age Moisture Damage and Asthma: A Birth Cohort Study By pediatrics.aappublications.org Published On :: 2015-02-16T00:05:27-08:00 Moisture damage and mold increase the risk of asthma and asthmatic symptoms. However, the location of the damage, or the specific group of children who are at greater risk of asthma, is rarely taken into account.Inspector-observed moisture damage or mold in the child’s bedroom, living room, or kitchen increased the risk of asthma and persistent asthma during a 6-year follow-up. Atopic children may be more susceptible to the effects of moisture damage and mold. (Read the full article) Full Article
age Racial-Ethnic Disparities in Management and Outcomes Among Children With Type 1 Diabetes By pediatrics.aappublications.org Published On :: 2015-02-16T00:05:26-08:00 Previous studies have demonstrated racial and ethnic differences in glycemic control even after adjustment for variables such as insulin dosage, diabetes duration, and socioeconomic status. It is controversial whether genetic, physiologic, cultural, socioeconomic, and/or provider-related factors underlie these disparities.This study in a large, racially/ethnically diverse sample of children with type 1 diabetes demonstrates that racial disparities in insulin treatment methods and diabetes outcomes remain even after adjustment for socioeconomic status. (Read the full article) Full Article
age Intellectual and Academic Functioning of School-Age Children With Single-Suture Craniosynostosis By pediatrics.aappublications.org Published On :: 2015-02-23T00:05:25-08:00 It is unclear whether developmental delays observed among infants with single-suture craniosynostosis (SSC) persist at school age. Few neurodevelopmental studies have examined children with SSC beyond age 3, with most having methodological limitations.This study is the first to follow and test infants with SSC and a control group at school age. Infancy delays among children with SSC persisted at school age in some areas (IQ, math) but not others (reading, spelling). (Read the full article) Full Article
age Gestational Age and Developmental Risk in Moderately and Late Preterm and Early Term Infants By pediatrics.aappublications.org Published On :: 2015-03-02T00:05:27-08:00 There is growing evidence reporting that moderately preterm, late preterm, and early term infants are at increased risk of developmental delay. The characteristics of this association are not well established in the literature.In a sample of infants born between 32 and 41 weeks, there was an inverse and "dose response" relationship between gestational age and developmental delay risk using the ASQ at 8 and 18 months of corrected postnatal age. (Read the full article) Full Article
age Early Intervention for Toddlers With Language Delays: A Randomized Controlled Trial By pediatrics.aappublications.org Published On :: 2015-03-02T00:05:24-08:00 Early language delay is common in toddlers and is associated with poor academic outcomes, reading difficulties, and persistent communication problems. Despite these long-term sequelae, few interventions for toddlers with early language delays yield positive expressive and receptive language results.A 28-session program delivered over 3 months can enhance parent language facilitation strategies. Unusually, the small short-term benefits were mainly in receptive, rather than expressive, language and vocabulary. Extended follow-up could determine the costs versus benefits of this promising approach. (Read the full article) Full Article
age Validity of the Strengths and Difficulties Questionnaire in Preschool-Aged Children By pediatrics.aappublications.org Published On :: 2015-04-06T00:05:21-07:00 Although the psychometric properties of the school-age Strengths and Difficulties Questionnaire (SDQ) have been extensively examined by using longitudinal data, the preschool version of the SDQ has only been explored in a limited number of cross-sectional studies.This is the first psychometric study of the preschool SDQ using longitudinal data. We report measurement invariance over time, satisfactory reliability, construct and criterion validity, and predictive utility for subsequent behavioral problems (4 years) and clinical disorders (2 years). (Read the full article) Full Article
age Childhood Vaccination Coverage Rates Among Military Dependents in the United States By pediatrics.aappublications.org Published On :: 2015-04-13T00:05:18-07:00 Current childhood vaccination coverage rates among military dependents in the United States are not known. Past studies on childhood vaccination coverage in military dependents have shown mixed results, with the majority showing lower than ideal coverage rates.This study analyzes a national database with 6 years of data and provider-confirmed vaccination status to describe the current documented vaccination coverage rates among military dependents in the United States. (Read the full article) Full Article
