moni Die acute Pneumonie, und ihre sichere Heilung mit Quecksilberchlorür ohne Blutentziehung / eine Monographie von Max Wittich. By feedproxy.google.com Published On :: Erlangen : F. Enke, 1850. Full Article
moni Die Welträthsel : gemeinverständliche Studien uber monistische Philosophie / von Ernst Haeckel. By feedproxy.google.com Published On :: Bonn : E. Strauss, 1899. Full Article
moni Diet and cholera : showing the vital importance of wholesome diet, and that its impurities and deficiencies are the chief cause of cholera, with its premonitory symptoms and treatment : in a series of letters, originally intended for insertion in the &quo By feedproxy.google.com Published On :: London : S. Highley, 1848. Full Article
moni Dr J. Matthews Duncan's testimonials etc : first series. By feedproxy.google.com Published On :: [Edinburgh] : [publisher not identified], 1870. Full Article
moni Du traitement de la pneumonie aiguë / par Victor Hanot. By feedproxy.google.com Published On :: Paris : J.-B. Baillière, 1880. Full Article
moni Essai critique sur le traitement de la pneumonie franche / par Baraduc. By feedproxy.google.com Published On :: Paris : Parent, 1874. Full Article
moni Minnesota bans large-scale high school graduation ceremonies By feedproxy.google.com Published On :: Fri, 08 May 2020 00:00:00 +0000 Full Article Minnesota
moni Women and drugs : a new era for research / editors, Barbara A. Ray, Monique C. Braude. By search.wellcomelibrary.org Published On :: Rockville, Maryland : National Institute on Drug Abuse, 1986. Full Article
moni Strategies for research on the interactions of drugs of abuse / editors, Monique C. Braude, Harold M. Ginzburg. By search.wellcomelibrary.org Published On :: Rockville, Maryland : National Institute on Drug Abuse, 1986. Full Article
moni Monitoring and evaluation : alcoholism and other drug dependence services. By search.wellcomelibrary.org Published On :: Chicago, Ill. : Joint Commission on Accreditation of Healthcare Organizations, 1987. Full Article
moni Mnemonics Training: Multi-Class Incremental Learning without Forgetting. (arXiv:2002.10211v3 [cs.CV] UPDATED) By arxiv.org Published On :: Multi-Class Incremental Learning (MCIL) aims to learn new concepts by incrementally updating a model trained on previous concepts. However, there is an inherent trade-off to effectively learning new concepts without catastrophic forgetting of previous ones. To alleviate this issue, it has been proposed to keep around a few examples of the previous concepts but the effectiveness of this approach heavily depends on the representativeness of these examples. This paper proposes a novel and automatic framework we call mnemonics, where we parameterize exemplars and make them optimizable in an end-to-end manner. We train the framework through bilevel optimizations, i.e., model-level and exemplar-level. We conduct extensive experiments on three MCIL benchmarks, CIFAR-100, ImageNet-Subset and ImageNet, and show that using mnemonics exemplars can surpass the state-of-the-art by a large margin. Interestingly and quite intriguingly, the mnemonics exemplars tend to be on the boundaries between different classes. Full Article
moni Classification of pediatric pneumonia using chest X-rays by functional regression. (arXiv:2005.03243v1 [stat.AP]) By arxiv.org Published On :: An accurate and prompt diagnosis of pediatric pneumonia is imperative for successful treatment intervention. One approach to diagnose pneumonia cases is using radiographic data. In this article, we propose a novel parsimonious scalar-on-image classification model adopting the ideas of functional data analysis. Our main idea is to treat images as functional measurements and exploit underlying covariance structures to select basis functions; these bases are then used in approximating both image profiles and corresponding regression coefficient. We re-express the regression model into a standard generalized linear model where the functional principal component scores are treated as covariates. We apply the method to (1) classify pneumonia against healthy and viral against bacterial pneumonia patients, and (2) test the null effect about the association between images and responses. Extensive simulation studies show excellent numerical performance in terms of classification, hypothesis testing, and efficient computation. Full Article
moni Health Worker Data Alliance: Monitoring Emotional, Physical and... By www.prweb.com Published On :: Surveys provide secure, anonymous feedback from staff at all levels of healthcare organizations(PRWeb May 06, 2020)Read the full story at https://www.prweb.com/releases/health_worker_data_alliance_monitoring_emotional_physical_and_occupational_health_of_healthcare_workers_during_covid_19/prweb17101008.htm Full Article
