Systematic Analysis of Cell Cycle Effects of Common Drugs Leads to the Discovery of a Suppressive Interaction between Gemfibrozil and Fluoxetine

Screening chemical libraries to identify compounds that affect overall cell proliferation is common. However, in most cases, it is not known whether the compounds tested alter the timing of particular cell cycle transitions. Here, we evaluated an FDA-approved drug library to identify pharmaceuticals that alter cell cycle progression in yeast, using DNA content measurements by flow cytometry. This approach revealed strong cell cycle effects of several commonly used pharmaceuticals. We show that the antilipemic gemfibrozil delays initiation of DNA replication, while cells treated with the antidepressant fluoxetine severely delay progression through mitosis. Based on their effects on cell cycle progression, we also examined cell proliferation in the presence of both compounds. We discovered a strong suppressive interaction between gemfibrozil and fluoxetine. Combinations of interest among diverse pharmaceuticals are difficult to identify, due to the daunting number of possible combinations that must be evaluated. The novel interaction between gemfibrozil and fluoxetine suggests that identifying and combining drugs that show cell cycle effects might streamline identification of drug combinations with a pronounced impact on cell proliferation

Counseling patients about sexual health when considering post-prostatectomy radiation treatment

Prostate cancer is the second most frequently diagnosed cancer in men in the United States. Many men with clinically localized prostate cancer survive for 15 years or more. Although early detection and successful definitive treatments are increasingly common, a debate regarding how aggressively to treat prostate cancer is ongoing because of the effect of aggressive treatment on the quality of life, including sexual functioning. We examined current research on the effect of post-prostatectomy radiation treatment on sexual functioning, and suggest a way in which patient desired outcomes might be taken into consideration while making decisions with regard to the timing of radiation therapy after prostatectomy

Spontaneous Breathing in Early Acute Respiratory Distress Syndrome: Insights From the Large Observational Study to UNderstand the Global Impact of Severe Acute Respiratory FailurE Study

OBJECTIVES: To describe the characteristics and outcomes of patients with acute respiratory distress syndrome with or without spontaneous breathing and to investigate whether the effects of spontaneous breathing on outcome depend on acute respiratory distress syndrome severity. DESIGN: Planned secondary analysis of a prospective, observational, multicentre cohort study. SETTING: International sample of 459 ICUs from 50 countries. PATIENTS: Patients with acute respiratory distress syndrome and at least 2 days of invasive mechanical ventilation and available data for the mode of mechanical ventilation and respiratory rate for the 2 first days. INTERVENTIONS: Analysis of patients with and without spontaneous breathing, defined by the mode of mechanical ventilation and by actual respiratory rate compared with set respiratory rate during the first 48 hours of mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Spontaneous breathing was present in 67% of patients with mild acute respiratory distress syndrome, 58% of patients with moderate acute respiratory distress syndrome, and 46% of patients with severe acute respiratory distress syndrome. Patients with spontaneous breathing were older and had lower acute respiratory distress syndrome severity, Sequential Organ Failure Assessment scores, ICU and hospital mortality, and were less likely to be diagnosed with acute respiratory distress syndrome by clinicians. In adjusted analysis, spontaneous breathing during the first 2 days was not associated with an effect on ICU or hospital mortality (33% vs 37%; odds ratio, 1.18 [0.92-1.51]; p = 0.19 and 37% vs 41%; odds ratio, 1.18 [0.93-1.50]; p = 0.196, respectively ). Spontaneous breathing was associated with increased ventilator-free days (13 [0-22] vs 8 [0-20]; p = 0.014) and shorter duration of ICU stay (11 [6-20] vs 12 [7-22]; p = 0.04). CONCLUSIONS: Spontaneous breathing is common in patients with acute respiratory distress syndrome during the first 48 hours of mechanical ventilation. Spontaneous breathing is not associated with worse outcomes and may hasten liberation from the ventilator and from ICU. Although these results support the use of spontaneous breathing in patients with acute respiratory distress syndrome independent of acute respiratory distress syndrome severity, the use of controlled ventilation indicates a bias toward use in patients with higher disease severity. In addition, because the lack of reliable data on inspiratory effort in our study, prospective studies incorporating the magnitude of inspiratory effort and adjusting for all potential severity confounders are required

