Amoxicillin duration and dose for community-acquired pneumonia in children: the CAP-IT factorial non-inferiority RCT.

BACKGROUND: Data are limited regarding the optimal dose and duration of amoxicillin treatment for community-acquired pneumonia in children. OBJECTIVES: To determine the efficacy, safety and impact on antimicrobial resistance of shorter (3-day) and longer (7-day) treatment with amoxicillin at both a lower and a higher dose at hospital discharge in children with uncomplicated community-acquired pneumonia. DESIGN: A multicentre randomised double-blind 2 × 2 factorial non-inferiority trial in secondary care in the UK and Ireland. SETTING: Paediatric emergency departments, paediatric assessment/observation units and inpatient wards. PARTICIPANTS: Children aged > 6 months, weighing 6-24 kg, with a clinical diagnosis of community-acquired pneumonia, in whom treatment with amoxicillin as the sole antibiotic was planned on discharge. INTERVENTIONS: Oral amoxicillin syrup at a dose of 35-50 mg/kg/day compared with a dose of 70-90 mg/kg/day, and 3 compared with 7 days' duration. Children were randomised simultaneously to each of the two factorial arms in a 1 : 1 ratio. MAIN OUTCOME MEASURES: The primary outcome was clinically indicated systemic antibacterial treatment prescribed for respiratory tract infection (including community-acquired pneumonia), other than trial medication, up to 28 days after randomisation. Secondary outcomes included severity and duration of parent/guardian-reported community-acquired pneumonia symptoms, drug-related adverse events (including thrush, skin rashes and diarrhoea), antimicrobial resistance and adherence to trial medication. RESULTS: A total of 824 children were recruited from 29 hospitals. Ten participants received no trial medication and were excluded. Participants [median age 2.5 (interquartile range 1.6-2.7) years; 52% male] were randomised to either 3 (n = 413) or 7 days (n = 401) of trial medication at either lower (n = 410) or higher (n = 404) doses. There were 51 (12.5%) and 49 (12.5%) primary end points in the 3- and 7-day arms, respectively (difference 0.1%, 90% confidence interval -3.8% to 3.9%) and 51 (12.6%) and 49 (12.4%) primary end points in the low- and high-dose arms, respectively (difference 0.2%, 90% confidence interval -3.7% to 4.0%), both demonstrating non-inferiority. Resolution of cough was faster in the 7-day arm than in the 3-day arm for cough (10 days vs. 12 days) (p = 0.040), with no difference in time to resolution of other symptoms. The type and frequency of adverse events and rate of colonisation by penicillin-non-susceptible pneumococci were comparable between arms. LIMITATIONS: End-of-treatment swabs were not taken, and 28-day swabs were collected in only 53% of children. We focused on phenotypic penicillin resistance testing in pneumococci in the nasopharynx, which does not describe the global impact on the microflora. Although 21% of children did not attend the final 28-day visit, we obtained data from general practitioners for the primary end point on all but 3% of children. CONCLUSIONS: Antibiotic retreatment, adverse events and nasopharyngeal colonisation by penicillin-non-susceptible pneumococci were similar with the higher and lower amoxicillin doses and the 3- and 7-day treatments. Time to resolution of cough and sleep disturbance was slightly longer in children taking 3 days' amoxicillin, but time to resolution of all other symptoms was similar in both arms. FUTURE WORK: Antimicrobial resistance genotypic studies are ongoing, including whole-genome sequencing and shotgun metagenomics, to fully characterise the effect of amoxicillin dose and duration on antimicrobial resistance. The analysis of a randomised substudy comparing parental electronic and paper diary entry is also ongoing. TRIAL REGISTRATION: Current Controlled Trials ISRCTN76888927, EudraCT 2016-000809-36 and CTA 00316/0246/001-0006. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 60. See the NIHR Journals Library website for further project information

Resilience Analysis of Service Oriented Collaboration Process Management systems

Collaborative business process management allows for the automated coordination of processes involving human and computer actors. In modern economies it is increasingly needed for this coordination to be not only within organizations but also to cross organizational boundaries. The dependence on the performance of other organizations should however be limited, and the control over the own processes is required from a competitiveness perspective. The main objective of this work is to propose an evaluation model for measuring a resilience of a Service Oriented Architecture (SOA) collaborative process management system. In this paper, we have proposed resilience analysis perspectives of SOA collaborative process systems, i.e. overall system perspective, individual process model perspective, individual process instance perspective, service perspective, and resource perspective. A collaborative incident and maintenance notification process system is reviewed for illustrating our resilience analysis. This research contributes to extend SOA collaborative business process management systems with resilience support, not only looking at quantification and identification of resilience factors, but also considering ways of improving the resilience of SOA collaborative process systems through measures at design and run-time

Amoxicillin duration and dose for community-acquired pneumonia in children: the CAP-IT factorial non-inferiority RCT.

