pot Performance Metrics After Changes in Screening Protocol for Congenital Hypothyroidism By pediatrics.aappublications.org Published On :: 2012-10-08T00:07:34-07:00 Significant variation in congenital hypothyroidism screening operations/performance has been observed in the United States. The origin of this variation remains unknown, in part because of a lack of evaluation. Accordingly, debates persist about optimal screening operations including laboratory testing methods.Four distinct screening protocols applied to Michigan resident infants are compared in detecting congenital hypothyroidism overall and specific to cases characterized by high initial thyrotropin concentrations thought to have a more severe form of the disease. (Read the full article) Full Article
pot Hypothalamic-Pituitary-Adrenal Axis Suppression in Asthmatic School Children By pediatrics.aappublications.org Published On :: 2012-11-12T00:08:30-08:00 Hypothalamic-pituitary-adrenal axis suppression caused by inhaled corticosteroids is considered rare. Adrenal crisis has been described in children treated with high doses of inhaled fluticasone propionate. It was recommended that doses licensed for children should not be exceeded.Biochemically confirmed hypothalamic-pituitary-adrenal axis dysfunction may occur in two-thirds of children treated with corticosteroids. Suppression may occur at low doses and especially with concomitant nasal steroids. Children with poor adherence or obesity may be less prone to adrenal crisis. (Read the full article) Full Article
pot Informed Choice for Newborn Blood Spot Screening in the United Kingdom: A Survey of Parental Perceptions By pediatrics.aappublications.org Published On :: 2012-11-12T00:08:28-08:00 Newborn screening is often seen as a fait accompli, even in programs that ostensibly proceed on the basis of informed choice and parental consent.The study reports details of parental understanding, perceived ability to make an informed choice, and the availability of choice together with variables predictive of parental assessments of having made an informed choice. (Read the full article) Full Article
pot Potential Sources of Bisphenol A in the Neonatal Intensive Care Unit By pediatrics.aappublications.org Published On :: 2013-02-18T00:06:43-08:00 Bisphenol A (BPA) is an environmental endocrine disruptor that can leach from polycarbonate plastics and epoxy resins, leading to widespread exposure. Fetal and early postnatal periods are particularly vulnerable to exposure to BPA.This study identified medical devices as a potential source of exposure to BPA among premature infants in the NICU, even when efforts to reduce polycarbonate plastics were taken. (Read the full article) Full Article
pot Neonatal Visual Evoked Potentials in Infants Born to Mothers Prescribed Methadone By pediatrics.aappublications.org Published On :: 2013-02-18T00:06:42-08:00 Impaired visual development has been reported in infants born to mothers prescribed methadone in pregnancy. Immature visual evoked potentials have been reported in this population, but data were confounded by gestation, growth restriction, and illicit drug use.Visual evoked potentials are small and immature in infants exposed to methadone and other drugs of misuse in utero. These changes are independently associated with methadone exposure and persist after controlling for gestation, socioeconomic deprivation, alcohol consumption, and cigarette smoking. (Read the full article) Full Article
pot Use of Antihypotensive Therapies in Extremely Preterm Infants By pediatrics.aappublications.org Published On :: 2013-05-06T00:07:30-07:00 Extremely preterm infants who receive antihypotensive therapy have worse outcomes than untreated infants. The reasons for this are not clear. High-quality randomized trials have not been performed to date because of logistical challenges, thereby necessitating alternative methods of investigation.Antihypotensive therapy administration was not associated with improved in-hospital outcomes for any of the 15 definitions of low blood pressure investigated. Alternative methods of deciding who to treat are needed to maximize patient benefit and minimize harm. (Read the full article) Full Article
pot Plastic Bags for Prevention of Hypothermia in Preterm and Low Birth Weight Infants By pediatrics.aappublications.org Published On :: 2013-06-03T00:07:03-07:00 Preterm neonates in resource-poor settings frequently develop hypothermia. Plastic bags or wraps are a low-cost intervention for the prevention of hypothermia in infants in developed countries.For preterm infants born in a resource-poor health facility, placement in a plastic bag at birth can reduce the incidence of hypothermia at 1 hour after birth. (Read the full article) Full Article
