expe Gardening: Discover the best virtual gardens, podcasts and expert advice By www.heraldscotland.com Published On :: Sat, 09 May 2020 05:00:00 +0100 If you're yearning for all the gardening shows that have been cancelled, you can still be inspired by exploring gorgeous virtual gardens now and throughout the summer, from the comfort of your armchair. Full Article
expe Graeme Macpherson: Limited expectations and dreaming big key for fans of smaller clubs By www.heraldscotland.com Published On :: Sun, 03 May 2020 12:33:34 +0100 THE most important lesson in life is to always travel in hope rather than expectation. That way the almost inevitable disappointment that follows isn’t quite as crushing. A cheery thought for these troubled times. Full Article
expe One-Fifth of Children Experience Cyberbullying, According to Their Parents By blogs.edweek.org Published On :: Thu, 30 May 2019 00:00:00 +0000 Almost 20 percent of children, including some as young as 6-10, report being cyberbullied via social media sites and apps, according to a new study. Full Article Bullying
expe Unexpected love and respect By feedproxy.google.com Published On :: Mon, 05 Aug 2019 05:03:17 +0000 Rosario, Argentina :: Church members from a vulnerable community learn about human trafficking and experience care and respect. Full Article
expe Professionalism Expectations Seen Through the Eyes of Resident Physicians and Patient Families By pediatrics.aappublications.org Published On :: 2011-01-17T04:01:20-08:00 The professionalism of physicians can have an impact on patient care and satisfaction and physician career success and is increasingly emphasized in residency training programs. This study was an examination of the perspectives of families of pediatric patients and of pediatrics residents on the attributes of professionalism in physicians. Important overlaps were found between the attributes of professionalism prioritized by patient families and resident physicians. (Read the full article) Full Article
expe Early Experiences and Predictors of Recruitment Success for the National Children's Study By pediatrics.aappublications.org Published On :: 2011-01-24T04:01:38-08:00 The National Children's Study, a large-scale, longitudinal, birth cohort study of US children that endeavors to identify preventable and environmental origins of chronic diseases, has begun recruitment. In a highly diverse, urban setting, pregnant women can be recruited to participate in the National Children's Study at rates similar to those obtained in clinic settings. Refinements to the pregnancy screener and other components are needed to optimize implementation. (Read the full article) Full Article
expe Shared Decision-Making and Health Care Expenditures Among Children With Special Health Care Needs By pediatrics.aappublications.org Published On :: 2011-12-19T00:08:47-08:00 Children with special health care needs (CSHCN) account for more than one-third of pediatric health care costs. Little is known regarding the impact of shared decision-making (SDM) over time on child health care expenditures and utilization.In a national sample, we found that increasing SDM was associated with decreased health care costs and utilization for CSHCN. Results support prospective studies to determine if pediatric interventions to foster SDM reduce the financial burden of caring for CSHCN. (Read the full article) Full Article
expe Calculation of Expected Body Weight in Adolescents With Eating Disorders By pediatrics.aappublications.org Published On :: 2012-01-04T00:08:02-08:00 Eating disorders are characterized by preoccupation with weight and shape, which is manifested by a refusal to maintain a normal weight. An exact determination of expected body weight (EBW) is critical for diagnosis and clinical management of these disorders.The McLaren and Moore methods present with several limitations when calculating EBW for adolescents with eating disorders. A commonly agreed upon method for EBW calculation such as the BMI percentile method is recommended for clinical and research purposes. (Read the full article) Full Article
expe Tenfold Medication Errors: 5 Years' Experience at a University-Affiliated Pediatric Hospital By pediatrics.aappublications.org Published On :: 2012-04-02T00:07:10-07:00 Tenfold medication error is a well-recognized risk of pharmacotherapy in pediatric practice but little evidence describes the circumstances of such errors.This study identified 252 tenfold medication errors, 22 of which resulted in patient harm. We identified opioids and other high-risk medications to be associated with tenfold medication error and frequent, recurrent causes, mechanisms, and error enablers that suggest areas for future improvements. (Read the full article) Full Article