BACKGROUND: Data are limited regarding the optimal dose and duration of amoxicillin treatment for community-acquired pneumonia in children. OBJECTIVES: To determine the efficacy, safety and impact on antimicrobial resistance of shorter (3-day) and longer (7-day) treatment with amoxicillin at both a lower and a higher dose at hospital discharge in children with uncomplicated community-acquired pneumonia. DESIGN: A multicentre randomised double-blind 2 × 2 factorial non-inferiority trial in secondary care in the UK and Ireland. SETTING: Paediatric emergency departments, paediatric assessment/observation units and inpatient wards. PARTICIPANTS: Children aged > 6 months, weighing 6-24 kg, with a clinical diagnosis of community-acquired pneumonia, in whom treatment with amoxicillin as the sole antibiotic was planned on discharge. INTERVENTIONS: Oral amoxicillin syrup at a dose of 35-50 mg/kg/day compared with a dose of 70-90 mg/kg/day, and 3 compared with 7 days' duration. Children were randomised simultaneously to each of the two factorial arms in a 1 : 1 ratio. MAIN OUTCOME MEASURES: The primary outcome was clinically indicated systemic antibacterial treatment prescribed for respiratory tract infection (including community-acquired pneumonia), other than trial medication, up to 28 days after randomisation. Secondary outcomes included severity and duration of parent/guardian-reported community-acquired pneumonia symptoms, drug-related adverse events (including thrush, skin rashes and diarrhoea), antimicrobial resistance and adherence to trial medication. RESULTS: A total of 824 children were recruited from 29 hospitals. Ten participants received no trial medication and were excluded. Participants [median age 2.5 (interquartile range 1.6-2.7) years; 52% male] were randomised to either 3 (n = 413) or 7 days (n = 401) of trial medication at either lower (n = 410) or higher (n = 404) doses. There were 51 (12.5%) and 49 (12.5%) primary end points in the 3- and 7-day arms, respectively (difference 0.1%, 90% confidence interval -3.8% to 3.9%) and 51 (12.6%) and 49 (12.4%) primary end points in the low- and high-dose arms, respectively (difference 0.2%, 90% confidence interval -3.7% to 4.0%), both demonstrating non-inferiority. Resolution of cough was faster in the 7-day arm than in the 3-day arm for cough (10 days vs. 12 days) (p = 0.040), with no difference in time to resolution of other symptoms. The type and frequency of adverse events and rate of colonisation by penicillin-non-susceptible pneumococci were comparable between arms. LIMITATIONS: End-of-treatment swabs were not taken, and 28-day swabs were collected in only 53% of children. We focused on phenotypic penicillin resistance testing in pneumococci in the nasopharynx, which does not describe the global impact on the microflora. Although 21% of children did not attend the final 28-day visit, we obtained data from general practitioners for the primary end point on all but 3% of children. CONCLUSIONS: Antibiotic retreatment, adverse events and nasopharyngeal colonisation by penicillin-non-susceptible pneumococci were similar with the higher and lower amoxicillin doses and the 3- and 7-day treatments. Time to resolution of cough and sleep disturbance was slightly longer in children taking 3 days' amoxicillin, but time to resolution of all other symptoms was similar in both arms. FUTURE WORK: Antimicrobial resistance genotypic studies are ongoing, including whole-genome sequencing and shotgun metagenomics, to fully characterise the effect of amoxicillin dose and duration on antimicrobial resistance. The analysis of a randomised substudy comparing parental electronic and paper diary entry is also ongoing. TRIAL REGISTRATION: Current Controlled Trials ISRCTN76888927, EudraCT 2016-000809-36 and CTA 00316/0246/001-0006. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 60. See the NIHR Journals Library website for further project information