pot Parental Knowledge of Potential Cancer Risks From Exposure to Computed Tomography By pediatrics.aappublications.org Published On :: 2013-07-08T00:07:25-07:00 Studies have highlighted a lack of patient awareness of potential increased cancer risks associated with computed tomography (CT) scans in adult patients and in nonurgent settings. However, little is known about parental awareness of these risks in an emergency setting.Approximately half of parents were aware of the potential cancer risks from CT scans in an emergency setting. Although risk disclosure moderately reduced willingness to proceed with recommended testing, almost all parents preferred an informed discussion before CT imaging. (Read the full article) Full Article
pot Randomized Trial of Plastic Bags to Prevent Term Neonatal Hypothermia in a Resource-Poor Setting By pediatrics.aappublications.org Published On :: 2013-08-26T00:07:46-07:00 Term neonates in resource-poor settings frequently develop hypothermia. Plastic bags or wraps are a low-cost intervention for the prevention of hypothermia in preterm and low birth weight infants that may also be effective in term infants.For term neonates born in a resource-poor health facility, placement in a plastic bag at birth can reduce the incidence of hypothermia at 1 hour after birth. (Read the full article) Full Article
pot 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
pot Identifying Potential Kidney Donors Among Newborns Undergoing Circulatory Determination of Death By pediatrics.aappublications.org Published On :: 2013-12-02T00:06:05-08:00 The demand for donor kidneys for transplantation exceeds supply. En bloc kidney transplantation and donation after determination of circulatory death from pediatric donors increases the potential donor pool.Newborn infants undergoing elective withdrawal of life support in the NICU are a previously unrecognized source of potential kidney donors. (Read the full article) Full Article
pot Postural Orthostatic Tachycardia Syndrome (POTS) and Vitamin B12 Deficiency in Adolescents By pediatrics.aappublications.org Published On :: 2013-12-23T00:06:52-08:00 Studies have shown dysfunction in the baroreflex mechanism and the autonomic nervous system, particularly in the sympathetic nervous system, in the pathophysiology of chronic fatigue syndrome, postural orthostatic tachycardia syndrome, and syncope.Vitamin B12 deficiency is associated with postural orthostatic tachycardia syndrome in adolescence. (Read the full article) Full Article
pot Xenon Ventilation During Therapeutic Hypothermia in Neonatal Encephalopathy: A Feasibility Study By pediatrics.aappublications.org Published On :: 2014-04-28T00:07:23-07:00 Hypothermia treatment of neonatal encephalopathy reduces death and disability from 66% to 50%; additional neuroprotective therapies are needed. We previously found in animal models that adding 50% xenon to the breathing gas during cooling doubled neuroprotection.This clinical feasibility study used 50% xenon for 3 to 18 hours in 14 cooled infants with cardiovascular, respiratory, and amplitude-integrated EEG monitoring. This depressed seizures, with no blood pressure reduction. Xenon is ready for randomized clinical trials in newborns. (Read the full article) Full Article
pot Prenatal Tobacco Exposure and Cotinine in Newborn Dried Blood Spots By pediatrics.aappublications.org Published On :: 2014-05-12T00:06:52-07:00 Cotinine assays for dried blood spots have been developed but not deployed in a large sample of newborn specimens.Cotinine levels consistent with active maternal smoking were detectable in 12% of newborn blood spots, although 41% of the mothers reportedly did not smoke. Data confirm that reported smoking during pregnancy is an imperfect measure of prenatal tobacco smoke exposure. (Read the full article) Full Article
pot Potential Drug-Drug Interactions in Infant, Child, and Adolescent Patients in Children's Hospitals By pediatrics.aappublications.org Published On :: 2014-12-15T00:06:45-08:00 Hospitalized pediatric patients are often exposed to many medications during an inpatient admission. Drug–drug interactions may increase the risk of developing medication-related adverse drug events, leading to serious clinical morbidity and mortality.Exposure to "major" potential drug–drug interactions occurs in 41% of pediatric hospitalizations in children’s hospitals. One-half of all these exposures were due to less common specific drug pairs (≤3% of patients exposed per hospital day) and thus may be less clinically familiar. (Read the full article) Full Article
