It's rare that you'll find discounts on Apple products through the company's own retail channels, but other storefronts are often happy to slash prices on such wares. You can find early Black Friday deals on a bunch of Apple products, including MacBooks. The M3 MacBook Air with 16GB of RAM has dropped to its lowest price to date at Amazon. The laptop will run you $899, which is $200 off the list price.

This is a 13-inch MacBook Air with 256GB of storage. Other configurations with more storage space are on sale too. One with 8GB of RAM and a 512GB SSD is $300 off at $999, though we'd recommend having at least 16GB of memory. It's not possible to upgrade the RAM in an Apple Silicon MacBook, but you can always add external storage if need be.

To that end, you can snag a 13-inch M3 MBA with 16GB of RAM and 512GB of built-in storage for $1,099. If a model with 24GB and the same SSD is what you're looking for, you can snap one up for $1,299. Both are $200 off.

Apple just released its first M4-powered Macs, but it has yet to slot the latest chip into the MacBook Air. To that end, we reckon the 13-inch M3 MacBook Air is the best laptop for most people. It's our pick for the best laptop for college students too.

The 13-inch MBA's blend of power and portability makes it a potent choice and we gave it a score of 90 in our review. It delivers fast performance and has a killer display. The design is sleek and sturdy and it sounds great thanks to a quad-speaker array. We like the trackpad and keyboard as well, while the upgrade to Wi-Fi 6E connectivity is a definite plus. Our main quibble is that the USB-C ports are on the same side of the unit as the one for the charger — having even one USB-C on the right side would be handy. But that's a minor complaint about an otherwise excellent laptop.

Check out all of the latest Black Friday and Cyber Monday deals here.

This article originally appeared on Engadget at https://www.engadget.com/deals/the-m3-macbook-air-with-16gb-of-ram-is-on-sale-for-899-ahead-of-black-friday-154922025.html?src=rss

I'm a big fan of Anker's chargers, especially its portable ones, as they tend to be sleek, fast and small enough to shove in my pocket (the last bit is a requirement for me). While the company's products run the gambit price-wise, there's a big sale on one of Anker's more expensive options: the 200W Prime Power Bank. Right now, you can get this power bank and its 100W charging base for just $110, down from $185 — a 41 percent discount.

Anker's 200W portable charger is our choice for best premium power bank thanks to features like charging an iPhone in an average of one hour and 48 minutes. One of the best parts of the power bank is its sleek screen, which shows the power coming in or out and how much battery the accessory is holding. This feature is much more exact than the four dots on my cheaper (but still loved) Anker Nano Power Bank. 

The power bank and charging base both offer one USB port and two USB-C ports so there's plenty of ways to charge your devices. The base also uses magnets to secure its pins to the power bank and charge it upright. Our biggest quip with the power bank was its high price, but with this sale it's definitely worth looking into. 

Check out all of the latest Black Friday and Cyber Monday deals here.

This article originally appeared on Engadget at https://www.engadget.com/deals/one-of-our-favorite-anker-power-banks-is-41-percent-off-for-black-friday-161543537.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

The blackest of Fridays is nearly upon us and companies have already begun rolling out the deals to separate consumers from their bank accounts. Here’s one for a well-regarded and budget-friendly robovac. The iRobot Roomba Essential Vac is on sale for just $140, which is a discount of 44 percent. The regular price is $250.

The Essential Vac features a similar design to the iRobot Roomba 694, which topped our list of the best budget robot vacuums. This one includes a three-stage cleaning system that works on both carpet and hard floors. It features the same smart navigation system as other iRoomba vacuums, so it’ll avoid stairs and work its way around items of furniture.

Despite being a budget-friendly robovac, there are some modern flourishes. The vacuum will automatically return to the charging station when the battery runs low, which is always nice. It also integrates with the Roomba app for setting cleaning schedules and for building a custom map of the home.

The battery life sits at around two hours, which is a decent metric for the price. That should be more than enough time to thoroughly clean a medium-sized home. The major caveat here is that this is a budget robovac, so it doesn’t mop and it doesn’t ship with a large debris canister. Still, the price is right for those curious about eliminating sweeping from that to-do list.

Check out all of the latest Black Friday and Cyber Monday deals here.

This article originally appeared on Engadget at https://www.engadget.com/deals/this-budget-roomba-robot-vacuum-is-nearly-half-off-ahead-of-black-friday-184426408.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

This year's action RPG Stellar Blade has been a solid win for Sony as a PlayStation 5 exclusive. Developer Shift Up revealed in a recent quarterly earnings report that sales "have remained steady even as the initial surge has calmed" following its spring launch. But there may be a second boost coming for the game, because the studio is planning a PC port of Stellar Blade some time next year.

"Given recent trends like Steam’s growing presence in the AAA games market and the global success of Black Myth: Wukong, we are expecting the PC version to perform even better than the console version," the Korean company said when asked about their PC plans during the presentation.

The title referenced, Black Myth: Wukong, was able to set a new record for concurrent players in a single-player game on Steam when it launched on the platform in August. That's a lofty goal for any game to reach, so we'll have to see how successful Shift Up can be in reaching an international audience on PC.

This article originally appeared on Engadget at https://www.engadget.com/gaming/ps5-exclusive-stellar-blade-is-coming-to-pc-231625263.html?src=rss

Leylah Fernandez et ses compatriotes auront fort à faire pour conserver leur titre.

Following a mother and son during the the Blitz, Nazi Germany's bombing campaign on London during the Second World War, director Steve McQueen's new drama understands the war film — perhaps a bit too well.