expe Comparison of Adolescent, Young Adult, and Adult Women's Maternity Experiences and Practices By pediatrics.aappublications.org Published On :: 2012-04-23T00:07:24-07:00 Some studies demonstrate that adolescents have different perinatal risks and outcomes than nonadolescents. Few studies have explored the maternity experiences or practices of adolescents that may underlie these differences, or compared these with nonadolescents by using a nationally representative sample.Adolescents and young adults were more likely to experience physical abuse, late prenatal care initiation, poor prenatal health behaviors, lower breastfeeding initiation and duration rates, postpartum depression, and lower folic acid supplementation than adult women. (Read the full article) Full Article
expe Integrated Personal Health Record Use: Association With Parent-Reported Care Experiences By pediatrics.aappublications.org Published On :: 2012-06-11T00:08:07-07:00 Regular use of an integrated personal health record (PHR) may lead to improved outcomes through improved care coordination, communication, and patient empowerment. A limited number of studies have examined integrated PHR use for children.Parents of children with chronic disease appear willing to use an integrated PHR to address health care needs for their child. PHRs may lead to improved health care and outcomes by enabling more coordinated care for children with chronic disease. (Read the full article) Full Article
expe Family Experiences and Pediatric Health Services Use Associated With Family-Centered Rounds By pediatrics.aappublications.org Published On :: 2012-07-09T00:07:44-07:00 Family-centered rounds (FCR) show promise for higher patient care satisfaction. Many previous studies are limited by small sample size and observational or pre-post designs, and health care service outcomes have not been previously examined.Our study uses an FCR assessment tool and a comparison group of non-FCR patients. We found that FCR are associated with improved family experiences, with no additional burden to health care service use. (Read the full article) Full Article
expe The Experience of Families With Children With Trisomy 13 and 18 in Social Networks By pediatrics.aappublications.org Published On :: 2012-07-23T00:07:46-07:00 Trisomy 13 and 18 are conditions with 1-year survival rates of less than 10% and have traditionally been treated with palliative care. There are increasing reports of ethical dilemmas caused by parental requests for clinical interventions.Parents who belong to social networks report an enriching family experience and describe surviving children as happy. Many of these parents describe challenging encounters with health care providers. (Read the full article) Full Article
expe Risk Factors for In-Hospital Mortality Among Children With Tuberculosis: The 25-Year Experience in Peru By pediatrics.aappublications.org Published On :: 2012-07-23T00:07:49-07:00 Because most childhood tuberculosis cases are sputum smear-negative, diagnosis relies largely upon clinical presentation, tuberculin skin testing, and chest radiograph. Diagnostic limitations contribute to treatment delays and high mortality. However, childhood tuberculosis (TB) mortality risk factors are not well documented.This study demonstrates that false-negative TST is common in children with active TB and is associated with increased risk of death. A negative TST should not delay anti-TB therapy. Improved diagnostic modalities are urgently needed in resource-limited settings. (Read the full article) Full Article
expe Beliefs and Expectations of Canadian Parents Who Bring Febrile Children for Medical Care By pediatrics.aappublications.org Published On :: 2012-09-10T00:07:56-07:00 Fever phobia is a ubiquitous problem throughout the world. As a result, fever is pharmacologically overtreated, and medical attention is frequently sought by worried parents.Most Canadian parents fear their child’s fever, resulting in aggressive surveillance and treatment. Parents expect information about fever etiology and how to care for their ill child. Few parents expect antibiotics and satisfaction with care is high. (Read the full article) Full Article
expe Pediatric Residents' Knowledge, Use, and Comfort With Expedited Partner Therapy for STIs By pediatrics.aappublications.org Published On :: 2012-09-17T00:07:37-07:00 Expedited partner therapy (EPT) is an effective method of partner treatment of sexually transmitted infections but is not used frequently. There are limited data on provider knowledge, practices, and comfort with EPT use in adolescents.California pediatric residents have knowledge gaps and discomfort providing EPT and presence of an adolescent medicine fellowship is associated with increased EPT knowledge, use, and comfort among residents. Our findings support the need to improve EPT education in pediatric residencies. (Read the full article) Full Article
