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When university and hospital trusts were called to the UK parliament last year to answer questions on why they were not following the rules on reporting results, we saw how effective the questioning from politicians was. Those of you who watched the parliamentary session saw the pressure the university representatives were put under. Because the politicians asked […]

Even by the already-painfully-embarrassingly-low standards of clinical trial enrollment in general, patient enrollment in cancer clinical trials is slow. Horribly slow. In many cancer trials, randomizing one patient every three or four months isn't bad at all – in fact, it's par for the course. The most
commonly-cited number is that only 3% of cancer patients participate in a trial – and although exact details of how that number is measured are remarkably difficult to pin down, it certainly can't be too far from reality.

Ultimately, the cost of slow enrollment is borne almost entirely by patients; their payment takes the form of fewer new therapies and less evidence to support their treatment decisions.

So when a couple dozen thousand of the world's top oncologists fly into Chicago to meet, you'd figure that improving accrual would be high on everyone’s agenda. You can't run your trial without patients, after all.

But every year, the annual ASCO meeting underdelivers in new ideas for getting more patients into trials. I suppose this a consequence of ASCO's members-only focus: getting the oncologists themselves to address patient accrual is a bit like asking NASCAR drivers to tackle the problems of aerodynamics, engine design, and fuel chemistry.

Nonetheless, every year, a few brave souls do try. Here is a quick rundown of accrual-related abstracts at this year’s meeting, conveniently sorted into 3 logical categories:

1. As Lord Kelvin may or may not have said, “If you cannot measure it, you cannot improve it.”

• Abstract e15572: Inadequate data availability on clinical trial accrual and its effect on progress in cancer research

Probably the most sensible of this year's crop, because rather than trying to make something out of nothing, the authors measure exactly how pervasive the nothing is. Specifically, they attempt to obtain fairly basic patient accrual data for the last three years' worth of clinical trials in kidney cancer. Out of 108 trials identified, they managed to get – via search and direct inquiries with the trial sponsors – basic accrual data for only 43 (40%).

That certainly qualifies as “terrible”, though the authors content themselves with “poor”.

Interestingly, exactly zero of the 32 industry-sponsored trials responded to the authors' initial survey. This fits with my impression that pharma companies continue to think of accrual data as proprietary, though what sort of business advantage it gives them is unclear. Any one company will have only run a small fraction of these studies, greatly limiting their ability to draw anything resembling a valid conclusion.

• Abstract TPS6645: Predictors of accrual success for cooperative group trials: The Cancer and Leukemia Group B (Alliance) experience

CALGB investigators look at 110 trials over the past 10 years to see if they can identify any predictive markers of successful enrollment. Unfortunately, the trials themselves are pretty heterogeneous (accrual periods ranged from 6 months to 8.8 years), so finding a consistent marker for successful trials would seem unlikely.

And, in fact, none of the usual suspects (e.g., startup time, disease prevalence) appears to have been significant. The exception was provision of medication by the study, which was positively associated with successful enrollment.

The major limitation with this study, apart from the variability of trials measured, is in its definition of “successful”, which is simply the total number of planned enrolled patients. Under both of their definitions, a slow-enrolling trial that drags on for years before finally reaching its goal is successful, whereas if that same trial had been stopped early it is counted as unsuccessful. While that sometimes may be the case, it's easy to imagine situations where allowing a slow trial to drag on is a painful waste of resources – especially if results are delayed enough to bring their relevance into question.

Even worse, though, is that a trial’s enrollment goal is itself a prediction. The trial steering committee determines how many sites, and what resources, will be needed to hit the number needed for analysis. So in the end, this study is attempting to identify predictors of successful predictions, and there is no reason to believe that the initial enrollment predictions were made with any consistent methodology.

2. If you don't know, maybe ask somebody?

• Abstract 8592: Strategies to overcome barriers to accrual (BtA) to NCI-sponsored clinical trials: A project of the NCI-Myeloma Steering Committee Accrual Working Group (NCI-MYSC AWG)
  
• Abstract 1596: Rapid online feedback to improve clinical trial accrual: CODEL anaplastic glioma (AG) (NCCTG/Alliance N0577) as a model

With these two abstracts we celebrate and continue the time-honored tradition of alchemy, whereby we transmute base opinion into golden data. The magic number appears to be 100: if you've got 3 digits' worth of doctors telling you how they feel, that must be worth something.