Un mois après la mystérieuse disparition d’un comptable sans histoire de Saint-Jean-sur-Richelieu, le corps de l’homme de 68 ans a été retrouvé.

Amoury Lapointe a résisté à son arrestation lors d’une intervention de routine à laquelle il refusait de se soumettre dans son «véhicule diplomatique»

Attaque avec une voiture en Chine: 35 morts et des dizaines de blessés.

Donald Trump va nommer la représentante Elise Stefanik, républicaine du nord de l’État de New York, ambassadrice des États-Unis à l’ONU.

An internal report on workplace racism and harassment at the highest levels of the federal public service shows that not even the federal government’s top executives are immune from the problem.

La majorité des billets encore offerts en ligne pour aller voir Taylor Swift à Toronto sont des arnaques, constate un expert en cybersécurité.

DOCTORS from a top Australian university say they too were hit with erroneous Centrelink debt notices — and even a PhD can’t sort out the mess.

The deal secured by the Hull facility is for the East Anglia TWO project off the Suffolk coast.

The Grattan Institute has warned Victoria’s gas moratorium may have to be partially lifted to save the smelter.

Une étude rapporte que la perturbation de l’équilibre du microbiote intestinal par le stress dérègle la fonction des cellules immunitaires.

The office of the Additional Director General of Foreign Trade (CLA DGFT) has announced an Export Obligation Discharge Certificate (EODC) Camp scheduled from November 11 to 22, 2024. The camp is

The Department of Pharmaceuticals (DoP) has upheld the retail price fixation of National Pharmaceutical Pricing Authority (NPPA) for Mumbai─based Aristo Pharmaceuticals for its multivitamin tablets with

The Subject Expert Committee (SEC), which advises the national drug regulator on approval of new drugs and clinical trials, has recommended grant of market authorisation for Dr Reddy's Laboratories' Siponimod

Two exclusive conferences focusing on "Reference Material (RM) Producers" organized by National Accreditation Board for Testing and Calibration Laboratories (NABL) are scheduled to be held on January 10,

The National Accreditation Board for Testing and Calibration Laboratories (NABL), under the Quality Council of India (QCI), has announced a collaborative effort with Man─Made Textile Research Association (MANTRA) in Surat to deliver a specialized technical training programme on medical textiles testing.

Election polls are increasingly vulnerable to huge mistakes

Long before it orbited Earth, the Hubble Space Telescope starred in a famous Superman comic

Focusing on size in health care might be doing more harm than good.

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

Charco Neurotech, a medtech company based in the United Kingdom, has developed CUE1, a non-invasive wearable that is intended to assist those with Parkinson’s disease to manage their motor symptoms. The device is typically affixed to the sternum, and provides vibratory action in a focused region of the body. The technology is based on the […]

A team at the University of Technology Sydney has developed an assistive technology for blind people and those with low vision. The system consists of glasses that can view their surroundings through an on-board camera, appraise the objects nearby using computer vision technology, and then play a sound that provides a cue for the wearer […]

Engineers at the University of British Columbia have collaborated with the Japanese automotive company Honda to develop an e-skin for robotic prostheses that allows such devices to sense their environment in significant detail. The soft skin is highly sensitive, letting robotic hands to perform tasks that require a significant degree of dexterity and tactile feedback, […]

On October 8, 2024, Drug Channels Institute will release our 2024-25 Economic Report on Pharmaceutical Wholesalers and Specialty Distributors. This report—our fifteenth edition—remains the most comprehensive, fact-based tool for understanding and analyzing the large and growing U.S. pharmaceutical distribution industry.

9 chapters, 350+ pages, 178 exhibits, 750+ endnotes: There is nothing else available that comes close to this valuable resource.

We are providing you with the opportunity to preorder this thoroughly updated, revised, and expanded 2024-25 edition at special discounted prices. This means that you can be among the first to access our new report. Those who preorder will receive a download link before October 8.

• Review pricing/license options and place a preorder

• Download a free pre-publication report overview (including key industry trends, What's New in this edition, the Table of Contents, and a List of Exhibits)

You can pay online with all major credit cards (Visa, MasterCard, American Express, and Discover) or via PayPal. Click here to contact us if you would like to pay by corporate check or ACH.

Special preorder and launch pricing discounts will be valid through October 23, 2024.

Read on for more details.
Read more »

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 »

I am pleased to announce Drug Channels Institute's new 2024–25 Economic Report on Pharmaceutical Wholesalers and Specialty Distributors, available for purchase and immediate download.

• Download a free report overview (including key industry trends, the Table of Contents, and a List of Exhibits)

• Review pricing/license options and download the full 2024-25 report

We’re offering special discounted pricing if you order before October 23, 2024.

2024–25 Economic Report on Pharmaceutical Wholesalers and Specialty Distributors—our 15th edition--remains the most comprehensive, fact-based tool for understanding and analyzing the large and growing U.S. pharmaceutical distribution industry. This 2024-25 edition includes substantial new material—outlined on page vii of the report overview.

9 chapters, 380+ pages, 178 exhibits, more than 750 endnotes: There is nothing else available that comes close to this valuable resource.

You can pay online with all major credit cards (Visa, MasterCard, American Express, and Discover) or via PayPal. Click here to contact us if you would like to pay by corporate check or ACH.

Email Paula Fein (paula@drugchannels.net) if you’d like to bundle your report purchase with access to DCI’s video webinars.

If you preordered the report, you should have already received an email with download instructions last week. Please contact us if you did not receive your email.