pot Potential Effect of Physical Activity Calorie Equivalent Labeling on Parent Fast Food Decisions By pediatrics.aappublications.org Published On :: 2015-01-26T00:05:26-08:00 Menu labels depicting physical activity calorie equivalents may lead to ordering of fast food meals totaling fewer calories for adults. The effects of physical activity calorie equivalent labeling on parents’ fast food decisions for their children have not been examined.Parents shown menus with any type of caloric content label may order fast food meals totaling fewer calories for their children. Menu labels showing physical activity equivalents may be more likely to influence parents to encourage their children to exercise. (Read the full article) Full Article
pot Special Education Funding Gets Moment in Spotlight at Democratic Debate By feedproxy.google.com Published On :: Thu, 19 Dec 2019 00:00:00 +0000 Advocates for increased federal funding for special education cheered Thursday when the issue was raised on the Democratic presidential debate stage in Los Angeles. Full Article Idea
pot 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
pot Online newsletter provides updates, recommendations on spotted lanternfly By news.psu.edu Published On :: Fri, 01 May 2020 15:40 -0400 A new online newsletter offered by Penn State Extension will give readers “the scoop” on the spotted lanternfly. Full Article
pot WITHDRAWN: Very strong synergy between modified RANTES and gp41 binding peptides leads to potent anti-HIV-1 activity [Article] By aac.asm.org Published On :: 2009-08-31T14:31:00-07:00 This article, published ahead of print on 28 July 2008, has been withdrawn by the authors. Although moderate synergy between P2-RANTES and C peptides can be observed with high statistical significance in cell fusion assays, this synergy was not able to be verified in HIV viral assays. The authors regret the overstatement of synergy and will revise the paper for publication at a later date. Full Article
pot 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
pot An engineered double lipid II binding motifs-containing lantibiotic displays potent and selective antimicrobial activity against E. faecium [Chemistry; Biosynthesis] By aac.asm.org Published On :: 2020-03-16T08:17:37-07:00 Lipid II is an essential precursor of the bacterial cell wall biosynthesis and thereby an important target for various antibiotics. Several lanthionine-containing peptide antibiotics target lipid II with lanthionine-stabilized lipid II-binding motifs. Here, we used the biosynthesis system of the lantibiotic nisin to synthesize a two lipid II binding motifs-containing lantibiotic, termed TL19, which contains the N-terminal lipid II binding motif of nisin and the distinct C-terminal lipid II binding motif of one peptide of the two-component haloduracin (i.e. HalA1). Further characterization demonstrated that (i) TL19 exerts 64-fold stronger antimicrobial activity against E. faecium than nisin (1-22), which has only one lipid II binding site, and (ii) both the N- and C-terminal domains are essential for the potent antimicrobial activity of TL19, as evidenced by mutagenesis of each single and double domains. These results show the feasibility of a new approach to synthesize potent lantibiotics with two different lipid II binding motifs to treat specific antibiotic-resistant pathogens. Full Article
pot Reconciling the potentially irreconcilable? Genotypic and phenotypic amoxicillin-clavulanate resistance in Escherichia coli [Mechanisms of Resistance] By aac.asm.org Published On :: 2020-03-23T08:47:35-07:00 Resistance to amoxicillin-clavulanate, a widely used beta-lactam/beta-lactamase inhibitor combination antibiotic, is rising globally, yet susceptibility testing remains challenging. To test whether whole-genome sequencing (WGS) could provide a more reliable assessment of susceptibility than traditional methods, we predicted resistance from WGS for 976 E. coli bloodstream infection isolates from Oxfordshire, UK, comparing against phenotypes from the BD Phoenix (calibrated against EUCAST guidelines). 339/976 (35%) isolates were amoxicillin-clavulanate resistant. Predictions based solely on beta-lactamase presence/absence performed poorly (sensitivity 23% (78/339)) but improved when genetic features associated with penicillinase hyper-production (e.g. promoter mutations, copy number estimates) were considered (sensitivity 82% (277/339); p<0.0001). Most discrepancies occurred in isolates with peri-breakpoint MICs. We investigated two potential causes; the phenotypic reference and the binary resistant/susceptible classification. We performed reference standard, replicated phenotyping in a random stratified subsample of 261/976 (27%) isolates using agar dilution, following both EUCAST and CLSI guidelines, which use different clavulanate concentrations. As well as disagreeing with each other, neither agar dilution phenotype aligned perfectly with genetic features. A random-effects model investigating associations between genetic features and MICs showed that some genetic features had small, variable and additive effects, resulting in variable resistance classification. Using model fixed-effects to predict MICs for the non-agar dilution isolates, predicted MICs were in essential agreement (±1 doubling dilution) with observed (BD Phoenix) MICs for 691/715 (97%) isolates. This suggests amoxicillin-clavulanate resistance in E. coli is quantitative, rather than qualitative, explaining the poorly reproducible binary (resistant/susceptible) phenotypes and suboptimal concordance between different phenotypic methods and with WGS-based predictions. Full Article