In the first abstract, a working group is formed to identify and vote on the major barriers to accrual in oncology trials. Then – and this is where the magic happens – that same group is asked to identify and vote on possible ways to overcome those barriers.

In the second, a diverse assortment of community oncologists were given an online survey to provide feedback on the design of a phase 3 trial in light of recent new data. The abstract doesn't specify who was initially sent the survey, so we cannot tell response rate, or compare survey responders to the general population (I'll take a wild guess and go with “massive response bias”).

Market research is sometimes useful. But what cancer clinical trial do not need right now are more surveys are working groups. The “strategies” listed in the first abstract are part of the same cluster of ideas that have been on the table for years now, with no appreciable increase in trial accrual.

3. The obligatory “What the What?” abstract

• Abstract 6564: Minority accrual on a prospective study targeting a diverse U.S. breast cancer population: An analysis of Wake Forest CCOP research base protocol 97609

The force with which my head hit my desk after reading this abstract made me concerned that it had left permanent scarring.

If this had been re-titled “Poor Measurement of Accrual Factors Leads to Inaccurate Accrual Reporting”, would it still have been accepted for this year’s meeting? That's certainly a more accurate title.

Let’s review: a trial intends to enroll both white and minority patients. Whites enroll much faster, leading to a period where only minority patients are recruited. Then, according to the authors, “an almost 4-fold increase in minority accrual raises question of accrual disparity.” So, sites will only recruit minority patients when they have no choice?

But wait: the number of sites wasn't the same during the two periods, and start-up times were staggered. Adjusting for actual site time, the average minority accrual rate was 0.60 patients/site/month in the first part and 0.56 in the second. So the apparent 4-fold increase was entirely an artifact of bad math.

This would be horribly embarrassing were it not for the fact that bad math seems to be endemic in clinical trial enrollment. Failing to adjust for start-up time and number of sites is so routine that not doing it is grounds for a presentation.

The bottom line

What we need now is to rigorously (and prospectively) compare and measure accrual interventions. We have lots of candidate ideas, and there is no need for more retrospective studies, working groups, or opinion polls to speculate on which ones will work best.  Where possible, accrual interventions should themselves be randomized to minimize confounding variables which prevent accurate assessment. Data needs to be uniformly and completely collected. In other words, the standards that we already use for clinical trials need to be applied to the enrollment measures we use to engage patients to participate in those trials.

This is not an optional consideration. It is an ethical obligation we have to cancer patients: we need to assure that we are doing all we can to maximize the rate at which we generate new evidence and test new therapies.

[Image credit: Logarithmic turtle accrual rates courtesy of Flikr user joleson.]

[Fair Warning: I have generally tried to keep this blog separate from my corporate existence, but am making an exception for two quick posts about the upcoming DIA 2013 Annual Meeting.]

Improving Enrollment in Pediatric Clinical Trials

Logistically, ethically, and emotionally, involving children in medical research is greatly different from the same research in adults. Some of the toughest clinical trials I've worked on, across a number of therapeutic areas, have been pediatric ones. They challenge you to come up with different approaches to introducing and explaining clinical research – approaches that have to work for doctors, kids, and parents simultaneously.

On Thursday June 27, Don Sickler, one of my team members, will be chairing a session titled “Parents as Partners: Engaging Caregivers for Pediatric Trials”. It should be a good session.

Joining Don are 2 people I've had the pleasure of working with in the past. Both of them combine strong knowledge of clinical research with a massive amount of positive energy and enthusiasm (no doubt a big part of what makes them successful).

However, they also differ in one key aspect: what they work on. One of them – Tristen Moors from Hyperion Therapeutics - works on an ultra-rare condition, Urea Cycle Disorder, a disease affecting only a few hundred children every year. On the other hand, Dr. Ann Edmunds is an ENT working in a thriving private practice. I met her because she was consistently the top enroller in a number of trials relating to tympanostomy tube insertion. Surgery to place “t-tubes” is one of the most common and routine outpatients surgeries there is, with an estimated half million kids getting tubes each year.

Each presents a special challenge: for rare conditions, how do you even find enough patients? For routine procedures, how do you convince parents to complicate their (and their children’s) lives by signing up for a multi-visit, multi-procedure trial?

Ann and Tristen have spent a lot of time tackling these issues, and should have some great advice to give.