Read on for some additional details.
Read more »

Community pharmacies should be reimbursed for their additional costs during the COVID-19 pandemic “as soon as possible”, the prime minister has told The Pharmaceutical Journal.

Consultations on the reclassification of two progestogen-only contraceptive pills from prescription-only to pharmacy medicines have been launched.

A new type of drug that targets chemotherapy directly to cancer cells reduces the risk of death from the most common type of bladder cancer by 30%, a phase III trial in the New England Journal of Medicine has suggested.

There has been considerable noise coming out of the UK lately about successes in clinical trial enrollment.

First, a couple months ago came the rather dramatic announcement that clinical trial participation in the UK had "tripled over the last 6 years". That announcement, by the chief executive of the

Sweet creature of bombast: is Sir John writing press releases for the NIHR?

National Institute of Health Research's Clinical Research Network, was quickly and uncritically picked up by the media.

That immediately caught my attention. In large, global trials, most pharmaceutical companies I've worked with can do a reasonable job of predicting accrual levels in a given country. I like to think that if participation rates in any given country had jumped that heavily, I’d have heard something.

(To give an example: looking at a quite-typical study I worked on a few years ago: UK sites were overall slightly below the global average. The highest-enrolling countries were about 2.5 times as fast. So, a 3-fold increase in accruals would have catapulted the UK from below average to the fastest-enrolling country in the world.)

Further inquiry, however, failed to turn up any evidence that the reported tripling actually corresponded to more human beings enrolled in clinical trials. Instead, there is some reason to believe that all we witnessed was increased reporting of trial participation numbers.

Now we have a new source of wonder, and a new giant multiplier coming out of the UK. As the Director of the NIHR's Mental Health Research Network, Til Wykes, put it in her blog coverage of her own paper:

Our research on the largest database of UK mental health studies shows that involving just one or two patients in the study team means studies are 4 times more likely to recruit successfully.

Again, amazing! And not just a tripling – a quadrupling!

Understand: I spend a lot of my time trying to convince study teams to take a more patient-focused approach to clinical trial design and execution. I desperately want to believe this study, and I would love having hard evidence to bring to my clients.

At first glance, the data set seems robust. From the King's College press release:

Published in the British Journal of Psychiatry, the researchers analysed 374 studies registered with the Mental Health Research Network (MHRN).

Studies which included collaboration with service users in designing or running the trial were 1.63 times more likely to recruit to target than studies which only consulted service users.  Studies which involved more partnerships - a higher level of Patient and Public Involvement (PPI) - were 4.12 times more likely to recruit to target.

But here the first crack appears. It's clear from the paper that the analysis of recruitment success was not based on 374 studies, but rather a much smaller subset of 124 studies. That's not mentioned in either of the above-linked articles.

And at this point, we have to stop, set aside our enthusiasm, and read the full paper. And at this point, critical doubts begin to spring up, pretty much everywhere.

First and foremost: I don’t know any nice way to say this, but the "4 times more likely" line is, quite clearly, a fiction. What is reported in the paper is a 4.12 odds ratio between "low involvement" studies and "high involvement" studies (more on those terms in just a bit).  Odds ratios are often used in reporting differences between groups, but they are unequivocally not the same as "times more likely than".

This is not a technical statistical quibble. The authors unfortunately don’t provide the actual success rates for different kinds of studies, but here is a quick example that, given other data they present, is probably reasonably close:

• A Studies: 16 successful out of 20 
• Probability of success: 80% 
• Odds of success: 4 to 1
• B Studies: 40 successful out of 80
• Probability of success: 50%
• Odds of success: 1 to 1

From the above, it’s reasonable to conclude that A studies are 60% more likely to be successful than B studies (the A studies are 1.6 times as likely to succeed). However, the odds ratio is 4.0, similar to the difference in the paper. It makes no sense to say that A studies are 4 times more likely to succeed than B studies.

This is elementary stuff. I’m confident that everyone involved in the conduct and analysis of the MHRN paper knows this already. So why would Dr Wykes write this? I don’t know; it's baffling. Maybe someone with more knowledge of the politics of British medicine can enlighten me.

If a pharmaceutical company had promoted a drug with this math, the warning letters and fines would be flying in the door fast. And rightly so. But if a government leader says it, it just gets recycled verbatim.

The other part of Dr Wykes's statement is almost equally confusing. She claims that the enrollment benefit occurs when "involving just one or two patients in the study team". However, involving one or two patients would seem to correspond to either the lowest ("patient consultation") or the middle level of reported patient involvement (“researcher initiated collaboration”). In fact, the "high involvement" categories that are supposed to be associated with enrollment success are studies that were either fully designed by patients, or were initiated by patients and researchers equally. So, if there is truly a causal relationship at work here, improving enrollment would not be merely a function of adding a patient or two to the conversation.

There are a number of other frustrating aspects of this study as well. It doesn't actually measure patient involvement in any specific research program, but uses just 3 broad categories (that the researchers specified at the beginning of each study). It uses an arbitrary and undocumented 17-point scale to measure "study complexity", which collapses and quite likely underweights many critical factors into a single number. The enrollment analysis excluded 11 studies because they weren't adequate for a factor that was later deemed non-significant. And probably the most frustrating facet of the paper is that the authors share absolutely no descriptive data about the studies involved in the enrollment analysis. It would be completely impossible to attempt to replicate its methods or verify its analysis. Do the authors believe that "Public Involvement" is only good when it’s not focused on their own work?

