Top Democrats on Tuesday evening filed a compromise economic development bill containing state support for the life sciences and climate technology industries, ticket sales regulations, a new live theater tax credit, educator diversity reforms and more.

Though many amature divers claim to have found the famous shipwreck, it's likely still below Lake Michigan's waves.

I’m a Celebrity... Get Me Out of Here!’s 2024 campmates were finally confirmed on Monday, 11 November.

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Scientists have discovered the oldest-known fossil of a tadpole, which lived among the Jurassic dinosaurs 160 million years ago.

Researchers say tornadoes in Harvey, Sheffield areas on Friday evening were record-breaking for the province.

Rachelle and Kelly Swan bought their house in Spiritwood two years ago. They gave up their keys to the bank voluntarily in May, closing the door on the bat-infested house.  

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Earthquakes are among the most powerful natural forces on Earth, often causing widespread devastation, triggering tsunamis and altering the landscape of a region. But how strong was the strongest earthquake of all time?

Nintendo is set to show off the Donkey Kong Country expansion of its Super Nintendo World theme park today (Monday, November 11) at 5PM ET, the company revealed in a post on X. That means the new Universal Studios Japan area might finally open soon, after being delayed from the previously announced launch window of Spring 2024. 

The new park attraction featuring Mario's barrel-throwing nemesis was first revealed in 2021. The centerpiece is a ride called Mine Cart Madness, named after the best level in the 1994 SNES game Donkey Kong Country. After being blasted out of a barrel cannon, you'll take a mine cart ride through the jungle that includes a "leap across a collapsed track" as Nintendo showed in a render earlier this year.  

The direct livestream appears to be focused on Donkey Kong world alone, and Nintendo specifically pointed out that "no game information will be featured" — so don't expect any news on the next-gen Switch 2 console either. 

Donkey Kong Country will expand the park size by up to 70 percent, Nintendo said when it was announced. Current attractions at the Japan park are the Mario Kart: Kuppa's Challenge rollercoaster and Yoshi Adventure. Nintendo recently announced that it would open a Super Nintendo World attraction at Universal Studios Orlando on May 22nd, 2025 with the same attractions as the park in Osaka. 

This article originally appeared on Engadget at https://www.engadget.com/gaming/nintendo/nintendo-will-show-off-donkey-kong-country-theme-park-expansion-at-live-event-today-130015655.html?src=rss

As the world turns, so do the console generations. The Nintendo Switch is over seven years old, so it’s due for a refresh. Nintendo Switch 2 rumors have been swirling for years, but now they are really heating up. A sequel to Nintendo's most successful home console ever is coming and it’s likely coming sooner rather than later.

Will it be a straight up sequel to the Switch with updated specs while retaining the same hybrid functionality or will Nintendo get weird with it? Will it even be called the Switch 2, or will the company go with something like the Super Switch or even the New Nintendo Switch? You can never tell with Nintendo. Heck, maybe it’ll call the thing the Switch U.

In any event, recent weeks have brought feverish speculation regarding all aspects of the forthcoming gaming console. It’s important to note, however, that very little information has been confirmed by Nintendo. The company operates on its own timetable. With that said, here are all of the rumors that are most likely to come true, given industry analysis.

When will the Nintendo Switch 2 be announced?

As previously mentioned, Nintendo marches to the beat of its own drum. We don’t exactly know when it’ll hold an event to reveal the console. It likely won't be in 2024, as the tech year is winding down and it's rare to get announcements of new harder in late November and December. 

Even Nintendo has trouble keeping the lid on a major console release, so we could learn something before the official reveal. There are parts that have to be sourced and shipments that have to be made. A senior analyst at MST Financial noted a spike in production equipment spending by Nintendo assembler Hosiden.

When will the Nintendo Switch 2 come out?

Once again, this is more or less a mystery. We aren’t totally in the dark, but it’s mostly rumor and speculation. One thing we know for sure is that Nintendo will announce the Nintendo Switch 2 (or whatever it chooses to call it) by March 2025, as the company confirmed back in May. Some are saying there will be a March release date, which makes sense given the OG Switch came out on March 17, 2017. However, other reports put the console’s release window later in 2025.

We can infer a lot from the announcement date. If the console is announced this year, March would be a safe bet, given that the original Switch was officially confirmed in October of 2016. However, the console likely won't be announced until next year, at this point, so expect a late 2025 release. 

Will it even be a proper Switch sequel?

Nintendo has a weird track record here. The baffling Wii U followed the massive success of the Wii. The Wii itself followed the more traditional GameCube. In other words, it’s possible it’ll be something out of left field and not exactly a true sequel to the Switch. However, this is unlikely this time around. As much as I would love to see wacky VR glasses or a completely bonkers console concept, all points indicate a more traditional approach.