For more information on the session, here’s Don’s posting on our news blog.

Are we looking at our enrollment data in the right way?

Session Details:

June 25, 1:45PM - 3:15PM

• Session Number: 241
• Room Number: 205B

1. Enrollment Analytics: Moving Beyond the Funnel
Paul Ivsin
VP, Consulting Director
CAHG Clinical Trials

2. Use of Analytics for Operational Planning
Diana Chung, MSc
Associate Director, Clinical Operations
Gilead
3. Using Enrollment Data to Communicate Effectively with Sites
Gretchen Goller, MA
Senior Director, Patient Access and Retention Services
PRA

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.

Sweat: We all do it. It plays an essential role in controlling body temperature by cooling the skin through evaporation. But it can also carry salts and other molecules out of the body in the process. In medieval Europe, people would lick babies; if the skin was salty, they knew that serious illness was likely. (We now know that salty skin can be an indicator for cystic fibrosis.)

Scientists continue to study how the materials in sweat can reveal details about an individual’s health, but often they must rely on gathering samples from subjects during strenuous exercise in order to get samples that are sufficiently large for analysis.

Now researchers in China have developed a wearable sensor system that can collect and process small amounts of sweat while providing continuous detection. They have named the design a “skin-interfaced intelligent graphene nanoelectronic” patch, or SIGN for short. The researchers, who described their work in a paper published in Advanced Functional Materials, did not respond to IEEE Spectrum’s interview requests.

The SIGN sensor patch relies on three separate components to accomplish its task. First, the sweat must be transported from the skin into microfluidic chambers. Next, a special membrane removes impurities from the fluid. Finally, this liquid is delivered to a bioreceptor that can be tuned to detect different metabolites.

The transport system relies on a combination of hydrophilic (water-attracting) and hydrophobic (water-repelling) materials. This system can move aqueous solutions along microchannels, even against gravity. This makes it possible to transport small samples with precision, regardless of the device’s orientation.

The fluid is transported to a Janus membrane, where impurities are blocked. This means that the sample that reaches the sensor is more likely to produce accurate results.

Finally, the purified sweat arrives at a flexible biosensor. This graphene sensor is activated by enzymes designed to detect the desired biomarker. The result is a transistor that can accurately measure the amount of the biomarker in the sample.

At its center, the system has a membrane that removes impurities from sweat and a biosensor that detects biomarkers.Harbin Institute of Technology/Shenyang Aerospace University

One interesting feature of the SIGN patch is that it can provide continuous measurements. The researchers tested the device through multiple cycles of samples with known concentrations of a target biomarker, and it was about as accurate after five cycles as it was after just one. This result suggests that it could be worn over an extended period without having to be replaced.

Continuous measurements can provide useful longitudinal data. However, Tess Skyrme, a senior technology analyst at the research firm IDTechEx, points out that continuous devices can have very different sampling rates. “Overall, the right balance of efficient, comfortable, and granular data collection is necessary to disrupt the market,” she says, noting that devices also need to optimize “battery life, calibration, and data accuracy.”

The researchers have focused on lactate—a metabolite that can be used to assess a person’s levels of exercise and fatigue—as the initial biomarker to be detected. This function is of particular interest to athletes, but it can also be used to monitor the health status of workers in jobs that require strenuous physical activity, especially in hazardous or extreme working conditions.

Not all experts are convinced that biomarkers in sweat can provide accurate health data. Jason Heikenfeld, director of the Novel Device Lab at the University of Cincinnati, has pivoted his research on wearable biosensing from sweat to the interstitial fluid between blood vessels and cells. “Sweat glucose and lactate are way inferior to measures that can be made in interstitial fluid with devices like glucose monitors,” he tells Spectrum.

The researchers also developed a package to house the sensor. It’s designed to minimize power consumption, using a low-power microcontroller, and it includes a Bluetooth communications chip to transmit data wirelessly from the SIGN patch. The initial design provides for 2 hours of continuous use without charging, or up to 20 hours in standby mode.

In 2010, Melanie Reid fell off a horse and was paralyzed below the shoulders.

“You think, ‘I am where I am; nothing’s going to change,’ ” she said, but many years after her accident, she participated in a medical trial of a new, noninvasive rehabilitative device that can deliver more electrical stimulation than similar devices without harming the user. For Reid, use of the device has led to small improvements in her ability to use her hands, and meaningful changes to her daily life.