expe Carnitine Palmitoyltransferase I and Sudden Unexpected Infant Death in British Columbia First Nations By pediatrics.aappublications.org Published On :: 2012-10-22T00:07:42-07:00 The CPT1A p.P479L variant is common to northern aboriginal populations, leads to reduced enzyme activity, and may be associated with increased infant mortality rates.The p.P479L variant is common in British Columbia First Nations with a coastal distribution correlated with regions of high infant mortality. Homozygotes display an altered acylcarnitine profile and are overrepresented in cases of sudden unexpected infant death in these areas. (Read the full article) Full Article
expe Expected Body Weight in Adolescents: Comparison Between Weight-for-Stature and BMI Methods By pediatrics.aappublications.org Published On :: 2012-11-12T00:08:24-08:00 In adolescents with eating disorders, percent expected body weight (EBW) is used for diagnosis and to make clinical decisions. The assumption is that the weight-for-stature (WFS) and BMI methods of determining EBW are equivalent, but that may not be true.This study demonstrates that EBWWFS is ~3.5% higher than EBWBMI. Differences are most pronounced at extremes of height. Compared with the EBWWFS method, sensitivity of EBWBMI to detect those <75% EBW is low. (Read the full article) Full Article
expe Influence of Tobacco Displays and Ads on Youth: A Virtual Store Experiment By pediatrics.aappublications.org Published On :: 2012-12-03T00:07:42-08:00 Youth exposure to retail tobacco advertisements and displays is associated with smoking initiation. The Family Smoking Prevention and Tobacco Control Act of 2009 gives states and local governments legal authority to regulate the time, place, and manner of tobacco advertising.This is the first experimental study using a virtual store environment to provide evidence that a policy banning tobacco product displays at the point of sale may deter youth from attempting to purchase tobacco products at retail stores. (Read the full article) Full Article
expe Weight-Based Victimization: Bullying Experiences of Weight Loss Treatment-Seeking Youth By pediatrics.aappublications.org Published On :: 2012-12-24T00:06:41-08:00 Studies have linked bullying with BMI, with overweight and obese youth vulnerable to bullying and its negative psychological and health consequences. However, there has been little comprehensive assessment of weight-based victimization, especially in weight loss treatment–seeking samples of youth.WBV is prevalent in treatment-seeking youth, who report victimization from peers (92%), friends (70%), parents (37%), and teachers (27%). Providers should discuss WBV in their assessment and treatment of pediatric patients who are overweight or obese. (Read the full article) Full Article
expe Tracheostomy for Infants Requiring Prolonged Mechanical Ventilation: 10 Years' Experience By pediatrics.aappublications.org Published On :: 2013-04-08T00:06:51-07:00 Advances in the treatment of critically ill infants have increased survival of extremely low/very low birth weight and medically complex infants. Improved survival can result in prolonged mechanical ventilation and sometimes tracheostomy. Current tracheostomy rates for these infants are unknown.This long-term review of infants discharged from a NICU with tracheostomies is the first to describe tracheostomy rates specifically in extremely low/very low birth weight infants. It focuses on long-term clinical outcomes and comorbidities rather than surgical complications. (Read the full article) Full Article
expe Neonatal End-of-Life Care: A Single-Center NICU Experience in Israel Over a Decade By pediatrics.aappublications.org Published On :: 2013-05-13T00:07:00-07:00 Neonatal mortality rate and causes of death have been relatively stable in recent years. Decision-making practices preceding death of sick neonates affect the circumstances of death. These practices vary worldwide according to the team approach and local population background.Although our population is mostly religious, we observed a decline in maximal intensive care along with increasing redirection of care over a decade. Changes in the team approach and increasing level of parental involvement influence type and duration of treatment. (Read the full article) Full Article
