Associations between depressive symptoms and disease progression in older patients with chronic kidney disease: results of the EQUAL study

Background Depressive symptoms are associated with adverse clinical outcomes in patients with end-stage kidney disease; however, few small studies have examined this association in patients with earlier phases of chronic kidney disease (CKD). We studied associations between baseline depressive symptoms and clinical outcomes in older patients with advanced CKD and examined whether these associations differed depending on sex. Methods CKD patients (>= 65 years; estimated glomerular filtration rate <= 20 mL/min/1.73 m(2)) were included from a European multicentre prospective cohort between 2012 and 2019. Depressive symptoms were measured by the five-item Mental Health Inventory (cut-off <= 70; 0-100 scale). Cox proportional hazard analysis was used to study associations between depressive symptoms and time to dialysis initiation, all-cause mortality and these outcomes combined. A joint model was used to study the association between depressive symptoms and kidney function over time. Analyses were adjusted for potential baseline confounders. Results Overall kidney function decline in 1326 patients was -0.12 mL/min/1.73 m(2)/month. A total of 515 patients showed depressive symptoms. No significant association was found between depressive symptoms and kidney function over time (P = 0.08). Unlike women, men with depressive symptoms had an increased mortality rate compared with those without symptoms [adjusted hazard ratio 1.41 (95% confidence interval 1.03-1.93)]. Depressive symptoms were not significantly associated with a higher hazard of dialysis initiation, or with the combined outcome (i.e. dialysis initiation and all-cause mortality). Conclusions There was no significant association between depressive symptoms at baseline and decline in kidney function over time in older patients with advanced CKD. Depressive symptoms at baseline were associated with a higher mortality rate in men

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Colitis alters oxysterol metabolism and is affected by 4β-hydroxycholesterol administration.

BACKGROUND AND AIMS: Inflammatory bowel diseases (IBD) represent a challenging health issue with a complex etiology implicating genetic and environmental parameters. Although the understanding of their pathophysiology has improved, much remains to be explored. In this context, bioactive lipids, more specifically oxysterols, i.e. oxygenated derivatives of cholesterol, represent an interesting avenue to investigate. Indeed, oxysterols or their receptors are involved in inflammation and immune regulation. Therefore, we set out to study the oxysterome in IBD. METHODS: We used both HPLC-MS and molecular biology tools to quantify oxysterol levels and the expression of their metabolic enzymes in several models of murine colitis (both acute and chronic), as well as in colon biopsies from patients with Crohn's disease and ulcerative colitis. RESULTS: We found that the oxysterome is altered in IBD, both in acute and chronic murine models as well as in human IBD. Two of the oxysterols quantified, 4β-hydroxycholesterol and 25-hydroxycholesterol, were consistently altered in all of our models and therefore could be of interest in this context. Hence, we administered them to mice with colitis. While 25-hydroxycholesterol had no effect, 4β-hydroxycholesterol worsened colon inflammation. CONCLUSIONS: Our study addresses the potential involvement of oxysterols in colitis and clearly points towards an active role as well as a clinical relevance for these bioactive lipids

FOLFIRI plus BEvacizumab or aFLIbercept after FOLFOX-bevacizumab Failure for COlorectal Cancer (BEFLICO): An AGEO Multicenter Study.

International audienceAfter failure of first line FOLFOX-bevacizumab for metastatic colorectal cancer (mCRC), adding either bevacizumab or aflibercept to second-line FOLFIRI increases survival compared to FOLFIRI alone. In this French retrospective multicentre cohort, we included patients with a mCRC treated with either FOLFIRI-aflibercept or FOLFIRI-bevacizumab. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS), disease control rate (DCR: CR\,+\,PR\,+\,SD) and safety. We included 681 patients from 36 centers, 326 and 355 in the aflibercept and bevacizumab groups, respectively. Median age was 64.2\,years and 45.2% of patients were men. Most patients had RAS-mutated tumors (80.8%) and synchronous metastases (85.7%). After a median follow up of 31.2~months, median OS was 13.0~months (95% CI: 11.3-14.7) and 10.4~months (95% CI: 8.8-11.4) in the bevacizumab and aflibercept groups, respectively (P\,<\,.0001). Median PFS was 6.0~months (95% CI: 5.4-6.5) and 5.1~months (95% CI: 4.3-5.6) (P\,<\,.0001). After adjustment on age, PS, PFS of first line, primary tumor resection, metastasis location and RAS/BRAF status, bevacizumab was still associated with better OS (HR: 0.71, 95% CI: 0.59-0.86, P~=~.0003). FOLFIRI-bevacizumab combination was associated with longer OS and PFS, and a better tolerability, as compared to FOLFIRI-aflibercept after progression on FOLFOX-bevacizumab

Compositional variations in calciturbidites and calcidebrites in response to sea-level fluctuations (Exuma Sound, Bahamas)

compositional variation of Pleistocene carbonate gravity deposits from the Exuma Sound Basin, Bahamas, was determined. Two types of gravity deposit were present in the cores of ODP Leg 101, Site 632A, i.e., calciturbidites and calcidebrites. In analogy with earlier studies, the compositional variations in the calciturbidites could be linked to different sources on the carbonate margin, i.e., platform interior, platform edge, and platform slope. Calciturbidites deposited during interglacial, sea-level highstands show a dominance of non-skeletal grains, largely derived from the platform interior, while calciturbidites of glacial, sea-level lowstands, show a dominance of skeletal platform-edge to platform-slope-derived grains. Thus, the calciturbidite composition can be used to reconstruct the position of absolute sea level. In addition, the mud content of the calciturbidites increased after Marine Isotope Stage 11. In contrast, the composition of the calcidebrites remained unaltered through time and showed a clear dominance of platform-edge-derived sediments during varying sea-level positions. The Bahamian carbonate platform is located in a tectonically stable passive-margin setting and the gravity-flow deposits were laid down in an environment exclusively controlled by eustatic sea-level fluctuations. This study shows that all types of gravity-induced carbonate deposits, calciturbidites, and calcidebrites, were deposited in response to global eustatic sea-level variations. The sediment composition could be linked directly to sediment input from specific facies realms along the carbonate platform margin. Hence, sediment composition analysis is a strong tool that may be used to discriminate between gravity-induced deposition triggered by eustatic sea-level changes and that related to tectonic events, when analyzing resedimentation processes in sedimentary basins.Geoscience & EngineeringCivil Engineering and Geoscience

A multi-centre investigation towards reaching a consensus on the immunohistochemical detection of ER beta in archival formalin-fixed paraffin embedded human breast tissue

Estrogen receptor (ER) α is a well-established independent prognostic factor in breast cancer whose presence determines the clinical implications of adjuvant endocrine therapy. A second receptor, ERb has been described, and a number of studies have examined its expression in breast tissue. However elucidation of the role played by ERb has been hampered by published immunohistochemical studies employing a variety of protocols and scoring systems such that inter-laboratory comparisons are difficult. Here we present a multi-centre study designed to critically evaluate inter-laboratory differences in methodology. Six UK and Irish centres participated in this study. A small series of breast cancers were stained using centre-specific laboratory protocols and scored using both centrespecific and standard scoring protocols. There was generally poor agreement as to what constituted a positive or negative case when centre-specific scoring systems were used with less than half of all cases in agreement. Concordance was improved when a standard scoring system was used but varied according to threshold for positivity employed and primary antibody. Our results emphasise the need for further studies addressing the role of ERb to be based on a wider consensus on criteria for positivity. Ideally this should be based on calibration against clinical outcome