Title: Don't Use Pricey New HIV PrEP Drug When Generics Available: Study
Category: Health News
Created: 3/9/2020 12:00:00 AM
Last Editorial Review: 3/10/2020 12:00:00 AM

Contact between inflammatory cells and endothelial cells (ECs) is a crucial step in vascular inflammation. Recently, we demonstrated that the cell-surface level of endomucin (EMCN), a heavily O-glycosylated single-transmembrane sialomucin, interferes with the interactions between inflammatory cells and ECs. We have also shown that, in response to an inflammatory stimulus, EMCN is cleared from the cell surface by an unknown mechanism. In this study, using adenovirus-mediated overexpression of a tagged EMCN in human umbilical vein ECs, we found that treatment with tumor necrosis factor α (TNF-α) or the strong oxidant pervanadate leads to loss of cell-surface EMCN and increases the levels of the C-terminal fragment of EMCN 3- to 4-fold. Furthermore, treatment with the broad-spectrum matrix metalloproteinase inhibitor batimastat (BB94) or inhibition of ADAM metallopeptidase domain 10 (ADAM10) and ADAM17 with two small-molecule inhibitors, GW280264X and GI254023X, or with siRNA significantly reduced basal and TNFα-induced cell-surface EMCN cleavage. Release of the C-terminal fragment of EMCN by TNF-α treatment was blocked by chemical inhibition of ADAM10 alone or in combination with ADAM17. These results indicate that cell-surface EMCN undergoes constitutive cleavage and that TNF-α treatment dramatically increases this cleavage, which is mediated predominantly by ADAM10 and ADAM17. As endothelial cell-surface EMCN attenuates leukocyte–EC interactions during inflammation, we propose that EMCN is a potential therapeutic target to manage vascular inflammation.

This case study aims to identify the cubic capacity and geometry of the geological body of silt–organic sediments in the environment of a former gravel pit situated in a drainless depression of the alluvium of the Čierna voda River. It is located in the well-known geotourism locality of Slnečné Jazera in Senec, in the SW of Slovakia. To identify the body, electrical resistivity tomography was combined with the use of sonar. The research shows that this approach is appropriate for a number of activities that are subjects of engineering-geological investigations. The cubic capacity and geometry of specific aqueous engineering-geological environments must be determined in connection with the need for the management, control, quantification and extraction of selected sedimentary bodies. In addition, the management of sustainable development of reservoirs, sedimentation basins, industrial ponds, settling pits and natural pools for recreation (the subject of the case study) is important to control the limit amounts of sediments in such environments. The results of this study may be applied in analogous engineering-geological conditions. The drainless depression Slnečné Jazera contained a body of silt–organic sediments amounting to 23 000 m³ (41 Olympic-size pools of 25 m x 12.5 m x 1.8 m). The maximum thickness of the bottom sediments was about 6.3 m on the alluvium with an articulated morphology owing to the submerged digging of gravel. The proposed approach improved the control of extraction of the sedimentary body and optimized the engineering-geological conditions in this geotourism locality.

PF06821497 has been identified as an orally available small-molecule enhancer of zeste homolog 2 inhibitor. The objectives of the present study were to characterize pharmacokinetic-pharmacodynamic-disease relationships of PF06821497 in xenograft mouse models with diffuse large B-cell lymphoma (Karpas422). An indirect-response model reasonably fit dose-dependent pharmacodynamic responses [histone H3 on lysine 27 (H3K27) me3 inhibition] with an unbound EC₅₀ of 76 nM, whereas a signal-transduction model sufficiently fit dose-dependent disease responses (tumor growth inhibition) with an unbound tumor stasis concentration (T_sc) of 168 nM. Thus, effective concentration for 70% of maximal effect (EC₇₀) for H3K27me3 inhibition was roughly comparable to T_sc, suggesting that 70% H3K27me3 inhibition could be required for tumor stasis. Consistently, an integrated pharmacokinetic-pharmacodynamic-disease model adequately describing tumor growth inhibition also suggested that ~70% H3K27me3 inhibition was associated with tumor stasis. Based on these results, we would propose that an EC₇₀ estimate for H3K27me3 inhibition corresponding to tumor stasis could be considered a minimum target efficacious concentration of PF06821497 in cancer patients.