pot The Impact of Intrinsic Resistance Mechanisms on Potency of QPX7728, a New Ultra-Broad-Spectrum Beta-lactamase Inhibitor of Serine and Metallo Beta-Lactamases in Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii. [Mechanisms of Resis By aac.asm.org Published On :: 2020-03-30T10:04:32-07:00 QPX7728 is an ultra-broad-spectrum boronic acid beta-lactamase inhibitor that demonstrates inhibition of key serine and metallo beta-lactamases at a nano molar range in biochemical assays with purified enzymes. The broad-spectrum inhibitory activity of QPX7728 observed in biochemical experiments translates into enhancement of the potency of many beta-lactams against strains of target pathogens producing beta-lactamases. The impact of bacterial efflux and permeability on inhibitory potency were determined using isogenic panels of KPC-3 producing isogenic strains of K. pneumoniae and P. aeruginosa and OXA-23-producing strains of A. baumannii with various combinations of efflux and porin mutations. QPX7728 was minimally affected by multi-drug resistance efflux pumps in either Enterobacteriaceae, or in non-fermenters such as P. aeruginosa or A. baumannii. In P. aeruginosa, the potency of QPX7728 was further enhanced when the outer membrane is permeabilized. The potency of QPX7728 in P. aeruginosa is not affected by inactivation of the carbapenem porin OprD. While changes in OmpK36 (but not OmpK35) reduced the potency of QPX7728 (8-16-fold), QPX7728 (4 μg/ml) nevertheless completely reversed KPC-mediated meropenem resistance in strains with porin mutations, consistent with a lesser effect of these mutations on the potency of QPX7728 compared to other agents. The ultra-broad-spectrum beta-lactamase inhibition profile combined with enhancement of the activity of multiple beta-lactam antibiotics with varying sensitivity to the intrinsic resistance mechanisms of efflux and permeability indicate QPX7728 is a useful inhibitor for use with multiple beta-lactam antibiotics. Full Article
pot OPC-167832, a novel carbostyril derivative with potent anti-tuberculosis activity as a DprE1 inhibitor [Pharmacology] By aac.asm.org Published On :: 2020-03-30T10:04:32-07:00 There is an urgent need for new, potent anti-tuberculosis (TB) drugs with novel mechanisms of action that can be included in new regimens to shorten the treatment period for TB. After screening a library of carbostyrils, we optimized 3, 4-dihydrocarbostyril derivatives and identified OPC-167832 as having potent anti-tuberculosis activity. The minimum inhibitory concentrations of the compound for Mycobacterium tuberculosis ranged from 0.00024 to 0.002 μg/mL. It had bactericidal activity against both growing and intracellular bacilli, and the frequency of spontaneous resistance for Mycobacterium tuberculosis H37Rv was less than 1.91 x 10-7. It did not show antagonistic effects with other anti-TB agents in an in vitro checkerboard assay. Whole genome and targeted sequencing of resistant isolates to OPC-167832 identified the decaprenylphosphoryl-β-D-ribose 2'-oxidase (DprE1), an essential enzyme for cell wall biosynthesis, as the target of this compound, and further studies demonstrated inhibition of the DprE1 enzymatic activity by OPC-167832. In a mouse model of chronic TB, OPC-167832 showed potent bactericidal activities starting at a dose of 0.625 mg/kg. Further, it exhibited significant combination effects in 2-drug combinations with delamanid, bedaquiline, or levofloxacin. Finally, 3-4 drug regimens comprised of delamanid and OPC-167832 as the core along with bedaquiline, moxifloxacin, or linezolid showed superior efficacy in reducing bacterial burden and preventing relapse compared to the standard treatment regimen. In summary, these results suggest that OPC-167832 is a novel and potent anti-TB agent and regimens containing OPC-167832 and new or repurposed anti-TB drugs may have the potential to shorten the duration of treatment for TB. Full Article
