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Monday Interview: Building resilience against illness and climate change

By Kristy Dorsey




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Diary at Large: Glasgow bids farewell to an Italian restaurant that became an institution for Rangers players

IT’S almost time for the last supper. Though not quite. Another 24 hours will have to pass before the concluding morsel is munched, the final nibble on the edge of no more. After that, a little part of Scotland’s living history will die.




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Virtual Education Dilemma: Scheduled Classroom Instruction vs. Anytime Learning

K-12 teachers are faced with a question many likely thought they'd never have to ask: How often during the school day do my students need to see me and when?




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Scottish Government asks Westminster for universities to be bailed out

SCOTTISH Government ministers have appealed to Westminster for financial support to be handed over to universities during the Covid-19 pandemic amid a pledge that Holyrood is “ready to stand by” institutions.




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Is Your School Affirming Institutional Racism During Black History Month?

One particularly tense staff meeting helped educator Robert Parker rethink how his school celebrated Black History Month.




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Could the Next Strike in Education Be Against the Teachers' Union?

The staff union for the National Education Association is threatening to strike over contract negotiations.




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Coronavirus: Scottish Government given 'insufficient time' to consider Westminster proposals

SCOTLAND’S Economy Secretary has penned a letter to the UK Government venting her frustration at being given “insufficient time” to consider workplace safety proposals.




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What Differentiated Instruction Is Not: A Teacher's Perspective

Taking differentiation to mean "everything all the time" isn’t a sustainable model, warns English teacher Chad Towarnicki.




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Judge Dismisses Concussion Lawsuit Against Illinois High School Association

An Illinois judge has dismissed the nation's first class-action lawsuit against a state high school association over its handling of concussions, ruling that it had made strides in that regard since the filing of the lawsuit.




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Judge Allows Lawsuit Against Pop Warner to Proceed to Trial

A Los Angeles judge ruled that a teenage football player may proceed to trial against the national Pop Warner organization, four years after he suffered an on-field injury that left him a quadriplegic.




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6 Steps to Data-Driven Literacy Instruction

A district reading intervention specialist explains how she makes sense of a sea of data to foster more proficient readers.




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In Battle Against Bullies, Some Schools Target Parents

Looking for new ways to combat kids who bully, some communities are threatening to fine parents with no evidence that the approach is effective.




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Why Instructional Coaching Matters in Independent Schools

While independent schools can feel quite different from their public, charter, and parochial counterparts, the glue that holds all schools together is this noble charge we call teaching.




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Gates Foundation Eyes Middle Years Math Instruction

It's part of the foundation's $425 million research and development push, announced last fall.




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Congruence of Reproductive Concerns Among Adolescents With Cancer and Parents: Pilot Testing an Adapted Instrument

Survival takes precedence for adolescent patients with cancer and their families. Patients may not discuss their treatments’ potential to damage their reproductive capacity, which has significant psychological late effects in survivorship.

Strong reproductive concerns of adolescents with cancer may not be captured on current health-related quality of life instruments and may be neglected by parents’ unawareness. Parent-proxy reports of adolescent reproductive concerns are not suitable for capturing specific emotions and feelings. (Read the full article)




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The Outcome of ELBW Infants Treated With NCPAP and InSurE in a Resource-Limited Institution

The survival of extremely low birth weight infants in resource-limited situations is dismal due to limited neonatal intensive care facilities. Nasal continuous positive airway pressure resulted in an increased survival of these infants, but many still require back-up ventilation.

Nasal continuous positive airway pressure and intubation, surfactant, and extubation practiced in a neonatal high care ward with limited resources and limited back-up ventilatory facilities can improve the survival of extremely low birth weight infants. (Read the full article)




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Potential Asphyxia and Brainstem Abnormalities in Sudden and Unexpected Death in Infants

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)




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Indiscriminate Behaviors in Previously Institutionalized Young Children

Children who have experienced early psychosocial deprivation are at high risk of persistent, socially indiscriminate behaviors. These behaviors may decline slowly with high-quality caregiving but generally are associated with ongoing impairment.

