The risk of cancer in statin users : a clinical and genetic approach

Les statines, inhibiteurs de la 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) réductase sont efficaces et largement utilisées dans le traitement des troubles lipidiques, surtout pour l’hypercholestérolémie. Dans plusieurs essais contrôlés randomisés, les statines réduisent significativement le risque d’événements cardiovasculaires tant en termes de morbidité que de mortalité. Une littérature importante s’est développée démontrant une association entre la statine et le cancer, toute type confondue, dans la dernière décennie, sans consensus sur la question de savoir si cette relation existe vraiment. De plus, il n’est pas clair que si cette relation existe réellement, si elle est positive ou négative. Dû au manque de consensus sur ce sujet, nous avons cherché à étudier l’effet de la statine à forte dose contre faible dose sur l’incidence du cancer et la mortalité par cancer d’un point de vue clinique et génétique. Du point de vue clinique, nous avons utilisé les cohortes TNT et IDEAL, qui visaient à l’origine à examiner l’effet de la statine à forte dose par rapport à la statine à faible dose sur le risque de maladie cardiovasculaire pour la prévention secondaire après un infarctus du myocarde dans un contexte randomisé pour effectuer une analyse post-hoc afin de comparer le risque de cancer ou de décès par cancer entre les utilisateurs de statines à haute et à faible dose. Par la suite, des sous-analyses supplémentaires ont été réalisées en se concentrant exclusivement chez les personnes âgées de 55 ans et plus, les hommes et les femmes. Du point de vue génétique, nous avons réalisé une étude d’association à l’échelle du génome (GWAS) en reliant les données génétiques de la cohorte TNT avec l’incidence du cancer. Notre étude n’a pas trouvé d’association significative entre la statine à dose plus élevée et le cancer dans l’évaluation clinique. De plus, les résultats du GWAS n’étaient pas en mesure d’identifier une variante génétique fiable associée aux paramètres testés, dont l’incidence de cancer ou la mortalité par cancer. Nous concluons que l’utilisation de la statine à plus haute dose n’était pas associée avec un risque de cancer, ou de mortalité par cancer plus ou moins élevé.Statins, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, are efficient and widely used drugs in the treatment of lipid disorders, especially hypercholesterolemia. In several large randomized-controlled trials, statins significantly reduced the risk of cardiovascular events both in terms of morbidity and mortality. Nonetheless, a significant body of literature affirming the association between statin use and cancer has continued to progress in the last decade, with no consensus on whether this relationship truly exists, and if it does, whether it’s a positive or negative relationship. Based on the lack of consensus, we sought to investigate the effect of high-dose vs. low-dose statin on incident cancer and cancer mortality from a clinical and genetic perspective. From the clinical perspective, we relied on data obtained from the TNT and IDEAL cohorts, two randomized-controlled studies that were originally intended to examine the effect of high-dose statin vs. low or usual-dose statin on the risk of cardiovascular disease for secondary prevention after myocardial infarction. We performed post-hoc analysis and evaluated the risk of cancer or cancer mortality between high and low-dose statin users. Additional sub-analyses were performed focusing exclusively on those aged ≥55 years old, men, and women. From the genetic perspective, we performed a genome-wide association study (GWAS) using the TNT cohort with available genetic data on cancer incidence. Overall, our study failed to find any significant association between higher dose statin and cancer incidence or cancer mortality using clinical data. Furthermore, findings from the GWAS were not able to identify a reliable genetic variant associated with the tested endpoints. We conclude that the use of higher dose statins was not associated with a higher or lower risk of cancer diagnosis or cancer mortality

Disparities in selective referral for cancer surgeries: implications for the current healthcare delivery system

