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.

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.

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.

Cyclophilins play a key role in the lifecycle of coronaviruses. Alisporivir (Debio 025) is a non-immunosuppressive analogue of cyclosporin A with potent cyclophilin inhibition properties. Alisporivir reduced SARS-CoV-2 RNA production in a dose-dependent manner in VeroE6 cell line, with an EC₅₀ of 0.46±0.04 μM. Alisporivir inhibited a post-entry step of the SARS-CoV-2 lifecycle. These results justify that a proof-of-concept Phase 2 trial be rapidly conducted with alisporivir in patients with SARS-CoV-2 infection.

Six sources confirmed Apple changed its mind on end-to-end encrypted backups two years ago following an FBI complaint and concerns users could lose access to their own data.

Avast is harvesting users' browser histories on the pretext that the data has been 'de-identified,' thus protecting your privacy. But the data, which is being sold to third parties, can be linked back to people's real identities, exposing every click and search they've made.

The password-fatigued masses will be pleased to find Keeper's new 30 percent off deal, which brings it down to $20.99 per year from its typical $29.99.

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

In number 10 in our countdown, I tried to offer a few thoughts to funders as they embraced new agendas and looked to avoid repeating yesterday's missteps.

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:

The association of dietary fat distribution with markers of subclinical atherosclerosis during early life is unknown. We examined whether success in achieving the main target of an infancy-onset dietary intervention based on the distribution of dietary fat was associated with aortic and carotid intima-media thickness (IMT) and distensibility from childhood to young adulthood.

BACKGROUND:

Pediatricians are less frequently sued than other physicians. When suits are successful, however, the average payout is higher. Little is known about changes in the risk of litigation over time. We sought to characterize malpractice lawsuit trends for pediatricians over time.

Penn State Health Milton S. Hershey Medical Center has begun enrolling participants in an international clinical trial evaluating an investigational antiviral drug, remdesivir, for treatment of coronavirus disease 2019 (COVID-19).

Lehigh Valley's Practical Nursing Program has moved to the Shadow Health Digital Clinical Experience so students can continue clinical rotations through virtual simulations.

Extremely low or negative yields in global markets make it challenging for investors to generate meaningful returns, says Brian McMillan of Investec Structured Products.

Many teachers scrapped their lesson plans on Monday and gave their students space to talk about Kobe Bryant.

Effective immediately and for the foreseeable future, the Entrepreneurship and Assistance Clinic is expanding its scope and service offerings to small Pennsylvania businesses, in response to the COVID-19 pandemic.

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.

The Z8H 8K LED vibrates the frame of the television to emit audio and give the impression that the sound is coming directly from the screen itself.

All of the TVs on sale come standard with Roku TV, meaning you can access all of your favorite streaming platforms.

The 65-inch LG 65SM8600AUA 4K HDR smart LED TV is marked down to just $769.99, a 48 percent discount off its $1,469 list price.

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.

The Education Department says federal law should not be used to prevent schools from offering online learning to all students, including those with disabilities.

THE SPFL were tonight criticised for giving Scotland’s clubs hope that league reconstruction was a possibility in their controversial end-of-season resolution.

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

Falkirk chairman Gary Deans tonight slammed Ladbrokes Premiership clubs for scuppering league reconstruction hopes - and called for change at the top of Scottish football.

PARTICK Thistle today branded the SPFL a "disgrace" for failing to inform them that league reconstruction had been abandoned and revealed they are "deeply angered" by Ladbrokes Premiership clubs scuppering the plans.

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.

IT’S a bank holiday weekend and we are now several weeks into a gruelling lockdown.

Already home to a thriving ecosystem of private school choice, the state’s lawmakers want vouchers for thousands of new students.

The IMpact-RSV Study Group
Sep 1, 1998; 102:531-537
ARTICLES

Nearly every state in the nation has experienced enrollment declines, with some states seeing steep declines of more than 50 percent.

Student-teachers are grappling with uncertainty over housing, graduation requirements, and their ability to meet requirements for the edTPA licensing test.

When people can’t leave their houses to attend an event, you bring the event to them. With residents across Pennsylvania sheltering in place during the COVID-19 pandemic, Penn State Dickinson Law’s Business Law Society is converting two upcoming entrepreneur pop-up clinics to virtual sessions, allowing people to participate from their homes.

History teacher Bill Tolley offers tips on adapting to learning environments that combine face-to-face instruction with self-directed online experiences.

The champion of disruptive innovation in business and education passed away this month. One of Christensen's co-authors of "Disrupting Class," Michael B. Horn, assesses the impact his late colleague had on schools.

At its final meeting of the 2019-20 academic year, the Penn State Faculty Senate passed landmark legislation updating its full-time faculty hiring policy for the first time in more than 20 years, as one step in continued efforts to advance the University’s commitment to diversity, equity and inclusion.

"With unparalleled technology support, digital and curriculum innovation, a flexible structure including our Commonwealth and University Park campuses, effective outreach programming, and a wide array of top-ranked academic programs, Penn State is uniquely prepared for the arrival of the Class of 2024," wrote President Eric J. Barron in a message inviting accepted students to attend a four-part virtual series titled "Welcome to the Penn State Community."

Media literacy belongs in science class, insists Media Literacy Now’s Andy Zucker. Here’s how to bring it there.

Microsoft originally sought to become a 'carbon neutral' company, meaning it could generate carbon emissions as long as it offset them through other means, but "in short, neutral is not enough to address the world's needs," says Microsoft President Brad Smith.

Retail stores, corporate offices, and contact centers in China are closed through February 9 as the coronavirus spreads globally. Apple's online store will remain open, though.

Chinese manufacturer TCL will no longer make BlackBerry-branded phones, nor will it have the right to 'design, manufacture or sell any new BlackBerry mobile devices' after August 2020.

The OnePlus 7T Pro 5G McLaren is a wickedly powerful Android phone which falls just short of the Galaxy S20 series on performance, for considerably less coin.

Many of Penn State Behrend's student clubs and organizations have moved online due to COVID-19 restrictions. One benefit of the new model: It's easier to bring in guest speakers.

Four Penn State World Campus energy and sustainability policy majors spent the year working with Pennsylvania boroughs to inventory greenhouse gas emissions, and coming up with climate action plans for reducing them.