Identifying associations between diabetes and acute respiratory distress syndrome in patients with acute hypoxemic respiratory failure: an analysis of the LUNG SAFE database

Background: Diabetes mellitus is a common co-existing disease in the critically ill. Diabetes mellitus may reduce the risk of acute respiratory distress syndrome (ARDS), but data from previous studies are conflicting. The objective of this study was to evaluate associations between pre-existing diabetes mellitus and ARDS in critically ill patients with acute hypoxemic respiratory failure (AHRF). Methods: An ancillary analysis of a global, multi-centre prospective observational study (LUNG SAFE) was undertaken. LUNG SAFE evaluated all patients admitted to an intensive care unit (ICU) over a 4-week period, that required mechanical ventilation and met AHRF criteria. Patients who had their AHRF fully explained by cardiac failure were excluded. Important clinical characteristics were included in a stepwise selection approach (forward and backward selection combined with a significance level of 0.05) to identify a set of independent variables associated with having ARDS at any time, developing ARDS (defined as ARDS occurring after day 2 from meeting AHRF criteria) and with hospital mortality. Furthermore, propensity score analysis was undertaken to account for the differences in baseline characteristics between patients with and without diabetes mellitus, and the association between diabetes mellitus and outcomes of interest was assessed on matched samples. Results: Of the 4107 patients with AHRF included in this study, 3022 (73.6%) patients fulfilled ARDS criteria at admission or developed ARDS during their ICU stay. Diabetes mellitus was a pre-existing co-morbidity in 913 patients (22.2% of patients with AHRF). In multivariable analysis, there was no association between diabetes mellitus and having ARDS (OR 0.93 (0.78-1.11); p = 0.39), developing ARDS late (OR 0.79 (0.54-1.15); p = 0.22), or hospital mortality in patients with ARDS (1.15 (0.93-1.42); p = 0.19). In a matched sample of patients, there was no association between diabetes mellitus and outcomes of interest. Conclusions: In a large, global observational study of patients with AHRF, no association was found between diabetes mellitus and having ARDS, developing ARDS, or outcomes from ARDS. Trial registration: NCT02010073. Registered on 12 December 2013

Epidemiology and patterns of tracheostomy practice in patients with acute respiratory distress syndrome in ICUs across 50 countries

Background: To better understand the epidemiology and patterns of tracheostomy practice for patients with acute respiratory distress syndrome (ARDS), we investigated the current usage of tracheostomy in patients with ARDS recruited into the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG-SAFE) study. Methods: This is a secondary analysis of LUNG-SAFE, an international, multicenter, prospective cohort study of patients receiving invasive or noninvasive ventilation in 50 countries spanning 5 continents. The study was carried out over 4 weeks consecutively in the winter of 2014, and 459 ICUs participated. We evaluated the clinical characteristics, management and outcomes of patients that received tracheostomy, in the cohort of patients that developed ARDS on day 1-2 of acute hypoxemic respiratory failure, and in a subsequent propensity-matched cohort. Results: Of the 2377 patients with ARDS that fulfilled the inclusion criteria, 309 (13.0%) underwent tracheostomy during their ICU stay. Patients from high-income European countries (n = 198/1263) more frequently underwent tracheostomy compared to patients from non-European high-income countries (n = 63/649) or patients from middle-income countries (n = 48/465). Only 86/309 (27.8%) underwent tracheostomy on or before day 7, while the median timing of tracheostomy was 14 (Q1-Q3, 7-21) days after onset of ARDS. In the subsample matched by propensity score, ICU and hospital stay were longer in patients with tracheostomy. While patients with tracheostomy had the highest survival probability, there was no difference in 60-day or 90-day mortality in either the patient subgroup that survived for at least 5 days in ICU, or in the propensity-matched subsample. Conclusions: Most patients that receive tracheostomy do so after the first week of critical illness. Tracheostomy may prolong patient survival but does not reduce 60-day or 90-day mortality. Trial registration: ClinicalTrials.gov, NCT02010073. Registered on 12 December 2013