However, my feelings about the study and paper are an insignificant fraction of the frustration I feel about the public portrayal of the data by people who should clearly know better. After all, limited evidence is still evidence, and every study can add something to our knowledge. But the public misrepresentation of the evidence by leaders in the area can only do us harm: it has the potential to actively distort research priorities and funding.

Why This Matters

We all seem to agree that research is too slow. Low clinical trial enrollment wastes time, money, and the health of patients who need better treatment options.

However, what's also clear is that we lack reliable evidence on what activities enable us to accelerate the pace of enrollment without sacrificing quality. If we are serious about improving clinical trial accrual, we owe it to our patients to demand robust evidence for what works and what doesn’t. Relying on weak evidence that we've already solved the problem ("we've tripled enrollment!") or have a method to magically solve it ("PPI quadrupled enrollment!") will cause us to divert significant time, energy, and human health into areas that are politically favored but less than certain to produce benefit. And the overhyping those results by research leadership compounds that problem substantially. NIHR leadership should reconsider its approach to public discussion of its research, and practice what it preaches: critical assessment of the data.
Ennis L, & Wykes T (2013). Impact of patient involvement in mental health research: longitudinal study. The British journal of psychiatry : the journal of mental science PMID: 24029538

1. Misstated an odds ratio of 4 as “4 times more likely to”
2. Overstated the recruitment success findings as being based on a sample 3 times larger than it actually was
3. Re-interpreted, without reservation, a statistical association as a causal relationship
4. Misstated the difference between the patient involvement categories as being a matter of merely “involving just one or two patients in the study team”

And you did these consistently and repeatedly – in Dr Wykes's blog post, in the KCL press release, and in the NIHR-written Guardian article.

The articles identified through the search had to match the corresponding trial in terms of the information registered at ClinicalTrials.gov (i.e., same objective, same sample size, same primary outcome, same location, same responsible party, same trial phase, and same sponsor) and had to present results for the primary outcome. 

So it appears that a reviewed had to score the journal article as an exact match on 8 criteria in order for the trial to be considered the same. That could easily lead to exclusion of journal articles on the basis of very insubstantial differences. The authors provide no detail on this; and again, that would be easy to verify if the study dataset was published. 

The reason I harp on this, and worry about the matching methodology, is that two of the authors of this study were also involved in a methodologically opaque and flawed study about clinical trial results posted in the JCO. In that study, as well, the authors appeared to use an incorrect methodology to identify published clinical trials. When I pointed the issues out, the corresponding author merely reiterated what was already (insufficiently) in the paper's Methodology section.

I find it strange beyond belief, and more than a little hypocritical, that researchers would use a public, taxpayer-funded database as the basis of their studies, and yet refuse to provide their data for public review. There are no technological or logistical issues preventing this kind of sharing, and there is an obvious ethical point in favor of transparency.

But if the authors are reasonably close to correct in their results, I'm not sure what to make of this study. 

The Nature article covering this study contend that

[T]he [ClinicalTrials.gov] database was never meant to replace journal publications, which often contain longer descriptions of methods and results and are the basis for big reviews of research on a given drug.

I suppose that some journal articles have better methodology sections, although this is far from universally true (and, like this study here, these methods are often quite opaquely described and don't support replication). As for results, I don't believe that's the case. In this study, the opposite was true: ClinicalTrial.gov results were generally more complete than journal results. And I have no idea why the registry wouldn't surpass journals as a more reliable and complete source of information for "big reviews".

Perhaps it is a function of my love of getting my hands dirty digging into the data, but if we are witnessing a turning point where journal articles take a distant back seat to the ClinicalTrials.gov registry, I'm enthused. ClinicalTrials.gov is public, free, and contains structured data; journal articles are expensive, unparsable, and generally written in painfully unclear language. To me, there's really no contest. 

Carolina Riveros, Agnes Dechartres, Elodie Perrodeau, Romana Haneef, Isabelle Boutron, & Philippe Ravaud (2013). Timing and Completeness of Trial Results Posted at ClinicalTrials.gov and Published in Journals PLoS Medicine DOI: 10.1371/journal.pmed.1001566

The decade following passage of FDAAA has been one of easing standards for drug approvals in the US, most notably with the advent of “breakthrough” designation created by FDASIA in 2012 and the 21st Century Cures Act in 2016.

Although, as of this writing, there is no nominee for FDA Commissioner, it appears to be safe to say that the current administration intends to accelerate the pace of deregulation, mostly through further lowering of approval requirements. In fact, some of the leading contenders for the position are on record as supporting a return to pre-Kefauver-Harris days, when drug efficacy was not even considered for approval.

Build a better mouse model, and pharma will beat a path to your door - no laws needed.

In this context, it is at least refreshing to read a proposal to increase efficacy standards. This comes from two bioethicists at McGill University, who make the somewhat-startling case for a higher degree of efficacy evaluation before a drug begins any testing in humans.

We contend that a lack of emphasis on evidence for the efficacy of drug candidates is all too common in decisions about whether an experimental medicine can be tested in humans. We call for infrastructure, resources and better methods to rigorously evaluate the clinical promise of new interventions before testing them on humans for the first time.

The author propose some sort of centralized clearinghouse to evaluate efficacy more rigorously. It is unclear what they envision this new multispecialty review body’s standards for green-lighting a drug to enter human testing. Instead they propose three questions:

• What is the likelihood that the drug will prove clinically useful?
• Assume the drug works in humans. What is the likelihood of observing the preclinical results?
• Assume the drug does not work in humans. What is the likelihood of observing the preclinical results?