This study suggests that placement in foster care reduces indiscriminate behaviors to an intermediate level between those in institutional care and community control subjects. It also demonstrates the importance of disorganized early attachment in predicting later indiscriminate behaviors. (Read the full article)




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Validity of Brief Screening Instrument for Adolescent Tobacco, Alcohol, and Drug Use

The widely disseminated National Institute on Alcohol Abuse and Alcoholism screening tool for adolescent alcohol use was developed based on epidemiologic data. It has not been validated in a clinical sample and does not screen for tobacco or drug use.

This study found that a measure that expanded the National Institute on Alcohol Abuse and Alcoholism adolescent alcohol use tool to include tobacco and drugs was sensitive and specific for identifying substance use disorders in a pediatric clinic patient population. (Read the full article)




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Sensitivity of the Automated Auditory Brainstem Response in Neonatal Hearing Screening

Adding second-stage automated auditory brainstem response (ABR) testing for infants who failed the initial OAE test in a two-stage neonatal hearing screening has been shown to reduce false referrals to the hearing clinic.

Infants with hearing loss may be missed by a 2-stage hearing screening because they pass the automated ABR test. In our study, a significant number of infants with hearing loss >45 decibel hearing level passed screening with automated ABR. (Read the full article)




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Cognitively-Guided Instruction: Supporting Students to Create Their Own Mathematical Understanding

A student-centered approach to teaching mathematics enables students to develop conceptual understanding and to grow as confident mathematicians.




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How Schools Are Putting Equity First in Math Instruction

Educators are changing instructional priorities, altering lessons, and working on ways to help teachers grow professionally, all in an effort to raise math achievement.




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Fin24.com | Saudi Arabia vows retaliation against punitive measures

United States President Donald Trump told CBS’s 60 Minutes that he would added pressure on Saudi Arabia, vowing "severe punishment" should the kingdom’s leaders be linked to the disappearance of Washington Post columnist Jamal Khashoggi.




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UN Must Stop Backing Congo's Disastrous Operation Against Marauding Rebel Militias




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Tchad : La victoire facile d'un Etat fragile contre les institutions internationales

Dans de nombreux pays, le pétrole suscite des débats controversés sur son rôle de moteur de changements économiques, sociaux et géopolitiques. Depuis quelques années, les réflexions sur la question du pétrole ont démontré une corrélation négative entre son exploitation, le développement socioéconomique, la gouvernance et le regain des conflits dans les pays producteurs.




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Oil in Chad: The Fragile State’s Easy Victory over International Institutions

In numerous countries, the exploitation of oil has generated debate about its economic, social and geopolitical consequences.




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Centrafrique: Les élections de l'instabilité

Le processus électoral hors délai constitutionnel qui se déroule depuis le 23 janvier en Centrafrique n'est pas seulement une nouvelle opportunité manquée pour la démocratisation du pays mais c'est aussi un risque sérieux pour la paix.




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An engineered double lipid II binding motifs-containing lantibiotic displays potent and selective antimicrobial activity against E. faecium [Chemistry; Biosynthesis]

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.




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Evaluation of the efficacy of antibiotic combinations against multidrug-resistant Pseudomonas aeruginosa in automated time-lapse microscopy and static time-kill experiments [Clinical Therapeutics]

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.




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Ceftobiprole Activity against Bacteria from Skin and Skin Structure Infections in the United States from 2016 through 2018 [Susceptibility]