expe Effectiveness of Preventive Dental Visits in Reducing Nonpreventive Dental Visits and Expenditures By pediatrics.aappublications.org Published On :: 2013-05-27T00:06:56-07:00 Early preventive pediatric dental visits are widely recommended. However, the effectiveness of pediatric preventive dental visits in reducing the need for subsequent, more expensive oral health treatment has not been well established.Using an econometric method that accounts for time-invariant differences between children, and thus helps mitigate selection bias, we found a positive impact of preventive dental visits on oral health. However, there is less evidence regarding the cost-effectiveness of preventive visits. (Read the full article) Full Article
expe Unexpected Relationship Between Tympanometry and Mortality in Children With Nontraumatic Coma By pediatrics.aappublications.org Published On :: 2013-08-12T00:07:18-07:00 Tympanometry provides a measure of middle ear function. There has been no description of the relationship between measurements of middle ear function in the absence of gross anatomic defects and clinical outcome among children with acute nontraumatic coma.This study reveals an unexpected association between abnormal middle ear function and death in childhood acute coma. These findings call for more investigations on the relationship between middle and inner ear anatomy and function and intracranial dynamics and clinical outcomes. (Read the full article) Full Article
expe Potential Asphyxia and Brainstem Abnormalities in Sudden and Unexpected Death in Infants By pediatrics.aappublications.org Published On :: 2013-11-11T00:07:42-08:00 Certain characteristics of the sleep environment increase the risk for sleep-related, sudden, and unexplained infant death. These characteristics have the potential to generate asphyxia. The relationship between the deaths occurring in these environments and neurochemical abnormalities in the brainstem that may impair protective responses to asphyxia is unknown.We report neurochemical brainstem abnormalities underlying cases of sudden infant death that are associated with and without potential asphyxial situations in the sleep environment at death. The means to detect and treat these abnormalities in infants at risk are needed. (Read the full article) Full Article
expe Adverse Childhood Experiences of Low-Income Urban Youth By pediatrics.aappublications.org Published On :: 2014-06-16T00:06:35-07:00 Adverse childhood experiences have been shown to have long-term impacts on health and well-being. However, little work has been done to incorporate the voices of youth in understanding the range of adverse experiences that low-income urban children face.Study participants cited a broad range of adverse experiences beyond those listed in the initial adverse childhood experience studies. Domains of adverse experiences included family relationships, community stressors, personal victimization, economic hardship, peer relationships, discrimination, school, health, and child welfare/juvenile justice systems. (Read the full article) Full Article
expe Pediatric Advance Directives: Parents' Knowledge, Experience, and Preferences By pediatrics.aappublications.org Published On :: 2014-07-07T05:07:04-07:00 As the number of chronically ill children grows in the United States, end-of-life discussions and advance directives (AD) will become increasingly important. Although pediatric palliative care is gaining interest, little is known about parental preferences regarding ADs for chronically ill children.Knowledge about ADs is limited among caregivers of children who have chronic illness. However, interest in creating ADs is high, suggesting an unmet need and opportunity for health care providers to improve the care of children who have chronic illness. (Read the full article) Full Article
expe Precollege and In-College Bullying Experiences and Health-Related Quality of Life Among College Students By pediatrics.aappublications.org Published On :: 2014-12-22T00:06:49-08:00 American Public Health Association reported >3.2 million students in the United States are bullied each year; 160 000 students skip school every day for fear of bullying. Little is known about whether bullying affects health-related quality of life (HRQOL) among college students.Different types of bullying experiences affected different domains of HRQOL. Precollege bullying had long-term effects on HRQOL. Verbal/relational bullying-victimization experiences, mediated via depression, affected psychological HRQOL. Findings inform preventive and clinical practice to ameliorate the impact of bullying. (Read the full article) Full Article
