The course of chronic obstructive pulmonary disease (COPD) is different in men and women. There are limited data in Latin America regarding COPD exacerbations (ECOPD) in women. This study aims to ...determine the sociodemographic and clinical profile of ECOPD adjusted by gender.
Cross-sectional analytical study of all patients hospitalised due to an ECOPD in a tertiary university hospital in Colombia between 2015 and 2019. A group comparison analysis was performed between male and female groups.
A total of 81 patients met the inclusion criteria (35.8% were women). The mean age was 71.49 years. Most of the patients were GOLD (Global Initiative for Obstructive Lung Disease) 3 and 4. A history of TB was present in 15% of our cohort. While the proportion of smokers was higher among men (OR 5.11;
= 0.013), exposure to wood smoke was significantly higher in women (OR 24;
< 0.001). Females were associated with a lower probability of having forced expiratory volume in 1 sec >0,87 L (OR 0.11;
= 0.013) and were associated with an increased probability of receiving inhaled corticosteroids during hospitalisation (OR 3.33;
= 0.023). No differences in terms of mortality or complications were found.
Women with COPD are underrepresented in literature. This study was able to identify some factors related to female sex among patients hospitalised for severe ECOPD.
The connection of diverse and sometimes non-Grid enabled resource types to the CMS Global Pool, which is based on HTCondor and glideinWMS, has been a major goal of CMS. These resources range in type ...from a high-availability, low latency facility at CERN for urgent calibration studies, called the CAF, to a local user facility at the Fermilab LPC, allocation-based computing resources at NERSC and SDSC, opportunistic resources provided through the Open Science Grid, commercial clouds, and others, as well as access to opportunistic cycles on the CMS High Level Trigger farm. In addition, we have provided the capability to give priority to local users of beyond WLCG pledged resources at CMS sites. Many of the solutions employed to bring these diverse resource types into the Global Pool have common elements, while some are very specific to a particular project. This paper details some of the strategies and solutions used to access these resources through the Global Pool in a seamless manner.
The CMS Global Pool, based on HTCondor and glideinWMS, is the main computing resource provisioning system for all CMS workflows, including analysis, Monte Carlo production, and detector data ...reprocessing activities. The total resources at Tier-1 and Tier-2 grid sites pledged to CMS exceed 100,000 CPU cores, while another 50,000 to 100,000 CPU cores are available opportunistically, pushing the needs of the Global Pool to higher scales each year. These resources are becoming more diverse in their accessibility and configuration over time. Furthermore, the challenge of stably running at higher and higher scales while introducing new modes of operation such as multi-core pilots, as well as the chaotic nature of physics analysis workflows, places huge strains on the submission infrastructure. This paper details some of the most important challenges to scalability and stability that the CMS Global Pool has faced since the beginning of the LHC Run II and how they were overcome.
Abstract Moxifloxacin is reported to have increased distribution into the prostate compared with older fluoroquinolones such as norfloxacin and ciprofloxacin, being able to reach tissue-to-plasma ...concentration ratios greater than unity. However, most of these studies use tissue homogenates derived from biopsy samples, which can lead to overestimation of free concentrations as fluoroquinolones tend to accumulate in the intracellular space. The aim of this study was to investigate moxifloxacin pharmacokinetics in rat prostate interstitial fluid by microdialysis. Tissue pharmacokinetics was assessed by implanting a small microdialysis catheter in the prostate gland. Blood samples were simultaneously collected for assessing plasma pharmacokinetics. Analysis of plasma ( N = 154) and microdialysis ( N = 344) concentrations after a single intravenous dose of 6 or 12 mg/kg moxifloxacin was conducted in the non-linear mixed-effect modelling software NONMEM v.6 as well by a non-compartmental approach. Moxifloxacin showed a significant tissue distribution in the prostate (AUCprostate,ISF / fu ·AUCplasma = 1.24 ± 0.37), 59% higher than the value obtained for levofloxacin in a previous study. A three-compartment model with non-linear kinetics could adequately describe moxifloxacin pharmacokinetics in terms of curve fitting and precision in parameter estimation. The developed pharmacokinetic model indicates that passive diffusion and active transport are the mechanisms involved in moxifloxacin distribution to the prostate. These findings suggest that moxifloxacin could be a better alternative to levofloxacin for the treatment of chronic bacterial prostatitis owing to its enhanced tissue penetration and higher AUCtissue /MIC ratios, even though it is not yet approved by the US FDA for this indication.
Pre-workout supplements purportedly enhance feelings of energy, reduce fatigue and improve exercise performance. The purpose of this study was to examine the performance effects of caffeinated and ...non-caffeinated multi-ingredient pre-workout supplements.
