One of the reasons for the lengthy tuberculosis (TB) treatment is the difficult to treat non-multiplying mycobacterial subpopulation. In order to assess the ability of (new) TB drugs to target this subpopulation, we need to incorporate dormancy models in our pre-clinical drug development pipeline. In most available dormancy models it takes a long time to create a dormant state and it is difficult to identify and quantify this non-multiplying condition.

The Mycobacterium tuberculosis 18b strain might overcome some of these problems, because it is dependent on streptomycin for growth and becomes non-multiplying after 10 days of streptomycin starvation, but still can be cultured on streptomycin-supplemented culture plates. We developed our 18b dormancy time-kill kinetic model to assess the difference in the activity of isoniazid, rifampicin, moxifloxacin and bedaquiline against log-phase growth compared to the non-multiplying M. tuberculosis subpopulation by CFU counting including a novel AUC-based approach as well as time-to-positivity (TTP) measurements.

We observed that isoniazid and moxifloxacin were relatively more potent against replicating bacteria, while rifampicin and high dose bedaquiline were equally effective against both subpopulations. Moreover, the TTP data suggest that including a liquid culture-based method could be of additional value as it identifies a specific mycobacterial subpopulation that is non-culturable on solid media.

In conclusion, the results of our study underline that the time-kill kinetics 18b dormancy model in its current form is a useful tool to assess TB drug potency and thus has its place in the TB drug development pipeline.

A case of M. leprae rifampicin resistance after irregular anti-leprosy treatments since 1971 is reported. Whole-genome sequencing from four longitudinal samples indicated relapse due to acquired rifampicin resistance and not to reinfection with another strain. A putative compensatory mutation in rpoC was also detected. Clinical improvement was achieved using an alternative therapy.

Background: MRSA pose significant therapeutic challenges, related to their: frequency in clinical infections; innate virulence properties; and propensity for multi-antibiotic resistance. MRSA are among the most common causes of endovascular infections, including infective endocarditis (IE).

Objective: To employ transthoracic echocardiography (TTE) to evaluate the effect of exebacase, a novel direct lytic agent, in experimental aortic valve MRSA IE.

Study Design: TTE was utilized to evaluate the in vivo effect of exebacase on MRSA-infected vegetation progression when combined with daptomycin (vs daptomycin alone). Primary intravegetation outcomes were: maximum size; weights at sacrifice; and MRSA counts at infection baseline vs after 4 days of daptomycin treatment (alone or in addition to exebacase administered once on treatment Day 1).

Results: A single dose of exebacase in addition to daptomycin cleared significantly more intravegetation MRSA than daptomycin alone. This was associated with a statistical trend toward reduced maximum vegetation size in the exebacase + daptomycin vs the daptomycin-alone therapy groups (p = 0.07). Also, mean vegetation weights in the exebacase-treated group were significantly lower vs daptomycin-alone (p < 0.0001). Maximum vegetation size by TTE correlated with vegetation weight (p = 0.005). In addition, intravegetation MRSA counts in the combination group were significantly lower vs untreated controls (p<0.0001) and the daptomycin-alone group (p<0.0001).

Conclusion: This study suggests that exebacase has a salutary impact on MRSA-infected vegetation progression when combined with daptomycin, especially in terms of vegetation MRSA burden, size and weight. Moreover, TTE appears to be an efficient non-invasive tool to assess therapeutic efficacies in experimental MRSA IE.

Many transferable quinolone-resistance mechanisms have been already identified in Gram-negative bacteria. The plasmid-encoded 65 amino-acid long ciprofloxacin-modifying enzyme, namely CrpP, was recently identified in Pseudomonas aeruginosa. We analyzed a collection of 100 clonally-unrelated and multidrug-resistant P. aeruginosa clinical isolates among which 46 (46%) were found positive for crpP-like genes, encoding five CrpP variants conferring variable levels of reduced susceptibility to fluoroquinolones. Those crpP-like genes were chromosomally located, as part of PAGI-like pathogenicity genomic islands.

Introduction: This study was performed to evaluate the impacts of vanA-positivity of Enterococcus faecium (EFM) exhibiting diverse susceptibility phenotypes to glycopeptides on clinical outcomes in patients with a bloodstream infection (BSI) through a prospective, multicenter, observational study.

Methods: A total of 509 patients with an EFM BSI from eight sentinel hospitals in South Korea during a two-year period were enrolled in this study. Risk factors of the hosts and causative EFM isolates were assessed to determine associations with the 30-day mortality of EFM BSI patients via multivariable logistic regression analyses.