moni Surface temperature monitoring in liver procurement via functional variance change-point analysis By projecteuclid.org Published On :: Wed, 15 Apr 2020 22:05 EDT Zhenguo Gao, Pang Du, Ran Jin, John L. Robertson. Source: The Annals of Applied Statistics, Volume 14, Number 1, 143--159.Abstract: Liver procurement experiments with surface-temperature monitoring motivated Gao et al. ( J. Amer. Statist. Assoc. 114 (2019) 773–781) to develop a variance change-point detection method under a smoothly-changing mean trend. However, the spotwise change points yielded from their method do not offer immediate information to surgeons since an organ is often transplanted as a whole or in part. We develop a new practical method that can analyze a defined portion of the organ surface at a time. It also provides a novel addition to the developing field of functional data monitoring. Furthermore, numerical challenge emerges for simultaneously modeling the variance functions of 2D locations and the mean function of location and time. The respective sample sizes in the scales of 10,000 and 1,000,000 for modeling these functions make standard spline estimation too costly to be useful. We introduce a multistage subsampling strategy with steps educated by quickly-computable preliminary statistical measures. Extensive simulations show that the new method can efficiently reduce the computational cost and provide reasonable parameter estimates. Application of the new method to our liver surface temperature monitoring data shows its effectiveness in providing accurate status change information for a selected portion of the organ in the experiment. Full Article
moni Efficient real-time monitoring of an emerging influenza pandemic: How feasible? By projecteuclid.org Published On :: Wed, 15 Apr 2020 22:05 EDT Paul J. Birrell, Lorenz Wernisch, Brian D. M. Tom, Leonhard Held, Gareth O. Roberts, Richard G. Pebody, Daniela De Angelis. Source: The Annals of Applied Statistics, Volume 14, Number 1, 74--93.Abstract: A prompt public health response to a new epidemic relies on the ability to monitor and predict its evolution in real time as data accumulate. The 2009 A/H1N1 outbreak in the UK revealed pandemic data as noisy, contaminated, potentially biased and originating from multiple sources. This seriously challenges the capacity for real-time monitoring. Here, we assess the feasibility of real-time inference based on such data by constructing an analytic tool combining an age-stratified SEIR transmission model with various observation models describing the data generation mechanisms. As batches of data become available, a sequential Monte Carlo (SMC) algorithm is developed to synthesise multiple imperfect data streams, iterate epidemic inferences and assess model adequacy amidst a rapidly evolving epidemic environment, substantially reducing computation time in comparison to standard MCMC, to ensure timely delivery of real-time epidemic assessments. In application to simulated data designed to mimic the 2009 A/H1N1 epidemic, SMC is shown to have additional benefits in terms of assessing predictive performance and coping with parameter nonidentifiability. Full Article
moni Engineering researcher’s non-invasive aid to monitoring pressure in the skull wins gold medal By www.raeng.org.uk Published On :: Wed, 11 Mar 2020 11:49:33 +00:00 Full Article
moni Cyber Defense Monitoring and Forensics Training By cert-mu.govmu.org Published On :: Tue, 20 Mar 2018 10:14:26 GMT The Computer Emergency Response Team of Mauritius (CERT-MU) in collaboration with the Command and Control Centre of Kenya organised a 3-day training programme on Cyber Defense Monitoring and Forensics at Voilà Hotel, Bagatelle from the 27th February – 1st March 2018. The training course provided an introduction to Network Security Monitoring (NSM), Security Information and Events Management (SIEM), Malware Analysis and Digital Forensics. Major part of the course was hands-on case studies and analysis exercises using real world data. The main focus of the training programme was on intensive hands-on sessions on addressing key challenges faced by local organizations in all sectors/industries. A wide range of commercial and open source tools were used to equip cyber defenders with the necessary skills to anticipate, detect, respond and contain adversaries. The training programme was followed by 23 participants from the public and private sector. Full Article
moni Basel III monitoring results based on end-June 2019 data published by the Basel Committee By www.bis.org Published On :: 2020-04-08T09:00:00Z BCBS Press release "Basel III monitoring results based on end-June 2019 data published by the Basel Committee", 8 April 2020 Full Article
moni First Nations worried by suspension of oilsands environmental monitoring By www.cbc.ca Published On :: Thu, 7 May 2020 15:40:55 EDT The leader of a First Nation surrounded by oilsands development is frustrated by the Alberta Energy Regulator's decision to suspend a wide array of environmental reporting requirements for oilsands companies. Full Article News/Canada/Edmonton
moni Customers of Kamloops pharmacy asked to isolate, monitor for COVID-19 symptoms By www.cbc.ca Published On :: Thu, 26 Mar 2020 22:06:13 EDT Interior Health officials are asking people who went to the Save-On-Foods pharmacy in Columbia Place Shopping Centre in Kamloops, March 10, 13 and 14 along with March 16 to 21 to self-isolate following a positive case of COVID-19 at the store. Full Article News/Canada/British Columbia