These seem like reasonable questions, I suppose – and are likely questions that are already being asked of preclinical data. They certainly do not rise to the level of providing a clear standard for regulatory approval, though perhaps it’s a reasonable place to start.

The most obvious counterargument here is one that the authors curiously don’t pick up on at all: if we had the ability to accurately (or even semiaccurately) predict efficacy preclinically, pharma sponsors would already be doing it. The comment notes: “More-thorough assessments of clinical potential before trials begin could lower failure rates and drug-development costs.” And it’s hard not to agree: every pharmaceutical company would love to have even an incrementally-better sense of whether their early pipeline drugs will be shown to work as hoped.

The authors note

Commercial interests cannot be trusted to ensure that human trials are launched only when the case for clinical potential is robust. We believe that many FIH studies are launched on the basis of flimsy, underscrutinized evidence.

However, they do not produce any evidence that industry is in any way deliberately underperforming their preclinical work, merely that preclinical efficacy is often difficult to reproduce and is poorly correlated with drug performance in humans.

Pharmaceutical companies have many times more candidate compounds than they can possibly afford to put into clinical trials. Figuring out how to lower failure rates – or at least the total cost of failure - is a prominent industry obsession, and efficacy remains the largest source of late-stage trial failure. This quest to “fail faster” has resulted in larger and more expensive phase 2 trials, and even to increased efficacy testing in some phase 1 trials. And we do this not because of regulatory pressure, but because of hopes that these efforts will save overall costs. So it seems beyond probable that companies would immediately invest more in preclinical efficacy testing, if such testing could be shown to have any real predictive power. But generally speaking, it does not.

As a general rule, we don’t need regulations that are firmly aligned with market incentives, we need regulations if and when we think those incentives might run counter to the general good. In this case, there are already incredibly strong market incentives to improve preclinical assessments. Where companies have attempted to do something with limited success, it would seem quixotic to think that regulatory fiat will accomplish more.

(One further point. The authors try to link the need for preclinical efficacy testing to the 2016 Bial tragedy. This seems incredibly tenuous: the authors speculate that perhaps trial participants would not have been harmed and killed if Bial had been required to produce more evidence of BIA102474’s clinical efficacy before embarking on their phase 1 trials. But that would have been entirely coincidental in this case: if the drug had in fact more evidence of therapeutic promise, the tragedy still would have happened, because it had nothing at all to do with the drug’s efficacy.

This is to some extent a minor nitpick, since the argument in favor of earlier efficacy testing does not depend on a link to Bial. However, I bring it up because a) the authors dedicate the first four paragraphs of their comment to the link, and b) there appears to be a minor trend of using the death and injuries of that trial to justify an array of otherwise-unrelated initiatives. This seems like a trend we should discourage.)

[Update 2/23: I posted this last night, not realizing that only a few hours earlier, John LaMattina had published on this same article. His take is similar to mine, in that he is suspicious of the idea that pharmaceutical companies would knowingly push ineffective drugs up their pipeline.]

Kimmelman, J., & Federico, C. (2017). Consider drug efficacy before first-in-human trials Nature, 542 (7639), 25-27 DOI: 10.1038/542025a

President-elect Donald Trump tried unsuccessfully to get rid of the Affordable Care Act during his first term. What action will he take this time around?

Sudan's civil war has displaced 10 million citizens. Here are profiles of two young people from the most vulnerable groups: an unaccompanied minor caring for twin brothers, a woman who was raped.

Journalist Annie Lowrey has a rare disease that causes a near-constant itch that doesn't respond to most treatments. She likens the itchiness to a car alarm: "You can't stop thinking about it."

Cochlear implants—the neural prosthetic cousins of standard hearing aids—can be a tremendous boon for people with profound hearing loss. But many would-be users are turned off by the device’s cumbersome external hardware, which must be worn to process signals passing through the implant. So researchers have been working to make a cochlear implant that sits entirely inside the ear, to restore speech and sound perception without the lifestyle restrictions imposed by current devices.

A new biocompatible microphone offers a bridge to such fully internal cochlear implants. About the size of a grain of rice, the microphone is made from a flexible piezoelectric material that directly measures the sound-induced motion of the eardrum. The tiny microphone’s sensitivity matches that of today’s best external hearing aids.

Cochlear implants create a novel pathway for sounds to reach the brain. An external microphone and processor, worn behind the ear or on the scalp, collect and translate incoming sounds into electrical signals, which get transmitted to an electrode that’s surgically implanted in the cochlea, deep within the inner ear. There, the electrical signals directly stimulate the auditory nerve, sending information to the brain to interpret as sound.

But, says Hideko Heidi Nakajima, an associate professor of otolaryngology at Harvard Medical School and Massachusetts Eye and Ear, “people don’t like the external hardware.” They can’t wear it while sleeping, or while swimming or doing many other forms of exercise, and so many potential candidates forgo the device altogether. What’s more, incoming sound goes directly into the microphone and bypasses the outer ear, which would otherwise perform the key functions of amplifying sound and filtering noise. “Now the big idea is instead to get everything—processor, battery, microphone—inside the ear,” says Nakajima. But even in clinical trials of fully internal designs, the microphone’s sensitivity—or lack thereof—has remained a roadblock.

Nakajima, along with colleagues from MIT, Harvard, and Columbia University, fabricated a cantilever microphone that senses the motion of a bone attached behind the eardrum called the umbo. Sound entering the ear canal causes the umbo to vibrate unidirectionally, with a displacement 10 times as great as other nearby bones. The tip of the “UmboMic” touches the umbo, and the umbo’s movements flex the material and produce an electrical charge through the piezoelectric effect. These electrical signals can then be processed and transmitted to the auditory nerve. “We’re using what nature gave us, which is the outer ear,” says Nakajima.