Ceftobiprole medocaril is an advanced-generation cephalosporin prodrug that has qualified infectious disease product status granted by the US-FDA and is currently being evaluated in phase 3 clinical trials in patients with acute bacterial skin and skin structure infections (ABSSSIs) and in patients with Staphylococcus aureus bacteremia. In this study, the activity of ceftobiprole and comparators was evaluated against more than 7,300 clinical isolates collected in the United States from 2016 through 2018 from patients with skin and skin structure infections. The major species/pathogen groups were S. aureus (53%), Enterobacterales (23%), Pseudomonas aeruginosa (7%), β-hemolytic streptococci (6%), Enterococcus spp. (4%), and coagulase-negative staphylococci (2%). Ceftobiprole was highly active against S. aureus (MIC50/90, 0.5/1 mg/L; 99.7% susceptible by EUCAST criteria; 42% methicillin-resistant S. aureus [lsqb]MRSA[rsqb]). Ceftobiprole also exhibited potent activity against other Gram-positive cocci. The overall susceptibility of Enterobacterales to ceftobiprole was 84.8% (>99.0% susceptible for isolate subsets that exhibited a non-extended-spectrum β-lactamase [lsqb]ESBL[rsqb]-phenotype). A total of 74.4% of P. aeruginosa, 100% of β-hemolytic streptococci and coagulase-negative staphylococci, and 99.6% of Enterococcus faecalis isolates were inhibited by ceftobiprole at ≤4 mg/L. As expected, ceftobiprole was largely inactive against Enterobacterales that contained ESBL genes and Enterococcus faecium. Overall, ceftobiprole was highly active against most clinical isolates from the major Gram-positive and Gram-negative skin and skin structure pathogen groups collected at U.S. medical centers participating in the SENTRY Antimicrobial Surveillance Program during 2016–2018. The broad-spectrum activity of ceftobiprole, including potent activity against MRSA, supports its further evaluation for the potential ABSSSI indication.




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Updated approaches against SARS-CoV-2 [Minireviews]

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lies behind the ongoing outbreak of coronavirus disease 2019 (COVID-19). There is a growing understanding of SARS-CoV-2 in the virology, epidemiology and clinical management strategies. However, no anti-SARS-CoV-2 drug or vaccine has been officially approved due to the absence of adequate evidence. Scientists are racing towards the development of treatment for COVID-19. Recent studies have revealed many attractive threptic options, even if some of them remain to be further confirmed in rigorous preclinical models and clinical trials. In this minireview, we aim to summarize the updated potential approaches against SARS-CoV-2. We emphasize that further efforts are warranted to develop the safest and most effective approach.




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Spectrum of Beta-Lactamase Inhibition by the Cyclic Boronate QPX7728, an Ultra-Broad-Spectrum Beta-lactamase Inhibitor of Serine and Metallo Beta-Lactamases: Enhancement of Activity of Multiple Antibiotics Against Isogenic Strains Expressing Single {beta}

QPX7728 is an ultra-broad-spectrum boronic acid beta-lactamase inhibitor with potent inhibition of key serine and metallo beta-lactamases observed in biochemical assays. Microbiological studies using characterized strains were used to provide a comprehensive characterization of the spectrum of beta-lactamase inhibition by QPX7728. The MIC of multiple IV only (ceftazidime, piperacillin, cefepime, ceftolozane and meropenem) and orally bioavailable (ceftibuten, cefpodoxime, tebipenem) antibiotics alone and in combination with QPX7728 (4 μg/ml), as well as comparator agents, were determined against the panels of laboratory strains of P. aeruginosa and K. pneumoniae expressing over 55 diverse serine and metallo beta-lactamases. QPX7728 significantly enhanced the potency of antibiotics against the strains expressing Class A extended spectrum beta-lactamases (CTX-M, SHV, TEM, VEB, PER) and carbapenemases (KPC, SME, NMC-A, BKC-1), consistent with beta-lactamase inhibition demonstrated in biochemical assays. It also inhibits both plasmidic (CMY, FOX, MIR, DHA) and chromosomally encoded (P99, PDC, ADC) Class C beta-lactamases and Class D enzymes including carbapenemases such as OXA-48 from Enterobacteriaceae and OXA enzymes from Acinetobacter baumannii (OXA-23/24/72/58). QPX7728 is also a potent inhibitor of many class B metallo beta-lactamases (NDM, VIM, CcrA1, IMP, GIM but not SPM or L1). Addition of QPX7728 (4 μg/ml) reduced the MICs in a majority of strains to the level observed for the vector alone control, indicative of complete beta-lactamase inhibition. The ultra-broad-spectrum beta-lactamase inhibition profile makes QPX7728 a viable candidate for further development.




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Efficacy of bedaquiline, alone or in combination with imipenem, against Mycobacterium abscessus in C3HeB/FeJ mice [Experimental Therapeutics]

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.




