Progression of Renal Impairment and Chronic Kidney Disease in Chronic Heart Failure:An Analysis From GISSI-HF

AbstractBackgroundData on the natural change in renal function in patients with chronic heart failure (HF) are limited.Methods and ResultsEstimated glomerular filtration rate (eGFR) was assessed over 36 months in 6934 patients included in the GISSI-HF study. Associations from baseline, changes in renal function, and occurrence of cardiovascular death or HF hospitalization were assessed. Mean age was 67 years, mainly men (78%), and mean eGFR was 68 mL • min−1 • 1.73 m−2. Change in eGFR in the 1st year was −1.5 ± 16 mL • min−1 • 1.73 m−2, and over 36 months it was −3.7 ± 18 mL • min−1 • 1.73 m−2. Over the latter period, only 25% deteriorated ≥1 Kidney Disease Outcomes Quality Initiatives (KDOQI) class of chronic kidney disease (CKD). Fifteen percent of patients had >15 mL • min−1 • 1.73 m−2 decrease in eGFR in the 1st 12 months. Lower eGFR was associated with outcome: hazard ratio (HR) 1.10, 95% confidence interval (CI) 1.08–1.10 (P < .001) per 10 mL • min−1 • 1.73 m−2 decrease, as well as every 10 mL • min−1 • 1.73 m−2 decrease over the 1st year (HR 1.10, 95% CI 1.04–1.17; P < .001). A deterioration in eGFR >15 mL • min−1 • 1.73 m−2 in the 1st year showed the highest risk of events (HR 1.22, 95% CI 1.10–1.36; P < .001).ConclusionsMean decrease in renal function over time in patients with chronic HF was modest. Only 25% deteriorated ≥1 KDOQI class of CKD after 3 years. Any decrease in eGFR over time was associated with strongly increased event rates

Intrathecal tigecycline is a safe and effective treatment for central nervous system infections

Both the safety and effectiveness of intrathecal tigecycline (TGC) for treatment of infections of the central nervous system (CNS) are discussed using the clinical findings from a study of a recent patient who came to our attention, along with a literature review. Although penetration into the CNS is low (approximately 11%), intraventricular TGC could help treat patients with severe post-neurosurgical CNS infections. The use of multiple routes of TGC administration appears to be encouraging and should be considered in managing life-threatening intraventricular infections

Candida guilliermondii Peritonitis During Peritoneal Dialysis. Case Report and Literature Review

Peritonitis is the most frequent complication of peritoneal dialysis (PD) and 3–6% of episodes have fungal origin. Candida guilliermondii is an uncommon species of Candida with invasive behavior in patients affected by severe underlying disorders or using indwelling vascular devices. Here we report the case of an 84-year-old woman undergoing outpatient PD for 4 years who had fever, chills, and diffuse increasing abdominal pain. After empiric antimicrobial therapy, based on teicoplanin in the dialytic circuit plus oral ciprofloxacin plus fluconazole, the patient was hospitalized. Afterwards, the culture from the peritoneal fluid showed the presence of C. guilliermondii. PD-related fungal peritonitis is an infrequent event, but the morbidity and mortality rates are significant. In this scenario, appropriate prevention strategies including antifungal prophylaxis during antibiotic treated bacterial peritonitis should be evaluated

Maqui and Omega 3: effects on lipid profile, oxidative stress levels and psycho-physical items in human subjects

Aims: to assess short-term efficacy of supplementation with Maqui (Aristotelia Chilensis (Mol.Stuntz)), a polyphenol with antioxidant power, and EPA/DHA concerning metabolism, oxidative stress and mental/physical state. Patients and Methods: a pilot prospective observational clinical/laboratory study was performed on 17 apparently healthy subjects (8 males and 9 females, mean age 47 years). All subjects received for two months: a) Maqui 600 mg per day and b) 360 mg of EPA and 240 mg of DHA (salmon oil) daily. At day 0 and day 60 all subjects underwent nine laboratory tests related to inflammation, metabolism (lipid profile mainly) and oxidative stress parameters. Pre-post treatment weight and BMI was calculated. A few physical and mental parameters were assessed by means of Short-Form 12 questionnaire. Statistical analysis was applied to the resulting data through Wilcoxon test and t-paired test. Results: laboratory results before and after Maqui + EPA/DHA supplementation were respectively (mean and p-value for the comparison): total cholesterol 228.8/199.8 mg/dl, p=0.23; low density lipoproteins 127.4/122.1 mg/dl, p=0.13; high density lipoproteins 59.1/57.6 mg/dl, p=0.25; Reactive C Protein 0.18/0.09 mg/dl, p=0.32; triglycerides 106.1/91.1 mg/dl p=0.09, glycemia 92.9/92.8 mg/dl p= 0.92; total free radicals 338.0/303.6 U.Carr., p=0.002; serum anti-oxidant capacity 2075/2190 umol/l, p= 0.04; oxidized lipoproteins 641.8/553.1 uEq/l, p=0.10. SF12 physical and mental items (mean values and SD) were 51.2 (+/- 6.2) and 41.2 (+/- 3,3) at day 0 and 54.6 (+/- 11.6) and 47.2 (+/- 9.7) at day 60 respectively. One case of transient constipation was recorded. Conclusions: daily supplementation with Maqui 600 mg + Omega 3 fatty acids (EPA 360 mg + DHA 240 mg) in apparently healthy middle-aged subjects resulted in a statistically significant improvement of oxidative stress parameters. An overall (non statistically significant) improvement of dysmetabolism biomarkers was achieved. Mental and physical parameters have mildly improved