“Everyone thinks with spinal injury all you want to do is be able to walk again, but if you’re a tetraplegic or quadriplegic, what matters most is working hands,” said Reid, a columnist for The Times, as part of a press briefing. “There’s no miracles in spinal injury, but tiny gains can be life-changing.”

For the study, Reid used a new noninvasive therapeutic device produced by Onward Medical. The device, ARC-EX (“EX” indicating “external”), uses electrodes placed along the spine near the site of injury—in the case of quadriplegia, the neck—to promote nerve activity and growth during physical-therapy exercises. The goal is to not only increase motor function while the device is attached and operating, but the long-term effectiveness of rehabilitation drills. A study focused on arm and hand abilities in patients with quadriplegia was published 20 May in Nature Medicine.

Researchers have been investigating electrical stimulation as a treatment for spinal cord injury for roughly 40 years, but “one of the innovations in this system is using a very high-frequency waveform,” said coauthor Chet Moritz, a neurotechnologist at the University of Washington. The ARC-EX uses a 10-kilohertz carrier frequency overlay, which researchers think may numb the skin beneath the electrode, allowing patients to tolerate five times as much amperage as from similar exploratory devices. For Reid, this manifested as a noticeable “buzz,” which felt strange, but not painful.

The study included 60 participants across 14 sites around the world. Each participant undertook two months of standard physical therapy, followed by two months of therapy combined with the ARC-EX. Although aspects of treatment such as electrode placement were fairly standardized, the current amplitude was personalized to each patient, and sometimes individual exercises, said Moritz.

The ARC-EX uses a 10-kilohertz current to provider stronger stimulation for people with spinal cord injuries.

Over 70 percent of patients showed an increase in at least one measurement of both strength and function between standard therapy and ARC-EX therapy. These changes also meant that 87 percent of study participants noted some improvement in quality of life in a followup questionnaire. No major safety concerns tied to the device or rehabilitation process were reported.

Onward will seek approval from the U.S. Food and Drug Administration for the device by the end of 2024, said study coauthor Grégoire Courtine, a neuroscientist and cofounder of Onward Medical. Onward is also working on an implantable spinal stimulator called ARC-IM; other prosthetic approaches, such as robotic exoskeletons, are being investigated elsewhere. ARC-EX was presented as a potentially important cost-accessible, noninvasive treatment option, especially in the critical window for recovery a year or so after a spinal cord injury. However, the price to insurers or patients of a commercial version is still subject to negotiation.

The World Health Organization says there are over 15 million people with spinal cord injuries. Moritz estimates that around 90 percent of patients, even many with no movement in their hands, could benefit from the new therapy.

Dimitry Sayenko, who studies spinal cord injury recovery at Houston Methodist and was not involved in the study, praised the relatively large sample size and clear concern for patient safety. But he stresses that the mechanisms underlying spinal stimulation are not well understood. “So far it’s literally plug and play,” said Sayenko. “We don’t understand what’s happening under the electrodes for sure—we can only indirectly assume or speculate.”

The new study supports the idea that noninvasive spinal cord stimulation can provide some benefit to some people but was not designed to help predict who will benefit, precisely how people will benefit, or how to optimize care. The study authors acknowledged the limited scope and need for further research, which might help turn currently “tiny gains” into what Sayenko calls “larger, more dramatic, robust effects.”

The future of an innovative retinal implant and dozens of its users just got brighter, after Science, a bioelectronics startup run by Neuralink’s cofounder, Max Hodak, acquired Pixium’s technology at the last minute.

Pixium Vision, whose Prima system to tackle vision loss is implanted in 47 people across Europe and the United States, was in danger of disappearing completely until Science stepped in to buy the French company’s assets in April, for an undisclosed amount.

Pixium has been developing Prima for a decade, building on work by Daniel Palanker, a professor of ophthalmology at Stanford University. The 2-by-2-millimeter square implant is surgically implanted under the retina, where it turns infrared data from camera-equipped glasses into pulses of electricity. These replace signals generated by photoreceptor rods and cones, which are damaged in people suffering from age-related macular degeneration (AMD).

Early feasibility studies in the E.U. and the United States suggested Prima was safe and potentially effective, but Pixium ran out of money last November before the final results of a larger, multiyear pivotal trial in Europe.

“It’s very important to us to avoid another debacle like Argus II.”