Why a cochlear implant needs low-noise, low-power electronics

Making a biocompatible microphone that can detect the eardrum’s minuscule movements isn’t easy, however. Jeff Lang, a professor of electrical engineering at MIT who jointly led the work, points out that only certain materials are tolerated by the human body. Another challenge is shielding the device from internal electronics to reduce noise. And then there’s long-term reliability. “We’d like an implant to last for decades,” says Lang.

In tests of the implantable microphone prototype, a laser beam measures the umbo’s motion, which gets transferred to the sensor tip. JEFF LANG & HEIDI NAKAJIMA

The researchers settled on a triangular design for the 3-by-3-millimeter sensor made from two layers of polyvinylidene fluoride (PVDF), a biocompatible piezoelectric polymer, sandwiched between layers of flexible, electrode-patterned polymer. When the cantilever tip bends, one PVDF layer produces a positive charge and the other produces a negative charge—taking the difference between the two cancels much of the noise. The triangular shape provides the most uniform stress distribution within the bending cantilever, maximizing the displacement it can undergo before it breaks. “The sensor can detect sounds below a quiet whisper,” says Lang.

Emma Wawrzynek, a graduate student at MIT, says that working with PVDF is tricky because it loses its piezoelectric properties at high temperatures, and most fabrication techniques involve heating the sample. “That’s a challenge especially for encapsulation,” which involves encasing the device in a protective layer so it can remain safely in the body, she says. The group had success by gradually depositing titanium and gold onto the PVDF while using a heat sink to cool it. That approach created a shielding layer that protects the charge-sensing electrodes from electromagnetic interference.

The other tool for improving a microphone’s performance is, of course, amplifying the signal. “On the electronics side, a low-noise amp is not necessarily a huge challenge to build if you’re willing to spend extra power,” says Lang. But, according to MIT graduate student John Zhang, cochlear implant manufacturers try to limit power for the entire device to 5 milliwatts, and just 1 mW for the microphone. “The trade-off between noise and power is hard to hit,” Zhang says. He and fellow student Aaron Yeiser developed a custom low-noise, low-power charge amplifier that outperformed commercially available options.

“Our goal was to perform better than or at least equal the performance of high-end capacitative external microphones,” says Nakajima. For leading external hearing-aid microphones, that means sensitivity down to a sound pressure level of 30 decibels—the equivalent of a whisper. In tests of the UmboMic on human cadavers, the researchers implanted the microphone and amplifier near the umbo, input sound through the ear canal, and measured what got sensed. Their device reached 30 decibels over the frequency range from 100 hertz to 6 kilohertz, which is the standard for cochlear implants and hearing aids and covers the frequencies of human speech. “But adding the outer ear’s filtering effects means we’re doing better [than traditional hearing aids], down to 10 dB, especially in speech frequencies,” says Nakajima.

Plenty of testing lies ahead, at the bench and on sheep before an eventual human trial. But if their UmboMic passes muster, the team hopes that it will help more than 1 million people worldwide go about their lives with a new sense of sound.

The work was published on 27 June in the Journal of Micromechanics and Microengineering.

Blood pressure is one of the critical vital signs for health, but standard practice can only capture a snapshot, using a pressure cuff to squeeze arteries. Continuous readings are available, but only by inserting a transducer directly into an artery via a needle and catheter. Thanks to researchers at Caltech, however, it may soon be possible to measure blood pressure continuously at just about any part of the body.

In a paper published in July in PNAS Nexus, the researchers describe their resonance sonomanometry (RSM) approach to reading blood pressure. This new technology uses ultrasound to measure the dimensions of artery walls. It also uses sound waves to find resonant frequencies that can reveal the pressure within those walls via arterial wall tension. This information is sufficient to calculate the absolute pressure within the artery at any moment, without the need for calibration.

This last factor is important, as other non-invasive approaches only provide relative changes in blood pressure. They require periodic calibration using readings from a traditional pressure cuff. The RSM technology eliminates the need for calibration, making continuous readings more reliable.

How resonance sonomanometry works

The researchers’ RSM system uses an ultrasound transducer to measure the dimensions of the artery. It also transmits sound waves at different frequencies. The vibrations cause the arterial walls to move in and out in response, creating a distinct pattern of motion. When the resonant frequency is transmitted, the top and bottom of the artery will move in and out in unison.

This resonant frequency can be used to determine the tension of the artery walls. The tension in the walls is directly correlated with the fluid pressure of the blood within the artery. As a result, the blood pressure can be calculated at any instant based on the dimensions of the artery and its resonant frequency.

The researchers have validated this approach with both mockups and human subjects. They first tested the technology on an arterial model that used a thin-walled rubber tubing and a syringe to vary the pressure. They tested this mockup using multiple pressures and tubing of different diameters.

The researchers then took measurements with human subjects at their carotid arteries (located in the neck), using a standard pressure cuff to take intermittent measurements. The RSM technology was successful, and subsequently was also demonstrated on axillary (shoulder), brachial (arm), and femoral (leg) arteries. The readings were so clear that the researchers mention that they might even be able to detect blood pressure changes related to respiration and its impact on thoracic pressure.

Unlike traditional pressure cuff approaches, RSM provides data during the entire heartbeat cycle, and not just the systolic and diastolic extremes (In other words, the two numbers you receive during a traditional blood pressure measurement). And the fact that RSM works with different-sized arteries means that it should be applicable across different body sizes and types. Using ultrasound also eliminates possible complications such as skin coloration that can affect light-based devices.