expe Medical Providers' Understanding of Sex Trafficking and Their Experience With At-Risk Patients By pediatrics.aappublications.org Published On :: 2015-03-16T00:05:25-07:00 Existing literature discusses the unique medical and psychological needs of sex trafficking victims and highlights the importance of screening patients with risk factors. However, little is known about providers’ knowledge and confidence in their ability to provide care to victims.The study summarizes the knowledge gaps and barriers providers face when assisting pediatric sex trafficking victims. It also highlights the impact of training on providers’ confidence and ability to appropriately care for victims. (Read the full article) Full Article
expe Point-of-Care Child Psychiatry Expertise: The Massachusetts Child Psychiatry Access Project By pediatrics.aappublications.org Published On :: 2015-04-20T00:05:23-07:00 A program to support pediatric primary care providers in mental health care using point-of-care, telephone-based advice from specialists has been available since 2005 in Massachusetts. Other US states are implementing similar models. Little is known about how providers use this service.There is wide variability in adoption and use of this program. Patterns are associated with panel size, enrollment timing, and assignment to the program team at the pilot site. Findings will help new programs establish expectations and design implementation interventions. (Read the full article) Full Article
expe Family Experiences With Feeding Tubes in Neurologic Impairment: A Systematic Review By pediatrics.aappublications.org Published On :: 2015-06-29T00:07:57-07:00 Gastrostomy tube placement is a difficult decision for families of children with neurologic impairment. Better understanding the impact of these tubes on the lives of children and families will help improve decision-making and support from health care providers.Gastrostomy tube placement has broad-reaching implications for children and their families. There are physical, emotional, and relational challenges and benefits for the child, the parents, and the family unit. Exploring potential outcomes with families may improve decision-making conversations and support. (Read the full article) Full Article
expe Early Career Experiences of Pediatricians Pursuing or Not Pursuing Fellowship Training By pediatrics.aappublications.org Published On :: 2015-09-07T00:07:56-07:00 Choosing career paths can be a difficult decision for residents contemplating fellowship training. Limited resources are available to residents to help guide their choices.This article provides additional descriptions and insight into actual lifestyle and workplace environments for pediatric residents who choose fellowship training compared with those who do not. (Read the full article) Full Article
expe Reentry to Pediatric Residency After Global Health Experiences By pediatrics.aappublications.org Published On :: 2015-09-21T00:07:35-07:00 Although nonphysician reentry transitions have been characterized in the literature, little is known about the reentry of residents after either short-term (1-month elective) or long-term (12-month training) global health experiences abroad.Reverse culture shock may be a useful conceptual framework for understanding the range of emotions felt by pediatric residents when they reenter residency after global health experiences, particularly if these experiences were long term. (Read the full article) Full Article
expe Physician and Nurse Nighttime Communication and Parents' Hospital Experience By pediatrics.aappublications.org Published On :: 2015-10-26T00:07:21-07:00 Communication between parents and providers is an important driver of parent experience of care. The impact of nighttime communication, which has become increasingly relevant after changes in resident physician duty hours, on parent experience is unknown.Parent communication with nighttime doctors and nurses, and parent perceptions of communication and teamwork between these providers, may be important drivers of parent experience. Efforts to improve nighttime communication, both with parents and between team members, may improve parent experience. (Read the full article) Full Article
expe Playing Plague Inc. Doesn't Make You a Coronavirus Expert By www.pcmag.com Published On :: The developer, Ndemic Creations, wants to remind people that Plague Inc. is just a game, not a scientific model. The game's popularity has skyrocketed amid the ongoing coronavirus outbreak, which has managed to spread to the US. Full Article