Results: The vanA gene was detected in 35.2% (179/509) of EFM isolates; 131 EFM isolates exhibited typical VanA phenotypes (group vanA-VanA), while the remaining 48 EFM isolates exhibited atypical phenotypes (group vanA-Atypical), including VanD (n = 43) and vancomycin-variable phenotypes (n = 5). A multivariable logistic regression indicated that vanA-positivity of causative pathogens was independently associated with the increased 30-day mortality rate in the patients with an EFM BSI; however, there was no significant difference in the survival rates between the patients of the vanA-VanA and vanA-Atypical groups (log-rank test, P = 0.904).

Conclusions: A high 30-day mortality rate was observed in patients with vanA-positive EFM BSIs, and vanA-positivity of causative EFM was an independent risk factor for early mortality irrespective of the susceptibility phenotypes to glycopeptides; thus, intensified antimicrobial stewardship is needed to improve clinical outcome of patients with vanA-positive EFM BSI.

Omadacycline, a novel aminomethylcycline antibiotic with activity against Gram-positive and -negative organisms, including tetracycline-resistant pathogens, received FDA approval in October, 2018 for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). A previously-developed population pharmacokinetic (PK) model based on Phase 1 intravenous and oral PK data was refined using data from infected patients. Data from 10 Phase 1 studies used to develop the previous model were pooled with data from three additional Phase 1 studies, a Phase 1b uncomplicated urinary tract infection study, one Phase 3 CABP study, and two Phase 3 ABSSSI studies. The final population PK model was a three-compartment model with first-order absorption using transit compartments to account for absorption delay following oral dosing and first-order elimination. Epithelial lining fluid (ELF) concentrations were modeled as a sub-compartment of the first peripheral compartment. A food effect on oral bioavailability was included in the model. Sex was the only significant covariate identified, with 15.6% lower clearance for females relative to males. Goodness-of-fit diagnostics indicated a precise and unbiased fit to the data. The final model, which was robust in its ability to predict plasma and ELF exposures following omadacycline administration, was also able to predict the central tendency and variability in concentration-time profiles using an external Phase 3 ABSSSI dataset. A population PK model, which described omadacycline PK in healthy subjects and infected patients, was developed and subsequently used to support pharmacokinetic-pharmacodynamic (PK-PD) and PK-PD target attainment assessments.

As resistance to artemisinins (current frontline drugs in malaria treatment) emerges in south East Asia, there is an urgent need to identify the genetic determinants and understand the molecular mechanisms underpinning such resistance. Such insights could lead to prospective interventions to contain resistance and prevent the eventual spread to other malaria endemic regions. Artemisinin reduced susceptibility in South East Asia (SEA) has been primarily linked to mutations in P. falciparum Kelch-13, which is currently widely recognised as a molecular marker of artemisinin resistance. However, 2 mutations in a ubiquitin hydrolase, UBP-1, have been previously associated with artemisinin reduced susceptibility in a rodent model of malaria and some cases of UBP-1 mutation variants associating with artemisinin treatment failure have been reported in Africa and SEA. In this study, we have employed CRISPR-Cas9 genome editing and pre-emptive drug pressures to test these artemisinin susceptibility associated mutations in UBP-1 in P. berghei sensitive lines in vivo. Using these approaches, we have shown that the V2721F UBP-1 mutation results in reduced artemisinin susceptibility, while the V2752F mutation results in resistance to chloroquine and moderately impacts tolerance to artemisinins. Genetic reversal of the V2752F mutation restored chloroquine sensitivity in these mutant lines while simultaneous introduction of both mutations could not be achieved and appears to be lethal. Interestingly, these mutations carry a detrimental growth defect, which would possibly explain their lack of expansion in natural infection settings. Our work has provided independent experimental evidence on the role of UBP-1 in modulating parasite responses to artemisinin and chloroquine under in vivo conditions.

Chagas disease, caused by the protozoan Trypanosoma cruzi, is one of the main causes of death due to cardiomyopathy and heart failure in Latin American countries. The treatment of Chagas disease is directed at eliminating the parasite, decreasing the probability of cardiomyopathy, and disrupting the disease transmission cycle. Benznidazole (BZ) and nifurtimox (NFX) are recognized as effective drugs for the treatment of Chagas disease by the World Health Organization, but both have high toxicity and limited efficacy, especially in the chronic disease phase. At low doses, aspirin (ASA) has been reported to protect against T. cruzi infection. We evaluated the effectiveness of BZ in combination with ASA at low doses during the acute disease phase and evaluated cardiovascular aspects and cardiac lesions in the chronic phase. ASA treatment prevented the cardiovascular dysfunction (hypertension and tachycardia) and typical cardiac lesions. Moreover, BZ+ASA-treated mice had a smaller cardiac fibrotic area than that in BZ-treated mice. These results were associated with an increase in the number of eosinophils and reticulocytes and level of nitric oxide in the plasma and cardiac tissue of ASA-treated mice relative to respective controls. These effects of ASA and BZ+ASA in chronically infected mice were inhibited by pretreatment with the LXA₄ receptor antagonist, Boc-2, indicating that the protective effects of ASA are mediated by ASA-triggered lipoxin. These results emphasize the importance of exploring new drug combinations for treatments of acute phase of Chagas disease that are beneficial for chronic patients.