Developers have already seen the hardware, though in a much earlier form, and it seems to be a regular old console. While Nintendo hasn't confirmed hybrid functionality, it’d be a weird omission given the absolute financial firestorm of the Switch. We’ve also heard rumors of a Mini-LED display, which would track for a hybrid console. It’s highly likely this will be a straight-up Switch 2, or something like it, calling to mind the Super Nintendo.

To that end, recent rumors suggest a design that recalls the original Switch. According to reporting by VGC, photos of the console have appeared online and they show an 8-inch screen and magnetic Joy-Con controllers. There looks to be SL/SR buttons and front-facing player LEDs on these controllers. 

Is the Nintendo Switch 2 backwards compatible?

If it’s a sequel to the Switch, the next question has to be about backwards compatibility. The Switch’s library is absolutely massive, and continues to grow, so gamers would be rightfully peeved if they couldn’t play Tears of the Kingdom on their new next-gen console. There’s good news on this front.

The company has officially announced in a recent earnings report that the console will be fully backwards compatible. It will also feature access to Nintendo Online, so users will be able to play all of those old retro titles. 

What about specs?

The rumors regarding specs are all over the place, so it’s tough to pin down. We know one thing for sure: It’ll be more powerful than the ancient Switch hardware, which was already antiquated back in 2017. One analyst allegedly got a hold of a spec sheet from the Korean United Daily News that said the Switch 2 would boast an eight-core Cortex-A78AE processor, 8GB of RAM, and 64GB of internal eMMC storage. This tracks for me, as these specs are about as underpowered in 2024 as the original Switch was in 2017. However, some reports do indicate that the console would include 12GB of RAM. 

Another source suggests that the eight-core CPU will be packaged inside an NVIDIA-produced Tegra239 SoC (system on a chip). Given the current Switch runs on an NVIDIA chip, that makes a lot of sense. The CPU will be more powerful, but it's the Switch 2's new GPU that will be a major differentiator. It's all-but-confirmed that the Switch 2 will support DLSS, NVIDIA's "deep learning supersampling" upscaling tech, which would allow the console to render games at a low resolution internally while outputting a high-resolution image. (Fun fact: We actually wrote about how perfect DLSS was for the Nintendo Switch 2 when the technology was announced alongside the RTX 20 series back in 2018.)

There are still questions about the Switch 2 and DLSS: Will the system support newer DLSS features like frame generation? Will existing games be automatically tidied up by NVIDIA's algorithm? Regardless of the exact implementation, DLSS upscaling will be a huge leap over the rudimentary techniques available to Nintendo Switch developers.

As for the display, there are many conflicting rumors. Early reports from solid sources suggested the Switch 2 would have an 8-inch display LCD display, but there have also been rumors about an 7-inch display with a 120Hz refresh rate. Some analysts have suggested this would be an OLED screen, while others have said it would be a Mini-LED display. A Mini-LED display is basically an LCD display that has a backlight made of (surprise!) mini-LEDs rather than edge lighting. This allows for local dimming, making the blacks more black. I’m hedging my bets here. I think it’ll be a standard LCD, to cut costs, with an OLED or Mini-LED model coming later down the line. However, Mini-LED screens are slightly cheaper than OLED displays, so that’s certainly a possibility at launch.

As for resolution, recent reporting suggests that the console will output 1080p in handheld and 4K when docked. That's much better than the OG Switch. 

How much will the Nintendo Switch 2 cost?

We don't have too much information regarding price but we do have plenty of history to work with. The original Nintendo Switch launched at $300, which is pretty much the "magic number" when it comes to Nintendo console releases in recent years. The Wii U also came in at $300. 

However, there are plenty of rumors circulating that Nintendo could be upping the asking price for the Switch 2. Numerous outlets have reported it'll be $400, or potentially even more expensive. However, the same analysts who say the console will be $400 were also fairly certain it would be out by the end of 2024 and, well, it looks like that ain't happening. 

Dipping back into history, there is some precedence for a price uptick. The GameCube was $200 and the Wii was $250. The Wii U and Switch increased to $300 and, well, numbers like to go up. A $400 price tag would make it nearly as expensive as a PS5 and Xbox Series X. That would also put it at the same price as the 256GB LCD Steam Deck. 

Do we know about any launch games?

Nope! But it’s certainly been a long time since we’ve gotten a proper 3D Mario adventure, right? That would be one heck of a system seller. Other than that, your guess is as good as mine. Past as prologue, we can expect something from Ubisoft and an off-the-wall title like 1-2-Switch. 

If there’s a gimmick or hook involved with the console, we’ll also get a game that takes advantage of that. A dual release of Metroid Prime 4, just like Breath of the Wild and Twilight Princess before that, is also a possibility.