age Bayley-III Cognitive and Language Scales in Preterm Children By pediatrics.aappublications.org Published On :: 2015-04-20T00:05:23-07:00 There is concern that the Bayley-III overestimates developmental functioning in preterm populations. The ability of the Bayley-III Cognitive and Language scales to predict later functioning in very preterm children has not been examined.The norms on the Bayley-III Cognitive and Language scales at 24 months had low sensitivity for impairment across general cognitive, verbal and nonverbal reasoning domains at 4 years, which was better detected using cut-points based on local term-born reference data. (Read the full article) Full Article
age Heart Rates in Hospitalized Children by Age and Body Temperature By pediatrics.aappublications.org Published On :: 2015-04-27T00:05:21-07:00 Heart rate (HR) increases with increasing body temperature. Previous studies have characterized the relationship among HR, age, and temperature for patients in primary care and emergency department settings but not in hospitalized children.Our data demonstrate an overall increase in HR by ~10 beats/minute for each 1°C increase in body temperature. Expected heart rates for hospitalized children differ from those for primary care and emergency department patients at the same age and temperature. (Read the full article) Full Article
age Maternal Prepregnancy Body Mass Index and Child Psychosocial Development at 6 Years of Age By pediatrics.aappublications.org Published On :: 2015-04-27T00:05:21-07:00 Both obesity and developmental disabilities have increased in recent decades; however, the full long-term effects of prepregnancy obesity on a child’s psychosocial development remain unknown. Limited studies suggest associations between maternal prepregnancy obesity and child psychosocial development.This study in 6-year-old children provides evidence that severe prepregnancy obesity is associated with adverse child psychosocial outcomes, including attention-deficit/hyperactivity disorder. These findings were not explained by many pregnancy and postpartum factors related to maternal obesity or child development. (Read the full article) Full Article
age Diagnostic Accuracy of the Urinalysis for Urinary Tract Infection in Infants <3 Months of Age By pediatrics.aappublications.org Published On :: 2015-05-25T00:06:48-07:00 The sensitivity of the urinalysis (UA) traditionally has been considered suboptimal in young infants. Whether the finding of a negative UA and a positive urine culture represents a false-negative UA versus a false-positive urine culture remains unclear.In infants <3 months with bacteremic urinary tract infection, a condition that represents true infection, the UA sensitivity is higher than previously reported for urinary tract infection in general, suggesting that the UA is reliable even in young infants. (Read the full article) Full Article
age Thrombocytopenia in Small-for-Gestational-Age Infants By pediatrics.aappublications.org Published On :: 2015-07-27T00:08:18-07:00 Small-for-gestational-age neonates are at risk for thrombocytopenia during the first days and weeks after birth. However, the incidence, duration, severity, responsible mechanism, value of platelet transfusions, and risk of death from this variety of neonatal thrombocytopenia are unknown.Ten percent of thrombocytopenic small-for-gestational-age neonates have a recognized cause for low platelets (aneuploidy, extracorporeal membrane oxygenation, disseminated intravascular coagulation); they have a high mortality rate (65%). Ninety percent have a moderate, transient (2 weeks), hyporegenerative thrombocytopenia with a low mortality rate (2%). (Read the full article) Full Article
age Inappropriate Use of Ultrasound in Management of Pediatric Cryptorchidism By pediatrics.aappublications.org Published On :: 2015-08-10T00:07:46-07:00 The value of ultrasound imaging for the diagnosis, prognosis, and surgical planning of cryptorchidism is limited at best.Ultrasound remains grossly overused by referring physicians throughout Ontario, Canada, which resulted in a 3-month delay to definitive surgery and unnecessary expenditures. (Read the full article) Full Article
age Two-Year Outcomes of a Population-Based Intervention for Preschool Language Delay: An RCT By pediatrics.aappublications.org Published On :: 2015-09-07T00:07:56-07:00 Preschool language delay predicts poorer academic performance, employment opportunities, and social relationships. Language for Learning, a systematic, population-based intervention for 4-year-olds with low language, is feasible, acceptable and has short-term benefits, but long-term benefits are unknown.Population ascertainment at age 4 followed by a yearlong, one-on-one home program benefited phonological skills (an important literacy determinant) at age 6, but not the primary language outcomes. To be cost-effective, future follow-up would need to demonstrate lasting academic benefits. (Read the full article) Full Article