pot Fenbendazole controls in vitro growth, virulence potential and animal infection in the Cryptococcus model [Experimental Therapeutics] By aac.asm.org Published On :: 2020-04-06T08:49:25-07:00 The human diseases caused by the fungal pathogens Cryptococcus neoformans and C. gattii are associated with high indices of mortality, and toxic and/or cost-prohibitive therapeutic protocols. The need for affordable antifungals to combat cryptococcal disease is unquestionable. Previous studies suggested benzimidazoles as promising anti-cryptococcal agents combining low cost and high antifungal efficacy, but their therapeutic potential has not been demonstrated so far. In this study, we investigated the antifungal potential of fenbendazole, the most effective anti-cryptococcal benzimidazole. Fenbendazole was inhibitory against 17 different isolates of C. neoformans and C. gattii at a low concentration. The mechanism of anti-cryptococcal activity of fenbendazole involved microtubule disorganization, as previously described for human parasites. In combination with fenbendazole, the concentrations of the standard antifungal amphotericin B required to control cryptococcal growth were lower than those required when this antifungal was used alone. Fenbendazole was not toxic to mammalian cells. During macrophage infection, the anti-cryptococcal effects of fenbendazole included inhibition of intracellular proliferation rates and reduced phagocytic escape through vomocytosis. Fenbendazole deeply affected the cryptococcal capsule. In a mice model of cryptococcosis, the efficacy of fenbendazole to control animal mortality was similar to that observed for amphotericin B. These results indicate that fenbendazole is a promising candidate for the future development of an efficient and affordable therapeutic tool to combat cryptococcosis. Full Article
pot Safety, Pharmacokinetics, and Drug:Drug Interaction Potential of Intravenous Durlobactam, a {beta}-lactamase Inhibitor, in Healthy Subjects [Pharmacology] By aac.asm.org Published On :: 2020-04-13T08:15:30-07:00 Durlobactam (DUR, also known as ETX2514) is a novel β-lactamase inhibitor with broad activity against Ambler class A, C, and D β-lactamases. Addition of DUR to sulbactam (SUL) in vitro restores SUL activity against clinical isolates of Acinetobacter baumannii. The safety and pharmacokinetics (PK) of DUR alone and with SUL and/or imipenem/cilastatin (IMI/CIL) were evaluated in healthy subjects. This was a randomized, placebo-controlled study. In Part A, subjects including an elderly cohort (DUR 1 g) received single ascending doses of DUR 0.25-8 g. In Part B, multiple ascending dose of DUR 0.25-2 g were administered every 6 hours (q6h) for 29 doses. In Parts C and D, the drug-drug interaction (DDI) potential, including safety, of DUR (1 g) with SUL (1 g) and/or IMI/CIL (0.5/0.5 g) was investigated after single and multiple doses. Plasma and urine concentrations of DUR, SUL, and IMI/CIL were determined. Among 124 subjects, DUR was generally safe and well tolerated either alone or in combination with SUL and/or IMI/CIL. After single and multiple doses, DUR demonstrated linear dose proportional exposure across the studied dose ranges. Renal excretion was a predominant clearance mechanism. No drug:drug interaction potential was identified between DUR and SUL and/or IMI/CIL. SUL-DUR, 1 g (of each component) administered q6h with a 3 hour IV infusion, is under development for the treatment of serious infections due to A. baumannii. Full Article
pot Phase 2a Pharmacokinetic, Safety, and Exploratory Efficacy Evaluation of Oral Gepotidacin (GSK2140944) in Female Participants With Uncomplicated Urinary Tract Infection (Acute Uncomplicated Cystitis) [Clinical Therapeutics] By aac.asm.org Published On :: 2020-04-13T08:15:31-07:00 Gepotidacin, a triazaacenaphthylene bacterial type II topoisomerase inhibitor, is in development for treatment of uncomplicated urinary tract infection (uUTI). This Phase 2a study in female participants with uUTI evaluated the pharmacokinetics (primary objective), safety, and exploratory efficacy of gepotidacin. Eligible participants (N = 22) were confined to the clinic at baseline, received oral gepotidacin 1,500 mg twice daily for 5 days (on-therapy; Days 1 to 5), and returned to the clinic for test-of-cure (Days 10 to 13) and follow-up (Day 28±3). Pharmacokinetic, safety, clinical, and microbiological assessments were performed. Maximum plasma concentrations were observed approximately 1.5 to 2 hours postdose. Steady state was attained by Day 3. Urinary exposure over the dosing interval increased from 3,742 μg.h/ml (Day 1) to 5,973 μg.h/ml (Day 4), with trough concentrations of 322 to 352 μg/ml from Day 3 onward. Gepotidacin had an acceptable safety-risk profile with no treatment-limiting adverse events and no clinically relevant safety trends. Clinical success was achieved in 19 (86%) and 18 (82%) of 22 participants at test-of-cure and follow-up, respectively. Eight participants had a qualifying baseline uropathogen (growth; ≥105 CFU/ml). A therapeutic (combined clinical and microbiological [no growth; <103 CFU/ml]) successful response was achieved in 6 (75%) and 5 (63%) of 8 participants at test-of-cure and follow-up, respectively. Plasma area under the free-drug concentration-time curve over 24 hours at steady state divided by the MIC (fAUC0-24/MIC) and urine AUC0-24/MIC ranged from 6.99 to 90.5 and 1,292 to 121,698, respectively. Further evaluation of gepotidacin in uUTI is warranted. (NCT03568942) Full Article