Exploring different ways of minimising linezolid toxicity without compromising efficacy is a major quest in the treatment of drug resistant tuberculosis (TB)....

Treatment of exacerbations of chronic Pseudomonas aeruginosa infections in patients with cystic fibrosis (CF) is highly challenging due to hypermutability, biofilm formation and an increased risk of resistance emergence. We evaluated the impact of ciprofloxacin and meropenem as monotherapy and in combination in the dynamic in vitro CDC biofilm reactor (CBR). Two hypermutable P. aeruginosa strains, PAOmutS (MIC_{ciprofloxacin} 0.25 mg/L, MIC_meropenem 2 mg/L) and CW44 (MIC_{ciprofloxacin} 0.5 mg/L, MIC_meropenem 4 mg/L), were investigated for 120h. Concentration-time profiles achievable in epithelial lining fluid (ELF) following FDA-approved doses were simulated in the CBR. Treatments were ciprofloxacin 0.4g every 8h as 1h-infusions (80% ELF penetration), meropenem 6 g/day as continuous infusion (CI; 30% and 60% ELF penetration) and their combinations. Counts of total and less-susceptible planktonic and biofilm bacteria and MICs were determined. Antibiotic concentrations were quantified by UHPLC-PDA. For both strains, all monotherapies failed with substantial regrowth and resistance of planktonic (≥8log₁₀ CFU/mL) and biofilm (>8log₁₀ CFU/cm²) bacteria at 120h (MIC_{ciprofloxacin} up to 8 mg/L, MIC_meropenem up to 64 mg/L). Both combination treatments demonstrated synergistic bacterial killing of planktonic and biofilm bacteria of both strains from ~48h onwards and suppressed regrowth to ≤4log₁₀ CFU/mL and ≤6log₁₀ CFU/cm² at 120h. Overall, both combination treatments suppressed amplification of resistance of planktonic bacteria for both strains, and biofilm bacteria for CW44. The combination with meropenem at 60% ELF penetration also suppressed amplification of resistance of biofilm bacteria for PAOmutS. Thus, combination treatment demonstrated synergistic bacterial killing and resistance suppression against difficult-to-treat hypermutable P. aeruginosa strains.

We thank Kim and colleagues for their interest in our study....

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.

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.

Google has made it easier to join the company's Advanced Protection Program, which is designed to stop the most sophisticated hackers from breaking into your Gmail account. Before you needed two security keys to enroll. Now you just need a smartphone.

Security researchers are demonstrating how you can use the Windows 10 flaw, CVE-2020-0601, to spoof the trusted digital certificates for official website domains on Google's Chrome browser. These same certificates can warn you about hacking attempts.

The FBI seizes the internet domain to WeLeakInfo.com, a site that was cataloging billions of records, such as email addresses and passwords, from more than 10,300 data breaches at various companies and service providers.

On Tuesday, Avast responded to a PCMag-Motherboard investigation into the company's browser history collection practices, saying it was entirely legal. Avast users should expect to see a prompt from the antivirus products, asking them to consent to the data harvesting.

'As CEO of Avast, I feel personally responsible and I would like to apologize to all concerned,' wrote Ondrej Vlcek following a PCMag-Motherboard investigation into the privacy risks around the data harvesting.

Watch out for suspicious interview requests. 'The main focus of this phishing campaign was stealing email account information of the victims, and finding information about their contacts/networks,' the cybersecurity experts at Certfa Lab warned on Wednesday.

The JSE fell on Tuesday as global markets tumbled on the back of a rout in crude oil prices.

"The entire energy market is still on a knife edge," says an economist.

The local bourse inched higher on Wednesday as global stocks took a breather following consecutive sessions of weakness.

Local stocks advanced for a second consecutive session on Thursday as global markets remained resurgent.

Global markets rallied on the back of optimism that most governments were gearing up to at least partially reopen their economies following lockdowns to prevent the spread of the coronavirus.