In a counterbalanced, double-blind, placebo-controlled design, eccentric and concentric force production during lower body resistance exercise on a mechanized squat device were assessed after supplement ingestion. Repetitions-in-reserve/RPE and subjective feelings of energy, focus and fatigue were also examined. Twenty-one resistance-trained adults (12 F, 9 M) completed three conditions in random order: caffeinated supplement, non-caffeinated supplement and placebo. Subjects were not informed of the presence of a placebo condition. Thirty minutes after supplement ingestion, a 3-repetition maximum test and 5 sets of 6 repetitions were completed using the squat device. Each repetition involved 4-s eccentric and concentric phases, and the force signal throughout each repetition was sampled from a load cell contained within the squat device. The scaled and filtered force signals were analyzed using customized software. Repeated measures analysis of variance and appropriate follow-up analyses were utilized to compare dependent variables, and relevant effect sizes (d) were calculated.
Supplement or placebo ingestion led to similar subjective responses (
> 0.05). Energy (+8 to 44%; d = 0.3 to 0.8) and focus (+8 to 25%; d = 0.3 to 0.5) were acutely increased by supplement or placebo ingestion and decreased as the exercise session progressed. Fatigue was acutely decreased by supplement or placebo ingestion (-7 to 38%; d = -0.1 to -0.6) and increased as the exercise session progressed. Eccentric and concentric forces were unimproved by supplementation during the exercise sets for both sexes. In the non-caffeinated supplement condition only, maximal eccentric force production was lower during sets 3 to 5, as compared to set 1 (
< 0.05). Effect size data indicated that both the caffeinated and non-caffeinated supplements may contribute to small increases in concentric force production in males (+5 to 20%, d = 0.2 to 0.4 relative to placebo), but not females.
As compared to placebo, caffeinated and non-caffeinated multi-ingredient pre-workout supplements failed to improve concentric and eccentric force production. In males, effect size data indicate a possible small benefit of supplementation on concentric force production, although this was not statistically significant. When resistance-trained subjects were unaware of the presence of a placebo, resistance exercise performance was similar regardless of whether a placebo or multi-ingredient supplement was ingested.
The CMS experiment at CERN employs a distributed computing infrastructure to satisfy its data processing and simulation needs. The CMS Submission Infrastructure team manages a dynamic HTCondor pool, ...aggregating mainly Grid clusters worldwide, but also HPC, Cloud and opportunistic resources. This CMS Global Pool, which currently involves over 70 computing sites worldwide and peaks at 350k CPU cores, is employed to successfully manage the simultaneous execution of up to 150k tasks. While the present infrastructure is sufficient to harness the current computing power scales, CMS latest estimates predict a noticeable expansion in the amount of CPU that will be required in order to cope with the massive data increase of the High-Luminosity LHC (HL-LHC) era, planned to start in 2027. This contribution presents the latest results of the CMS Submission Infrastructure team in exploring and expanding the scalability reach of our Global Pool, in order to preventively detect and overcome any barriers in relation to the HL-LHC goals, while maintaining high effciency in our workload scheduling and resource utilization.
The CMS experiment collects and analyzes large amounts of data coming from high energy particle collisions produced by the Large Hadron Collider (LHC) at CERN. This involves a huge amount of real and ...simulated data processing that needs to be handled in batch-oriented platforms. The CMS Global Pool of computing resources provide +100K dedicated CPU cores and another 50K to 100K CPU cores from opportunistic resources for these kind of tasks and even though production and event processing analysis workflows are already managed by existing tools, there is still a lack of support to submit final stage condor-like analysis jobs familiar to Tier-3 or local Computing Facilities users into these distributed resources in an integrated (with other CMS services) and friendly way. CMS Connect is a set of computing tools and services designed to augment existing services in the CMS Physics community focusing on these kind of condor analysis jobs. It is based on the CI-Connect platform developed by the Open Science Grid and uses the CMS GlideInWMS infrastructure to transparently plug CMS global grid resources into a virtual pool accessed via a single submission machine. This paper describes the specific developments and deployment of CMS Connect beyond the CI-Connect platform in order to integrate the service with CMS specific needs, including specific Site submission, accounting of jobs and automated reporting to standard CMS monitoring resources in an effortless way to their users.
Several paediatric malignancies, including anaplastic large cell lymphoma (ALCL), inflammatory myofibroblastic tumour (IMT), neuroblastoma, and rhabdomyosarcoma, harbour activation of anaplastic ...lymphoma kinase (ALK) through different mechanisms. Here, we report the safety, pharmacokinetics, and efficacy of ceritinib in paediatric patients with ALK-positive malignancies.