age Alcohol Interventions Among Underage Drinkers in the ED: A Randomized Controlled Trial By pediatrics.aappublications.org Published On :: 2015-09-07T00:07:55-07:00 Intervention strategies are needed to reduce underage drinking. Meta-analyses of youth alcohol brief interventions (BIs) conclude that therapist-delivered BIs are efficacious; however, to maximize public health impact, recommendations include using technology to streamline intervention delivery, for which evidence is lacking.A single-session BI, delivered by a computer or therapist in the emergency department, shows promise for underage drinkers. Findings for the stand-alone computer BI are particularly appealing given the ease of future implementation. (Read the full article) Full Article
age Early-Onset Neutropenia in Small-for-Gestational-Age Infants By pediatrics.aappublications.org Published On :: 2015-10-12T00:07:19-07:00 Small for gestational age neonates (weight <10th percentile) are at risk for neutropenia during the first days after birth. However, the duration, responsible mechanism, and outcomes of this variety of neonatal neutropenia are not precisely known.Six percent of small for gestational age neonates had neutrophils <1000/μL, with an average neutropenia duration of 7 days. Neutropenia was more closely linked with small for gestational age status than maternal hypertension. This neutropenia is associated with elevated nucleated red blood cell count and increased odds of necrotizing enterocolitis. (Read the full article) Full Article
age Psychosocial Adjustment in School-age Girls With a Family History of Breast Cancer By pediatrics.aappublications.org Published On :: 2015-10-19T00:07:48-07:00 Many families share genetic cancer risk information with their children, and some parents and providers believe BRCA1/2 testing should be permitted in adolescence. The psychosocial effects and impact on health and risk behaviors of this knowledge is unknown.In our cohort of 869 mother-daughter pairs, we found no differences in general adjustment, but 10- to 13-year-old girls with breast cancer family histories reported higher breast cancer–specific distress and perceived breast cancer risk. Mother distress was associated with daughter distress. (Read the full article) Full Article
age HPV Vaccination Coverage of Male Adolescents in the United States By pediatrics.aappublications.org Published On :: 2015-10-26T00:07:21-07:00 HPV is the most common sexually transmitted infection in the United States. More than 50% of sexually active men and women will acquire HPV infection in their lifetime. In 2011, HPV was recommended for routine use among male adolescents. (Read the full article) Full Article
age Google's iOS Gboard Can Translate Text Into 103 Languages By www.pcmag.com Published On :: Over one hundred languages should help make a few conversations easier to get through, but that's still well short of the hundreds of languages Gboard typing supports. Full Article
age Lion Cage pitch competition winner aiming to reduce rotator cuff re-tear rates By news.psu.edu Published On :: Fri, 17 Apr 2020 08:45 -0400 Saif Khalil, founder and CEO of Aevumed, won first place at the REV-UP Center for Entrepreneurship's Lion Cage pitch competition. Aevumed develops medical devices designed to help reduce rotator cuff re-tear rates. Full Article
age Women's World Cup qualifying group stage draw By www.uefa.com Published On :: Tue, 25 Apr 2017 13:00:00 GMT Two-time winners Germany will take on Iceland, the Czech Republic, Slovenia and the Faroe Islands in Group 5 following the qualifying group stage draw in Nyon. Full Article general
age Roy Horn of magical duo Siegfried & Roy dies of COVID-19, aged 75 By www.timesofisrael.com Published On :: Sat, 09 May 2020 14:10:00 GMT Source: www.timesofisrael.com - Saturday, May 09, 2020 Vegas fixture's work with exotic animals came to violent end in 2003 when he was attacked on stage, critically hurt, by a 400-pound white tigerAll Related | More on Siegfried Full Article
age Math Teachers Take a Page From English/Language Arts: Comic Books! By feedproxy.google.com Published On :: Tue, 24 Sep 2019 00:00:00 +0000 Comic books and graphic novels, popular in many language arts and social studies classes, are just now tiptoeing into the world of K-12 math. Full Article Mathematics