pot Development of Novel Anti-influenza Thiazolides with Relatively Broad-spectrum Antiviral Potentials [Antiviral Agents] By aac.asm.org Published On :: 2020-04-20T08:36:46-07:00 Seasonal and pandemic influenza causes 650,000 deaths annually in the world. The emergence of drug-resistance to specific anti-influenza drugs such as oseltamivir and baloxavir marboxil highlights the urgency of novel anti-influenza chemical entity discovery. In this study, we report a series of novel thiazolides derived from an FDA-approved drug nitazoxanide with antiviral activity against influenza and a broad range of viruses. The preferred candidates 4a and 4d showed significantly enhanced anti-influenza potentials with 10-fold improvement, compared with nitazoxanide, and were effective against a variety of influenza subtypes including oseltamivir-resistant strains. Notably, the combination using of compounds 4a/4d and oseltamivir carboxylate or zanamivir displayed synergistic antiviral effect against oseltamivir-resistant strain. Mode of action analysis demonstrated that compounds 4a/4d acted at the late phase of viral infection cycle through inhibiting viral RNA transcription and replication. Further experiments showed that treatment with compounds 4a/4d significantly inhibited influenza virus infection in human lung organoids, suggesting the druggability of the novel thiazolides. In-depth transcriptome analysis revealed a series of up-regulated cellular genes that may contribute to the antiviral activities of 4a/4d. Together, our study pointed the optimization direction of nitazoxanide as anti-influenza drug, and discovered two novel-structured candidates 4a/4d with relatively broad-spectrum antiviral potential. Full Article
pot Manogepix (APX001A) displays potent in vitro activity against human pathogenic yeast, but with an unexpected correlation to fluconazole MICs [Susceptibility] By aac.asm.org Published On :: 2020-05-04T08:49:24-07:00 Manogepix (APX001A) is the active moiety of the novel drug candidate fosmanogepix (APX001). We previously reported the broad-spectrum activity of manogepix but also observed a correlation between increased manogepix and fluconazole MICs. Here we extended this study and included isolates with acquired fluconazole resistance.Isolates (n=835) were identified using CHROMagar, MALDI-TOF and, when needed, ITS-sequencing. EUCAST E.Def 7.3.1 susceptibility testing included manogepix, amphotericin B, anidulafungin, micafungin, fluconazole and voriconazole. Manogepix wildtype-upper-limit (WT-UL) values were established following EUCAST-principles for ECOFF setting allowing wildtype/non-wildtype classification. Drug-specific MIC correlations were investigated using Pearson's correlation.Manogepix modal MICs were low (range 0.004-0.06 mg/L against 16/20 included species). Exceptions were C. krusei and C. inconspicua, and to a lesser extent C. kefyr and Pichia kluyveri. The activity was independent of Fks echinocandin hot-spot alterations (n=17). Adopting the WT-UL established for C. albicans, C. dubliniensis, C. glabrata, C. parapsilosis and C. tropicalis, 14/724 (1.9%) isolates were non-wildtype for manogepix. Twelve of these (85.7%) were also non-wildtype for fluconazole. A statistically significant correlation was observed between manogepix and fluconazole MICs for C. albicans, C. dubliniensis, C. glabrata, C. parapsilosis and C. tropicalis (Pearson r=0.401-0.575), but not between manogepix and micafungin or amphotericin B MICs for any species except C. tropicalis (r=0.519 for manogepix versus micafungin).Broad-spectrum activity was confirmed for manogepix against contemporary yeast. However, a 1-4 two-fold-dilution increase in manogepix MICs is observed in a subset of isolates with acquired fluconazole resistance. Further studies on the potential underlying mechanism and implication for optimal dosing are warranted. Full Article
pot HubSpot CRM By www.pcmag.com Published On :: HubSpot CRM does a great job delivering a high-quality CRM for small business customers. With a fast-growing portfolio of new platforms and features, HubSpot might also evolve into an end-to-end martech ecosystem for many customers. Full Article
pot Champions League Fantasy popular picks and potential differentials By www.uefa.com Published On :: Mon, 17 Feb 2020 14:00:00 GMT Ahead of Matchday 7, UEFA.com looks at some obvious selections and some lesser-owned options. Full Article general
pot How to Spot Fake News Online By www.pcmag.com Published On :: Not sure which sources to trust when you're online? These browser plug-ins and online tools can help you figure out how to detect fake news sites. Full Article