With the financial and legal clock ticking down, the trial data finally arrived in March this year. “And the results from that were just pretty stunning,” says Max Hodak, Science’s founder and CEO, in his first interview since the acquisition.

Although neither Pixium nor Science has yet released the full dataset, Hodak shared with IEEE Spectrum videos of three people using Prima, each of them previously unable to read or recognize faces due to AMD. The videos show them slowly but fluently reading a hardback book, filling in a crossword puzzle, and playing cards.

“This is legit ‘form vision’ that I don’t think any device has ever done,” says Hodak. Form vision is the ability to recognize visual elements as parts of a larger object. “It’s this type of data that convinced us. And from there we were like, this should get to patients.”

As well as buying the Prima technology, Hodak says that Science will hire the majority of Pixium’s 35 engineering and regulatory staff, in a push to get the technology approved in Europe as quickly as possible.

The Prima implant receives visual data and is powered by near-infrared signals beamed from special spectacles.Pixium

Another priority is supporting existing Prima patients, says Lloyd Diamond, Pixium’s outgoing CEO. “It’s very important to us to avoid another debacle like Argus II,” he says, referring to another retinal implant whose manufacturer went out of business in 2022, leaving users literally in the dark.

Diamond is excited to be working with Science, which is based in Silicon Valley with a chip foundry in North Carolina. “They have a very deep workforce in software development, in electronic development, and in biologic research,” he says. “And there are probably only a few foundries in the world that could manufacture an implant such as ours. Being able to internalize part of that process is a very big advantage.”

Hodak hopes that a first-generation Prima product could quickly be upgraded with a wide-angle camera and the latest electronics. “We think that there’s one straight shrink, where we’ll move to smaller pixels and get higher visual acuity,” he says. “After that, we’ll probably move to a 3D electrode design, where we’ll be able to get closer to single-cell resolution.” That could deliver even sharper artificial vision.

In parallel, Science will continue Pixium’s discussions with the FDA in the United States about advancing a clinical trial there.

The success of Prima is critical, says Hodak, who started Science in 2021 after leaving Neuralink, a brain-computer interface company he cofounded with Elon Musk. “Elon can do whatever he wants for as long as he wants, but we need something that can finance future development,” he says. “Prima is big enough in terms of impact to patients and society that it is capable of helping us finance the rest of our ambitions.”

These include a next-generation Prima device, which Hodak says he is already talking about with Palanker, and a second visual prosthesis, currently called the Science Eye. This will tackle retinitis pigmentosa, a condition affecting peripheral vision—the same condition targeted by Second Sight’s ill-fated Argus II device.

“The Argus II just didn’t work that well,” says Hodak. “In the end, it was a pure bridge to nowhere.” Like the Argus II and Prima, the Science Eye relies on camera glasses and an implant, but with the addition of optogenetic therapy. This uses a genetically engineered virus to deliver a gene to specific optic nerve cells in the retina, making them light-sensitive at a particular wavelength. A tiny implanted display with a resolution sharper than an iPhone screen then enables fine control over the newly sensitized cells.

That system is still undergoing animal trials, but Hodak is almost ready to pull the trigger on its first human clinical studies, likely in Australia and New Zealand.

“In the long term, I think precision optogenetics will be more powerful than Prima’s electrical stimulation,” he says. “But we’re agnostic about which approach works to restore vision.”

One thing he does believe vehemently, unlike Musk, is that the retina is the best place to put an implant. Neuralink and Cortigent (the successor company of Second Sight) are both working on prosthetics that target the brain’s visual cortex.

“There’s a lot that you can do in cortex, but vision is not one of them,” says Hodak. He thinks the visual cortex is too complex, too distributed, and too difficult to access surgically to be useful.

“As long as the optic nerve is intact, the retina is the ideal place to think about restoring vision to the brain,” he says. “This is all a question of effect size. If someone has been in darkness for a decade, with no light, no perception, and you can give them any type of visual stimulus, they’re going to be into it. The Pixium patients can intuitively read, and that was really what convinced us that this was worth picking up and pursuing.”

Elemind, a 5-year-old startup based in Cambridge, Mass., today unveiled a US $349 wearable for neuromodulation, the company’s first product. According to cofounder and CEO Meredith Perry, the technology tracks the oscillation of brain waves using electroencephalography (EEG) sensors that detect the electrical activity of the brain and then influence those oscillations using bursts of sound delivered via bone conduction.