age Protect Your Investment in Innovation: Engage in Change Management By feedproxy.google.com Published On :: Tue, 19 Mar 2019 00:00:00 +0000 Every time an education institution loses a funding source, rethinks program delivery, revises positions, incorporates technology, or changes curriculum, it is making an investment in change. These are sizable, important investments, so why not protect them? Full Article Innovation
age Gothenburg to stage 2021 Women's Champions League final By www.uefa.com Published On :: Wed, 29 May 2019 15:30:00 GMT Gamla Ullevi, Gothenburg will stage the 2021 UEFA Women's Champions League final Full Article general
age SB 13-26 Regulatory Reform (Scotland) Bill - Stage 1 By www.scottish.parliament.uk Published On :: 2016-12-04 08:18:21 16 May 2013The Regulatory Reform (Scotland) Bill was introduced in the Scottish Parliament on 27 March 2013. This briefing provides background information on existing regulatory regimes, and the introduction of the Bill. Full Article
age SB 14-03 Regulatory Reform (Scotland) Bill: Stage 3 By www.scottish.parliament.uk Published On :: 2016-12-04 08:18:21 13 January 2013This briefing provides a summary of the parliamentary scrutiny of the Regulatory Reform (Scotland) Bill prior to Stage 3 proceedings which are scheduled to take place on 16 January 2014. Full Article
age SB 14-31 Procurement (Reform) (Scotland) Bill – Parliamentary consideration prior to Stage 3 By www.scottish.parliament.uk Published On :: 2016-12-04 08:18:21 8 May 2014This briefing summarises Stage 1 and Stage 2 consideration of the Procurement (Reform) (Scotland) Bill, introduced in the Parliament on 3rd October 2013. Full Article
age Rock 'n' roll pioneer Little Richard dies at age 87: Rolling Stone By www.reuters.com Published On :: Sat, 09 May 2020 14:55:00 GMT Source: www.reuters.com - Saturday, May 09, 2020 Little Richard, the self-proclaimed "architect of rock 'n' roll" who built his ground-breaking sound with a boiling blend of boogie-woogie, rhythm and blues and gospel, died on Saturday at the age of 87, Rolling Stone magazine reported.All Related Full Article
age The World as Multimedia Village By feedproxy.google.com Published On :: Wed, 30 Apr 1997 00:00:00 +0000 Have you noticed that the Internet is changing the world into a Full Article Multimedia
age Education in Indian Country: An Education Week Multimedia Package By feedproxy.google.com Published On :: Wed, 04 Dec 2013 00:00:00 +0000 Education Week takes a close look at the obstacles and opportunities for American Indian children in finding success in school and beyond. Full Article Multimedia
age How Much Will Flash Change Enterprise Storage? By forwardthinking.pcmag.com Published On :: As I attended the annual Storage Visions conference a couple of weeks ago, I was struck again by just how much flash is being used in enterprise systems, and what the potential is for future uses going forward. Full Article
age Box Customers Can Tap Into Amazon, IBM Storage Overseas By www.pcmag.com Published On :: With Box Zones, Box customers can use Amazon Web Services and IBM Cloud to store data overseas. Full Article
age Today's Deals: Get 35 Percent Off SanDisk Storage By www.pcmag.com Published On :: You won't want to miss these great deals. Full Article
age Personalize Learning and Build Agency By Using the 4 PLC Questions By feedproxy.google.com Published On :: Wed, 22 Aug 2018 00:00:00 +0000 In this episode of the podcast, Tom chats with Tim Stuart about his new book, Personalized Learning in a PLC at Work: Student Agency Through the Four Critical Questions. Full Article Professionaldevelopment
age 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
age Journey through Congo. A new chance for Africa's ravaged heart By feedproxy.google.com Published On :: Mon, 03 Nov 2003 23:00:00 GMT Full Article
age Elections in Burundi: The Peace Wager By feedproxy.google.com Published On :: Wed, 08 Dec 2004 23:00:00 GMT Full Article
age DR Congo: Another Modern Tragedy By feedproxy.google.com Published On :: Wed, 15 Mar 2006 23:00:00 GMT Full Article
age Congo: Staying Engaged after the Elections By feedproxy.google.com Published On :: Mon, 08 Jan 2007 23:00:00 GMT Full Article
age Congo's Peace: Miracle or Mirage? By feedproxy.google.com Published On :: Sun, 22 Apr 2007 22:00:00 GMT Full Article
age Congo: A Stalled Democratic Agenda By feedproxy.google.com Published On :: Wed, 07 Apr 2010 22:00:00 GMT State building in the Democratic Republic of Congo is at risk of failing without a new impetus to support democratic consolidation in 2010. Full Article