Objectives: Among considerable efforts to improve quality of surgical care, expedited measures such as a selective referral to high-volume institutions have been advocated. Our objective was to examine whether racial, insurance and/or socioeconomic disparities exist in the use of high-volume hospitals for complex surgical oncological procedures within the USA. Design, setting and participants Patients undergoing colectomy, cystectomy, oesophagectomy, gastrectomy, hysterectomy, lung resection, pancreatectomy or prostatectomy were identified retrospectively, using the Nationwide Inpatient Sample, between years 1999 and 2009. This resulted in a weighted estimate of 2 508 916 patients. Primary outcome measures Distribution of patients according to race, insurance and income characteristics was examined according to low-volume and high-volume hospitals (highest 20% of patients according to the procedure-specific mean annual volume). Generalised linear regression models for prediction of access to high-volume hospitals were performed. Results: Insurance providers and county income levels varied differently according to patients’ race. Most Caucasians resided in wealthier counties, regardless of insurance types (private/Medicare), while most African Americans resided in less wealthy counties (≤$24 999), despite being privately insured. In general, Caucasians, privately insured, and those residing in wealthier counties (≥$45 000) were more likely to receive surgery at high-volume hospitals, even after adjustment for all other patient-specific characteristics. Depending on the procedure, some disparities were more prominent, but the overall trend suggests a collinear effect for race, insurance type and county income levels. Conclusions: Prevailing disparities exist according to several patient and sociodemographic characteristics for utilisation of high-volume hospitals. Efforts should be made to directly reduce such disparities and ensure equal healthcare delivery

Synthesis of microcapsules for carbon capture via needle-based droplet microfluidics

“Off-the-shelf” devices have attracted much consideration lately, especially in emulsions production in droplet-based microfluidics. While many simple and cost-effective designs have been proposed and demonstrated, the functionability of these purported simple devices has been questioned, especially in emulsions generation for commercial scale. In this work, a simple needle-based device was used in the production of functional core-shell microcapsules of uniform sizes, typically in the range of 600 to 720 µm, and shell thickness of 20 to 110 µm, and C.V of 0.97 to 3.0%. These core-shell microcapsules are a new form of carbon capture materials, with carbon solvent encapsulated in thin polymeric shell. The microcapsules synthesized were subjected to absorption-desorption tests. This work has successfully demonstrated the use of off-the-shelf microdevice and its reliability for the production of functional microcapsules

National trends in hospital-acquired preventable adverse events after major cancer surgery in the USA

Objectives: While multiple studies have demonstrated variations in the quality of cancer care in the USA, payers are increasingly assessing structure-level and process-level measures to promote quality improvement. Hospital-acquired adverse events are one such measure and we examine their national trends after major cancer surgery. Design: Retrospective, cross-sectional analysis of a weighted-national estimate from the Nationwide Inpatient Sample (NIS) undergoing major oncological procedures (colectomy, cystectomy, oesophagectomy, gastrectomy, hysterectomy, lung resection, pancreatectomy and prostatectomy). The Agency for Healthcare Research and Quality Patient Safety Indicators (PSIs) were utilised to identify trends in hospital-acquired adverse events. Setting: Secondary and tertiary care, US hospitals in NIS Participants: A weighted-national estimate of 2 508 917 patients (>18 years, 1999–2009) from NIS. Primary outcome measures Hospital-acquired adverse events. Results: 324 852 patients experienced ≥1-PSI event (12.9%). Patients with ≥1-PSI experienced higher rates of in-hospital mortality (OR 19.38, 95% CI 18.44 to 20.37), prolonged length of stay (OR 4.43, 95% CI 4.31 to 4.54) and excessive hospital-charges (OR 5.21, 95% CI 5.10 to 5.32). Patients treated at lower volume hospitals experienced both higher PSI events and failure-to-rescue rates. While a steady increase in the frequency of PSI events after major cancer surgery has occurred over the last 10 years (estimated annual % change (EAPC): 3.5%, p<0.001), a concomitant decrease in failure-to-rescue rates (EAPC −3.01%) and overall mortality (EAPC −2.30%) was noted (all p<0.001). Conclusions: Over the past decade, there has been a substantial increase in the national frequency of potentially avoidable adverse events after major cancer surgery, with a detrimental effect on numerous outcome-level measures. However, there was a concomitant reduction in failure-to-rescue rates and overall mortality rates. Policy changes to improve the increasing burden of specific adverse events, such as postoperative sepsis, pressure ulcers and respiratory failure, are required