pot Apple Music vs. Spotify: Which Is Best? By www.pcmag.com Published On :: Today, Apple takes on the biggest name in music streaming, Spotify. How do they measure up to each other? Full Article
pot Amazon Music Unlimited vs. Spotify: How Do They Compare? By www.pcmag.com Published On :: The big difference between Spotify and Amazon Music Unlimited is Amazon offers an affordable tier of service available on just one Echo device. Here's how else they differ. Full Article
pot Spotify By www.pcmag.com Published On :: Spotify, available in both free and premium versions, remains a top-tier streaming music thanks to its deep library, collaborative playlists, early album access, and podcasts. Full Article
pot Netgear Teases Better 5G Hotspot, Probably for AT&T By www.pcmag.com Published On :: The Netgear M5 is the 5G hotspot we've been waiting for, but it isn't coming out until the second half of the year. A separate Netgear CES announcement, meanwhile, showed another weakness of 5G in the US right now. Full Article
pot Champions League Fantasy popular picks and potential differentials By www.uefa.com Published On :: Wed, 04 Mar 2020 15:00:00 GMT Ahead of Matchday 8, UEFA.com looks at some obvious #UCLfantasy selections and those who could cause a surprise. Full Article general
pot Spotlight on education at Matteo Ricci College By feedproxy.google.com Published On :: Wed, 24 Aug 2016 00:00:00 -0600 By Sr. Joan L. Roccasalvo, C.S.J.Matteo Ricci College (MRC) is one of eight schools and colleges that form part of Seattle University, a Catholic institution conducted by the Society of Jesus. With the Humanities as its core, MRC offers three degrees: a Bachelor of Arts in Humanities (BAH), a Bachelor of Arts in Humanities for Leadership (BAHL), and a Bachelor of Arts in Humanities for Teaching (BAHT). Mission of MRC MRC educates teachers and leaders for a just and humane world. The study of Western culture is the surest place to begin. Pseudo-educators claim it’s a waste of time. Yet, the facts don’t lie. We are the beneficiaries of Greco-Roman culture preserved, reinterpreted, and handed down through the Catholic Church’s medieval monastic tradition and continued through the Italian Renaissance. To be human is to be in a story, and to forget one's story leaves a person without a present identity, without a past and without a future. At MRC, cultural history is taught so that students can draw moral lessons from it. Those who don’t learn from these lessons are condemned to repeat and relive them. With the small class size at MRC, professors can take a personal interest in each student. In this environment conducive to learning, a close collaboration between student and professor is pursued. This encourages greater participation in class. Shouldn’t MRC be the envy of most serious students? You would think so. What’s in a Name? MRC is named after the 16th - century Jesuit priest Matteo Ricci (1552-1610) who spent his adult life as an educator and missionary in China. At that time, the doors of the Chinese empire were closed to foreigners from the West. It was Ricci who brought Western civilization to China, and Chinese literati reciprocated by sharing with him their ancient and venerable culture. For him, inculturation was a reality centuries before the term was invented. He founded the modern Chinese Catholic Church. Ricci astonished the Chinese because he loved them. An authority on so many subjects and disciplines—mathematics, astronomy, apologetics, literature, popular catechesis, poetry, art and music—he brought this treasury of gifts to his mission. His intellectual gifts were prodigious: a photographic memory, linguistic ability to speak flawless Chinese, ingenuity to write maps, assemble clocks, read the stars. As if this weren’t enough, Ricci had a keen ear for music and reportedly sang with great sweetness. This “wise man from the west” is recognized as “the most cultivated man of his time and one of the most remarkable and brilliant men of history.” Known throughout the realm as Li-Ma-T’ou, this missionary scholar remains the most respected and beloved foreign figure in Chinese culture. Some in the Chinese government view him as the “Second Founder of Modern China.” This is the man after whom MRC is named. He is its model of a complete liberal arts education cast in the Jesuit mold. Student Protest against the Curriculum of MRC In May, some two hundred enrolled students at (MRC) staged a week-long sit-in objecting to the core curriculum: The focus on Western culture and values was declared irrelevant. Studies in Western Civilization had failed to serve the academic interests of these students. The students demanded of the administration that the classic core curriculum in the Humanities