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.

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.

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.

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.

BACKGROUND:

Approximately 25% of children with concussion have persistent postconcussive symptoms (PPCS) with resultant significant impacts on quality of life. Melatonin has significant neuroprotective properties, and promising preclinical data suggest its potential to improve outcomes after traumatic brain injury. We hypothesized that treatment with melatonin would result in a greater decrease in PPCS symptoms when compared with a placebo.

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.

Although it's pricey, the intuitive Salesforce Pardot offers standout features, making it a leader among today's marketing automation platforms.

Two Erling Braut Haaland strikes have given Dortmund an advantage to take to Paris, although Neymar's away goal could prove crucial.

Noy shares her journey of experiencing God's love for herself and forgiving the community that persecuted her family.

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Beth E. Michalec, lecturer of corporate communication at Penn State Lehigh Valley, earned a doctorate in rhetoric from Duquesne University. Michalec was selected as a Fulbright specialist in June 2019 by the U.S. Department of State.

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Noy shares her journey of experiencing God's love for herself and forgiving the community that persecuted her family.

It's only a matter of time before your Windows 10 PC begins to run slowly. You can kick the operating system back into high gear with these useful tips. And they won't cost you a penny.

Loading and running Windows 10 from a USB drive is a handy option when you're using a computer saddled with an older version of Windows.

The Windows 10 search feature seems pretty simple, but it can be even more effective. Here are some ways to control your searches and find things faster.

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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.

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Google removes the free WireGuard app from the Play Store for having a donation button, reigniting a debate over whether its policy hurts the open-source community.

Get organized and complete tasks more quickly and more reliably by using the right to-do app. These are the top performers in our tests.

Save on the second-generation Apple AirPods with the wireless charging case, Logitech gaming gear, Dell laptops, the Nintendo Switch, and more today.

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Right now you can grab an Amazon Echo Dot two-speaker bundle for just $50. Plus, the 55-inch Vizio M-Series Quantum 4K Smart TV and Anker charging accessories are on sale.

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The Government Accountability Office finds that parents often have a hard time initiating complaints about special education services, but that these barriers don't affect all parents in the same way.

Perhaps there were some who had hoped for a dossier of lurid juiciness.

RANGERS vice-chairman John Bennett last night dismissed a claim that Ibrox chairman Douglas Park had threatened SPFL chief executive Neil Doncaster as “unfounded”.

A family of four was caught flouting lockdown restrictions after attempting to travel to Motherwell for a mini-break.

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As educators, we need to be critical consumers of educational research before assuming that findings present the "truth."

Hongyan “Red” Yuan, an instructional designer at Penn State Berks and member of the board of the Reading Chinese Association (RCA), recently helped to coordinate the donation of 1,500 surgical masks to Penn State Health St. Joseph.

The Colorado Supreme Court decided Douglas County's Choice Scholarship Program is unconstitutional.

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Armenia's most famous footballing son, Henrikh Mkhitaryan is the U19 EURO ambassador and looks back at his own youth career.