Morbidity and Mortality After Benign Prostatic Hyperplasia Surgery: Data from the American College of Surgeons National Surgical Quality Improvement Program

Background and Purpose: With the aging population, it is becoming increasingly important to identify patients at risk for postsurgical complications who might be more suited for conservative treatment. We sought to identify predictors of morbidity after surgical treatment of benign prostatic hyperplasia (BPH) using a large national contemporary population-based cohort. Methods: Relying on the American College of Surgeons National Surgical-Quality Improvement Program (ACS-NSQIP; 2006?2011) database, we evaluated outcomes after transurethral resection of the prostate (TURP), laser vaporization of the prostate (LVP), and laser enucleation of the prostate (LEP). Outcomes included blood-transfusion rates, length of stay, complications, reintervention rates, and perioperative mortality. Multivariable logistic-regression analysis evaluated the predictors of perioperative morbidity and mortality. Results: Overall, 4794 (65.2%), 2439 (33.1%), and 126 (1.7%) patients underwent TURP, LVP, and LEP, respectively. No significant difference in overall complications (P=0.3) or perioperative mortality (P=0.5) between the three surgical groups was found. LVP was found to be associated with decreased blood transfusions (odds ratio [OR]=0.21; P=0.001), length of stay (OR=0.12; P30%) levels were the only predictors of lower overall complications and perioperative mortality. Conclusions: All three surgical modalities for BPH management were found to be safe. Advanced age and non-Caucasian race were independent predictors of adverse outcomes after BPH surgery. In patients with these attributes, conservative treatment might be a reasonable alternative. Also, preoperative hematocrit and albumin levels represent reliable predictors of adverse outcomes, suggesting that these markers should be evaluated before BPH surgery.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140378/1/end.2013.0805.pd

peri operative mortality and long term survival after partial versus radical cystectomy for muscle invasive bladder cancer

Objective: The aim of the study was to compare partial cystectomy (PC) and radical cystectomy (RC) with respect to 90-day mortality as well as long-term, all cause (ACM) and cancer specific mortality (CSM). Methods: Using the SEER-Medicare database 3913 patients with T2-T3 urothelial carcinoma of the urinary bladder (UCUB) who underwent either RC (n = 3419) or PC (n = 494) were identified. After propensity score matching to reduce potential treatment selection bias, 90-day mortality, ACM-free and CSM-free rates between patients treated with PC and RC were estimated. Multivariable regression models (MVA) addressed 90-day mortality as well as 5-years ACM and CSM. Results: After matching, 33% (n = 494) and 67% (n = 988) patients treated respectively with PC or RC remained. Median follow-up was 26 months. The 90-day mortality rate was 3.2% (n = 16) after PC and 8.1% (n = 80) after RC (P = 0.001). In MVA, PC vs. RC was associated with a lower 90-day mortality (P < 0.001). At 5 years the ACM-free survival rate was 38% after PC and 40% after RC (P = 0.3) and failed to differ in MVA (P = 0.9). At 5 years the CSM-free survival rate was 59% after PC and 62% after RC (P = 0.2) and also failed to differ in MVA (P = 0.57). The same results were observed after restriction to patients with pT2N0 UCUB. Conclusions: Relative to RC, PC is associated with lower short-term mortality and the same long-term ACM and CSM rates. These observations should encourage greater consideration to PC in those selected cases when this type of surgery may be applied

Antibody-mediated inhibition of the FGFR1c isoform induces a catabolic lean state in Siberian hamsters