expe Understanding the impacts of unexpected shift to digital learning By news.psu.edu Published On :: Mon, 04 May 2020 12:16 -0400 The unexpected transition to online classes due to the COVID-19 pandemic has prompted many changes for undergraduate students and their instructors. To understand the magnitude of these impacts and potentially improve digital learning, researchers in the Penn State School of Engineering Design and Professional Programs have received a $196,136 grant from the National Science Foundation. Full Article
expe Penn College offering summer manufacturing experience By news.psu.edu Published On :: Mon, 02 Mar 2020 09:33 -0500 Pennsylvania College of Technology will expose high schoolers to the rewarding possibilities of manufacturing careers, thanks to a grant-supported initiative. The college will host the Thingamajig Fabricators Pre-College Program from July 19-23 on its main campus. Students entering grades 9-12 are eligible for the session, featuring hands-on experience with 3D-design software, mills and lathes, and welding. Full Article
expe How to Handle IEPs During the Coronavirus Crisis? Some Expert Advice By feedproxy.google.com Published On :: Fri, 03 Apr 2020 00:00:00 +0000 Very carefully, experts say, while understanding that federal laws governing special education were not written with online education in mind. Full Article Idea
expe Why We Need Transformative Learning Experiences By feedproxy.google.com Published On :: Tue, 23 Apr 2019 00:00:00 +0000 Two things are true as I sort through my reflections on transformative learning experiences: We need intensive, immersive opportunities for learning (such as a trip to Kenya) and we also need to build in mini-opportunities for transformative learning every day. Full Article Professionaldevelopment
expe Teaching in the U.S. Should Be More 'Intellectually Attractive,' Global Expert Says By feedproxy.google.com Published On :: Thu, 20 Jun 2019 00:00:00 +0000 A panel of experts—including a national teacher's union president and an official from the Department of Education—discussed how to make teaching a more attractive profession. Full Article Professionaldevelopment
expe Fin24.com | IAN MANN REVIEWS | SA experts weigh in on managing organisations during coronavirus By www.fin24.com Published On :: Sat, 02 May 2020 17:47:24 +0200 As editor Wilhelm Crous puts it, "We haven't seen this movie before." Full Article
expe First hatches reported: Spotted lanternfly expert provides tips for management By news.psu.edu Published On :: Tue, 28 Apr 2020 12:32 -0400 Even before the recent news of the season’s first confirmed spotted lanternfly hatches in the Philadelphia region, homeowners in many parts of Pennsylvania were gearing up for their annual battle with the destructive pest. Full Article
expe Graduating food-science student parlays undergrad research experience into job By news.psu.edu Published On :: Wed, 06 May 2020 17:50 -0400 Gabriella Pinto provides a great example of what undergraduate research can do for a student. The Penn State food science major, who graduates this month, is headed for a good job armed with a wealth of experience and knowledge from her research, which gives her a leg up on her career. Full Article
expe Which States Expect the Most or Least From Students? By feedproxy.google.com Published On :: Tue, 22 May 2018 00:00:00 +0000 Mostly, states are holding to a higher bar for student achievement than they did a decade ago. But Iowa, Texas, and Virginia continue to show large gaps between their state proficiency standards and NAEP's. Full Article Assessment+Accountability+Achievement
expe In Vitro and In Vivo Characterization of Potent Antileishmanial Methionine Aminopeptidase-1 Inhibitors [Experimental Therapeutics] By aac.asm.org Published On :: 2020-03-16T08:17:37-07:00 Leishmania major is the causative agent of cutaneous leishmaniasis (CL). No human vaccine is available for CL and current drug regimens present several drawbacks such as emerging resistance, severe toxicity, medium effectiveness, and/or high cost. Thus, the need for better treatment options against CL is a priority. In the present study, we validate the enzyme methionine aminopeptidase-1 (MetAP1), a metalloprotease that catalyzes the removal of N-terminal methionine from peptides and proteins, as a chemotherapeutic target against CL infection. The in vitro antileishmanial activity of eight novel MetAP1 inhibitors (OJT001-OJT008) were investigated. Three compounds OJT006, OJT007, and OJT008 demonstrated potent anti-proliferative effect in macrophages infected with L. major amastigotes and promastigotes at submicromolar concentrations, with no cytotoxicity against host cells. Importantly, the leishmanicidal effect was diminished by almost 10-fold in transgenic L. major promastigotes overexpressing MetAP1LM in comparison to wild-type promastigotes. Furthermore, the in vivo activity of OJT006, OJT007, and OJT008 were investigated in L. major-infected BALB/c mice. In comparison to the control group, OJT008 significantly decreased footpad parasite load by 86%, and exhibited no toxicity against in treated mice. We propose MetAP1 inhibitor OJT008 as a potential chemotherapeutic candidate against CL infection caused by L. major infection. Full Article