moni Anaerobic Necrotizing Pneumonia: Another Potential Life-threatening Complication of Vaping? By pediatrics.aappublications.org Published On :: 2020-04-01T01:00:57-07:00 An adolescent girl with a history of frequent electronic cigarette use of nicotine was hospitalized with severe necrotizing pneumonia. Blood cultures obtained before the administration of empirical broad-spectrum intravenous antibiotics had positive results for the growth of Fusobacterium necrophorum. The pathogen is an uncommon but well-known cause of anaerobic pneumonia with unique features that are collectively referred to as Lemierre syndrome or postanginal sepsis. The syndrome begins as a pharyngeal infection. Untreated, the infection progresses to involve the ipsilateral internal jugular vein, resulting in septic thrombophlebitis with direct spread from the neck to the lungs causing multifocal necrotizing pneumonia. The teenager we present in this report had neither a preceding pharyngeal infection nor Doppler ultrasonographic evidence for the presence of deep neck vein thrombi, leading us to explore alternative mechanisms for her pneumonia. We propose the possibility that her behavior of frequent vaping led to sufficient pharyngeal irritation such that F necrophorum colonizing her oropharynx was inhaled directly into her lungs during electronic cigarette use. Preexisting, but not yet recognized, vaping-related lung injury may have also contributed to her risk of developing the infection. The patient was hospitalized for 10 days. At follow-up one month later, she still became short of breath with minimal exertion. Full Article
moni Eosinophilic Pneumonia and Lymphadenopathy Associated With Vaping and Tetrahydrocannabinol Use By pediatrics.aappublications.org Published On :: 2020-04-01T01:00:57-07:00 Idiopathic acute eosinophilic pneumonia is a rare and potentially life-threatening condition that is defined by bilateral pulmonary infiltrates and fever in the presence of pulmonary eosinophilia. It often presents acutely in previously healthy individuals and can be difficult to distinguish from infectious pneumonia. Although the exact etiology of idiopathic acute eosinophilic pneumonia remains unknown, an acute hypersensitivity reaction to an inhaled antigen is suggested, which is further supported by recent public health risks of vaping (electronic cigarette) use and the development of lung disease. In this case, a patient with a year-long history of vaping in conjunction with tetrahydrocannabinol cartridge use who was diagnosed with idiopathic acute eosinophilic pneumonia with associated bilateral hilar lymphadenopathy is described. Full Article
moni Survey Tracker: Monitoring How K-12 Educators Are Responding to Coronavirus By feedproxy.google.com Published On :: Tue, 28 Apr 2020 00:00:00 +0000 Track how educators and district leaders are responding to challenges related to COVID-19 through recurring surveys from The EdWeek Research Center. Full Article Classroom+management
moni Music: Swedish Philharmonia/Martin, Usher Hall, Edinburgh, four stars By www.heraldscotland.com Published On :: Mon, 16 Mar 2020 11:36:15 +0000 Music Full Article
moni Penn State Schuylkill honors student scholars at award ceremonies By news.psu.edu Published On :: Mon, 27 Apr 2020 14:42 -0400 Penn State Schuylkill hosted two online celebrations for its Honors Program students, outstanding student scholars and tutors the week of April 20, 2020. Full Article
moni Adjunct Corticosteroids in Children Hospitalized With Community-Acquired Pneumonia By pediatrics.aappublications.org Published On :: 2011-01-10T04:01:27-08:00 Corticosteroids inhibit the expression of many proinflammatory cytokines released during the course of community-acquired pneumonia infection. Corticosteroids have been found in some studies to be associated with improved clinical outcomes in adults with pneumonia. No studies have investigated corticosteroid use in children with pneumonia. Results showed that corticosteroid treatment in children with pneumonia is common and its use is highly variable across institutions. Although corticosteroid therapy may benefit children with acute wheezing treated with β-agonists, corticosteroid therapy may lead to worse outcomes for children without wheezing. (Read the full article) Full Article
moni Impact of a Guideline on Management of Children Hospitalized With Community-Acquired Pneumonia By pediatrics.aappublications.org Published On :: 2012-02-20T00:08:21-08:00 Community-acquired pneumonia (CAP) is a common pediatric illness caused by Streptococcus pneumoniae. New pediatric Infectious Diseases Society of America CAP guidelines are now available recommending ampicillin as empirical treatment of children hospitalized with uncomplicated CAP.This study found that a CAP guideline led to an increase in the narrow-spectrum antibiotic ampicillin. Additionally, an increase in the use of amoxicillin at discharge was observed. Furthermore, change in therapy did not lead to increased adverse outcomes. (Read the full article) Full Article