PROXY EXPOSURE INDICATORS FOR INDOOR AIR POLLUTION, HEALTH IMPACT AND DEPRIVATION IN THE MARCHE REGION, ITALY

Literature supports the correlation between worse indoor air quality, lower socio-economic status and disease, such as asthma, Extrinsic Allergic Alveolitis (EAA) and Carbon Monoxide Intoxication (COI). In order to determine the extent of the phenomenon in the Marche Region, hospitalization risk for asthma, EAA and CO intoxication was assessed in association with Particulate Matter 2.5 (PM2.5) air concentration and socio-economic Deprivation Index (DI).Hospital discharge records of residents of the Marche Region with diagnosis of asthma, EAA and COI were analysed between 2006-2013. We then identified DI value and average PM2.5 levels for each municipality, using atmospheric modelling systems. Association between these proxy indicators of indoor air quality and relative risk (Confidence Interval - CI 90%) of hospitalization for the considered health outcomes was evaluated.Data analysis shows a higher number of hospitalizations for asthma with the increase of PM2.5 concentration quintiles and suggests a possible correlation between socio-economic deprivation and EAA and CO intoxication

Protocollo metodologico per revisione sistematica sull’inquinamento atmosferico come fattore di rischio per sindrome metabolica nella popolazione sana

Introduzione La sindrome metabolica rappresenta un gruppo di anomalie metaboliche che includono ipertensione, obesità centrale, insulino-resistenza e dislipidemia aterogenica. Questa condizione colpisce circa un quarto della popolazione europea ed è fortemente associata ad un aumentato rischio di sviluppo di diabete e malattie cardiovascolari, pertanto la sua prevenzione rappresenta una sfida essenziale per la salute dell’individuo e per quella pubblica. La patogenesi della sindrome metabolica coinvolge sia fattori genetici che acquisiti, tra cui diversi studi sembrano indicare un’associazione con l’esposizione ad inquinamento atmosferico. Per queste ragioni si è deciso di condurre una revisione sistematica per l’individuazione delle evidenze disponibili ad oggi sull’associazione tra esposizione ad inquinamento atmosferico e sindrome metabolica. Materiali e metodi Il quesito di ricerca è stato tradotto in uno specifico PICOS, utilizzato per costruire una strategia di ricerca sensibile. Sono stati ricercati articoli pubblicati fino al 23/04/2019 reperibili tramite le banche-dati elettroniche MEDLINE, SCOPUS e CINHAL. In seguito all’eliminazione dei duplicati due operatori hanno proceduto allo screening per titoli ed abstract e selezionato gli articoli di cui è stata ritenuta necessaria la lettura dei full-text, rispettando precisi criteri di inclusione ed esclusione fissati a priori. Sono stati ritenuti includibili reviews, trials randomizzati, studi caso-controllo e di coorte condotti su popolazione altrimenti sana, in cui fosse analizzata l’associazione tra esposizione ad inquinamento atmosferico di qualsiasi tipologia e sindrome metabolica. Sono stati esclusi gli studi in lingue diverse dall’inglese e dall’italiano. Gli articoli selezionati verranno letti integralmente per stabilirne l’opportunità di inclusione nella sintesi qualitativa/quantitativa, previa valutazione della loro qualità metodologica. Risultati Sono stati reperiti 2565 articoli (407 record da MEDLINE, 452 da CINHAL e 1706 da SCOPUS). 588 record sono stati eliminati in quanto duplicati. I titoli e gli abstract dei restanti 1.977 articoli sono stati sottoposti a screening e 17 studi sono stati selezionati per le successive fasi dell’analisi. Conclusioni La conduzione di una revisione sistematica sulla possibile associazione tra inquinamento atmosferico e sindrome metabolica, argomento di sempre maggiore interesse nell’ambito dell’epidemiologia ambientale, permetterà di sintetizzare le conoscenze finora reperite portando alla formulazione di nuove ipotesi o alla consapevolezza di aree ancora poco esplorate della ricerca su cui concentrare maggiormente l’attenzione nei futuri studi. L’individuazione dell’inquinamento atmosferico quale chiaro fattore di rischio porterebbe a interrogarsi sulla necessità di importanti interventi a tutela della salute pubblica