The bioprocessing industry uses recombinant mammalian cell lines to generate therapeutic biologic drugs. To ensure consistent product quality of the therapeutic proteins, it is imperative to have a controlled production process. Regulatory agencies and the biotechnology industry consider cell line "clonal origin" an important aspect of maintaining process control. Demonstration of clonal origin of the cell substrate, or production cell line, has received considerable attention in the past few years, and the industry has improved methods and devised standards to increase the probability and/or assurance of clonal derivation. However, older production cell lines developed before the implementation of these methods, herein referred to as "legacy cell lines," may not meet current regulatory expectations for demonstration of clonal derivation. In this article, the members of the IQ Consortium Working Group on Clonality present our position that the demonstration of process consistency and product comparability of critical quality attributes throughout the development life cycle should be sufficient to approve a license application without additional genetic analysis to support clonal origin, even for legacy cell lines that may not meet current day clonal derivation standards. With this commentary, we discuss advantages and limitations of genetic testing methods to support clonal derivation of legacy cell lines and wish to promote a mutual understanding with the regulatory authorities regarding their optional use during early drug development, subsequent to Investigational New Drug (IND) application and before demonstration of product and process consistency at Biologics License Applications (BLA) submission.

The substantial discrepancy between the strong effects of functional foods and various drugs, especially traditional Chinese medicines (TCMs), and the poor bioavailability of these substances remains a perplexing problem. Understanding the gut microbiota, which acts as an effective bioreactor in the human intestinal tract, provides an opportunity for the redefinition of bioavailability. Here, we discuss four different pathways associated with the role of the gut microbiota in the transformation of parent compounds to beneficial or detrimental small molecules, which can enter the body’s circulatory system and be available to target cells, tissues, and organs. We further describe and propose effective strategies for improving bioavailability and alleviating side effects with the help of the gut microbiota. This review also broadens our perspectives for the discovery of new medicinal components.

ABSTRACTBackground:Some opportunities to routinely capture and improve respectful maternity care (RMC) during facility-based childbirth include quality improvement (QI) initiatives, community-based monitoring efforts through community score cards (CSC), and performance-based financing (PBF) initiatives. But there is limited guidance on which types of RMC indicators are best suited for inclusion in these initiatives. We sought to provide practical evidence-based recommendations on indicators that may be used for routine measurement of RMC in programs.Methods:We used a rapid review approach, which included (1) reviewing existing documents and publications to extract RMC indicators and identify which have or can be used in facility-based QI, CSCs, and PBF schemes; (2) surveying RMC and maternal health experts to rank indicators, and (3) analyzing survey data to select the most recommended indicators.Results:We identified 49 indicators spanning several domains of RMC and mistreatment including dignified/nondignified care, verbal and physical abuse, privacy/confidentiality, autonomy/loss of autonomy, supportive care/lack thereof, communication, stigma, discrimination, trust, facility environment/culture, responsiveness, and nonevidence-based care. Based on the analysis of the survey data, we recommend 33 indicators (between 2 and 6 indicators for each RMC domain) that may be suited for incorporation in both facility-based QI and CSC-related monitoring efforts.Conclusion:Integrating RMC indicators into QI and CSC initiatives, as well as in other maternal and neonatal health programs, could help improve RMC at the facility and community level. More research is needed into whether RMC can be integrated into PBF initiatives. Integration of RMC indicators into programs to improve quality of care and other health system outcomes will facilitate routine monitoring and accountability around experience of care. Measurement and improvement of women's experiences will increase maternal health service utilization and improve quality of care as a means of reducing maternal and neonatal morbidity and mortality.

Dalbavancin offers a possible treatment option for infectious peritonitis associated with peritoneal dialysis (PD) due to its coverage of Gram-positive bacteria and pharmacokinetic properties. We aimed to evaluate the clinical pharmacokinetics (PK) and pharmacodynamics of dalbavancin in a prospective, randomized, open-label, crossover PK study of adult patients with end-stage renal disease ESRD who were receiving PD. Sampling occurred prior to a single 30-min infusion of dalbavancin at 1,500 mg and at 1, 2, 3, 4, and 6 h and 7 and 14 days postadministration. Concentration-time data were analyzed via noncompartmental analysis. Pharmacodynamic parameters against common infectious peritonitis-causing pathogens were evaluated. Ten patients were enrolled. Patients were a median of 55 years old and had a median weight of 78.2 kg, 50% were female, and 70% were Caucasian. The terminal plasma half-life of dalbavancin was 181.4 ± 35.5 h. The day 0 to day 14 dalbavancin mean area under the curve (AUC) was 40,573.2 ± 9,800.3 mg·h/liter. The terminal-phase half-life of dalbavancin within the peritoneal fluid was 4.309 x 10⁸ ± 1.140 x 10⁹ h. The day 0 to day 14 dalbavancin mean peritoneal fluid AUC was 2,125.0 ± 1,794.3 mg·h/liter. The target plasma AUC/MIC was attained with the intravenous dose in all 10 patients for all Staphylococcus and Streptococcus species at the recommended MIC breakpoints. The intraperitoneal arm of the study was stopped early, because the first 3 patients experienced moderate to severe pain and bloating within 1 h following the administration of dalbavancin. Dalbavancin at 1,500 mg administered intravenously can be utilized without dose adjustment in peritoneal dialysis patients and will likely achieve the necessary peritoneal fluid concentrations to treat peritonitis caused by typical Gram-positive pathogens.