moni A Randomized Controlled Trial of Zinc as Adjuvant Therapy for Severe Pneumonia in Young Children By pediatrics.aappublications.org Published On :: 2012-03-05T00:08:26-08:00 Pneumonia is still a significant problem in young children from developing countries where zinc deficiency is prevalent. Although zinc supplementation reduces the risk of childhood pneumonia, the effect of adjunct zinc on severe pneumonia is unclear with conflicting results.The overall effect, if any, of zinc as adjuvant therapy for World Health Organization–defined severe pneumonia in young children is small. (Read the full article) Full Article
moni Influence of Hospital Guidelines on Management of Children Hospitalized With Pneumonia By pediatrics.aappublications.org Published On :: 2012-10-22T00:07:42-07:00 There are limited data on current testing and treatment patterns for children hospitalized with pneumonia, and on whether institutional guidelines affect care.The use of institutional clinical practice guidelines was not associated with changes in diagnostic testing, hospital length of stay, or costs for children hospitalized with pneumonia, but was associated with increased use of narrow-spectrum antibiotics. (Read the full article) Full Article
moni Variation in Emergency Department Diagnostic Testing and Disposition Outcomes in Pneumonia By pediatrics.aappublications.org Published On :: 2013-07-22T00:07:44-07:00 There is wide variation in testing and treatment of children hospitalized with pneumonia. Limited data are available on diagnostic testing patterns and the association of test utilization with disposition outcomes for children with pneumonia evaluated in the emergency department (ED).Significant variation exists in testing for pediatric pneumonia. EDs that use more testing have higher hospitalization rates. However, ED revisit rates were not significantly different between high- and low-utilizing EDs, suggesting an opportunity to reduce testing without negatively affecting outcomes. (Read the full article) Full Article
moni Childhood Anemia at High Altitude: Risk Factors for Poor Outcomes in Severe Pneumonia By pediatrics.aappublications.org Published On :: 2013-10-07T00:07:05-07:00 Pneumonia is the leading cause of death in young children worldwide. Anemia, widely prevalent globally, is not routinely assessed when treating pneumonia. The effect of anemia and high altitude on outcome of pneumonia is not well described.Anemia at high altitude increases the risk of poor outcome with severe pneumonia. Children with severe pneumonia at high altitude present with more severe hypoxemia and have a longer time to recovery than children at low altitude. (Read the full article) Full Article
moni Narrow Vs Broad-spectrum Antimicrobial Therapy for Children Hospitalized With Pneumonia By pediatrics.aappublications.org Published On :: 2013-10-28T01:06:45-07:00 Recent guidelines for the management of childhood pneumonia recommend narrow-spectrum antimicrobial agents (eg, ampicillin) for most children; however, few studies have directly compared the effectiveness of narrow-spectrum agents to the broader spectrum third-generation cephalosporins commonly used among children hospitalized with pneumonia.By using data from 43 children’s hospitals in the United States, we demonstrate equivalent outcomes and costs for children hospitalized with pneumonia and treated empirically with either narrow- (ampicillin/penicillin) or broad-spectrum (ceftriaxone/cefotaxime) antimicrobial therapy. (Read the full article) Full Article
moni Longitudinal Validation of a Tool for Asthma Self-Monitoring By pediatrics.aappublications.org Published On :: 2013-11-11T00:07:44-08:00 To prevent asthma exacerbations, asthma guidelines recommend ongoing monitoring of patients’ asthma symptoms to promote timely adjustments of therapy to achieve and maintain optimal control. Existing tools, validated for ongoing monitoring, have significant limitations in children.Our study established longitudinal validation of the Asthma Symptom Tracker, a novel tool designed for use by children or their parents to facilitate ongoing monitoring of patients’ asthma symptoms and proactive medical decision-making to prevent acute exacerbations. (Read the full article) Full Article
moni Comparative Effectiveness of Empiric Antibiotics for Community-Acquired Pneumonia By pediatrics.aappublications.org Published On :: 2013-12-09T00:06:37-08:00 Broad-spectrum antibiotics are frequently used to empirically treat children hospitalized with community-acquired pneumonia despite recent national recommendations to use narrow-spectrum antibiotics.Narrow-spectrum antibiotics are similar to broad-spectrum antibiotics for the treatment of children hospitalized with community-acquired pneumonia in terms of clinical outcomes and resource utilization. This study provides scientific evidence to support national consensus guidelines. (Read the full article) Full Article
