severe asthmatic patients after eight weeks of therapy, and a correlation was found between miR-1246 and eosinophil counts, including a number of exacerbations per year in these severe asthmatics. In silico pathway analysis revealed that these three miRNAs are regulators of the MAPK signaling pathway, regulating target genes implicated in asthma such as NFKB2, NFATC3, DUSP1, DUSP2, DUSP5 and DUSP16. In this study, we observed an altered expression of miR-1246, miR-5100 and miR-338-3p after eight weeks of benralizumab administration, which could be used as early response markers.This manuscript was funded by Fondo de Investigación Sanitaria–FIS and FEDER (Fondo Europeo de Desarrollo Regional) [PI15/00803, PI18/00044, and FI16/00036], CIBER de Enfermedades Respiratorias (CIBERES), Merck Health Foundation funds, and Ministerio de Ciencia, Innovación y Universidades (RTC-2017-6501-1

A DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin

Predictive biomarkers of trabectedin represent an unmet need in advanced soft-tissue sarcomas (STS). DNA damage repair (DDR) genes, involved in homologous recombination or nucleotide excision repair, had been previously described as biomarkers of trabectedin resistance or sensitivity, respectively. The majority of these studies only focused on specific factors (ERCC1, ERCC5, and BRCA1) and did not evaluate several other DDR-related genes that could have a relevant role for trabectedin efficacy. In this retrospective translational study, 118 genes involved in DDR were evaluated to determine, by transcriptomics, a predictive gene signature of trabectedin efficacy. A six-gene predictive signature of trabectedin efficacy was built in a series of 139 tumor samples from patients with advanced STS. Patients in the high-risk gene signature group showed a significantly worse progression-free survival compared with patients in the low-risk group (2.1 vs 6.0 months, respectively). Differential gene expression analysis defined new potential predictive biomarkers of trabectedin sensitivity (PARP3 and CCNH) or resistance (DNAJB11 and PARP1). Our study identified a new gene signature that significantly predicts patients with higher probability to respond to treatment with trabectedin. Targeting some genes of this signature emerges as a potential strategy to enhance trabectedin efficacy.This study was funded by the Spanish Group for Research on Sarcoma (GEIS) and partially by PharmaMar. The authors would like to thank the GEIS data center for data management. The authors also thank the donors and the Hospital Universitario Virgen del Rocío—Instituto de Biomedicina de Sevilla Biobank (Andalusian Public Health System Biobank and ISCIII-Red de Biobancos PT17/0015/0041) for part of the human specimens used in this study. David S. Moura is recipient of a Sara Borrell postdoctoral fellowship funded by the National Institute of Health Carlos III (ISCIII) (CD20/00155)

How reliably can algorithms identify eosinophilic asthma phenotypes using non-invasive biomarkers?

Asthma is a heterogeneous respiratory disease that encompasses different inflammatory and functional endophenotypes. Many non-invasive biomarkers has been investigated to its pathobiology. Heany et al proposed a clinical algorithm that classifies severe asthmatic patients into likely-eosinophilic phenotypes, based on accessible biomarkers: PBE, current treatment, FeNO, presence of nasal polyps (NP) and age of onset.We assessed the concordance between the algorithm proposed by Heany et al. with sputum examination, the gold standard, in 145 asthmatic patients of the MEGA cohort with varying grades of severity.No correlation was found between both classifications 0.025 (CI = 0.013-0.037). Moreover, no relationship was found between sputum eosinophilia and peripheral blood eosinophilia count in the total studied population.In conclusion, our results suggest that grouping the biomarkers proposed by Heany et al. are insufficient to diagnose eosinophilic phenotypes in asthmatic patients. Sputum analysis remains the gold standard to assess airway inflammation.© 2022 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology

Impact of interstitial lung disease on the survival of systemic sclerosis with pulmonary arterial hypertension