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That's everything we know about the Nintendo Switch 2 today. We'll update this article with rumors we trust and with information we gather directly from sources. Any changes made to the article after its initial publishing will be listed below.

Update, November 11, 2024, 9:00 AM ET: This story has been updated with details about the Switch 2's backwards compatibility as well as more details about the current expected announcement and release timeline.

This article originally appeared on Engadget at https://www.engadget.com/gaming/nintendo/nintendo-switch-2-everything-we-know-about-the-coming-release-110023903.html?src=rss

For the first time in over two years, Overwatch 2 players will be able to group up in teams of six. A three-week event featuring that format starts tomorrow, November 12. But there’s a twist: you won’t be able to select Kiriko or Sombra, or battle it out with an additional player on each side on Push maps just yet. That’s because in Overwatch 2’s first real taste of 6v6, Blizzard is taking us all the way back to the beginning with a limited-time mode called Overwatch: Classic.

You will be able to experience Overwatch almost exactly as it was upon its May 2016 debut. That means you can choose from the first 21 heroes, who all have their original kits and abilities. That means Hanzo loses his Lunge jump but regains his dreaded Scatter Arrow, Bastion and Torbjorn are vastly different than they are now and Cassidy's Flashbang once again stun locks enemies for a moment. 

Symmetra reverts to being a support who can teleport allies almost anywhere on the map from the spawn room, while Mercy can will once again bring five dead teammates back to life. Ultimate abilities will charge up faster too.

In addition, just like in Overwatch for a brief period at the very beginning, there are initially no limits on hero selection. So if you and your teammates want to run with a composition of four Winstons and two Lucios, have at it. However, this will only apply for the first few days, after which Blizzard will apply the single hero limit rule for the rest of the event. Games will take place under the Quick Play ruleset, rather than the Competitive format.

The original 12 maps will be available too — including the assault maps that Blizzard retired from the main modes during the transition to Overwatch 2. While assault maps are still available in the Arcade and custom games, you'll once again be dealing with the notorious choke points of the otherwise gorgeous Hanamura, Temple of Anubis and Volskaya Industries.

Blizzard Entertainment

Things won't be exactly as they were in May 2016, however. Original maps that have seen major reworks over the years — Dorado, Numbani, Route 66 and Watchpoint: Gibraltar — will appear as they are in the current game. You'll only be able to use the original default Overwatch skins and no, there are no loot boxes. The user interface remains the same too, which hopefully means the ping system will still be in place.

Blizzard doesn't plan for this to be a one-and-done deal. There will be other Overwatch: Classic events in the future, focusing on various moments in the game's history, like the infamous triple-tank, triple-support GOATS meta. This limited-time mode is also separate from the other 6v6 tests Blizzard plans to run in the coming months as it looks to measure players' interest in that format and garner feedback.

There's a good chance that this limited-time mode will bring some lapsed players back into the mix, even just for a sip of nostalgia. I first played Overwatch several months after its debut, so it'll be fun to see roughly how the game felt at the very beginning. I will be instalocking Mei every match so I can remember what it's like to freeze an opponent before giving them a cheeky wave and firing an icicle into their skull. Ah, memories...

This article originally appeared on Engadget at https://www.engadget.com/gaming/an-overwatch-classic-event-will-take-fans-all-the-way-back-to-the-beginning-171538261.html?src=rss

Fujifilm is developing a medium-format, 102-megapixel cinema camera, the company said in a surprise announcement. Due next year, the GFX Eterna will carry a boxy, modular design reminiscent of Sony's FX6 or the new Blackmagic Pyxis and will likely be launched with a top handle, electronic viewfinder and other optional accessories.

The new camera will have a medium format GFX 102-megapixel (MP) CMOS II HS sensor, the same one used on the GFX100 II. That sensor is 43.8mm x 32.9 mm in size, or 1.7 times larger than the full-frame sensor found on the aforementioned FX or Pyxis. That will be one of the largest cinema camera sensors available, even bigger than RED's V-Raptor XL sensor.

The benefits will be extra dynamic range, potentially high resolution and a very shallow depth of field that should allow for cinematic shots when paired with the right lens. That does bring up the fact that Fujifilm currently has no GFX glass designed specifically for film production. However, the company said it's developing a 32-90mm power zoom lens (24-70mm full-frame equivalent) and will have a mount adapter for GFX to PL lenses, which are widely used in cinema. 

One other concern might be rolling shutter distortion. RED's V-Raptor XL uses a global shutter that has zero distortion, but the sensor Fujifilm will employ has a fair bit of it . In addition, the GFX100 II captures 8K with a 1.53x crop, negating many of the benefits of a medium format sensor — so, hopefully Fujifilm will resolve those issues with its cinema camera. 