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In vitro and in vivo study on the synergistic effect of minocycline and azoles against pathogenic fungi [Susceptibility]

In vitro and in vivo interactions of minocycline and azoles including itraconazole, voriconazole, and posaconazole against filamentous pathogenic fungi were investigated. A total of 56 clinical isolates were studied in vitro via broth microdilution checkerboard technique, including 20 strains of Aspergillus fumigatus, 7 strains of A. flavus, 16 strains of Exophiala dermatitidis, 10 strains of Fusarium solani and 3 strain s of F. oxysporum. The results revealed that minocycline individually did not exhibit any significant antifungal activity against all tested strains. However, favorable synergy of minocycline with itraconazole, voriconazole, or posaconazole were observed against 34 (61%), 28 (50%), and 38 (69%) isolates, respectively, including azole resistant A. fumigatus and Fusarium spp. with inherently high MICs of azoles. Synergistic combinations resulted in 4 fold to 16-fold reduction of effective MICs of minocycline and azoles. No antagonism was observed. In vivo effect of minocycline-azole combinations were evaluated by survival assay in Galleria mellonella model infected with E. dermatitidis strain BMU00034, F. solani strain FS9, A. fumigatus strain AF293, AFR1 and AFR2 . Minocycline acted synergistically with azoles and significantly increased larvae survival in all isolates (P<0.001), including azole resistant A. fumigatus and azole-inactive Fusarium spp.. In conclusion, the results suggested that minocycline combined with azoles may help to enhance the antifungal susceptibilities of azoles against pathogenic fungi and had the potential to overcome azole resistance issues.




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The Added Value of Longitudinal Imaging for Preclinical In vivo Efficacy Testing of Therapeutic Compounds against Cerebral Cryptococcosis [Experimental Therapeutics]

Brain infections with Cryptococcus neoformans are associated with significant morbidity and mortality. Cryptococcosis typically presents as meningoencephalitis or fungal mass lesions called cryptococcomas. Despite frequent in vitro discoveries of promising novel antifungals, the clinical need for drugs that can more efficiently treat these brain infections remains. A crucial step in drug development is the evaluation of in vivo drug efficacy in animal models. This mainly relies on survival studies or post-mortem analyses in large groups of animals, but these techniques only provide information on specific organs of interest at predefined time points. In this proof-of-concept study, we validated the use of non-invasive preclinical imaging to obtain longitudinal information on the therapeutic efficacy of amphotericin B or fluconazole monotherapy in meningoencephalitis and cryptococcoma mouse models. Bioluminescence imaging (BLI) enabled the rapid in vitro and in vivo evaluation of drug efficacy while complementary high-resolution anatomical information obtained by magnetic resonance imaging (MRI) of the brain allowed a precise assessment of the extent of infection and lesion growth rates. We demonstrated a good correlation between both imaging readouts and the fungal burden in various organs. Moreover, we identified potential pitfalls associated with the interpretation of therapeutic efficacy based solely on post-mortem studies, demonstrating the added value of this non-invasive dual imaging approach compared to standard mortality curves or fungal load endpoints. This novel preclinical imaging platform provides insights in the dynamic aspects of the therapeutic response and facilitates a more efficient and accurate translation of promising antifungal compounds from bench to bedside.




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Novel ionophores active against La Crosse virus identified through rapid antiviral screening [Antiviral Agents]

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.




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Pharmacokinetic-Pharmacodynamic Characterization of Omadacycline Against Haemophilus influenzae Using a One-Compartment In Vitro Infection Model [Pharmacology]