Tobacco smoking is the primary risk factor for lung cancer, driven by the addictive nature of nicotine and the indisputable carcinogenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) as well as other compounds. The integration of lung cancer chemoprevention with smoking cessation is one potential approach to reduce this risk and mitigate lung cancer mortality. Experimental data from our group suggest that kava, commonly consumed in the South Pacific Islands as a beverage to promote relaxation, may reduce lung cancer risk by enhancing NNK detoxification and reducing NNK-derived DNA damage. Building upon these observations, we conducted a pilot clinical trial to evaluate the effects of a 7-day course of kava on NNK metabolism in active smokers. The primary objective was to compare urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL plus its glucuronides, major metabolites of NNK) before and after kava administration as an indicator of NNK detoxification. Secondary objectives included determining kava's safety, its effects on DNA damage, tobacco use, and cortisol (a biomarker of stress). Kava increased urinary excretion of total NNAL and reduced urinary 3-methyladenine in participants, suggestive of its ability to reduce the carcinogenicity of NNK. Kava also reduced urinary total nicotine equivalents, indicative of its potential to facilitate tobacco cessation. Plasma cortisol and urinary total cortisol equivalents were reduced upon kava use, which may contribute to reductions in tobacco use. These results demonstrate the potential of kava intake to reduce lung cancer risk among smokers.

Microsoft and Turn 10 Studios announced Forza Street is now available worldwide for free on iOS and Android.

View the launch trailer below:

Here is an overview of the game:

This all-new Forza experience lets you jump into the game for quick, under-a-minute races where you compete to unlock new cars and upgrade parts to grow your car collection. We are excited for iOS and Android players to jump into this free to play mobile experience designed to be played anytime, anywhere, and excite anyone who loves cars.

Forza Street was also designed to be an evolving experience. The game is based in a street racing world with interesting characters, mystery, and  intrigue,  explored through a narrative driven campaign, weekly Spotlight Events, and limited time Themed Events, all of which provide players an opportunity to expand their car collections. For players looking for an additional challenge, weekly Rivals events let them take their collections against other players in the community in leaderboard based asynchronous challenges.

As a special gift to everyone who plays Forza Street between today and June 5 2020, players will receive a 2017 Ford GT and added in-game credits and gold to help you unlock new cars and grow your car collection! Don’t miss out on this chance to get this rare supercar added to your garage.

For gamers joining the fun via the Samsung Galaxy Store, we have two more gifts for you: anyone who downloads through the Galaxy Store on their Samsung devices will receive the 2015 Ford Mustang GT with a custom Galaxy themed paint. If players have the latest Galaxy S20 devices, they will also receive the 2015 Chevrolet Corvette Z06 with a Custom Galaxy, and in-game credits and gold.

Want to play Forza Street across multiple device? We got you covered – Forza Street supports Xbox Live. When you sign in with Xbox Live, players will be able to unlock Xbox Achievements and transfer game progress across your Windows, iOS, and Android devices.

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel dedicated to gaming Let's Plays and tutorials. You can contact the author at wdangelo@vgchartz.com or on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/443397/forza-street-now-available-for-ios-and-android/

Artist DIY is a series of videos made by artists in collaboration with FACT in response to the COVID-19 pandemic. FACT edits each episode remotely, while the artist shoots at their home or studio with whatever equipment they have available. In this episode, drummer, producer and DJ Iggor Cavalera records an improvised modular synth performance […]

The post Artist DIY: Iggor Cavalera appeared first on FACT Magazine.