Fujifilm will show off the GFX Eterna starting tomorrow at the InterBEE 2024 media exhibition in Chiba City, Japan. It's set to be released sometime in 2025, with an exact date and pricing yet to be announced.

This article originally appeared on Engadget at https://www.engadget.com/cameras/fujifilm-is-developing-a-102mp-medium-format-cinema-camera-130027537.html?src=rss

Waymo has announced expanded availability of its driverless rideshare service throughout Los Angeles. That’s right. Waymo One is now available to all customers anywhere in LA county, which is 80 square miles. The company has dropped the waitlist for area residents. Now LA residents will get to experience sitting in endless traffic with a series of cameras and navigational algos leading the way instead of a person.

This expanded service starts today and it offers “fully autonomous rides” at any time of the day or night. Let’s hear it for some drunken late night bonding with an algorithm. Waymo also says it’ll further expand the service area in the future. After all, Los Angeles comprises five counties. 

It’s been offering driverless rides to LA customers for a while now, but with a mandatory waitlist. Waymo One also started small in San Francisco and Phoenix before announcing similar expansions. The service will be coming to Austin and Atlanta in the near future.

All told, the company says over 300,000 Los Angeles residents have joined the waitlist for the service and Waymo One has completed “hundreds of thousands of paid trips across the city.” Waymo says these driverless rides are also highly rated, with an average rating of 4.7 stars out of five. A recent survey indicated that 98 percent of customers are satisfied with the service.

This article originally appeared on Engadget at https://www.engadget.com/transportation/waymos-driverless-cars-in-la-county-are-now-available-to-everyone-173237519.html?src=rss

Cadillac is adding to its fleet of EVs with a new luxury SUV. The 2026 Cadillac Vistiq is a three-row, all-electric SUV that will hit showrooms and dealerships sometime next summer with a starting price of $78,790.

The Vistiq’s dual-motor, all-wheel drive system runs on a 102 kWh battery pack with a range of 300 miles that produces 615 horsepower and 650 pound-feet of torque. The Vistiq also supports vehicle-to-home (V2H) bidirectional charging capabilities: it can charge at home, and also deliver electricity to your house during a power outage. Using the features requires buying the GM Energy V2H bundle though.

The SUV’s design borrows aesthetically from other Cadillac EVs. Like the Lyriq, it has flush door handles, and features similar looking lights and side panels. It also matches the Lyriq’s 300 mile range. The “swept-back windshield” and “Black Crystal Shield grill” evoke the Escalade IQ.

Of course, the Vistiq's power and price are different from its Cadillac EV's. The new Cadillac EV SUV is less expensive than an Escalade IQ ($129,990) but more than a Lyriq ($58,595), and the Escalade IQ has a higher peak battery range at 450 miles.

The Vistiq comes with a 23-speaker AKG7 Studio Audio system with Dolby Atmos. The Android-powered infotainment system is baked into a 33-inch high resolution LED display. The Verge also reported that the new EV’s navigation system uses Google Maps and can run other apps from the Google Play Store.

Apple CarPlay and Android Auto won’t be available in Cadillac’s newest EV. General Motors is phasing out Apple CarPlay and Android Auto from its EVs and plans to go with Android Automotive. GM’s Executive Director of Digital Cockpit Experience Edward Kummer said in a Reuters interview that the carmaker didn’t want any features in its EVs “that are dependent on a person having a cellphone.”

This article originally appeared on Engadget at https://www.engadget.com/transportation/evs/cadillac-reveals-the-2026-vistiq-ev-suv-191557412.html?src=rss

Amazon is closing down Freevee, its free ad-supported video on demand service. This platform was home to original programming as well as more than 100 originals from the Prime Video roster. Freevee will be phased out over the coming weeks, and its content will become available as part of Prime Video. The ad-supported tier of Prime Video is included as part of Amazon's Prime membership for $15 a month.

"To deliver a simpler viewing experience for customers, we have decided to phase out Freevee branding," an Amazon spokesperson told Variety. "There will be no change to the content available for Prime members, and a vast offering of free streaming content will still be accessible for non-Prime members, including select originals from Amazon MGM Studios, a variety of licensed movies and series, and a broad library of FAST channels – all available on Prime Video."

The free viewing platform went through several rebrands since its original launch as IMDb Freedive in January 2019. It entered its final phase as Freevee in April 2022.

This article originally appeared on Engadget at https://www.engadget.com/entertainment/streaming/amazon-sunsets-freevee-platform-for-ad-supported-streaming-video-000614080.html?src=rss

FIRST came the smash, now comes the grab. It’s the crime wave that will send terror into the heart of every cafe owner worried that their stock standard breakfast basic is under threat of extinction.