be discarded in favor of a new program of studies to reflect special interest groups of race, class, gender, and disability. Additionally, they demanded that only qualified faculty be hired to teach courses that reflected their interest in identity group studies of race, class, gender, and disability. The Dean of the MRC was to be fired. Student demands focused on “dissatisfaction, traumatization, and boredom,” that is, “the Humanities program as it exists today” which “ignores and erases the humanity of its students and of peoples around the globe.” . . . “We are diverse, with many different life experiences, also shaped by colonization, U.S., and Western imperialist, neo-politics, and oppression under racist, sexist, classist, heteronormative and homophobic, transphobic, queerphobic, ableist, nationalistic, xenophobic systems which perpetuate conquest, genocide of indigenous peoples, and pervasive systemic inequities.” Students spoke of oppression perpetrated by the Administration: “The first manifest demand is a complete change in the curriculum from a Whiteness-dominated curriculum to a non-Eurocentric interdisciplinary curriculum. If the (MRC) is unable to tackle these requirements, we demand that it be converted into a department so as to be accountable to another college.” What Students at MRC Seek If MRC students are seeking social justice and equality for all, if they are to make sense of this complex world, they ought to study the Humanities. If they are curious about how other cultures have learned to develop feelings of compassion, tolerance, respect, empathy, they ought to study the Humanities. If they are curious about how creative other people can be, if students are determined to live in a democracy of free citizens, the Humanities should be studied. Without the Humanities, democracy would not exist. The Crisis of Higher Education In this country, we are experiencing an intellectual crisis that has already affected our work force, our politics, and our culture. Western civilization, the human culmination of centuries of learning is under attack by an identity-driven student population exemplified by the protesters at MRC. Whereas many academic leaders fail to uphold the purpose of teaching Western civilization, the faculty at MRC values it. Whereas academic leaders don’t believe that the Humanities have any fundamental influence on their students, the faculty at MRC is invested in it. Shared values—this is what brings the world together. MRC is not alone in promoting a Humanities core curriculum. Many non-sectarian and private colleges proudly offer a core curriculum around which other subjects are framed. At least twenty-five colleges and universities in the United States offer the Great Books tradition to their undergraduates. These books are part of the great conversation about the universal ideas of cultures and civilizations, always related to ethical and religious values. Many educators believe that nearly half of college graduates show no measurable improvement in knowledge or critical thinking. They speak and write incorrectly; they do not read. Their constant companions? Electronic devices with accompanying head sets. Weaker academic requirements, greater specialization in the departments, a rigid orthodoxy and doctrinaire views on liberalism are now part of the university’s politics and cultural life. Clash of Goals If the demands of these special interest groups—race, class, gender, and disability, were met, MRC would cease to exist. A program of identity studies clashes with the raison d’être of a college named after Matteo Ricci, a name synonymous with the richest of classic studies. The student protesters are demanding to be extricated from the program that distinguishes itself in the pantheon of Catholic higher education. Who would be so foolish as to look down on, much less protest, such a rich curriculum that prompts the most influential employers to hire MRC’s crême de la crème? Let the disgruntled students go elsewhere with their partisan interests and narrow viewpoint. They lose. Ricci Speaks to College Students Matteo Ricci has left us several proverbs that can inspire college students. But not just college students: “Man is a stranger in this world.” “The virtuous person speaks little.” “Time past must be thought of as gone forever. Don’t waste time.” “True longevity is reckoned not by number of years but according to progress in virtue. If the Lord of Heaven grants me one day more of life, He does so that I may correct yesterday’s faults; failures to do this would be a sign of great ingratitude.” The canonization of Father Matteo Ricci, S.J. ranks high on the ‘to-do list’ of Pope Francis whose high regard and love for him are well known. This is the Servant of God, Matteo Ricci, S.J. 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