There’s nothing like crash-landing on an alien planet. Journey to the Savage Planet doesn't always get it right, but it has echoes of classic Metroid Prime, says Jacob Aron

Venus’s surface is covered in strange wiggling lines that may form when colossal stacks of lava are carved by gentle winds over hundreds of millions of years

Human movements can teach robots the skills they need to dig holes and—maybe someday—build the first colonies on Mars

The new Nightlife reactive skin is now live ahead of the Fortnite Party Royale event which starts later today.

Final Fantasy XI announces its plans for its golden years. Fossil Fighters still exists. Then Phil either recommends or doesn’t recommend Avernum. I’m still not...

Defenders face an uphill struggle to win individual awards even before a ball has been kicked, according to Fabio Cannavaro.

Players at the back face an uphill struggle to win awards even before a ball has been kicked, according to the last defender to win the coveted prize

PIERS MORGAN launched another blistering attack on Boris Johnson, accusing the prime minister of encouraging the public to break the lockdown through "absurdly reckless" leaks to the media.

Londoners locked out of galleries can find an alternative art fix on a wall under under some railway arches after street artist Lionel Stanhope painted a Caravaggio classic, updated for the coronavirus age.

Read our live coronavirus updates HERE Coronavirus: the symptoms

The Government's new portal for arranging coronavirus tests has sparked confusion today, following a message suggesting home tests had run out by 9am.

Two teenagers have been arrested after a young boy was shot in east London and left with potentially life-changing injuries.

A man has been charged with aggravated burglary over an incident in which a young boy was shot in Upminster, east London.

The National Lottery website is down due to a power failure, leaving users unable to check results or enter Wednesday's draw.

https://shop.cookingmamacookstar.com/

In stock right now (8am CST 4/15/2020) $39.99 plus $5 shipping.

There’s been a bunch of scuttlebutt around this game being delisted from the eShop, supposedly mining bitcoin and a disagreement between the publisher and the IP owner. No matter the truth, grab it at retail pricing and don’t pay scalpers on eBay.

Margaret Spillane

The post Eavan Boland, Pillar of Irish Poetry: 1944–2020 appeared first on The Nation.

"Now there is a stage three and stage four of digitisation, we will take a call on this only after taking all things into account."

New Zealand’s handling of the coronavirus pandemic means that shooting on Avatar and Lord Of The Rings can resume. is already back underway in the country.

Coronavirus pandemic has caused production shutdowns and delays

Sia's video stars dancer Maddie Ziegler and stylist Tonya Brewer

Coronavirus pandemic has caused production shutdowns and delays

On losing a little sister and having a junkie as a dad

Nicola Sturgeon has warned Scottish football fans they should have no "false expectations" of attending matches in the near future, also stressing the dangers of behind-closed-doors events.

Chelsea have received a boost in their pursuit of Ajax goalkeeper Andre Onana and Fiorentina forward Federico Chiesa.

The state's African Americans face some of the country’s worst pollution — and some of its most severe COVID-19 outcomes. The two may well be linked.

The closure of the Navajo Generating Station in 2019 presents the opportunity for a renewable future on the Navajo Nation.

Extreme winds are churning up dust from Broken Hill to Sydney, with some parts of the central west turning red and forcing residents to eat dinner under bedsheets so as not to spoil their food.

MORNING BRIEFING: The $2.9 million awarded to Australian actor Geoffrey Rush in his defamation case will be challenged in court today, while much-needed rain has fallen in some of the state's driest areas.

Miss Tina runs the Beyhive.

"I really want to cry right now like oh my god!!!!"

Former Prime Minister Gordon Brown has called for "more than 200,000" coronavirus tests to be carried out.

Perth Airport is using heavy machinery and company vehicles to block a number of Virgin Australia aircraft from taking off over what it says are $16 million in unpaid debts.

Kathmandu (AFP) May 1, 2020
A search team on Friday recovered the last remaining two bodies missing after a Himalayan avalanche in January buried four South Korean trekkers and three locals. A wall of snow hit the trekkers at about 3,200 metres (10,500 feet) near the Annapurna base camp in Nepal on January 17, covering them under metres of snow. Avalanches and more snowfall since then made it too dangerous to lau

En 2017, je me suis plongée dans la peau d’une préposée aux bénéficiaires. Cette fois, le travail est le même, mais le contexte est bien différent.

Guillaume Lemay-Thivierge n’allait pas être complètement stoppé dans son élan par le confinement. C’était une question d’équilibre mental.