Dhaka (AFP) Nov 7, 2024
Bangladesh is struggling to tamp down a surge in dengue cases as climate change turns the disease into a year-round crisis, leaving some paediatric wards packed with children squeezed two to a bed. The Aedes mosquito that spreads dengue - identifiable by its black and white striped legs - breeds in stagnant pools, and cases once slowed after the monsoon rains faded. "Normally, around t

The prolific British author discussed his latest book on Bookends with Mattea Roach.

Non aux rencontres amoureuses, au sexe, au mariage ou à élever des enfants avec un homme.

Donald Trump's second term as U.S. president carries implications at home and abroad. That includes potentially wreaking havoc on global economies through the aggressive use of tariffs.

The Canadian Food Inspection Agency has issued a recall for several brands of bread and buns due to pieces of metal in the products.

Multiple routers with multiple networks for your home are coming to Australia.

HE was spotted playing soccer in a park by a talent scout on holiday in Uruguay at age 15. Now Andrew Alvarenga has made the first grade side at top division soccer’s Club Atletico Cerro.

Dr Euan McBrearty, head of commerical & innovation, Wideblue shares five steps to successful medical device development.

When chemist Dora Richardson’s employer decided to terminate the breast cancer research on the drug Tamoxifen in the early 1970s, she and her colleagues continued the work in secret.

People are really stressed about the U.S. presidential election. A psychiatrist offers several self-help methods to reduce feelings of despair

Efficient machines, paper ballots and human checks make the U.S. voting system robust

A galaxy cluster bends light from seven background galaxies around it, letting astronomers peer into space and time

The new president-elect can go beyond just pulling out of the Paris Agreement. But it may be more difficult to roll back clean energy policies

The unexpected discovery of a geometric phase shows how math and physics are tightly intertwined

Autumn is here! Curl up with your favorite pumpkin-spiced blog and savor these acorns that we’ve squirrelled away for you:

• Johnson & Johnson Innovative Medicines gives a peek inside its $43 billion gross-to-net bubble

• Optum Rx joins the private label biosimilar bandwagon

• Biosimilars boom for provider-administered drugs

• Fresh evidence of how copay accumulators hurt patients

Plus, words of wisdom from Cencora's soon-to-be-former CEO Steve Collis.

P.S. Join my more than 58,000 LinkedIn followers for daily links to neat stuff along with thoughtful and provocative commentary from the DCI community.

There’s still time to request an invite to the inaugural Drug Channels Leadership Forum. Attendance will be highly limited. We have already begun extending invitations, so apply now to be considered. Click here to view the full agenda.

Read more »

Today’s guest post comes from Angie Franks, Chief Executive Officer of Kalderos.

Angie discusses how the Maximum Fair Price provision of the Inflation Reduction Act of 2022 will challenge providers, pharmacies, and manufacturers. She explains how Kalderos’ Truzo platform could reduce duplicate claims and address compliance issues.

To learn more, register for Kalderos’ October 25 webinar Cracking the MFP Code: How Flexible Technology Helps You Navigate an Evolving Landscape.

Read on for Angie’s insights.
Read more »

Chicken was once an expensive delicacy. In 1928, America’s quest for a better diet and a better standard of living was summarized by the campaign promise of “a chicken in every pot.” Today, chicken is a ubiquitous, low-cost source of protein, which we largely take for granted. Despite depletion of ocean-based stocks, fish hold similar potential. To begin this transformation, FDA must approve a scientifically-based innovative product—a faster growing genetically-engineered (GE) Atlantic salmon. When FDA Matters wrote about this subject 18 months ago, I believed the agency was near to approval of this first-ever food product from a GE animal. It is still not resolved and there are implications for all innovations that require FDA approval.

<p> <b>Abstract</b><br />CinnaGen, the largest biopharmaceutical company in the MENA region, is a leader in developing follow-on biologicals/biosimilars. Dr&nbsp;Haleh Hamedifar, Chairperson of CinnaGen, spoke to GaBI<i>&nbsp;</i>(Generics and Biosimilars Initiative) about the company’s strategic focus, which includes expanding its product portfolio, entering highly regulated global markets, and advancing affordable treatments for conditions such as multiple sclerosis and&nbsp;immunological diseases—transforming healthcare in underserved regions.</p><p><b>Keywords</b>: Biosimilars, clinical development, commercialization, MENA</p>

The government implied wholesalers had more personal protective equipment in stock than was the case during the first wave of the COVID-19 pandemic, the Healthcare Distribution Association has said.

The latest information about the novel coronavirus identified in Wuhan, China, and advice on how pharmacists can help concerned patients and the public.