Hypothalamic tanycytes are considered to function as sensors of peripheral metabolism [1]. To facilitate this role, they express a wide range of receptors, including fibroblast growth factor receptor 1 (FGFR1). Using a monoclonal antibody (IMC-H7) that selectively antagonizes the FGFR1c isoform [2], we investigated possible actions of FGFR1c in a natural animal model of adiposity, the Siberian hamster. Infusion of IMC-H7 into the third ventricle suppressed appetite and increased energy expenditure. Likewise, peripheral treatment with IMC-H7 decreased appetite and body weight and increased energy expenditure and fat oxidation. A greater reduction in body weight and caloric intake was observed in response to IMC-H7 during the long-day fat state as compared to the short-day lean state. This enhanced response to IMC-H7 was also observed in calorically restricted hamsters maintained in long days, suggesting that it is the central photoperiodic state rather than the peripheral adiposity that determines the response to FGFR1c antagonism. Hypothalamic thyroid hormone availability is controlled by deiodinase enzymes (DIO2 and DIO3) expressed in tanycytes and is the key regulator of seasonal cycles of energy balance [3 and 4]. Therefore, we determined the effect of IMC-H7 on hypothalamic expression of these deiodinase enzymes. The reductions in food intake and body weight were always associated with decreased expression of DIO2 in the hypothalamic ependymal cell layer containing tanycytes. These data provide further support for the notion the tanycytes are an important component of the mechanism by which the hypothalamus integrates central and peripheral signals to regulate energy intake and expenditure

Pharmacogenomics of the efficacy and safety of Colchicine in COLCOT

© 2021 The Authors. Circulation: Genomic and Precision Medicine is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited and is not used for commercial purposes.Background: The randomized, placebo-controlled COLCOT (Colchicine Cardiovascular Outcomes Trial) has shown the benefits of colchicine 0.5 mg daily to lower the rate of ischemic cardiovascular events in patients with a recent myocardial infarction. Here, we conducted a post hoc pharmacogenomic study of COLCOT with the aim to identify genetic predictors of the efficacy and safety of treatment with colchicine. Methods: There were 1522 participants of European ancestry from the COLCOT trial available for the pharmacogenomic study of COLCOT trial. The pharmacogenomic study's primary cardiovascular end point was defined as for the main trial, as time to first occurrence of cardiovascular death, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina requiring coronary revascularization. The safety end point was time to the first report of gastrointestinal events. Patients' DNA was genotyped using the Illumina Global Screening array followed by imputation. We performed a genome-wide association study in colchicine-treated patients. Results: None of the genetic variants passed the genome-wide association study significance threshold for the primary cardiovascular end point conducted in 702 patients in the colchicine arm who were compliant to medication. The genome-wide association study for gastrointestinal events was conducted in all 767 patients in the colchicine arm and found 2 significant association signals, one with lead variant rs6916345 (hazard ratio, 1.89 [95% CI, 1.52-2.35], P=7.41×10-9) in a locus which colocalizes with Crohn disease, and one with lead variant rs74795203 (hazard ratio, 2.51 [95% CI, 1.82-3.47]; P=2.70×10-8), an intronic variant in gene SEPHS1. The interaction terms between the genetic variants and treatment with colchicine versus placebo were significant. Conclusions: We found 2 genomic regions associated with gastrointestinal events in patients treated with colchicine. Those findings will benefit from replication to confirm that some patients may have genetic predispositions to lower tolerability of treatment with colchicine.info:eu-repo/semantics/publishedVersio

The Confidence Database

Understanding how people rate their confidence is critical for the characterization of a wide range of perceptual, memory, motor and cognitive processes. To enable the continued exploration of these processes, we created a large database of confidence studies spanning a broad set of paradigms, participant populations and fields of study. The data from each study are structured in a common, easy-to-use format that can be easily imported and analysed using multiple software packages. Each dataset is accompanied by an explanation regarding the nature of the collected data. At the time of publication, the Confidence Database (which is available at https://osf.io/s46pr/) contained 145 datasets with data from more than 8,700 participants and almost 4 million trials. The database will remain open for new submissions indefinitely and is expected to continue to grow. Here we show the usefulness of this large collection of datasets in four different analyses that provide precise estimations of several foundational confidence-related effects

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049