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If humans still exist millions of years from now, they will face inhospitably warm conditions on a supercontinent centred at the equator. Most land mammals won't be able to survive

An area of the seabed north of Australia has been mapped in detail for the first time, revealing that large numbers of people could have lived there until it was inundated by rising seas

Experts predict that the number of cancer cases around the world will skyrocket, resulting in millions more fatalities by 2050

A new radiometric dating technique reveals that cave paintings on Sulawesi, Indonesia, are even older than previously thought, pushing back the earliest evidence of storytelling

DNA evidence from tombs in Sweden and Denmark suggests major plague outbreaks were responsible for the Neolithic decline in northern Europe

DNA and protein analysis has identified a white substance smeared on mummies in China as a kind of kefir cheese, made from cow and goat milk

Title: 3 Big Pharmacy Chains Must Pay $650 Million to Ohio Counties for Role in Opioid Crisis
Category: Health News
Created: 8/18/2022 12:00:00 AM
Last Editorial Review: 8/18/2022 12:00:00 AM

Compound probiotics have been widely used and commonly coadministered with other drugs for treating various chronic illnesses, yet their effects on drug pharmacokinetics remain underexplored. This study elucidated the impact of VSL#3 on the metabolism of probe drugs for cytochrome P450 enzymes (P450s), specifically omeprazole, tolbutamide, midazolam, metoprolol, phenacetin, and chlorzoxazone. Male Wistar rats were administered drinking water containing VSL#3 or not for 14 days and then intragastrically administered a P450 probe cocktail; this was done to investigate the host P450’s metabolic phenotype. Stool, liver/jejunum, and serum samples were collected for 16S ribosomal RNA sequencing, RNA sequencing, and bile acid profiling. The results indicated significant differences in both α and β diversity of intestinal microbial composition between the probiotic and vehicle groups in rats. In the probiotic group, the bioavailability of omeprazole increased by 269.9%, whereas those of tolbutamide and chlorpropamide decreased by 28.1% and 27.4%, respectively. The liver and jejunum exhibited 1417 and 4004 differentially expressed genes, respectively, between the two groups. In the probiotic group, most of P450 genes were upregulated in the liver but downregulated in the jejunum. The expression of genes encoding metabolic enzymes and drug transporters also changed. The serum-conjugated bile acids in the probiotic group were significantly reduced. Shorter duodenal villi and longer ileal villi were found in the probiotic group. In summary, VSL#3 administration altered the gut microbiota, host drug–processing gene expression, and intestinal structure in rats, which could be reasons for pharmacokinetic changes.

SIGNIFICANCE STATEMENT

This study focused on the effects of the probiotic VSL#3 on the pharmacokinetic profile of cytochrome P450 probe drugs and the expression of host drug metabolism genes. Compared with previous studies, the present study provides a comprehensive explanation for the host drug metabolism profile modified by probiotics, combined here with the bile acid profile and histopathological analysis.

Our knowledge of the roles of individual cytochrome P450 (P450) enzymes in drug metabolism has developed considerably in the past 30 years, and this base has been of considerable use in avoiding serious issues with drug interactions and issues due to variations. Some newer approaches are being considered for "phenotyping" metabolism reactions with new drug candidates. Endogenous biomarkers are being used for noninvasive estimation of levels of individual P450 enzymes. There is also the matter of some remaining "orphan" P450s, which have yet to be assigned reactions. Practical problems that continue in drug development include predicting drug-drug interactions, predicting the effects of polymorphic and other P450 variations, and evaluating interspecies differences in drug metabolism, particularly in the context of "metabolism in safety testing" regulatory issues ["disproportionate (human) metabolites"].

Significance Statement

Cytochrome P450 enzymes are the major catalysts involved in drug metabolism. The characterization of their individual roles has major implications in drug development and clinical practice.

The deadline to claim part of the $15 million Cash App settlement is November 18. Here's what to know.

The last two weeks have had an interesting mix of news, and it just might break Chris by the end of the show. Anna Marie is hijacking the Question of the Week, but it's definitely a unique question! Alex stealths his way into the cast alongside Kelley and Peter. How is it still only July?