Researchers around the world are working at record speed to find the best ways to treat and prevent COVID-19, from investigating the possibility of repurposing existing drugs to searching for novel therapies against the virus.

By Haojing Rong and Aimee Raleigh, as part of the From The Trenches feature of LifeSciVC This blog post is the second in a series on key diligence concepts and questions. If you missed the intro blog post yesterday, click

The post Pharmacology: The Anchor for Nearly Every Diligence appeared first on LifeSciVC.

“Children are not small adults.” We invoke this saying, in a vague and hand-wavy manner, whenever we talk about the need to study drugs in pediatric populations. It’s an interesting idea, but it really cries out for further elaboration. If they’re not small adults, what are they? Are pediatric efficacy and safety totally uncorrelated with adult efficacy and safety? Or are children actually kind of like small adults in certain important ways?

Pediatric post-marketing studies have been completed for over 200 compounds in the years since BPCA (2002, offering a reward of 6 months extra market exclusivity/patent life to any drug conducting requested pediatric studies) and PREA (2007, giving FDA power to require pediatric studies) were enacted. I think it is fair to say that at this point, it would be nice to have some sort of comprehensive idea of how FDA views the risks associated with treating children with medications tested only on adults. Are they in general less efficacious? More? Is PK in children predictable from adult studies a reasonable percentage of the time, or does it need to be recharacterized with every drug?

Essentially, my point is that BPCA/PREA is a pretty crude tool: it is both too broad in setting what is basically a single standard for all new adult medications, and too vague as to what exactly that standard is.

In fact, a 2008 published review from FDA staffers and a 2012 Institute of Medicine report both show one clear trend: in a significant majority of cases, pediatric studies resulted in validating the adult medication in children, mostly with predictable dose and formulation adjustments (77 of 108 compounds (71%) in the FDA review, and 27 of 45 (60%) in the IOM review, had label changes that simply reflected that use of the drug was acceptable in younger patients).

So, it seems, most of the time, children are in fact not terribly unlike small adults.

But it’s also true that the percentages of studies that show lack of efficacy, or bring to light a new safety issue with the drug’s use in children, is well above zero. There is some extremely important information here.

To paraphrase John Wanamaker: we know that half our PREA studies are a waste of time; we just don’t know which half.

This would seem to me to be the highest regulatory priority – to be able to predict which new drugs will work as expected in children, and which may truly require further study. After a couple hundred compounds have gone through this process, we really ought to be better positioned to understand how certain pharmacological properties might increase or decrease the risks of drugs behaving differently than expected in children. Unfortunately, neither the FDA nor the IOM papers venture any hypotheses about this – both end up providing long lists of examples of certain points, but not providing any explanatory mechanisms that might enable us to engage in some predictive risk assessment.

While FDASIA did not advance PREA in terms of more rigorously defining the scope of pediatric requirements (or, better yet, requiring FDA to do so), it did address one lingering concern by requiring that FDA publish non-compliance letters for sponsors that do not meet their commitments. (PREA, like FDAAA, is a bit plagued by lingering suspicions that it’s widely ignored by industry.)

The first batch of letters and responses has been published, and it offers some early insights into the problems engendered by the nebulous nature of PREA and its implementation.

These examples, unfortunately, are still a bit opaque – we will need to wait on the FDA responses to the sponsors to see if some of the counter-claims are deemed credible. In addition, there are a few references to prior deferral requests, but the details of the request (and rationales for the subsequent FDA denials) do not appear to be publicly available. You can read FDA’s take on the new postings on their blog, or in the predictably excellent coverage from Alec Gaffney at RAPS.

Looking through the first 4 drugs publicly identified for noncompliance, the clear trend is that there is no trend. All these PREA requirements have been missed for dramatically different reasons.

Here’s a quick rundown of the drugs at issue – and, more interestingly, the sponsor responses:

1. Renvela - Genzyme (full response)

Genzyme appears to be laying responsibility for the delay firmly at FDA’s feet here, basically claiming that FDA continued to pile on new requirements over time:

Genzyme’s correspondence with the FDA regarding pediatric plans and design of this study began in 2006 and included a face to face meeting with FDA in May 2009. Genzyme submitted 8 revisions of the pediatric study design based on feedback from FDA including that received in 4 General Advice Letters. The Advice Letter dated February 17, 2011  contained further recommendations on the study design, yet still required the final clinical study report  by December 31, 2011.

This highlights one of PREA’s real problems: the requirements as specified in most drug approval letters are not specific enough to fully dictate the study protocol. Instead, there is a lot of back and forth between the sponsor and FDA, and it seems that FDA does not always fully account for their own contribution to delays in getting studies started.