moni Baby-MONITOR: A Composite Indicator of NICU Quality By pediatrics.aappublications.org Published On :: 2014-06-02T00:06:38-07:00 The traditional process-focused approach to quality improvement has not remedied NICUs’ inconsistency in quality of care delivery across clinically important measures. Global measurement of quality may induce broad, systems-based improvement, but must be formally studied.We present a systematically developed and robust composite indicator, the Baby-MONITOR, to assess the quality of care delivered to very low birth weight infants in the NICU setting. (Read the full article) Full Article
moni Readmissions Among Children Previously Hospitalized With Pneumonia By pediatrics.aappublications.org Published On :: 2014-06-23T00:07:17-07:00 Pneumonia is a leading cause of hospitalization among children, and readmissions after discharge are common.Eight percent of children experience a readmission within 30 days after hospital discharge for pneumonia. Readmissions are most common among young children and those with chronic medical conditions, and are associated with substantial costs. (Read the full article) Full Article
moni Establishing Benchmarks for the Hospitalized Care of Children With Asthma, Bronchiolitis, and Pneumonia By pediatrics.aappublications.org Published On :: 2014-08-18T00:07:02-07:00 With the publication of evidence-based guidelines for asthma, bronchiolitis, and pneumonia, numerous efforts have been made to standardize and improve the quality of care. However, despite these guidelines, variation in care exists.This study establishes clinically achievable benchmarks of care for asthma, bronchiolitis, and pneumonia. Using a published method for achievable benchmarks of care, we calculated average utilization among the high-performers, which can serve as achievable goals for local quality improvement. (Read the full article) Full Article
moni Sinusitis and Pneumonia Hospitalization After Introduction of Pneumococcal Conjugate Vaccine By pediatrics.aappublications.org Published On :: 2014-11-10T00:06:19-08:00 Pneumococcal conjugated vaccines (PCVs) are known to decrease invasive pneumococcal disease in children, but their effect on pneumonia necessitating hospitalization is more variable across study sites, and effects on hospitalization for sinusitis have not been shown previously.There was a significant decrease in hospitalizations for sinusitis in children <2 years of age, and hospitalization for pneumonia decreased in children aged <5 years after sequential introduction of PCV7 and PCV13. (Read the full article) Full Article
moni Pneumonia in Childhood and Impaired Lung Function in Adults: A Longitudinal Study By pediatrics.aappublications.org Published On :: 2015-03-02T00:05:25-08:00 Early-life lower respiratory illnesses, including pneumonia, are associated with increased prevalence of asthma and diminished lung function in children. Whether early-life pneumonia is associated with subsequent impaired lung function and asthma in adults is not yet clear.This is the first article providing strong data for an association between early-life pneumonia in an outpatient setting and airflow limitation and asthma into adulthood, supporting the hypothesis of the early-life origins of chronic obstructive pulmonary disease. (Read the full article) Full Article
moni Improvement Methodology Increases Guideline Recommended Blood Cultures in Children With Pneumonia By pediatrics.aappublications.org Published On :: 2015-03-16T00:05:25-07:00 Blood cultures are the most widely available diagnostic tool to identify bacterial pathogens in community-acquired pneumonia (CAP). Despite a recent national guideline recommendation for blood culture performance in children with moderate/severe CAP, there is still wide variation across institutions.Using improvement methodology, we demonstrated that blood cultures can be routinely performed in children admitted for CAP, in accordance with a recent national guideline, without increasing length of stay in a setting with a low false-positive blood culture rate. (Read the full article) Full Article
moni Antibiotic Choice for Children Hospitalized With Pneumonia and Adherence to National Guidelines By pediatrics.aappublications.org Published On :: 2015-06-22T00:06:54-07:00 The 2011 national guidelines for the management of pediatric community-acquired pneumonia recommended narrow-spectrum antibiotic therapy (eg, ampicillin) for most children hospitalized with pneumonia. Before the release of the guidelines, the use of broader-spectrum antibiotics (eg, third-generation cephalosporins) was much more common.After release of the guidelines, third-generation cephalosporin use declined and penicillin/ampicillin use increased among children hospitalized with pneumonia. Changes were most apparent among institutions that proactively disseminated the guidelines, underscoring the importance of local efforts for timely guideline implementation. (Read the full article) Full Article