The post RPG Cast – Episode 550: “Gamer Girl Glue” appeared first on RPGamer.

Chris wonders if Pokémon is the future where the vegans win? Kelley just notices Josh's discord avatar is Joshua. Josh asks, "What is a mana game, but a miserable pile of menus?"

The post RPG Cast – Episode 650: “The Yodagrinch” appeared first on RPGamer.

Kelley doesn't want to bang Gambit that bad. Chris wants foilage in games. Jason discovers a new service at the spa. And Josh tells everyone, "Go away, I'm brooding."

The post RPG Cast – Episode 687: “Can I Interest You in 50 Slices of Kemco RPGs?” appeared first on RPGamer.

Microsoft and several retailers are currently running a promotion for the standard Xbox Series X in the US.

The Xbox Series X is available for $449, a $50 discount, at the Microsoft Store, GameStop, and Best Buy. It isn't known when this deal will end.

The recently released 1 TB All-Digital Robot White Xbox Series X, 2TB Disc Drive Galaxy Black Xbox Series, and the two Xbox Series S SKUs have not been discounted at this time.

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 and taking over the hardware estimates in 2017. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel. You can contact the author on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/463036/xbox-series-x-discounted-by-50-to-449/

The energy bill support has been described as a "crucial lifeline" for certain individuals who are often "overlooked".

Researchers have managed to encode enormous amounts of information, including images, into DNA at a rate hundreds of times faster than was previously possible

England beat New Zealand to reach women's hockey final

Australia crush England's hopes of second successive netball gold

Nick Miller wins gold for England in the hammer

India edge England to make T20 cricket final

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The number of people worldwide directly killed by antibiotic resistance will rise to 1.9 million a year by 2050, according to the most comprehensive study so far

Experts predict that the number of cancer cases around the world will skyrocket, resulting in millions more fatalities by 2050

The U.S. Food and Drug Administration has published the 2022 Food Code Supplement. The Supplement updates the 2022 Food Code with recommendations from regulatory officials, industry, academia, and consumers at the 2023 Biennial Meeting of the Conference for Food Protection.  The Food Code and its Supplement provide the government and industry with... Continue Reading

“I used to be proud of my work and excited about my future here. I don't feel that anymore."

Researchers show the average surface temperature on our planet has shifted between 51.8 to 96.8 degrees Fahrenheit

Shop these deep discounts of up to 50% off of loads of styles of Rebecca Minkoff handbags at Amazon's Big Summer Sale.

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Wall Street, crypto investors, and shareholders in Trump Media are all cheering the election results.

FPGA-powered hardware will capture CRT glow with "bespoke, purpose-built upscaler"

A voyage in this kind of spacecraft — while still conceptual — would take multiple lifetimes, crossing unimaginable gulfs of interstellar space. The theoretical exercise puts aside technical problems, including the propulsion system, and focusses on the design of the habitat and society.

We wouldn’t blame you if you try to do all of your tech shopping around the holidays. That’s when you can typically get the best sales, both on relatively affordable gear and (more importantly) on big-ticket items. But it would be wrong to think that only the most expensive tech is worth gifting. Since we at Engadget test a plethora of gadgets every year, we know that there are some hidden (and not so hidden) tech gems at lower price ranges — you just have to know where to find them. That’s where we come in — these are the best tech gifts under $50 that you can get this year.

Check out the rest of our gift ideas here.

This article originally appeared on Engadget at https://www.engadget.com/computing/accessories/best-gifts-under-50-holiday-stocking-stuffers-130049028.html?src=rss

The winter holidays are upon us and despite the festive feelings we might be hoping for, this time of year is often paired with increased stress, worry and anxiety. Fortunately, there are some great tools for helping to manage those negative emotions while promoting positive ones. One of those tools is the Headspace mental health app, which is running a three-week Black Friday deal. From November 12 through December 4, you can snag a Headspace annual plan for half off. This subscription normally costs $70 a year, but during this promotion, you can access the service for $35 billed annually. And what better time than the holiday chaos to gift someone (or heck, to gift yourself) a little bit of mindfulness?