2. Hectorol - Genzyme (full response)

In this one, Genzyme blames the FDA not for too much feedback, but for none at all:

On December 22, 2010, Genzyme submitted a revised pediatric development plan (Serial No. 212) which was intended to address FDA feedback and concerns that had been received to date. This submission included proposed protocol HECT05310. [...] At this time, Genzyme has not received feedback from the FDA on the protocol included in the December 22, 2010 submission.

If this is true, it appears extremely embarrassing for FDA. Have they really not provided feedback in over 2.5 years, and yet still sending noncompliance letters to the sponsor? It will be very interesting to see an FDA response to this.

3. Cleviprex – The Medicines Company (full response)

This is the only case where the pharma company appears to be clearly trying to game the system a bit. According to their response:

Recognizing that, due to circumstances beyond the company’s control, the pediatric assessment could not be completed by the due date, The Medicines Company notified FDA in September 2010, and sought an extension. At that time, it was FDA’s view that no extensions were available. Following the passage of FDASIA, which specifically authorizes deferral extensions, the company again sought a deferral extension in December 2012. 

So, after hearing that they had to move forward in 2010, the company promptly waited 2 years to ask for another extension. During that time, the letter seems to imply that they did not try to move the study forward at all, preferring to roll the dice and wait for changing laws to help them get out from under the obligation.

4. Twinject/Adrenaclick – Amedra (full response)

The details of this one are heavily redacted, but it may also be a bit of gamesmanship from the sponsor. After purchasing the injectors, Amedra asked for a deferral. When the deferral was denied, they simply asked for the requirements to be waived altogether. That seems backwards, but perhaps there's a good reason for that.

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This new 10-minute TEDMED talk is getting quite a bit of attention:


 (if embedded video does not work, try the TED site itself.)

In it, Roger Stein claims to have created an approach to advancing drugs through clinical trials that will "fundamentally change the way research for cancer and lots of other things gets done".

Because the costs of bringing a drug to market are so high, time from discovery to marketing is so long, and the chances of success of any individual drug are so grim, betting on any individual drug is foolish, according to Stein. Instead, risks for a large number of potential assets should be pooled, with the eventual winners paying for the losers.

To do this, Stein proposes what he calls a "megafund" - a large collection of assets (candidate therapies). Through some modeling and simulations, Stein suggests some of the qualities of an ideal megafund: it would need in the neighborhood of $3-15 billion to acquire and manage 80-150 drugs. A fund of this size and with these assets would be able to provide an equity yield of about 12%, which would be "right in the investment sweet spot of pension funds and 401(k) plans".

Here's what I find striking about those numbers: let's compare Stein's Megafund to everyone's favorite Megalosaurus, the old-fashioned Big Pharma dinosaur sometimes known as Pfizer:

	Megafund (Stein)	Megalosaurus (Pfizer)
Funding	$3-15 billion	$9 billion estimated 2013 R&D spend
Assets	80-150	81 (in pipeline, plus many more in preclinical)
Return on Equity	12% (estimated)	9.2% (last 10 years) to 13.2% (last 5)

Since Pfizer's a dinosaur, it can't possibly compete with the sleek, modern Megafund, right? Right?

These numbers look remarkably similar. Pfizer - and a number of its peers - are spending Megafund-sized budget each year to shepherd through a Megafund-sized number of compounds. (Note many of Pfizer's peers have substantially fewer drugs in their published pipelines, but they own many times more compounds - the pipeline is just the drugs what they've elected to file an IND on.)

What am I missing here? I understand that a fund is not a company, and there may be some benefits to decoupling asset management decisions from actual operations, but this won't be a tremendous gain, and would presumably be at least partially offset by increased transaction costs (Megafund has to source, contract, manage, and audit vendors to design and run all its trials, after all, and I don't know why I'd think it could do that any more cheaply than Big Pharma can). And having a giant drug pipeline's go/no go decisions made by "financial engineers" rather than pharma industry folks would seem like a scenario that's only really seen as an upgrade by the financial engineers themselves.
A tweet from V.S. Schulz pointed me to a post on Derek Lowe's In the Pipeline blog. which lead to a link to this paper by Stein and 2 others in Nature Biotechnology from a year and a half ago. The authors spend most of their time differentiating themselves from other structures in the technical, financial details rather than explaining why megafund would work better at finding new drugs. However, they definitely think this is qualitatively different from existing pharma companies, and offer a couple reasons. First,

[D]ebt financing can be structured to be more “patient” than private or public equity by specifying longer maturities; 10- to 20-year maturities are not atypical for corporate bonds. ... Such long horizons contrast sharply with the considerably shorter horizons of venture capitalists, and the even shorter quarterly earnings cycle and intra-daily price fluctuations faced by public companies.