expe Evaluation of the efficacy of antibiotic combinations against multidrug-resistant Pseudomonas aeruginosa in automated time-lapse microscopy and static time-kill experiments [Clinical Therapeutics] By aac.asm.org Published On :: 2020-03-16T08:17:37-07:00 Objectives: Antibiotic combination therapy is used for severe infections caused by multidrug-resistant (MDR) Gram-negative bacteria. Yet, data of which combinations are most effective is lacking. This study aimed to evaluate the in vitro efficacy of polymyxin B in combination with 13 other antibiotics against four clinical strains of MDR Pseudomonas aeruginosa.Methods: We evaluated the interactions of polymyxin B in combination with amikacin, aztreonam, cefepime, chloramphenicol, ciprofloxacin, fosfomycin, meropenem, minocycline, rifampicin, temocillin, thiamphenicol or trimethoprim by automated time-lapse microscopy using predefined cut-off values indicating inhibition of growth (≤106 CFU/mL) at 24 h. Promising combinations were subsequently evaluated in static time-kill experiments.Results: All strains were intermediate or resistant to polymyxin B, anti-pseudomonal β-lactams, ciprofloxacin and amikacin. Genes encoding β-lactamases (e.g., blaPAO and blaOXA-50) and mutations associated with permeability and efflux were detected in all strains. In the time-lapse microscopy experiments, positive interactions were found with 39 of 52 antibiotic combination/bacterial strain setups. Enhanced activity was found against all four strains with polymyxin B used in combination with aztreonam, cefepime, fosfomycin, minocycline, thiamphenicol and trimethoprim. Time kill experiments showed additive or synergistic activity with 27 of the 39 tested polymyxin B combinations, most frequently with aztreonam, cefepime, and meropenem.Conclusion: Positive interactions were frequently found with the tested combinations, also against strains that harboured several resistance mechanisms to the single drugs and with antibiotics that are normally not active against P. aeruginosa. Further study is needed to explore the clinical utility of these combinations. Full Article
expe ZN148 - a modular synthetic metallo-{beta}-lactamase inhibitor reverses carbapenem-resistance in Gram-negative pathogens in vivo [Experimental Therapeutics] By aac.asm.org Published On :: 2020-03-16T08:17:37-07:00 Carbapenem-resistant Gram-negative pathogens are a critical public health threat and there is an urgent need for new treatments. Carbapenemases (β-lactamases able to inactivate carbapenems) have been identified in both serine β-lactamase (SBL) and metallo β-lactamase (MBL) families. The recent introduction of SBL carbapenemase-inhibitors has provided alternative therapeutic options. Unfortunately, there are no approved inhibitors of MBL-mediated carbapenem-resistance and treatment options for infections caused by MBL-producing Gram-negatives are limited. Here, we present ZN148, a zinc-chelating MBL-inhibitor capable of restoring the bactericidal effect of meropenem and in vitro clinical susceptibility to carbapenems in >98% of a large international collection of MBL-producing clinical Enterobacterales strains (n=234). Moreover, ZN148 was able to potentiate the effect of meropenem against NDM-1-producing Klebsiella pneumoniae in a murine neutropenic peritonitis model. ZN148 showed no inhibition of the human zinc-containing enzyme glyoxylase II at 500 μM and no acute toxicity was observed in an in vivo mouse model with cumulative dosages up to 128 mg/kg. Biochemical analysis showed a time-dependent inhibition of MBLs by ZN148 and removal of zinc ions from the active site. Addition of exogenous zinc after ZN148 exposure only restored MBL activity by ~30%, suggesting an irreversible mechanism of inhibition. Mass-spectrometry and molecular modelling indicated potential oxidation of the active site Cys221 residue. Overall, these results demonstrate the therapeutic potential of a ZN148-carbapenem combination against MBL-producing Gram-negative pathogens and that ZN148 is a highly promising MBL inhibitor, capable of operating in a functional space not presently filled by any clinically approved compound. Full Article