moni Outbreak of Mycoplasma pneumoniae-Associated Stevens-Johnson Syndrome By pediatrics.aappublications.org Published On :: 2015-07-27T00:08:19-07:00 Stevens-Johnson syndrome (SJS) is a rare and severe immunologic phenomenon characterized by rash and mucous membrane disease. SJS may be triggered by medications and, less commonly, by infections such as Mycoplasma pneumoniae (Mp). Outbreaks of SJS are exceedingly rare.We describe the largest SJS outbreak reported in children, which was also Mp-associated. In the first case-control study of this disease, we identify predictors of Mp-associated SJS versus non–Mp-associated SJS, including fewer skin lesions, pneumonia, and elevated erythrocyte sedimentation rate. (Read the full article) Full Article
moni Impact of KPC-production and high-level meropenem resistance on all-cause mortality of ventilator-associated pneumonia in association with Klebisella pneumoniae [Clinical Therapeutics] By aac.asm.org Published On :: 2020-03-23T08:47:35-07:00 Objectives: Carbapenemase-producing Enterobacterales and specifically KPC-producing Klebsiella pneumoniae (KPC-Kp) are rapidly spreading worldwide. The prognosis of ventilator-associated pneumonia (VAP) caused by KPC-producing Klebsiella pneumoniae (KPC-Kp) is not well known. Our study tries to assess whether ventilator-associated pneumonia caused by a KPC-Kp strain is associated with higher all-cause mortality than if caused by carbapenem-susceptible isolates.Study design and methods: This is a retrospective cohort study of patients with VAP due to K. pneumoniae from a 35-bed polyvalent Intensive Care Unit in a university hospital (> 40,000 annual admissions) between January 2012 and December 2016. Adjusted multivariate analysis was used to study the association of KPC-Kp with 30-day all-cause mortality (Cox regression).Results. We analyze 69 cases of K. pneumoniae VAP of which 39 were produced by a KPC-Kp strain with high-level resistance to meropenem (MIC > 16 mg/mL). All-cause mortality at 30 days was 41% in the KPC-Kp group (16/39) and 33.3% in the carbapenem-susceptible cases (10/30). KPC-Kp etiology was not associated with higher mortality when controlled for confounders (adjusted hazard ratio [lsqb]HR[rsqb] 1.25; 95% CI: 0.46–3.41). Adequate targeted therapy (HR 0.03; 95% CI: <0.01–0.23) was associated with all-cause mortality.Conclussion. Assuming the limitations due to the available sample size, the prognosis of VAP caused by KPC-Kp is similar to VAPs caused by carbapenem-susceptible K. pneumoniae when appropriate treatment is used. Full Article
moni Towards harmonization of voriconazole CLSI and EUCAST breakpoints for Candida albicans using a validated in vitro pharmacokinetic/pharmacodynamic model [Susceptibility] By aac.asm.org Published On :: 2020-03-30T10:04:32-07:00 Background. CLSI and EUCAST susceptibility breakpoints for voriconazole and C. albicans differ by one dilution (≤0.125 and ≤0.06 mg/l, respectively) whereas the epidemiological cutoff values (ECOFF/ECV) with both methodologies are the same (0.03 mg/L). We therefore determined the pharmacokinetic-pharmacodynamic (PK/PD) breakpoints of voriconazole against C. albicans for both methodologies with an in vitro PK/PD model, which was validated using existing animal PK/PD data.Methods. Four clinical wild-type and non-wild-type C. albicans isolates (voriconazole MICs 0.008-0.125 mg/l) were tested in an in vitro PK/PD model. For validation purposes, mouse PK were simulated and in vitro PD were compared with in vivo outcome. Human PK were simulated and the exposure-effect relationship fAUC0-24/MIC was described for EUCAST and CLSI24/48h methods. PK/PD breakpoints were determined using the fAUC0-24/MIC associated with half-maximal activity (EI50) and Monte Carlo simulation analysis.Results. The in vitro 24h-PD EI50 of voriconazole against C. albicans were 2.5-5 (1.5-17) fAUC/MIC. However, the 72h-PD were higher, 133 (51-347) fAUC/MIC for EUCAST and 94 (35-252) fAUC/MIC for CLSI. The mean (95% confidence interval) probability of target attainment (PTA) was 100(95-100)%, 97(72-100)%, 83(35-99)%, and 49(8-91)% and 100(97-100)%, 99(85-100)%, 91(52-100)% and 68(17-96)% for EUCAST and CLSI MICs 0.03, 0.06, 0.125, and 0.25 mg/L, respectively. Significantly, >95% PTAs were found for EUCAST/CLSI MICs ≤0.03 mg/ll. For MICs 0.06-0.125 mg/l trough levels 1-4 mg/ll would be required.Conclusion. A PK/PD breakpoint of C. albicans voriconazole at the ECOFF/ECV of 0.03 mg/L was determined for both EUCAST/CLSI methods, indicating the need for breakpoint harmonization for the reference methodologies. Full Article