age Congo Crimes Should Be on the Agenda of the UN Security Council By feedproxy.google.com Published On :: Wed, 13 Oct 2010 22:00:00 GMT The UN's release of a long awaited report on crimes committed in the Democratic Republic of Congo between 1993-2003 is not only an opportunity to re-examine the historical record of mass violence in DRC -- the scale and nature of which was often overlooked in the wake of the genocide in neighboring Rwanda -- but is also a chance to correct the terms of the deceptive and fragile peace some leaders wish to proclaim in the resource-rich Great Lakes region of Africa. Full Article
age Assessment of drug resistance during phase 2b clinical trials of presatovir in adults naturally infected with respiratory syncytial virus [Antiviral Agents] By aac.asm.org Published On :: 2020-02-18T08:15:40-08:00 Background: This study summarizes drug resistance analyses in 4 recent phase 2b trials of the respiratory syncytial virus (RSV) fusion inhibitor presatovir in naturally infected adults.Methods: Adult hematopoietic cell transplant (HCT) recipients, lung transplant recipients, or hospitalized patients with naturally acquired, laboratory-confirmed RSV infection were enrolled in 4 randomized, double-blind, placebo-controlled studies with study-specific presatovir dosing. Full-length RSV F sequences amplified from nasal swabs obtained at baseline and postbaseline were analyzed by population sequencing. Substitutions at RSV fusion inhibitor resistance-associated positions are reported.Results: Genotypic analyses were performed on 233 presatovir-treated and 149 placebo-treated subjects. RSV F variant V127A was present in 8 subjects at baseline. Population sequencing detected treatment-emergent substitutions in 10/89 (11.2%) HCT recipients with upper and 6/29 (20.7%) with lower respiratory tract infection, 1/35 (2.9%) lung transplant recipients, and 1/80 (1.3%) hospitalized patients treated with presatovir; placebo-treated subjects had no emergent resistance-associated substitutions. Subjects with substitutions at resistance-associated positions had smaller decreases in viral load during treatment relative to those without, but similar clinical outcomes.Conclusions: Subject population type and dosing regimen may have influenced RSV resistance development during presatovir treatment. Subjects with vs without genotypic resistance development had decreased virologic responses but comparable clinical outcomes. Full Article
age MK-571, a cysteinyl leukotriene receptor-1 antagonist, inhibits hepatitis C virus (HCV) replication [Antiviral Agents] By aac.asm.org Published On :: 2020-03-16T08:17:37-07:00 The quinoline MK-571 is the most commonly used inhibitor of multidrug resistance protein-1 (MRP-1) but was originally developed as a cysteinyl leukotriene receptor 1 (CysLTR1) antagonist. While studying the modulatory effect of MRP-1 on anti-hepatitis C virus (HCV) direct acting-antivirals (DAA) efficiency, we observed an unexpected anti-HCV effect of compound MK-571 alone. This anti-HCV activity was characterized in Huh7.5 cells stably harboring a subgenomic genotype 1b replicon. A dose-dependent decrease of HCV RNA levels was observed upon MK-571 administration, with an EC50 of 9±0.3 μM and a maximum HCV RNA level reduction of approximatively 1 Log10. MK-571 also reduced the replication of the HCV full-length J6/JFH1 model in a dose-dependent manner. However, probenecid and apigenin homodimer (APN), two specific inhibitors of MRP-1, had no effect on HCV replication. In contrast, the CysLTR1 antagonists SR2640 increased HCV-SGR RNA levels in a dose-dependent manner, with a maximum increase of 10-fold. In addition, a combination of natural CysLTR1 agonist (LTD4) or antagonists (zafirlukast, cinalukast, and SR2640) with MK-571 completely reversed its antiviral effect, suggesting its anti-HCV activity is related to CysLTR1 rather to MRP-1 inhibition. In conclusion, we showed that MK-571 inhibits HCV replication in hepatoma cell cultures by acting as a CysLTR1 receptor antagonist, thus unraveling a new host-virus interaction in the HCV life cycle. Full Article
age Significant efficacy of single low dose primaquine compared to stand alone artemisinin combination therapy in reducing gametocyte carriage in Cambodian patients with uncomplicated multidrug resistant Plasmodium falciparum malaria [Epidemiology and Surveil By aac.asm.org Published On :: 2020-03-16T08:17:37-07:00 Since 2012, single low dose of primaquine (SLDPQ, 0.25mg/kg) has been recommended with artemisinin-based combination therapies, as first-line treatment of acute uncomplicated Plasmodium falciparum malaria, to interrupt its transmission, especially in low transmission settings of multidrug, including artemisinin, resistance. Policy makers in Cambodia have been reluctant to implement this recommendation due to primaquine safety concerns and lack of data on its efficacy.In this randomized controlled trial, 109 Cambodians with acute uncomplicated P. falciparum malaria received dihydroartemisinin-piperaquine (DP) alone or combined with SLDPQ on the first treatment day. Transmission-blocking efficacy of SLDPQ was evaluated on Days 0, 1, 2, 3, 7, 14, 21, 28 and recrudescence by reverse transcriptase polymerase chain reaction (RT-PCR) (gametocyte prevalence) and membrane-feeding assays with Anopheles minimus mosquitoes (gametocyte infectivity). Without the influence of recrudescent infections, DP+SLDPQ reduced gametocyte carriage 3 fold compared to DP. Of 48 patients tested on Day 0, only three patients were infectious to mosquitoes (~6%). Post-treatment, three patients were infectious: on D14 (3.5%, 1/29), and on the first and seventh day of recrudescence (8.3%, 1/12 for each); this overall low infectivity precluded our ability to assess its transmission blocking efficacy.Our study confirms effective gametocyte clearance of SLDPQ when combined with DP in multidrug resistant P. falciparum and the negative impact of recrudescent infections due to poor DP efficacy. Artesunate-mefloquine (ASMQ) has replaced DP and ASMQ-SLDPQ has been deployed to treat all P. falciparum symptomatic patients to further support the elimination of multidrug resistant P. falciparum in Cambodia. Full Article
age Rapid-Release Griffithsin Fibers for the Dual Prevention of HSV-2 and HIV-1 Infections [Antiviral Agents] By aac.asm.org Published On :: 2020-03-30T10:04:32-07:00 The biologic Griffithsin (GRFT) has recently emerged as a candidate to safely prevent sexually transmitted infections (STIs) including human immunodeficiency virus (HIV-1) and herpes simplex virus 2 (HSV-2). However, to date, there are few delivery platforms that are available to effectively deliver biologics to the female reproductive tract (FRT). The goal of this work was to evaluate rapid-release polyethylene oxide (PEO), polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP) fibers, that incorporate GRFT, in in vitro (HIV-1 and HSV-2) and in vivo (HSV-2) infection models. GRFT loading was determined via ELISA, and the bioactivity of GRFT fibers was assessed using in vitro HIV-1 pseudovirus and HSV-2 plaque assays. Afterwards, the efficacy of GRFT fibers was assessed in a murine model of lethal HSV-2 infection. Finally, murine reproductive tracts and vaginal lavages were evaluated for histology and cytokine expression, 24 and 72 hr after fiber administration, to determine safety. All rapid-release formulations achieved high levels of GRFT incorporation and were completely efficacious against in vitro HIV-1 and HSV-2 infections. Importantly, all rapid-release GRFT fibers provided potent protection in a murine model of HSV-2 infection. Moreover, histology and cytokine levels, evaluated from collected murine reproductive tissues and vaginal lavages treated with blank fibers, showed no increased cytokine production or histological aberrations, demonstrating the preliminary safety of rapid-release GRFT fibers in vaginal tissue. Full Article
age Population Pharmacokinetics and Dosage Optimization of Linezolid in Patients with Liver Dysfunction [Pharmacology] By aac.asm.org Published On :: 2020-04-06T08:49:25-07:00 Linezolid is the first synthetic oxazolidone agent to treat infections caused by Gram-positive pathogens. Infected patients with liver dysfunction (LD) are more likely to suffer from adverse reactions such as thrombocytopenia when standard-dose linezolid is used than patients with LD who didn't use linezolid. Currently, pharmacokinetics data of linezolid in patients with LD are limited. The study aimed to characterize pharmacokinetics parameters of linezolid in patients with LD, identify the factors influencing the pharmacokinetics, and propose an optimal dosage regimen. We conducted a prospective study and established population pharmacokinetics model with the Phoenix NLME. The final model was evaluated by goodness-of-fit plots, bootstrap analysis, and prediction corrected-visual predictive check. A total of 163 concentration samples from 45 patients with LD were adequately described by a one-compartment model with first-order elimination along with prothrombin activity (PTA) and creatinine clearance as significant covariates. Linezolid clearance (CL) was 2.68 L/h (95% confidence interval [CI]: 2.34-3.03 L/h); the volume of distribution (Vd) was 58.34 L (95% CI: 48.00-68.68 L). Model-based simulation indicated that the conventional dose was at risk for overexposure in patients with LD or severe renal dysfunction; reduced dosage (300 mg/12 h) would be appropriate to achieve safe (Cmin, ss at 2-8 ug/mL) and effective targets (the ratio of AUC0-24 at steady state to MIC, 80-100). In addition, for patients with severe LD (PTA <= 20%), the dosage (400 mg/24 h) was sufficient at an MIC <= 2 ug/mL. This study recommended therapeutic drug monitoring for patients with LD. Full Article