Elemind’s first application for this wearable aims to suppress alpha waves to help induce sleep. There are other wearables on the market that monitor brain waves and, through biofeedback, encourage users to actively modify their alpha patterns. Elemind’s headband appears to be the first device to use sound to directly influence the brain waves of a passive user.

In a clinical trial, says Perry [no relation to author], 76 percent of subjects fell asleep more quickly. Those who did see a difference averaged 48 percent less time to progress from awake to asleep. The results were similar to those of comparable trials of pharmaceutical sleep aids, Perry indicated.

“For me,” Perry said, “it cuts through my rumination, quiets my thinking. It’s like noise cancellation for the brain.”

I briefly tested Elemind’s headband in May. I found it comfortable, with a thick cushioned band that sits across the forehead connected to a stretchy elastic loop to keep it in place. In the band are multiple EEG electrodes, a processor, a three-axis accelerometer, a rechargeable lithium-polymer battery, and custom electronics that gather the brain’s electrical signals, estimate their phase, and generate pink noise through a bone-conduction speaker. The whole thing weighs about 60 grams—about as much as a small kiwi fruit.

My test conditions were far from optimal for sleep: early afternoon, a fairly bright conference room, a beanbag chair as bed, and a vent blowing. And my test lasted just 4 minutes. I can say that I didn’t find the little bursts of pink noise (white noise without the higher frequencies) unpleasant. And since I often wear an eye mask, feeling fabric on my face wasn’t disturbing. It wasn’t the time or place to try for sound sleep, but I—and the others in the room—noted that after 2 minutes I was yawning like crazy.

How Elemind tweaks brain waves

What was going on in my brain? Briefly, different brain states are associated with different frequencies of waves. Someone who is relaxed with eyes closed but not asleep produces alpha waves at around 10 hertz. As they drift off to sleep, the alpha waves are supplanted by theta waves, at around 5 Hz. Eventually, the delta waves of deep sleep show up at around 1 Hz.

Ryan Neely, Elemind’s vice president of science and research, explains: “As soon as you put the headband on,” he says, “the EEG system starts running. It uses straightforward signal processing with bandpass filtering to isolate the activity in the 8- to 12-Hz frequency range—the alpha band.”

“Then,” Neely continues, “our algorithm looks at the filtered signal to identify the phase of each oscillation and determines when to generate bursts of pink noise.”

To help a user fall asleep more quickly [top], bursts of pink noise are timed to generate a brain response that is out of phase with alpha waves and so suppresses them. To enhance deep sleep [bottom], the pink noise is timed to generate a brain response that is in phase with delta waves.Source: Elemind

These auditory stimuli, he explains, create ripples in the waves coming from the brain. Elemind’s system tries to align these ripples with a particular phase in the wave. Because there is a gap between the stimulus and the evoked response, Elemind tested its system on 21 people and calculated the average delay, taking that into account when determining when to trigger a sound.

To induce sleep, Elemind’s headband targets the trough in the alpha wave, the point at which the brain is most excitable, Neely says.

“You can think of the alpha rhythm as a gate for communication between different areas of the brain,” he says. “By interfering with that communication, that coordination between different brain areas, you can disrupt patterns, like the ruminations that keep you awake.”

With these alpha waves suppressed, Neely says, the slower oscillations, like the theta waves of light sleep, take over.

Elemind doesn’t plan to stop there. The company plans to add an algorithm that addresses delta waves, the low-frequency 0.5- to 2-Hz waves characteristic of deep sleep. Here, Elemind’s technology will attempt to amplify this pattern with the intent of improving sleep quality.

Is this safe? Yes, Neely says, because auditory stimulation is self-limiting. “Your brain waves have a natural space they can occupy,” he explains, “and this stimulation just moved it within that natural space, unlike deep-brain stimulation, which can move the brain activity outside natural parameters.”

Going beyond sleep to sedation, memory, and mental health

Applications may eventually go beyond inducing and enhancing sleep. Researchers at the University of Washington and McGill University have completed a clinical study to determine if Elemind’s technology can be used to increase the pain threshold of subjects undergoing sedation. The results are being prepared for peer review.

Elemind is also working with a team involving researchers at McGill and the Leuven Brain Institute to determine if the technology can enhance memory consolidation in deep sleep and perhaps have some usefulness for people with mild cognitive impairment and other memory disorders.