Headspace's service has features to help users with meditation, sleep tools, mindfulness and general mental health. Its holistic approach made Headspace stand out as one of our top picks for meditation apps. Reviewer Lawrence Bonk appreciated how well Headspace created progression across its courses, as well as the chance to pick from different instructors so that any user can find the meditation guidance that will work best for their individual brains. This app is also getting the AI treatment. Headspace has introduced an AI companion named Ebb that can help users by recommending meditations and activities to best match their current challenges. 

Since this is a year-long subscription, it's a gift that keeps on giving for whoever you choose to buy this plan for. Having a happier brain is a present anyone can appreciate.

Follow @EngadgetDeals on Twitter and subscribe to the Engadget Deals newsletter for the latest tech deals and buying advice.

This article originally appeared on Engadget at https://www.engadget.com/deals/headspaces-black-friday-deals-discounts-subscriptions-by-50-percent-140026483.html?src=rss

Apple has a history of eye-popping price tags, but the company is reaching new heights with a product that isn't even a gadget. After Apple Music unveiled a list of the 100 best albums of all time earlier this year, the streaming service is releasing a companion coffee table book. You can grab one of the 1,500 copies for a cool $450.

I find these endeavors to rank and quantify art hilarious, because music is subjective and personal by nature. But people do love to debate their own artistic opinions, so if that's your jam there's plenty to dig into with Apple Music's assessment. (And before you ask, the top spot was claimed by The Miseducation of Lauryn Hill.) This particular countdown was assembled by "Apple Music’s team of experts alongside an exclusive group of artists including Maren Morris, Pharrell Williams, J Balvin, Charli XCX, Mark Hoppus, Honey Dijon and Nia Archives, as well as songwriters, producers and industry professionals," according to the book listing.

I'm sure this limited-run hardcover will be very beautiful, and maybe the liner notes analyzing each entry are deeply insightful. But I also wonder who would bother to buy it. If you are one of those 1,500 people who wants one, the book is due to start shipping in January.

This article originally appeared on Engadget at https://www.engadget.com/entertainment/music/the-coffee-table-book-of-apple-musics-best-100-albums-will-set-you-back-450-193018825.html?src=rss

The company is handed its second biggest fine over the deaths of thousands of fish in two rivers.

Arriving in two boxes reminiscent of Apple product packaging – one for the chest piece (the part that contacts the body), and another for the detachable earpiece (tubes + ear tips) – the CORE 500 is clearly an upgrade from the Eko DUO stethoscope. Similar to its predecessor, the CORE 500 can be used with […]

It is a surprisingly common peril among analysts: we don’t have the data to answer the question we’re interested in, so we answer a related question where we do have data. Unfortunately, the new answer turns out to shed no light on the original interesting question.

This is sometimes referred to as the Streetlight Effect – a phenomenon aptly illustrated by Mutt and Jeff over half a century ago:

This is the situation that the Tufts Center for the Study of Drug Development seems to have gotten itself into in its latest "Impact Report".  It’s worth walking through the process of how an interesting question ends up in an uninteresting answer.

So, here’s an interesting question:

My company owns a drug that may be approvable through FDA’s 505(b)(2) pathway. What is the estimated time and cost difference between pursuing 505(b)(2) approval and conventional approval?

That’s "interesting", I suppose I should add, for a certain subset of folks working in drug development and commercialization. It’s only interesting to that peculiar niche, but for those people I suspect it’s extremely interesting - because it is a real situation that a drug company may find itself in, and there are concrete consequences to the decision.

Unfortunately, this is also a really difficult question to answer. As phrased, you'd almost need a randomized trial to answer it. Let’s create a version which is less interesting but easier to answer:

What are the overall development time and cost differences between drugs seeking approval via 505(b)(2) and conventional pathways?

This is much easier to answer, as pharmaceutical companies could look back on development times and costs of all their compounds, and directly compare the different types. It is, however, a much less useful question. Many new drugs are simply not eligible for 505(b)(2) approval. If those drugs

Extreme qualitative differences of 505(b)(2) drugs. Source: Thomson Reuters analysis via RAPS

are substantially different in any way (riskier, more novel, etc.), then they will change the comparison in highly non-useful ways. In fact, in 2014, only 1 drug classified as a New Molecular Entity (NME) went through 505(b)(2) approval, versus 32 that went through conventional approval. And in fact, there are many qualities that set 505(b)(2) drugs apart.