expe Combination Therapy with Ibrexafungerp (formerly SCY-078), a First-in-Class Triterpenoid Inhibitor of (1->3)-{beta}-D-Glucan Synthesis, and Isavuconazole for Treatment of Experimental Invasive Pulmonary Aspergillosis [Experimental Therapeutics] By aac.asm.org Published On :: 2020-03-16T08:17:36-07:00 Ibrexafungerp (formerly SCY-078) is a semisynthetic triterpenoid and potent (1->3)-β-D-glucan synthase inhibitor. We investigated the in vitro activity, pharmacokinetics, and in vivo efficacy of ibrexafungerp (SCY) alone and in combination with anti-mould triazole isavuconazole (ISA) against invasive pulmonary aspergillosis (IPA). The combination of ibrexafungerp and isavuconazole in in vitro studies resulted in an additive and synergistic interactions against Aspergillus spp. Plasma concentration-time curves of ibrexafungerp were compatible with linear dose proportional profile. In vivo efficacy was studied in a well established persistently neutropenic NZW rabbit model of experimental IPA. Treatment groups included untreated rabbits (UC) and rabbits receiving ibrexafungerp at 2.5(SCY2.5) and 7.5(SCY7.5) mg/kg/day, isavuconazole at 40(ISA40) mg/kg/day, or combinations of SCY2.5+ISA40 and SCY7.5+ISA40. The combination of SCY+ISA produced in vitro synergistic interaction. There was significant in vivo reduction of residual fungal burden, lung weights, and pulmonary infarct scores in SCY2.5+ISA40, SCY7.5+ISA40, and ISA40-treatment groups vs that of SCY2.5-treated, SCY7.5-treated and UC (p<0.01). Rabbits treated with SCY2.5+ISA40 and SCY7.5+ISA40 had prolonged survival in comparison to that of SCY2.5-, SCY7.5-, ISA40-treated or UC (p<0.05). Serum GMI and (1->3)-β-D-glucan levels significantly declined in animals treated with the combination of SCY7.5+ISA40 in comparison to those treated with SCY7.5 or ISA40 (p<0.05). Ibrexafungerp and isavuconazole combination demonstrated prolonged survival, decreased pulmonary injury, reduced residual fungal burden, lower GMI and (1->3)-β-D-glucan levels in comparison to those of single therapy for treatment of IPA. These findings provide an experimental foundation for clinical evaluation of the combination of ibrexafungerp and an anti-mould triazole for treatment of IPA. Full Article
expe Fosmanogepix (APX001) is Effective in the Treatment of Pulmonary Murine Mucormycosis Due to Rhizopus arrhizus [Experimental Therapeutics] By aac.asm.org Published On :: 2020-03-23T08:47:35-07:00 Mucormycosis is a life-threatening infection with high mortality that occurs predominantly in immunocompromised patients. Manogepix (MGX) is a novel antifungal that targets Gwt1, an early step in the conserved glycosylphosphotidyl inositol (GPI) post-translational modification pathway of surface proteins in eukaryotic cells. Inhibition of inositol acylation by MGX results in pleiotropic effects including inhibition of maturation of GPI-anchored proteins necessary for growth and virulence. MGX has been previously shown to have in vitro activity against some strains of Mucorales. Here we assessed the in vivo activity of the prodrug fosmanogepix, currently in clinical development for the treatment of invasive fungal infections, against two Rhizopus arrhizus strains with high (4.0 μg/ml) and low (0.25 μg/ml) minimum effective concentration (MEC) values. In both invasive pulmonary infection models, treatment of mice with 78 mg/kg or 104 mg/kg fosmanogepix, along with 1-aminobenzotriazole to enhance the serum half-live of MGX in mice, significantly increased median survival time and prolonged overall survival by day 21 post infection when compared to placebo. In addition, administration of fosmanogepix resulted in a 1-2 log reduction in both lung and kidney fungal burden. For the 104 mg/kg fosmanogepix dose, tissue clearance and survival were comparable to clinically relevant doses of isavuconazole (ISA), which is FDA approved for the treatment of mucormycosis. These results support continued development of fosmanogepix as a first in class treatment for invasive mucormycosis. Full Article
expe Efficacy of bedaquiline, alone or in combination with imipenem, against Mycobacterium abscessus in C3HeB/FeJ mice [Experimental Therapeutics] By aac.asm.org Published On :: 2020-04-06T08:49:26-07:00 Mycobacterium abscessus lung infections remain difficult to treat. Recent studies have recognized the power of new combinations of antibiotics such as bedaquiline and imipenem although in vitro data have questioned this combination. We report that the efficacy of the bedaquiline plus imipenem treatment relies essentially on the activity of bedaquiline in a C3HeB/FeJ mice model of infection with a rough variant of M. abscessus. The addition of imipenem contributed at clearing the infection in the spleen. Full Article