To assess severity markers and outcomes of patients with systemic sclerosis (SSc) with or without pulmonary arterial hypertension (PAH-SSc/non-PAH-SSc), and the impact of interstitial lung disease (ILD) on PAH-SSc. Non-PAH-SSc patients from the Spanish SSc registry and PAH-SSc patients from the Spanish PAH registry were included. A total of 364 PAH-SSc and 1589 non-PAH-SSc patients were included. PAH-SSc patients had worse NYHA-functional class (NYHA-FC), worse forced vital capacity (FVC) (81.2 +/- 20.6% vs 93.6 +/- 20.6%, P < 0.001), worse tricuspid annular plane systolic excursion (TAPSE) (17.4 +/- 5.2 mm vs 19.9 +/- 6.7 mm, P < 0.001), higher incidence of pericardial effusion (30% vs 5.2%, P < 0.001) and similar prevalence of ILD (41.8% vs. 44.9%). In individuals with PAH-SSc, ILD was associated with worse hemodynamics and pulmonary function tests (PFT). Up-front combination therapy was used in 59.8% and 61.7% of patients with and without ILD, respectively. Five-year transplant-free survival rate was 41.1% in PAH-SSc patients and 93.9% in non-PAH-SSc patients (P < 0.001). Global survival of PAH-SSc patients was not affected by ILD regardless its severity. The multivariate survival analysis in PAH-SSc patients confirmed age at diagnosis, worse NYHA-FC, increased PVR, reduced DLCO, and lower management with up-front combination therapy as major risk factors. In conclusion, in PAH-SSc cohort risk of death was greatly increased by clinical, PFT, and hemodynamic factors, whereas it was decreased by up-front combination therapy. Concomitant ILD worsened hemodynamics and PFT in PAH-SSc but not survival regardless of FVC impairment

Impact of interstitial lung disease on the survival of systemic sclerosis with pulmonary arterial hypertension

To assess severity markers and outcomes of patients with systemic sclerosis (SSc) with or without pulmonary arterial hypertension (PAH-SSc/non-PAH-SSc), and the impact of interstitial lung disease (ILD) on PAH-SSc. Non-PAH-SSc patients from the Spanish SSc registry and PAH-SSc patients from the Spanish PAH registry were included. A total of 364 PAH-SSc and 1589 non-PAH-SSc patients were included. PAH-SSc patients had worse NYHA-functional class (NYHA-FC), worse forced vital capacity (FVC) (81.2 ± 20.6% vs 93.6 ± 20.6%, P &lt; 0.001), worse tricuspid annular plane systolic excursion (TAPSE) (17.4 ± 5.2 mm vs 19.9 ± 6.7 mm, P &lt; 0.001), higher incidence of pericardial effusion (30% vs 5.2%, P &lt; 0.001) and similar prevalence of ILD (41.8% vs. 44.9%). In individuals with PAH-SSc, ILD was associated with worse hemodynamics and pulmonary function tests (PFT). Up-front combination therapy was used in 59.8% and 61.7% of patients with and without ILD, respectively. Five-year transplant-free survival rate was 41.1% in PAH-SSc patients and 93.9% in non-PAH-SSc patients (P &lt; 0.001). Global survival of PAH-SSc patients was not affected by ILD regardless its severity. The multivariate survival analysis in PAH-SSc patients confirmed age at diagnosis, worse NYHA-FC, increased PVR, reduced DLCO, and lower management with up-front combination therapy as major risk factors. In conclusion, in PAH-SSc cohort risk of death was greatly increased by clinical, PFT, and hemodynamic factors, whereas it was decreased by up-front combination therapy. Concomitant ILD worsened hemodynamics and PFT in PAH-SSc but not survival regardless of FVC impairment

The Beaker phenomenon and the genomic transformation of northwest Europe

From around 2750 to 2500 bc, Bell Beaker pottery became widespread across western and central Europe, before it disappeared between 2200 and 1800 bc. The forces that propelled its expansion are a matter of long-standing debate, and there is support for both cultural diffusion and migration having a role in this process. Here we present genome-wide data from 400 Neolithic, Copper Age and Bronze Age Europeans, including 226 individuals associated with Beaker-complex artefacts. We detected limited genetic affinity between Beaker-complex-associated individuals from Iberia and central Europe, and thus exclude migration as an important mechanism of spread between these two regions. However, migration had a key role in the further dissemination of the Beaker complex. We document this phenomenon most clearly in Britain, where the spread of the Beaker complex introduced high levels of steppe-related ancestry and was associated with the replacement of approximately 90% of Britain’s gene pool within a few hundred years, continuing the east-to-west expansion that had brought steppe-related ancestry into central and northern Europe over the previous centuries