Omadacycline is a novel aminomethylcycline with activity against Gram-positive and -negative organisms, including Haemophilus influenzae, which is one of the leading causes of community-acquired bacterial pneumonia (CABP). The evaluation of antimicrobial agents against H. influenzae using standard murine infection models is challenging due to the low pathogenicity of this species in mice. Therefore, 24-hour dose-ranging studies using a one-compartment in vitro infection model were undertaken with the goal of characterizing the magnitude of the ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio) associated with efficacy for a panel of five clinical H. influenzae isolates. These five isolates, which had MIC values of 1 or 2 mg/L, were exposed to omadacycline total-drug epithelial lining fluid (ELF) concentration-time profiles based on those observed in healthy volunteers following intravenous omadacycline administration. Relationships between change in log10 colony forming units (CFU) from baseline at 24 hours and total-drug ELF AUC/MIC ratio for each isolate and the isolates pooled together were evaluated using Hill-type models and non-linear least squares regression. As evidenced by the high coefficient of determination (r2) of 0.88 to 0.98, total-drug ELF AUC/MIC ratio described the data well for each isolate and the isolates pooled together. The median total-drug ELF AUC/MIC ratio associated with net bacterial stasis and 1- and 2-log10 CFU/mL reductions from baseline at 24 hours was 6.91, 8.91, and 11.1, respectively. These data were useful to support the omadacycline dosing regimens selected for the treatment of patients with CABP, as well as susceptibility breakpoints for H. influenzae.




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Efficacy of neuraminidase inhibitors against H5N6 highly pathogenic avian influenza virus in a non-human primate model [Antiviral Agents]

Attention has been paid to H5N6 highly pathogenic avian influenza virus (HPAIV) because of its heavy burden on the poultry industry and human mortality. Since an influenza A virus carrying N6 neuraminidase (NA) has never spread in humans, the potential for H5N6 HPAIV to cause disease in humans and the efficacy of antiviral drugs against the virus need to be urgently assessed. We used non-human primates to elucidate the pathogenesis of H5N6 HPAIV as well as to determine the efficacy of antiviral drugs against the virus. H5N6 HPAIV infection led to high fever in cynomolgus macaques. The lung injury caused by the virus was severe with diffuse alveolar damage and neutrophil infiltration. In addition, an increase in IFN-α showed an inverse correlation with virus titers during the infection process. Oseltamivir was effective for reducing H5N6 HPAIV propagation, and continuous treatment with peramivir reduced virus propagation and severity of symptoms in the early stage. This study also showed the pathologically severe lung injury states in the cynomolgus macaques infected with H5N6 HPAIV, even in those that received early antiviral drug treatments, indicating the need for close monitoring and the need for further studies on the virus pathogenicity and new antiviral therapies.




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Manogepix (APX001A) displays potent in vitro activity against human pathogenic yeast, but with an unexpected correlation to fluconazole MICs [Susceptibility]

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.




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Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs [Antiviral Agents]

Drug repositioning is the only feasible option to address the COVID-19 global challenge immediately. We screened a panel of 48 FDA-approved drugs against SARS-CoV-2 which were pre-selected by an assay of SARS-CoV and identified 24 potential antiviral drug candidates against SARS-CoV-2 infection. Some drug candidates showed very low micromolar IC50s and in particular, two FDA-approved drugs - niclosamide and ciclesonide – were notable in some respects.




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Evaluation of leishmanicidal activity of an in silico screened novel inhibitor against ascorbate peroxidase of Leishmania donovani [Mechanisms of Action]

Peroxidases are a group of heterogeneous family of enzyme that plays diverse biological functions. Ascorbate peroxidase is a redox enzyme that is reduced by trypanothione, which plays a central role in the redox defence system of Leishmania. In view of developing new and novel therapeutics, we have performed in silico studies in order to search for ligand library and identification of new drug candidates and its physiological role against promastigotes and intracellular amastigotes of Leishmania donovani. Our results demonstrated that the selected inhibitor ZINC96021026 has significant anti-leishmanial effect and effectively killed both free and intracellular forms of the parasite. ZINC96021026 was found to be identical to ML-240, a selective inhibitor of Valosin-containing protein (VCP) or p97, a member of AAA-ATPase protein family which was derived from the scaffold of DBeQ, targeting the D2-ATPase domain of the enzyme. ZINC96021026 (ML-240) thus have broad range of cellular functions, thought to be derived from its ability to unfold proteins or disassemble protein complexes besides inhibiting the ascorbate peroxidase activity. ML-240 may inhibits the parasite's ascorbate peroxidase leading to extensive apoptosis and inducing generation of reactive oxygen species. Taken together, our results demonstrated that ML-240 could be an attractive therapeutic option for treatment against leishmaniasis.