The researchers tested their ultrasound-based blood pressure approach on subjects’ carotid arteries.Esperto Medical

“I’m a big fan of continuous monitoring; a yearly blood pressure reading in the doctor’s office is insufficient for decision making,” says Nick van Terheyden, M.D., the digital health leader with Iodine Software, a company providing machine learning technologies to improve healthcare insights. “A new approach based on good old rules of math and physics is an exciting development.”

The Caltech researchers have created a spinoff company, Esperto Medical, to develop a commercial product using RSM technology. The company has created a transducer module that is smaller than a deck of cards, making it practical to incorporate into a wearable armband. They hope to miniaturize the hardware to the point that it could be incorporated into a wrist-worn device. According to Raymond Jimenez, Esperto Medical’s chief technology officer, “this technology poses the potential to unlock accurate, calibration-free [blood pressure measurements] everywhere—in the clinic, at the gym, and even at home.”

It appears that there’s a significant market for such a product. “92 percent of consumers who intend to buy a wearable device are willing to pay extra for a health-related feature, and blood pressure ranks first among such features,” says Elizabeth Parks, the president of Internet of Things consulting firm Parks Associates.

In the future, rather than relying on arm-squeezing blood pressure cuffs, smart watches may be able to directly monitor blood pressure throughout the day, just as they already do for heart rate and other vital signs.

If you’ve ever tried to get a bandage to stick to your elbow, you understand the difficulty in creating wearable devices that attach securely to the human body. Add digital electronic circuitry, and the problem becomes more complicated. Now include the need for the device to fix breaks and damage automatically—and let’s make it biodegradable while we’re at it—and many researchers would throw up their hands in surrender.

Fortunately, an international team led by researchers at Korea University Graduate School of Converging Science and Technology (KU-KIST) persevered, and has developed conductor materials that it claims are stretchable, self-healing, and biocompatible. Their project was described this month in the journal Science Advances.

The biodegradable conductor offers a new approach to patient monitoring and delivering treatments directly to the tissues and organs where they are needed. For example, a smart patch made of these materials could measure motion, temperature, and other biological data. The material could also be used to create sensor patches that can be implanted inside the body, and even mounted on the surface of internal organs. The biocompatible materials can be designed to degrade after a period of time, eliminating the need for an invasive procedure to remove the sensor later.

“This new technology is a glimpse at the future of remote healthcare,” says Robert Rose, CEO of Rose Strategic Partners, LLC. “Remote patient monitoring is an industry still in its early stages, but already we are seeing the promise of what is not only possible, but close on the horizon. Imagine a device implanted at a surgical site to monitor and report your internal healing progress. If it is damaged, the device can heal itself, and when the job is done, it simply dissolves. It sounds like science fiction, but it’s now science fact.”

Self-healing elastics

After being cut a ribbonlike film was able to heal itself in about 1 minute.Suk-Won Hwang

The system relies on two different layers of flexible material, both self-healing: one is for conduction and the other is an elastomer layer that serves as a substrate to support the sensors and circuitry needed to collect data. The conductor layer is based on a substance known by the acronym PEDOT:PSS, which is short for Poly(3,4-ethylenedioxythiophene) polystyrene sulfonate. It’s a conductive polymer widely used in making flexible displays and touch panels, as well as wearable devices. To increase the polymer’s conductivity and self-healing properties, the research team used additives including polyethylene glycol and glycol, which helped increase conductivity as well as the material’s ability to automatically repair damage such as cuts or tears.

In order to conform to curved tissues and survive typical body motion, the substrate layer must be extremely flexible. The researchers based it on elastomers that can match the shape of curved tissues, such as skin or individual organs.

These two layers stick to each other, thanks to chemical bonds that can connect the polymer chains of the plastic films in each layer. Combined, these materials create a system that is flexible and stretchable. In testing, the researchers showed that the materials could survive stretching up to 500 percent.

The self-healing function arises from the material’s ability to reconnect to itself when cut or otherwise damaged. This self-healing feature is based on a chemical process called disulfide metathesis. In short, polymer molecules containing pairs of linked sulfur atoms, called disulfides, have the ability to reform themselves after being severed. The phenomenon arises from a chemical process called disulfide-disulfide shuffling reactions, in which disulfide bonds in the molecule break and then reform, not necessarily between the original partners. According to the KU-KIST researchers, after being cut, their material was able to recover conductivity in its circuits within about two minutes without any intervention. The material was also tested for bending, twisting, and its ability to function both in air and under water.

This approach offers many advantages over other flexible electronics designs. For example, silver nanowires and carbon nanotubes have been used as the basis for stretchable devices, but they can be brittle and lack the self-healing properties of the KU-KIST materials. Other materials such as liquid metals can self-heal, but they are typically difficult to handle and integrate into wearable circuitry.

As a demonstration, the team created a multifunction sensor that included humidity, temperature, and pressure sensors that was approximately 4.5 square centimeters. In spite of being cut in four separate locations, it was able to heal itself and continue to provide sensor readings.

Implant tested in a rat

To take the demonstration a step further, the researchers created a 1.8-cm² device that was attached to a rat’s bladder. The device was designed to wrap around the bladder and then adhere to itself, so no adhesives or sutures were required to attach the sensor onto the bladder. The team chose the bladder for their experiments because, under normal conditions, its size can change by 300 percent.