This multicentre, open-label, phase 1 trial was done at 23 academic hospitals in ten countries. Children (aged ≥12 months to <18 years) diagnosed with locally advanced or metastatic ALK-positive malignancies that had progressed despite standard therapy, or for which no effective standard therapy were available, were eligible. ALK-positive malignancies were defined as those with ALK rearrangement, amplification, point mutation, or in the case of rhabdomyosarcoma, expression in the absence of any genetic alteration. Eligible patients had evaluable or measurable disease as defined by either Response Evaluation Criteria in Solid Tumours, version 1.1 for patients with non-haematological malignancies, International Neuroblastoma Response Criteria scan for patients with neuroblastoma, or International Working Group criteria for patients with lymphoma. Other eligibility criteria were Karnofsky performance status score of at least 60% for patients older than 12 years or Lansky score of at least 50% for patients aged 12 years or younger. This study included a dose-escalation part, followed by a dose-expansion part, in which all patients received treatment at the recommended dose for expansion (RDE) established in the dose-escalation part. Both parts of the study were done in fasted and fed states. In the dose-escalation part, patients were treated with once-daily ceritinib orally, with dose adjusted for body-surface area, rounded to the nearest multiple of the 50 mg dose strength. The starting dose in the fasted state was 300 mg/m2 daily and for the fed state was 320 mg/m2 daily. The primary objective of this study was to establish the maximum tolerated dose (ie, RDE) of ceritinib in the fasted and fed states. The RDE was established on the basis of the incidence of dose-limiting toxicities in patients who completed a minimum of 21 days of treatment with safety assessments and at least 75% drug exposure, or who discontinued treatment earlier because of dose-limiting toxicity. Overall response rate (defined as the proportion of patients with a best overall response of complete response or partial response) was a secondary endpoint. Activity and safety analyses were done in all patients who received at least one dose of ceritinib. This trial is registered with ClinicalTrials.gov (NCT01742286) and is completed.
Between Aug 28, 2013, and Oct 17, 2017, 83 children with ALK-positive malignancies were enrolled to the dose-escalation (n=40) and dose-expansion (n=43) groups. The RDE of ceritinib was established as 510 mg/m2 (fasted) and 500 mg/m2 (fed). 55 patients (30 with neuroblastoma, ten with IMT, eight with ALCL, and seven with other tumour types) were treated with ceritinib at the RDE (13 patients at 510 mg/m2 fasted and 42 patients at 500 mg/m2 fed). The median follow-up was 33·3 months (IQR 24·8–39·3) for patients with neuroblastoma, 33·2 months (27·9–35·9) for those with IMT, 34·0 months (21·9–46·4) for those with ALCL, and 27·5 months (22·4–36·9) for patients with other tumour types. An overall response was recorded in six (20%; 95% CI 8–39) of 30 patients with neuroblastoma, seven (70%; 33–93) of ten patients with IMT, six (75%; 35–97) of eight patients with ALCL, and one (14%; <1–58) of seven patients with other tumours. The safety profile of ceritinib was consistent with that observed in adult patients. All patients had at least one adverse event. Grade 3 or 4 adverse events occurred in 67 (81%) of 83 patients and were mostly increases in aminotransferases (alanine aminotransferase increase in 38 46% patients and aspartate aminotransferase increase in 27 33% patients). At least one serious adverse event was reported in 40 (48%) of 83 patients and 31 (37%) of 83 patients had at least one grade 3 or 4 serious adverse event. 14 (17%) deaths occurred during the study, of which 12 were on-treatment deaths and two were after 30 days of the last dose. Of the 12 on-treatment deaths, ten were due to disease progression (neuroblastoma), one due to sepsis, and one due to intractable hypotension.
Ceritinib 500 mg/m2 once daily with food is the recommended dose for paediatric patients with ALK-positive malignancies. Ceritinib showed promising preliminary antitumour activity in patients with ALK-positive refractory or recurrent IMT or ALCL, and in a subset of patients with relapsed or refractory neuroblastoma, with a manageable safety profile. Our data support the notion that ALK inhibitors should be considered in therapeutic strategies for paediatric patients with malignancies with genetic ALK alterations.
Novartis Pharmaceutical Corporation.
The adenosine 2A receptor (A2AR) mediates the immunosuppressive effects of adenosine in the tumor microenvironment and is highly expressed in non-small cell lung cancer (NSCLC). Taminadenant ...(PBF509/NIR178) is an A2AR antagonist able to reactivate the antitumor immune response.
In this phase I/Ib, dose-escalation/expansion study, patients with advanced/metastatic NSCLC and ≥1 prior therapy received taminadenant (80-640 mg, orally, twice a day) with or without spartalizumab (anti-programmed cell death-1, 400 mg, i.v., every 4 weeks). Primary endpoints were safety, tolerability, and feasibility of the combination.
During dose escalation, 25 patients each received taminadenant alone or with spartalizumab; 19 (76.0%) and 9 (36.0%) had received prior immunotherapy, respectively. Dose-limiting toxicities (all Grade 3) with taminadenant alone were alanine/aspartate aminotransferase increase and nausea n = 1 (4.0%) each; 640 mg, and in the combination group were pneumonitis n = 2 (8.0%); 160 and 240 mg and fatigue and alanine/aspartate aminotransferase increase n = 1 (4.0%) each; 320 mg; pneumonitis cases responded to steroids rapidly and successfully. Complete and partial responses were observed in one patient each in the single-agent and combination groups; both were immunotherapy naïve. In the single-agent and combination groups, 7 and 14 patients experienced stable disease; 7 and 6 patients were immunotherapy pretreated, respectively.
Taminadenant, with and without spartalizumab, was well tolerated in patients with advanced NSCLC. The maximum tolerated dose of taminadenant alone was 480 mg twice a day, and 240 mg twice a day plus spartalizumab. Efficacy was neither a primary or secondary endpoint; however, some clinical benefit was noted regardless of prior immunotherapy or programmed cell death ligand-1 status.
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