I'm not sure where this line of though is coming from. Certainly all big pharma companies' plans extend decades into the future - there may be quarterly earnings reports to file, but that's a force exerted far more on sales and marketing teams than on drug development. The financing of pharmaceutical development is already extremely long term.

Even in the venture-backed world, Stein and team are wrong if they believe there is pervasive pressure to magically deliver drugs in record time. Investors and biotech management are both keenly aware of the tradeoffs between speed and regulatory success. Even this week's came-from-nowhere Cinderella story, Intercept Pharmaceuticals, was founded with venture money over a decade ago - these "longer maturities" are standard issue in biotech. We aren't making iPhone apps here, guys.

Second,

Although big pharma companies are central to the later stages of drug development and the marketing and distributing of approved drugs, they do not currently play as active a role at the riskier preclinical and early stages of development

Again, I'm unsure why this is supposed to be so. Of Pfizer's 81 pipeline compounds, 55 are in Phase 1 or 2 - a ratio that's pretty heavy on early, risky project, and that's not too different from industry as a whole. Pfizer does not publish data on the number of compounds it currently has undergoing preclinical testing, but there's no clear reason I can think of to assume it's a small number.

So, is Megafund truly a revolutionary idea, or is it basically a mathematical deck-chair-rearrangement for the "efficiencies of scale" behemoths we've already got?

[Image: the world's first known dino, Megalosaurus, via Wikipedia.]

This article is part of our exclusive IEEE Journal Watch series in partnership with IEEE Xplore.

Any imaging technique that allows scientists to observe the inner workings of a living organism, in real-time, provides a wealth of information compared to experiments in a test tube. While there are many such imaging approaches in existence, they require test subjects—in this case rodents—to be tethered to the monitoring device. This limits the ability of animals under study to roam freely during experiments.

Researchers have recently designed a new microscope with a unique feature: It’s capable of transmitting real-time imaging from inside live mice via Bluetooth to a nearby phone or laptop. Once the device has been further miniaturized, the wireless connection will allow mice and other test subject animals to roam freely, making it easier to observe them in a more natural state.

“To the best of our knowledge, this is the first Bluetooth wireless microscope,” says Arvind Pathak, a professor at the Johns Hopkins University School of Medicine.

Through a series of experiments, Pathak and his colleagues demonstrate how the novel wireless microscope, called BLEscope, offers continuous monitoring of blood vessels and tumors in the brains of mice. The results are described in a study published 24 September in IEEE Transactions on Biomedical Engineering.

Microscopes have helped shed light on many biological mysteries, but the devices typically require that cells be removed from an organism and studied in a test tube. Any opportunity to study the biological process as it naturally occurs in the in the body (“in vivo”) tends to offer more useful and thorough information.

Several different miniature microscopes designed for in vivo experiments in animals exist. However, Pathak notes that these often require high power consumption or a wire to be tethered to the device to transmit the data—or both—which may restrict an animal’s natural movements and behavior.

“To overcome these hurdles, [Johns Hopkins University Ph.D. candidate] Subhrajit Das and our team designed an imaging system that operates with ultra-low power consumption—below 50 milliwatts—while enabling wireless data transmission and continuous, functional imaging at spatial resolutions of 5 to 10 micrometers in [rodents],” says Pathak.

The researchers created BLEscope using an off-the-shelf, low-power image sensor and microcontroller, which are integrated on a printed circuit board. Importantly, it has two LED lights of different colors—green and blue—that help create contrast during imaging.

“The BLE protocol enabled wireless control of the BLEscope, which then captures and transmits images wirelessly to a laptop or phone,” Pathak explains. “Its low power consumption and portability make it ideal for remote, real-time imaging.”

Pathak and his colleagues tested BLEscope in live mice through two experiments. In the first scenario, they added a fluorescent marker into the blood of mice and used BLEscope to characterize blood flow within the animals’ brains in real-time. In the second experiment, the researchers altered the oxygen and carbon dioxide ratios of the air being breathed in by mice with brain tumors, and were able to observe blood vessel changes in the fluorescently marked tumors.

“The BLEscope’s key strength is its ability to wirelessly conduct high-resolution, multi-contrast imaging for up to 1.5 hours, without the need for a tethered power supply,” Pathak says.

However, Pathak points out that the current prototype is limited by its size and weight. BLEscope will need to be further miniaturized, so that it doesn’t interfere with animals’ abilities to roam freely during experiments.

“We’re planning to miniaturize the necessary electronic components onto a flexible light-weight printed circuit board, which would reduce weight and footprint of the BLEscope to make it suitable for use on freely moving animals,” says Pathak.

This story was updated on 14 October 2024, to correct a statement about the size of the BLEscope.

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