The device incorporated both electrodes and pressure sensors, which were able to detect changes in the bladder pressure. The electrodes could detect bladder voiding, through electromyography signals, as well as stimulate the bladder to induce urination. As with the initial demonstration, intentional damage to the device’s circuitry healed on its own, without intervention.

The biocompatible and biodegradable nature of the materials is important because it means that devices fabricated with them can be worn on the skin, as well as implanted within the body. The fact that the materials are biodegradable means that implants would not need a second surgical procedure to remove them. They could be left in place after serving their purpose, and they would be absorbed by the body.

According to Suk-Won Hwang, assistant professor at KU-KIST, a few hurdles remain on the path to commercialization. “We need to test the biocompatibility of some of the materials used in the conductor and substrate layers. While scalable production appears to be feasible, the high cost of disulfide derivatives might make the technology too expensive, aside from some special applications,” he says. “Biocompatibility testing and material synthesis optimization will take one to two years, at least.”

Neuralink’s visual prosthesis Blindsight has been designated a breakthrough device by the U.S. Food and Drug Administration, which potentially sets the technology on a fast track to approval.

In confirming the news, an FDA spokesperson emphasized that the designation does not mean that Blindsight is yet considered safe or effective. Technologies in the program have potential to improve the current standard of care and are novel compared to what’s available on the market, but the devices still have to go through full clinical trials before seeking FDA approval.

Still, the announcement is a sign that Neuralink is moving closer to testing Blindsight in human patients. The company is recruiting people with vision loss for studies in the United States, Canada, and the United Kingdom.

Visual prostheses work by capturing visual information with a video camera, typically attached to glasses or a headset. Then a processor converts the data to an electrical signal that can be relayed to the nervous system. Retinal implants have been a common approach, with electrodes feeding the signal to nerves in the retina, at the back of the eye, from where it travels on to the brain. But Blindsight uses a brain implant to send the signal directly to neurons in the visual cortex.

In recent years, other companies developing artificial vision prosthetics have reached clinical research trials or beyond, only to struggle financially, leaving patients without support. Some of these technologies live on with new backing: Second Sight’s Orion cortical implant project is now in a clinical trial with Cortigent, and Pixium Vision’s Prima system is now owned by Science, with ex-Neuralink founder Max Hodak at the helm. No company has yet commercialized a visual prosthetic that uses a brain implant.

Elon Musk’s Claims About Blindsight

Very little information about Blindsight is publicly available. As of this writing, there is no official Blindsight page on the Neuralink website, and Neuralink did not respond to requests for comment. It’s also unclear how exactly Blindsight relates to a brain-computer interface that Neuralink has already implanted in two people with paralysis, who use their devices to control computer cursors.

Experts who spoke with IEEE Spectrum felt that, if judged against the strong claims made by Neuralink’s billionaire co-founder Elon Musk, Blindsight will almost certainly disappoint. However, some were still open to the possibility that Neuralink could successfully bring a device to market that can help people with vision loss, albeit with less dramatic effects on their sense of sight. While Musk’s personal fortune could help Blindsight weather difficulties that would end other projects, experts did not feel it was a guarantee of success.

After Neuralink announced on X (formerly Twitter) that Blindsight had received the breakthrough device designation, Musk wrote:

The Blindsight device from Neuralink will enable even those who have lost both eyes and their optic nerve to see.

Provided the visual cortex is intact, it will even enable those who have been blind from birth to see for the first time.

To set expectations correctly, the vision will be at first be [sic] low resolution, like Atari graphics, but eventually it has the potential be [sic] better than natural vision and enable you to see in infrared, ultraviolet or even radar wavelengths, like Geordi La Forge.

Musk included a picture of La Forge, a character from the science-fiction franchise Star Trek who wears a vision-enhancing visor.

Experts Puncture the Blindsight Hype

“[Musk] will build the best cortical implant we can build with current technology. It will not produce anything like normal vision. [Yet] it might produce vision that can transform the lives of blind people,” said Ione Fine, a computational neuroscientist at the University of Washington, who has written about the potential limitations of cortical implants, given the complexity of the human visual system. Fine previously worked for the company Second Sight.

A successful visual prosthetic might more realistically be thought of as assistive technology than a cure for blindness. “At best, we’re talking about something that’s augmentative to a cane and a guide dog; not something that replaces a cane and a guide dog,” said Philip Troyk, a biomedical engineer at the Illinois Institute of Technology.

Restoring natural vision is beyond the reach of today’s technology. But among Musks recent claims, Troyk says that a form of infrared sensing is plausible and has already been tested with one of his patients, who used it for help locating people within a room. That patient has a 400-electrode device implanted in the visual cortex as part of a collaborative research effort called the Intracortical Visual Prosthesis Project (ICVP). By comparison, Blindsight may have more than 1,000 electrodes, if it’s a similar device to Neuralink’s brain-computer interface.

Experts say they’d like more information about Neuralink’s visual prosthetic. “I’m leery about the fact that they are very superficial in their description of the devices,” said Gislin Dagnelie, a vision scientist at Johns Hopkins University who has been involved in multiple clinical trials for vision prosthetics, including a Second Sight retinal implant, and who is currently collaborating on the ICVP. “There’s no clear evaluation or pre-clinical work that has been published,” says Dagnelie. “It’s all based on: ‘Trust us, we’re Neuralink.’”

In the short term, too much hype could mislead clinical trial participants. It could also degrade interest in small but meaningful advancements in visual prosthetics. “Some of the [Neuralink] technology is exciting, and has potential,” said Troyk. “The way the messaging is being done detracts from that, potentially.”

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.