The local bourse had managed to open firmer following a rally in Asian stocks in earlier trading.

Deep losses were recorded across most European benchmarks except the FTSE 100 which managed to trade relatively flat on the day.

Oil was headed for the longest run of daily gains in more than nine months on signs the worst of the supply glut may be over as production cuts start to take effect.

On the currency market, the rand traded softer against the greenback as it slipped to a session low of R18.77/$.

Oil headed for its first back-to-back weekly gain since February as output cuts from the biggest producers and a nascent recovery in demand began to rebalance a market awash with crude.

The rand strengthened against the greenback as it peaked at a session high of R18.30 before it was recorded trading 1.41% firmer at R18.32/$ at 17.00

Funders have been both fast and thoughtful about how to work with national and local partners to listen to needs from the field, identify best practices, and deploy resources quickly, says Celine Coggins.

"This pandemic has given us an opportunity to think boldly about students' educational needs and how to creatively respond to them," says Katherine Haley.

BACKGROUND AND OBJECTIVES:

Antibiotic therapy is often prescribed for suspected community-acquired pneumonia (CAP) in children despite a lack of knowledge of causative pathogen. Our objective in this study was to investigate the association between antibiotic prescription and treatment failure in children with suspected CAP who are discharged from the hospital emergency department (ED).

BACKGROUND AND OBJECTIVES:

Runaway youth and homeless youth are at risk for adverse mental health outcomes. These 2 populations are frequently pooled together in both research and interventions yet may have unique health needs. We sought to assess differences in mental health outcomes among these populations.

BACKGROUND AND OBJECTIVES:

Children with medical complexity (CMC) comprise only 6% of the pediatric population, account for ~40% of pediatric health care spending, and provide an important opportunity for cost saving. Savings in this group can have an important impact on pediatric health care costs. The objective of this study was to assess the impact of a multicenter care management program on spending and use in CMC.

BACKGROUND AND OBJECTIVES:

Rates of sexually transmitted infections (STIs) have increased over the decade. Guidelines recommend HIV testing with incident STIs. Prevalence and factors associated with HIV testing in acute STIs are unknown in adolescents. Our objective was to determine the prevalence of completed HIV testing among adolescents with incident STIs and identify patient and health care factors associated with HIV testing.

BACKGROUND:

In the United States, transgender youth are at especially high risk for HIV infection. Literature regarding HIV prevention strategies for this vulnerable, often-hidden population is scant. Before effective, population-based HIV prevention strategies may be adequately developed, it is necessary to first enhance the contextual understanding of transgender youth HIV risk and experiences with HIV preventive services.

BACKGROUND AND OBJECTIVES:

The albuterol dropper bottle used to prepare solutions for continuous nebulization contains the preservative benzalkonium chloride (BAC). BAC, by itself, has been shown to cause bronchospasm. We hypothesized that BAC would decrease the therapeutic efficacy of albuterol in patients with acute asthma exacerbations.

True to its name, Home Chef is the homiest of meal services we've tried. The recipes are simple and not too adventurous, but for some home chefs, that's a good thing.

Like its predecessor the Rival 700, the SteelSeries Rival 710 is a solid, pricey gaming mouse, with unique features (such as an on-body screen) that are more fun and flashy than technically useful.

UEFA.com runs the rule over some of the most expensive players in the game to assess who's worth splashing out for.

Led by Serge Gnabry's first-leg double, Bayern München have one foot in the quarter-finals as Chelsea come to Germany.

Jose, an Argentinian worker serving in Southeast Asia, tells of how he entered overseas service and what he has seen God do through his not-so-typical ministry.

Buenos Aires, Argentina :: Maintenance crew share Christ's love with local welders helping repair Logos Hope.

Elizabeth Stringer Keefe, Becky Shiring, Katie Robinson, Dr. Sonny Magana and Dr. Monica Burns contribute their suggestions on using tech to differentiate instruction.

The Penn State Smeal College of Business has announced the recipients of its spring 2020 Senior Awards.

Emilee Yaeger, an undergraduate student in the Science BS/MBA accelerated joint degree program, has been selected as the recipient of the 2019 Eberly College of Science Cooperative Education Student of the Year Award. The award recognizes the student’s academic achievements and contributions to the participating employer, the University, the community, and the field of cooperative education.

In an effort to help mitigate the disruptive effects of the deadly COVID-19 virus, an interdisciplinary team of Penn State researchers are developing a novel methodology to analyze its spread and the impacts on policy to create better-prepared and more-resilient health care systems.