Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

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

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

Contains fulltext : 172380.pdf (publisher's version ) (Open Access

Biological and functional responses of in situ bioassays with Chironomus riparius larvae to assess river water quality and contamination

Single species responses have the potential to measure impacts at earlier stages than more traditional methods based in community structure. This study evaluates a bioassay with biological (survival, development, growth) and functional (post-exposure feeding rate) responses of Chironomus riparius larvae to assess water quality and contamination in rivers. The bioassay with C riparius third instar larvae was performed, in autumn and spring, in reference sites and in organic and metal contaminated sites in Portuguese rivers. Biotic, physical and chemical parameters were determined for each site. The relationship between both bioassays responses and biotic indices (IBMWP and IASPT) and the physical and chemical parameters of respective sites were determined. In general biotic indices were able to discriminate between contaminated and not contaminated sites although they demonstrated a poor ability to detect low level of metal contamination during autumn. IASPT was negatively related to ammonia concentrations in both seasons. No significant differences in survival and post-exposure feeding rate were found between sites. Development was inhibited in the most metal contaminated site during autumn, but pH and ammonia concentrations in water accounted for 82% of developmental variation during this season. Growth was highly inhibited in the most metal contaminated site during both seasons. In autumn, growth was also inhibited in the low metal contaminated site and, during this season, pH and Mn and Fe concentrations in water samples accounted for 97% of growth variation between sites. The results suggest that in situ bioassay with C riparius larvae using growth as the endpoint is a responsive and suitable tool that can be used as bioindicator of metal pollution and to biomonitor water quality in metal contaminated rivers. (c) 2006 Elsevier B.V. All rights reserved.FCT - SFRH/BD/2935/2000EC/TARGET project - EVK1- 1999-0000

Evolution and bad prognostic value of advanced glycation end products after acute heart failure: relation with body composition

Abstract Aim The role of advanced glycation end products (AGEs) and their soluble receptor (sRAGE) on the progression and prognosis of acute heart failure (HF) was analysed in relation with metabolic parameters as body composition and nutritional status. Methods A hundred and fifty consecutive patients were included in a prospective clinical study during hospitalization by acute HF. Detailed medical history, physical examination, electrocardiogram, echocardiogram and vein peripheral blood were taken for all patients. During the follow-up period [297 days (88–422 days)] blood samples for biochemical measurements were obtained 1 and 6 months after the inclusion. Dual-energy X-ray absorptiometry analyses were performed 1 week after discharge. Results AGEs and sRAGE levels continuously increased, up to 6 months, after acute HF, but AGEs increase was mainly observed in those patients with incident HF. Both AGEs and sRAGE levels were related with bad renal function and clinical malnutrition (CONUT score) and they were negatively related with body mass index or percentage of body fat. AGEs levels (≥40 a.u.) 1 month after discharge and basal sRAGE levels (>1000 pg/mL) were related with worse prognosis in terms of patient death and HF readmission (Log-rank <0.05 in Kaplan–Meier survival test), independently of age, gender, body mass index and other risk factors. Regression models also corroborated this finding. Conclusions AGEs and sRAGE are bad prognostic biomarkers for HF and useful markers of HF progression. Since their levels seem to be related with clinical malnutrition and body composition these parameters could serve to modulate them

Effects of Two Insecticides on Survival, Growth and Emergence of Chironomus riparius Meigen

Effects of chlorpyrifos and cypermethrin on the survival, growth and emergence of Chironomus riparius were determined on a life-cycle study. Although neither cypermethrin nor chlorpyrifos affected larval survival or growth, a decrease in the number of emerged midges and in the number of females over males, as well as in female biomass, were found for both insecticides. The results from this study indicate that multiple biological endpoints and extended periods of exposure are needed in order to achieve a better screening of insecticide toxicity.FCT - SFRH/BM/8402/2002FCT - PTDC/BIABDE/72841/200

Woody medicinal plants of the caatinga in the state of Pernambuco (Northeast Brazil)

Floristic and phytosociological studies undertaken in six areas of the state of Pernambuco were selected with the aim of analyzing the Relative Importance of the woody medicinal plant species of Pernambuco's caatinga from an ethnobotanical perspective. For the data analysis, only those identified up to the species level were selected and information on medicinal properties was obtained for each one from the literature. The Relative Importance was calculated for each species. From the 57 woody species, 22 had therapeutic indications; from these, Anacardium occidentale L., Tabebuia impetiginosa (Mart. ex DC) Standley, Schinopsis brasiliensis Engl., and Myracrodruon urundeuva (Engl.) Fr. All. had the greatest values of Relative Importance. The correlation analysis made clear that the Relative Importance of the species is negatively correlated with the Density and Relative Frequency (p<0.05). The most important species, in the ethnobotanical point view, are the most vulnerable, possible due to the systematic exploration they have been suffering. Schinopsis brasiliensis and Myracrodruon urundeuva are listed as endangered species and deserve special attention in the development of techniques of sustainable management, where both economic return and species conservation must be guaranteed. In depth studies that take into consideration each region's characteristics are necessary both from a floristic perspective and considering medicinal aspects, since each area seems to have its own woody medicinal flora, as suggested in the cluster analysis

Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies

Loss of nuclear TDP-43 is a hallmark of neurodegeneration in TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 mislocalization results in cryptic splicing and polyadenylation of pre–messenger RNAs (pre-mRNAs) encoding stathmin-2 (also known as SCG10), a protein that is required for axonal regeneration. We found that TDP-43 binding to a GU-rich region sterically blocked recognition of the cryptic 3′ splice site in STMN2 pre-mRNA. Targeting dCasRx or antisense oligonucleotides (ASOs) suppressed cryptic splicing, which restored axonal regeneration and stathmin-2–dependent lysosome trafficking in TDP-43–deficient human motor neurons. In mice that were gene-edited to contain human STMN2 cryptic splice-polyadenylation sequences, ASO injection into cerebral spinal fluid successfully corrected Stmn2 pre-mRNA misprocessing and restored stathmin-2 expression levels independently of TDP-43 binding