age Novel peptide from commensal Staphylococcus simulans blocks MRSA quorum sensing and protects host skin from damage [Mechanisms of Action] By aac.asm.org Published On :: 2020-04-06T08:49:25-07:00 Recent studies highlight the abundance of commensal coagulase-negative staphylococci (CoNS) on healthy skin. Evidence suggests that CoNS actively shape the skin immunological and microbial milieu to resist colonization or infection by opportunistic pathogens, including methicillin resistant Staphylococcus aureus (MRSA), in a variety of mechanisms collectively termed colonization resistance. One potential colonization resistance mechanism is the application of quorum sensing, also called the Accessory Gene Regulator (agr) system, which is ubiquitous among staphylococci. Common and rare CoNS make autoinducing peptides (AIPs) that function as MRSA agr inhibitors, protecting the host from invasive infection. In a screen of CoNS spent media we found that Staphylococcus simulans, a rare human skin colonizer and frequent livestock colonizer, released potent inhibitors of all classes of MRSA agr signaling. We identified three S. simulans agr classes, and have shown intraspecies cross-talk between non-cognate S. simulans agr types for the first time. The S. simulans AIP-I structure was confirmed, and the novel AIP-II and AIP-III structures were solved via mass spectrometry. Synthetic S. simulans AIPs inhibited MRSA agr signaling with nanomolar potency. S. simulans in competition with MRSA reduced dermonecrotic and epicutaneous skin injury in murine models. Addition of synthetic AIP-I also effectively reduced MRSA dermonecrosis and epicutaneous skin injury in murine models. These results demonstrate potent anti-MRSA quorum sensing inhibition by a rare human skin commensal, and suggest that cross-talk between CoNS and MRSA may be important in maintaining healthy skin homeostasis and preventing MRSA skin damage during colonization or acute infection. Full Article
age Novel ionophores active against La Crosse virus identified through rapid antiviral screening [Antiviral Agents] By aac.asm.org Published On :: 2020-04-13T08:15:30-07:00 Bunyaviruses are significant human pathogens, causing diseases ranging from hemorrhagic fevers to encephalitis. Among these viruses, La Crosse virus (LACV), a member of the California serogroup, circulates in the eastern and midwestern United States. While LACV infection is often asymptomatic, dozens of cases of encephalitis are reported yearly. Unfortunately, no antivirals have been approved to treat LACV infection. Here, we developed a method to rapidly test potential antivirals against LACV infection. From this screen, we identified several potential antiviral molecules, including known antivirals. Additionally, we identified many novel antivirals that exhibited antiviral activity without affecting cellular viability. Valinomycin, a potassium ionophore, was among our top targets. We found that valinomycin exhibited potent anti-LACV activity in multiple cell types in a dose-dependent manner. Valinomycin did not affect particle stability or infectivity, suggesting that it may preclude virus replication by altering cellular potassium ions, a known determinant of LACV entry. We extended these results to other ionophores and found that the antiviral activity of valinomycin extended to other viral families including bunyaviruses (Rift Valley fever virus, Keystone virus), enteroviruses (Coxsackievirus, rhinovirus), flavirivuses (Zika), and coronaviruses (HCoV-229E and MERS-CoV). In all viral infections, we observed significant reductions in virus titer in valinomycin-treated cells. In sum, we demonstrate the importance of potassium ions to virus infection, suggesting a potential therapeutic target to disrupt virus replication.Importance No antivirals are approved for the treatment of bunyavirus infection. The ability to rapidly screen compounds and identify novel antivirals is one means to accelerate drug discovery for viruses with no approved treatments. We used this approach to screen hundreds of compounds against La Crosse virus, an emerging bunyavirus that causes significant disease, including encephalitis. We identified several known and previously unidentified antivirals. We focused on a potassium ionophore, valinomycin, due to its promising in vitro antiviral activity. We demonstrate that valinomycin, as well as a selection of other ionophores, exhibits activity against La Crosse virus as well as several other distantly related bunyaviruses. We finally observe that valinomycin has activity against a wide array of human viral pathogens, suggesting that disrupting potassium ion homeostasis with valinomycin may be a potent host pathway to target to quell virus infection. Full Article