So we’re likely to get a lot of confounding factors in our comparison, and it’s unclear how the answer would (or should) guide us if we were truly trying to decide which route to take for a particular new drug. It might help us if we were trying to evaluate a large-scale shift to prioritizing 505(b)(2) eligible drugs, however.

Unfortunately, even this question is apparently too difficult to answer. Instead, the Tufts CSDD chose to ask and answer yet another variant:

What is the difference in time that it takes the FDA for its internal review process between 505(b)(2) and conventionally-approved drugs?

This question has the supreme virtue of being answerable. In fact, I believe that all of the data you’d need is contained within the approval letter that FDA posts publishes for each new approved drug.

But at the same time, it isn’t a particularly interesting question anymore. The promise of the 505(b)(2) pathway is that it should reduce total development time and cost, but on both those dimensions, the report appears to fall flat.

• Cost: This analysis says nothing about reduced costs – those savings would mostly come in the form of fewer clinical trials, and this focuses entirely on the FDA review process.
• Time: FDA review and approval is only a fraction of a drug’s journey from patent to market. In fact, it often takes up less than 10% of the time from initial IND to approval. So any differences in approval times will likely easily be overshadowed by differences in time spent in development. 

But even more fundamentally, the problem here is that this study gives the appearance of providing an answer to our original question, but in fact is entirely uninformative in this regard. The accompanying press release states:

The 505(b)(2) approval pathway for new drug applications in the United States, aimed at avoiding unnecessary duplication of studies performed on a previously approved drug, has not led to shorter approval times.

This is more than a bit misleading. The 505(b)(2) statute does not in any way address approval timelines – that’s not it’s intent. So showing that it hasn’t led to shorter approval times is less of an insight than it is a natural consequence of the law as written.

Most importantly, showing that 505(b)(2) drugs had a longer average approval time than conventionally-approved drugs in no way should be interpreted as adding any evidence to the idea that those drugs were slowed down by the 505(b)(2) process itself. Because 505(b)(2) drugs are qualitatively different from other new molecules, this study can’t claim that they would have been developed faster had their owners initially chosen to go the route of conventional approval. In fact, such a decision might have resulted in both increased time in trials and increased approval time.

This study simply is not designed to provide an answer to the truly interesting underlying question.

[Disclosure: the above review is based entirely on a CSDD press release and summary page. The actual report costs $125, which is well in excess of this blog’s expense limit. It is entirely possible that the report itself contains more-informative insights, and I’ll happily update that post if that should come to my attention.]

Acadia Pharmaceuticals did not disclose the buyer of the priority review voucher. The biotech received the voucher last year alongside the regulatory decision that made its drug Daybue the first FDA-approved treatment for the rare disease Rett syndrome.

The post Acadia Pharma Sells Voucher for Speedier FDA Drug Review for $150M appeared first on MedCity News.

This cable contains information which we hope will be useful to you in engaging host governments, media, and the public after the President's address.

In a wide-ranging meeting with CODEL McCaskill February 17, National Security Advisor Shivshankar Menon touched on several regional security and trade-related issues.

Benazir Bhutto's public comments that she would grant the IAEA access to Khan were highly controversial in Pakistan. Zardari's options for delivering on Benazir's promise is limited.

Apr 9, 2024

This paper delves into the evolution and future prospects of Global Navigation Satellite Systems (GNSS), with a particular focus on the United States' Global Positioning System (GPS) and Europe's Galileo. As GPS celebrates its 50th anniversary, it is a timely moment to assess its historical trajectory, current status, and future directions, especially considering the emergence of new competitors like China's BeiDou. Based on interviews with two GNSS experts from the European Commission, this study aims to analyze the potential for cooperation between GPS and Galileo, exploring avenues for collaboration and mutual learning.

#GeneralMills150 in :50 Seconds

Five charities win a share of $50,000 in Isle of Capri Casinos� Community Aces Challenge.

Learn more about the 2016 PetSafe� Bark for Your Park� grant-giving program in this video.

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