moni Proteomic changes of Klebsiella pneumoniae in response to colistin treatment and crrB mutation-mediated colistin resistance [Mechanisms of Resistance] By aac.asm.org Published On :: 2020-03-30T10:04:32-07:00 Polymyxins are increasingly used as the critical last-resort therapeutic options for multidrug-resistant gram-negative bacteria. Unfortunately, polymyxin resistance has increased gradually for the last few years. Although studies on mechanisms of polymyxin are expanding, system-wide analyses of the underlying mechanism for polymyxin resistance and stress response are still lacking. To understand how Klebsiella pneumoniae adapt to colistin (polymyxin E) pressure, we carried out proteomic analysis of Klebsiella pneumoniae strain cultured with different concentrations of colistin. Our results showed that the proteomic responses to colistin treatment in Klebsiella pneumoniae involving several pathways, including (i) gluconeogenesis and TCA cycle; (ii) arginine biosynthesis; (iii) porphyrin and chlorophyll metabolism; and (iv) enterobactin biosynthesis. Interestingly, decreased abundance of class A β-lactamases including TEM, SHV-11, SHV-4 were observed in cells treated with colistin. Moreover, we also present comprehensive proteome atlases of paired polymyxin-susceptible and -resistant Klebsiella pneumoniae strains. The polymyxin-resistant strain Ci, a mutant of Klebsiella pneumoniae ATCC BAA 2146, showed missense mutation in crrB. The crrB mutant Ci, which displayed lipid A modification with 4-amino-4-deoxy-L-arabinose (L-Ara4N) and palmitoylation, showed striking increases of CrrAB, PmrAB, PhoPQ, ArnBCADT and PagP. We hypothesize that crrB mutations induce elevated expression of the arnBCADTEF operon and pagP via PmrAB and PhoPQ. Moreover, multidrug efflux pump KexD, which was induced by crrB mutation, also contributed to colistin resistance. Overall, our results demonstrated proteomic responses to colistin treatment and the mechanism of CrrB-mediate colistin resistance, which may further offer valuable information to manage polymyxin resistance. Full Article
moni Pharmacodynamics of Cefepime Combined with the Novel Extended-Spectrum Beta Lactamase (ESBL) Inhibitor Enmetazobactam for Murine Pneumonia caused by ESBL-Producing Klebsiella pneumoniae [Pharmacology] By aac.asm.org Published On :: 2020-04-06T08:49:25-07:00 Klebsiella pneumoniae that produce extended spectrum beta lactamases (ESBLs) are a persistent public health threat. There are relatively few therapeutic options and there is undue reliance on carbapenems. Alternative therapeutic options are urgently required. A combination of cefepime and the novel beta lactamase inhibitor enmetazobactam is being developed for treatment of serious infections caused by ESBL-producing organisms. The pharmacokinetics-pharmacodynamics (PK-PD) of cefepime-enmetazobactam against ESBL-producing K. pneumoniae was studied in a neutropenic murine pneumonia model. Dose ranging studies were performed. Dose fractionation studies were performed to define the relevant PD index for the inhibitor. The partitioning of cefepime and enmetazobactam into the lung was determined by comparing area under the concentration time curve (AUC) in plasma and epithelial lining fluid. The magnitude of drug exposure for cefepime-enmetazobactam required for logarithmic killing in the lung was defined using 3 ESBL-producing strains. Cefepime 100 mg/kg q8h i.v. had minimal antimicrobial effect. When this background regimen of cefepime was combined with enmetazobactam half-maximal effect was induced with enmetazobactam 4.71 mg/kg q8h i.v. The dose fractionation study suggest both fT>threshold and fAUC:MIC are potentially relevant PD indices. The AUCELF:AUCplasma for cefepime and enmetazobactam was 73.4% and 61.5%, respectively. A ≥2-log kill in the lung was achieved with a plasma and ELF cefepime fT>MIC of ≥20% and enmetazobactam fT>2 mg/L of ≥20% of the dosing interval. These data and analyses provide the underpinning evidence for the combined use of cefepime and enmetazobactam for nosocomial pneumonia. Full Article
moni Imipenem population pharmacokinetics: therapeutic drug monitoring data collected in critically ill patients with or without extracorporeal membrane oxygenation [Pharmacology] By aac.asm.org Published On :: 2020-04-06T08:49:26-07:00 Carbapenem pharmacokinetic profiles are significantly changed in critically ill patients because of the drastic variability of the patients' physiological parameters. Published population PK studies have mainly focused on specific diseases and the majority of these studies had small sample sizes. The aim of this study was to develop a population PK model of imipenem in critically ill patients that estimated the influence of various clinical and biological covariates and the use of Extracorporeal Membrane Oxygenation (ECMO) and Continuous Renal Replacement Therapy (CRRT). A two-compartment population PK model with Creatinine clearance (CrCL), body weight (WT), and ECMO as fixed effects was developed using the non-linear mixed effect model (NONMEM). A Monte Carlo simulation was performed to evaluate various dosing schemes and different levels of covariates based on the pharmacokinetic/pharmacodynamic index (f%T>MIC) for the range of clinically relevant minimum inhibitory concentrations(MICs). The results showed that there may be insufficient drug use in the clinical routine drug dose regimen, and 750mg Q6h could achieve a higher treatment success rate. The blood concentrations of imipenem in ECMO patients were lower than that of non-ECMO patients, therefore dosage may need to be increased. The dosage may need adjustment for patients with CrCL ≤ 70ml/min, but dose should be lowered carefully to avoid the insufficient drug exposure. Dose adjustment is not necessary for patients within the WT ranging from 50-80 kg. Due to the large variation in PK profile of imipenem in critically ill patients, TDM should be carried out to optimize drug regimens. Full Article