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Activity of epigenetic inhibitors against Plasmodium falciparum asexual and sexual blood stages. [Susceptibility]

Earlier genetic and inhibitor studies have shown that epigenetic regulation of gene expression is critical for malaria parasite survival in multiple life stages and a promising target for new anti-malarials. We therefore evaluated the activity of 350 diverse epigenetic inhibitors against multiple stages of Plasmodium falciparum. We observed ≥90% inhibition at 10 μM for 28% of compounds against asexual blood stages and early gametocytes, of which a third retained ≥90% inhibition at 1 μM.




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Local Penn Staters participate in the fight against COVID-19

Two alumni and one community partner contribute clinical medicine and research experience during the pandemic




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Fitness instructors lead virtual classes during remote learning

Penn State Campus Recreation is now offering a library of more than 50 workouts online through YouTube as well as live classes that are held every business day on the Penn State Campus Recreation Instagram. Group fitness instructor Alexis "Lexi" Neimeyer talked about her experience on the transition to virtual fitness classes.




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Efficacy and Effectiveness of the PCV-10 and PCV-13 Vaccines Against Invasive Pneumococcal Disease

CONTEXT:

Pneumococcal conjugate vaccines (PCVs) (pneumococcal 13-valent conjugate vaccine [PCV-13] and pneumococcal 10-valent conjugate vaccine [PCV-10]) are available for prevention of pneumococcal infections in children.

OBJECTIVE:

To determine the vaccine effectiveness (VE) of PCV-13 and PCV-10 in preventing invasive pneumococcal disease (IPD) and acute otitis media (AOM) in children <5 years.

DATA SOURCES:

Systematic searches of Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, Web of Science, and Cochrane.

STUDY SELECTION:

Eligible studies examined the direct effectiveness and/or efficacy of PCV-10 and PCV-13 in reducing the incidence of disease in healthy children <5 years.

DATA EXTRACTION:

Two reviewers independently conducted data extraction and methodologic quality assessment.

RESULTS:

Significant effectiveness against vaccine-type IPD in children ≤5 years was reported for ≥1 dose of PCV-13 in the 3 + 1 (86%–96%) and 2 + 1 schedule (67.2%–86%) and for PCV-10 for the 3 + 1 (72.8%–100%) and 2 + 1 schedules (92%–97%). In children <12 months of age, PCV-13 VE against serotype 19A post–primary series was significant for the 3 + 1 but not the 2 + 1 schedule. PCV-10 crossprotection against 19A was significant in children ≤5 years with ≥1 dose (82.2% and 71%). Neither PCVs were found effective against serotype 3. PCV-13 was effective against AOM (86%; 95% confidence interval [CI]: 61 to 94). PCV-10 was effective against clinically defined (26.9%; 95% CI: 5.9 to 43.3) and bacteriologically confirmed AOM (43.3%; 95% CI: 1.7 to 67.3).

LIMITATIONS:

Because of the large heterogeneity in studies, a meta-analysis for pooled estimates was not done.

CONCLUSIONS:

Both PCVs afford protection against pneumococcal infections, with PCV-10 protecting against 19A IPD, but this VE has not been verified in the youngest age groups.




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Access to STEM Instruction Is Uneven




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Former Hearts chairman Leslie Deans urges club to take legal action against SPFL and clubs who 'voted for Hearts ejection from league'

Former Hearts chairman Leslie Deans has urged the club to take legal action against the SPFL as well as those who voted to end the season early, effectively relegating the Jambos.




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Validation of the National Institutes of Health Consensus Definition of Bronchopulmonary Dysplasia

Richard A. Ehrenkranz
Dec 1, 2005; 116:1353-1360
ARTICLES




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Neurodevelopmental and Functional Outcomes of Extremely Low Birth Weight Infants in the National Institute of Child Health and Human Development Neonatal Research Network, 1993-1994

Betty R. Vohr
Jun 1, 2000; 105:1216-1226
ARTICLES




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Using historical lessons and creative instruction to support students

Penn State Abington faculty are using the current situation as an opportunity to enrich students academically and support them personally during this period of remote learning. "What may be most inspiring of all is the deep-seated concern for our students that faculty efforts expose,” said Friederike Baer, division head for Arts and Humanities.