Off-Target Effects of Psychoactive Drugs Revealed by Genome-Wide Assays in Yeast

To better understand off-target effects of widely prescribed psychoactive drugs, we performed a comprehensive series of chemogenomic screens using the budding yeast Saccharomyces cerevisiae as a model system. Because the known human targets of these drugs do not exist in yeast, we could employ the yeast gene deletion collections and parallel fitness profiling to explore potential off-target effects in a genome-wide manner. Among 214 tested, documented psychoactive drugs, we identified 81 compounds that inhibited wild-type yeast growth and were thus selected for genome-wide fitness profiling. Many of these drugs had a propensity to affect multiple cellular functions. The sensitivity profiles of half of the analyzed drugs were enriched for core cellular processes such as secretion, protein folding, RNA processing, and chromatin structure. Interestingly, fluoxetine (Prozac) interfered with establishment of cell polarity, cyproheptadine (Periactin) targeted essential genes with chromatin-remodeling roles, while paroxetine (Paxil) interfered with essential RNA metabolism genes, suggesting potential secondary drug targets. We also found that the more recently developed atypical antipsychotic clozapine (Clozaril) had no fewer off-target effects in yeast than the typical antipsychotics haloperidol (Haldol) and pimozide (Orap). Our results suggest that model organism pharmacogenetic studies provide a rational foundation for understanding the off-target effects of clinically important psychoactive agents and suggest a rational means both for devising compound derivatives with fewer side effects and for tailoring drug treatment to individual patient genotypes

Genetic interactions between a phospholipase A2 and the Rim101 pathway components in S. cerevisiae reveal a role for this pathway in response to changes in membrane composition and shape

Modulating composition and shape of biological membranes is an emerging mode of regulation of cellular processes. We investigated the global effects that such perturbations have on a model eukaryotic cell. Phospholipases A2 (PLA2s), enzymes that cleave one fatty acid molecule from membrane phospholipids, exert their biological activities through affecting both membrane composition and shape. We have conducted a genome-wide analysis of cellular effects of a PLA2 in the yeast Saccharomyces cerevisiae as a model system. We demonstrate functional genetic and biochemical interactions between PLA2 activity and the Rim101 signaling pathway in S. cerevisiae. Our results suggest that the composition and/or the shape of the endosomal membrane affect the Rim101 pathway. We describe a genetically and functionally related network, consisting of components of the Rim101 pathway and the prefoldin, retromer and SWR1 complexes, and predict its functional relation to PLA2 activity in a model eukaryotic cell. This study provides a list of the players involved in the global response to changes in membrane composition and shape in a model eukaryotic cell, and further studies are needed to understand the precise molecular mechanisms connecting them

Преимущества и недостатки велосипедного движения

ntroduction Community-acquired pneumonia (CAP) is a common indication for antibiotic treatment in young children. Data are limited regarding the ideal dose and duration of amoxicillin, leading to practice variation which may impact on treatment failure and antimicrobial resistance (AMR). Community-Acquired Pneumonia: a randomIsed controlled Trial (CAP-IT) aims to determine the optimal amoxicillin treatment strategies for CAP in young children in relation to efficacy and AMR.Methods and analysis The CAP-IT trial is a multicentre, randomised, double-blind, placebo-controlled 2×2 factorial non-inferiority trial of amoxicillin dose and duration. Children are enrolled in paediatric emergency and inpatient environments, and randomised to receive amoxicillin 70–90 or 35–50 mg/kg/day for 3 or 7 days following hospital discharge. The primary outcome is systemic antibacterial treatment for respiratory tract infection (including CAP) other than trial medication up to 4 weeks after randomisation. Secondary outcomes include adverse events, severity and duration of parent-reported CAP symptoms, adherence and antibiotic resistance. The primary analysis will be by intention to treat. Assuming a 15% primary outcome event rate, 8% non-inferiority margin assessed against an upper one-sided 95% CI, 90% power and 15% loss to follow-up, 800 children will be enrolled to demonstrate non-inferiority for the primary outcome for each of duration and dose.Ethics and dissemination The CAP-IT trial and relevant materials were approved by the National Research Ethics Service (reference: 16/LO/0831; 30 June 2016). The CAP-IT trial results will be published in peer-reviewed journals, and in a report published by the National Institute for Health Research Health Technology Assessment programme. Oral and poster presentations will be given to national and international conferences, and participating families will be notified of the results if they so wish. Key messages will be constructed in partnership with families, and social media will be used in their dissemination.Trial registration number ISRCTN76888927, EudraCT2016-000809-36