moni Therapeutic efficacy of a mixed formulation of conventional and PEGylated liposomes containing meglumine antimoniate, combined with allopurinol, in dogs naturally infected with Leishmania infantum [Experimental Therapeutics] By aac.asm.org Published On :: 2020-04-13T08:15:31-07:00 Treatment of dogs naturally infected with Leishmania infantum using meglumine antimoniate (MA) encapsulated in conventional liposomes (LC) in association with allopurinol has been previously reported to promote marked reduction in the parasite burden in the main infection sites. Here, a new assay in naturally infected dogs was performed using a novel liposome formulation of MA consisting of a mixture of conventional and long-circulating (PEGylated) liposomes (LCP), with expected broader distribution among affected tissues of the mononuclear phagocyte system. Experimental groups of naturally infected dogs were as follows: LCP+Allop, receiving LCP intravenously as 2 cycles of 6 doses (6.5 mg Sb/kg/dose) at 4-day intervals, plus allopurinol at 30 mg/kg/12 h p.o. during 130 days; LC+Allop, receiving LC intravenously as 2 cycles of 6 doses (6.5 mg Sb/kg/dose), plus allopurinol during 130 days; Allop, treated with allopurinol only; non-treated control. Parasite loads were evaluated by quantitative PCR in liver, spleen and bone marrow and by immunohistochemistry in the ear skin, before, just after treatment and 4 months later. LCP+Allop and LC+Allop groups, but not the Allop group, showed significant suppression of the parasites in the liver, spleen and bone marrow 4 months after treatment, compared to the pre-treatment period or the control group. Only LCP+Allop group showed significantly lower parasite burden in the skin, in comparison to the control group. On the basis of clinical staging and parasitological evaluations, LCP formulation exhibited a more favorable therapeutic profile, when compared to LC one, being therefore promising for treatment of canine visceral leishmaniasis. Full Article
moni Mutation of kvrA causes OmpK35/36 porin downregulation and reduced meropenem/vaborbactam susceptibility in KPC-producing Klebsiella pneumoniae. [Mechanisms of Resistance] By aac.asm.org Published On :: 2020-04-20T08:36:46-07:00 Meropenem/vaborbactam resistance in Klebsiella pneumoniae is associated with loss of function mutations in the OmpK35 and OmpK36 porins. Here we identify two previously unknown loss of function mutations that confer cefuroxime resistance in K. pneumoniae. The proteins lost were NlpD and KvrA; the latter is a transcriptional repressor controlling capsule production. We demonstrate that KvrA loss reduces OmpK35 and OmpK36 porin production, which confers reduced susceptibility to meropenem/vaborbactam in a KPC-3 producing K. pneumoniae isolate. Full Article
moni Antibiotic Use and Outcomes in Children in the Emergency Department With Suspected Pneumonia By pediatrics.aappublications.org Published On :: 2020-04-01T01:00:57-07:00 BACKGROUND AND OBJECTIVES: Antibiotic therapy is often prescribed for suspected community-acquired pneumonia (CAP) in children despite a lack of knowledge of causative pathogen. Our objective in this study was to investigate the association between antibiotic prescription and treatment failure in children with suspected CAP who are discharged from the hospital emergency department (ED). METHODS: We performed a prospective cohort study of children (ages 3 months–18 years) who were discharged from the ED with suspected CAP. The primary exposure was antibiotic receipt or prescription. The primary outcome was treatment failure (ie, hospitalization after being discharged from the ED, return visit with antibiotic initiation or change, or antibiotic change within 7–15 days from the ED visit). The secondary outcomes included parent-reported quality-of-life measures. Propensity score matching was used to limit potential bias attributable to treatment selection between children who did and did not receive an antibiotic prescription. RESULTS: Of 337 eligible children, 294 were matched on the basis of propensity score. There was no statistical difference in treatment failure between children who received antibiotics and those who did not (odds ratio 1.0; 95% confidence interval 0.45–2.2). There was no difference in the proportion of children with return visits with hospitalization (3.4% with antibiotics versus 3.4% without), initiation and/or change of antibiotics (4.8% vs 6.1%), or parent-reported quality-of-life measures. CONCLUSIONS: Among children with suspected CAP, the outcomes were not statistically different between those who did and did not receive an antibiotic prescription. Full Article