PIK3CA Mutation in the ShortHER Randomized Adjuvant Trial for Patients with Early HER2\ufe Breast Cancer: Association with Prognosis and Integration with PAM50 Subtype.

Purpose: We explored the prognostic effect of PIK3CA mutation in HER2\ufe patients enrolled in the ShortHER trial. Patients and Methods: The ShortHER trial randomized 1,253 patients with HER2\ufe breast cancer to 9 weeks or 1 year of adjuvant trastuzumab combined with chemotherapy. PIK3CA hotspot mutations in exon 9 and 20 were analyzed by pyrosequencing. Expression of 60 genes, including PAM50 genes was measured using the nCounter platform. Results: A mutation of the PIK3CA gene was detected in 21.7% of the 803 genotyped tumors. At a median follow-up of 7.7 years, 5-year disease-free survival (DFS) rates were 90.6% for PIK3CA mutated and 86.2% for PIK3CA wild-type tumors [HR, 0.84; 95% confidence interval (CI), 0.56\u20131.27; P \ubc 0.417]. PIK3CA mutation showed a favorable prognostic impact in the PAM50 HER2-enriched subtype (n \ubc 232): 5-year DFS 91.8% versus 76.1% (log-rank P \ubc 0.049; HR, 0.46; 95% CI, 0.21\u20131.02). HER2-enriched/PIK3CA mutated versus wild-type tumors showed numerically higher tumor-infiltrating lymphocytes (TIL) and significant upregulation of immune-related genes (including CD8A, CD274, PDCD1, and MYBL2, a proliferation gene involved in immune processes). High TILs as well as the upregulation of PDCD1 and MYBL2 were associated with a significant DFS improvement within the HER2-enriched subtype (HR, 0.82; 95% CI, 0.68\u20130.99; P \ubc 0.039 for 10% TILs increment; HR, 0.81; 95% CI, 0.65\u20130.99; P \ubc 0.049 for PDCD1 expression; HR, 0.72; 95% CI, 0.53\u20130.99; P \ubc 0.042 for MYBL2 expression). Conclusions: PIK3CA mutation showed no prognostic impact in the ShortHER trial. Within the HER2-enriched molecular subtype, patients with PIK3CA mutated tumors showed better DFS versus PIK3CA wild-type, which may be partly explained by upregulation of immune-related genes

Ceftolozane/Tazobactam for Treatment of Severe ESBL-Producing Enterobacterales Infections: A Multicenter Nationwide Clinical Experience (CEFTABUSE II Study)

Background. Few data are reported in the literature about the outcome of patients with severe extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E) infections treated with ceftolozane/tazobactam (C/T), in empiric or definitive therapy.Methods. A multicenter retrospective study was performed in Italy (June 2016-June 2019). Successful clinical outcome was defined as complete resolution of clinical signs/symptoms related to ESBL-E infection and lack of microbiological evidence of infection. The primary end point was to identify predictors of clinical failure of C/T therapy.Results. C/T treatment was documented in 153 patients: pneumonia was the most common diagnosis (n = 46, 30%), followed by 34 cases of complicated urinary tract infections (22.2%). Septic shock was observed in 42 (27.5%) patients. C/T was used as empiric therapy in 46 (30%) patients and as monotherapy in 127 (83%) patients. Favorable clinical outcome was observed in 128 (83.7%) patients; 25 patients were considered to have failed C/T therapy. Overall, 30-day mortality was reported for 15 (9.8%) patients. At multivariate analysis, Charlson comorbidity index &gt;4 (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.9-3.5; P = .02), septic shock (OR, 6.2; 95% CI, 3.8-7.9; P &lt; .001), and continuous renal replacement therapy (OR, 3.1; 95% CI, 1.9-5.3; P = .001) were independently associated with clinical failure, whereas empiric therapy displaying in vitro activity (OR, 0.12; 95% CI, 0.01-0.34; P &lt; .001) and adequate source control of infection (OR, 0.42; 95% CI, 0.14-0.55; P &lt; .001) were associated with clinical success.Conclusions. Data show that C/T could be a valid option in empiric and/or targeted therapy in patients with severe infections caused by ESBL-producing Enterobacterales. Clinicians should be aware of the risk of clinical failure with standard-dose C/T therapy in septic patients receiving CRRT

Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990–2021:a systematic analysis for the Global Burden of Disease Study 2021

BackgroundUnderstanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021.MethodsThe GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk–outcome pairs. Pairs were included on the basis of data-driven determination of a risk–outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk–outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk–outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws.FindingsAmong the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7–9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4–9·2]), smoking (5·7% [4·7–6·8]), low birthweight and short gestation (5·6% [4·8–6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8–6·0]). For younger demographics (ie, those aged 0–4 years and 5–14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9–27·7]) and environmental and occupational risks (decrease of 22·0% [15·5–28·8]), coupled with a 49·4% (42·3–56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9–21·7] for high BMI and 7·9% [3·3–12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6–1·9) for high BMI and 1·3% (1·1–1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4–78·8) for child growth failure and 66·3% (60·2–72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP).InterpretationSubstantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions.FundingBill &amp; Melinda Gates Foundation.<br/

Checklist of the dipterofauna (Insecta) from Roraima, Brazil, with special reference to the Brazilian Ecological Station of Maracá

Roraima is a Brazilian state located in the northern portion of the Amazon basin, with few studies regarding its biodiversity. The Ecological Station of Maracá (Brazil, state of Roraima) harbors the third largest Brazilian pluvial island and is composed of a transitional landscape of savanna and Amazon rainforest components. Despite its ecological importance and strategic localization, few studies covered the dipterofauna of this locality. An updated checklist addressing 41 families of true flies (Diptera) occurring in Roraima is presented based on the literature and the specimens collected during a field expedition that occurred in 2015. This checklist brings several improvements such as new records of 165 taxa to the state of Roraima, 29 taxa to Brazil, and 259 morphotypes, mostly likely representing undescribed species

Gain- and Loss-of-Function CFTR Alleles Are Associated with COVID-19 Clinical Outcomes

Carriers of single pathogenic variants of the CFTR (cystic fibrosis transmembrane conductance regulator) gene have a higher risk of severe COVID-19 and 14-day death. The machine learning post-Mendelian model pinpointed CFTR as a bidirectional modulator of COVID-19 outcomes. Here, we demonstrate that the rare complex allele [G576V;R668C] is associated with a milder disease via a gain-of-function mechanism. Conversely, CFTR ultra-rare alleles with reduced function are associated with disease severity either alone (dominant disorder) or with another hypomorphic allele in the second chromosome (recessive disorder) with a global residual CFTR activity between 50 to 91%. Furthermore, we characterized novel CFTR complex alleles, including [A238V;F508del], [R74W;D1270N;V201M], [I1027T;F508del], [I506V;D1168G], and simple alleles, including R347C, F1052V, Y625N, I328V, K68E, A309D, A252T, G542*, V562I, R1066H, I506V, I807M, which lead to a reduced CFTR function and thus, to more severe COVID-19. In conclusion, CFTR genetic analysis is an important tool in identifying patients at risk of severe COVID-19

The European Reference Genome Atlas: piloting a decentralised approach to equitable biodiversity genomics.

ABSTRACT: A global genome database of all of Earth’s species diversity could be a treasure trove of scientific discoveries. However, regardless of the major advances in genome sequencing technologies, only a tiny fraction of species have genomic information available. To contribute to a more complete planetary genomic database, scientists and institutions across the world have united under the Earth BioGenome Project (EBP), which plans to sequence and assemble high-quality reference genomes for all ∼1.5 million recognized eukaryotic species through a stepwise phased approach. As the initiative transitions into Phase II, where 150,000 species are to be sequenced in just four years, worldwide participation in the project will be fundamental to success. As the European node of the EBP, the European Reference Genome Atlas (ERGA) seeks to implement a new decentralised, accessible, equitable and inclusive model for producing high-quality reference genomes, which will inform EBP as it scales. To embark on this mission, ERGA launched a Pilot Project to establish a network across Europe to develop and test the first infrastructure of its kind for the coordinated and distributed reference genome production on 98 European eukaryotic species from sample providers across 33 European countries. Here we outline the process and challenges faced during the development of a pilot infrastructure for the production of reference genome resources, and explore the effectiveness of this approach in terms of high-quality reference genome production, considering also equity and inclusion. The outcomes and lessons learned during this pilot provide a solid foundation for ERGA while offering key learnings to other transnational and national genomic resource projects.info:eu-repo/semantics/publishedVersio