Neely would love to see more applications investigated in the future.

“Inverse alpha stimulation [enhancing instead of suppressing the signal] could increase arousal,” he says. “That’s something I’d love to look into. And looking into mental-health treatment would be interesting, because phase coupling between the different brain regions appears to be an important factor in depression and anxiety disorders.”

Perry, who previously founded the wireless power startup UBeam, cofounded Elemind with four university professors with expertise in neuroscience, optogenetics, biomedical engineering, and artificial intelligence. The company has $12 million in funding to date and currently has 13 employees.

Preorders at $349 start today for beta units, and Elemind expects to start general sales later this year. The company will offer customers an optional membership at $7 to $13 monthly that will allow cloud storage of sleep data and access to new apps as they are released.

Last month when Google introduced its new AI search tool, called AI Overviews, the company seemed confident that it had tested the tool sufficiently, noting in the announcement that “people have already used AI Overviews billions of times through our experiment in Search Labs.” The tool doesn’t just return links to Web pages, as in a typical Google search, but returns an answer that it has generated based on various sources, which it links to below the answer. But immediately after the launch users began posting examples of extremely wrong answers, including a pizza recipe that included glue and the interesting fact that a dog has played in the NBA.

Renée DiResta has been tracking online misinformation for many years as the technical research manager at Stanford’s Internet Observatory.

While the pizza recipe is unlikely to convince anyone to squeeze on the Elmer’s, not all of AI Overview’s extremely wrong answers are so obvious—and some have the potential to be quite harmful. Renée DiResta has been tracking online misinformation for many years as the technical research manager at Stanford’s Internet Observatory and has a new book out about the online propagandists who “turn lies into reality.” She has studied the spread of medical misinformation via social media, so IEEE Spectrum spoke to her about whether AI search is likely to bring an onslaught of erroneous medical advice to unwary users.

I know you’ve been tracking disinformation on the Web for many years. Do you expect the introduction of AI-augmented search tools like Google’s AI Overviews to make the situation worse or better?

Renée DiResta: It’s a really interesting question. There are a couple of policies that Google has had in place for a long time that appear to be in tension with what’s coming out of AI-generated search. That’s made me feel like part of this is Google trying to keep up with where the market has gone. There’s been an incredible acceleration in the release of generative AI tools, and we are seeing Big Tech incumbents trying to make sure that they stay competitive. I think that’s one of the things that’s happening here.

We have long known that hallucinations are a thing that happens with large language models. That’s not new. It’s the deployment of them in a search capacity that I think has been rushed and ill-considered because people expect search engines to give them authoritative information. That’s the expectation you have on search, whereas you might not have that expectation on social media.

There are plenty of examples of comically poor results from AI search, things like how many rocks we should eat per day [a response that was drawn for an Onion article]. But I’m wondering if we should be worried about more serious medical misinformation. I came across one blog post about Google’s AI Overviews responses about stem-cell treatments. The problem there seemed to be that the AI search tool was sourcing its answers from disreputable clinics that were offering unproven treatments. Have you seen other examples of that kind of thing?

DiResta: I have. It’s returning information synthesized from the data that it’s trained on. The problem is that it does not seem to be adhering to the same standards that have long gone into how Google thinks about returning search results for health information. So what I mean by that is Google has, for upwards of 10 years at this point, had a search policy called Your Money or Your Life. Are you familiar with that?

I don’t think so.

DiResta: Your Money or Your Life acknowledges that for queries related to finance and health, Google has a responsibility to hold search results to a very high standard of care, and it’s paramount to get the information correct. People are coming to Google with sensitive questions and they’re looking for information to make materially impactful decisions about their lives. They’re not there for entertainment when they’re asking a question about how to respond to a new cancer diagnosis, for example, or what sort of retirement plan they should be subscribing to. So you don’t want content farms and random Reddit posts and garbage to be the results that are returned. You want to have reputable search results.

That framework of Your Money or Your Life has informed Google’s work on these high-stakes topics for quite some time. And that’s why I think it’s disturbing for people to see the AI-generated search results regurgitating clearly wrong health information from low-quality sites that perhaps happened to be in the training data.

So it seems like AI overviews is not following that same policy—or that’s what it appears like from the outside?

DiResta: That’s how it appears from the outside. I don’t know how they’re thinking about it internally. But those screenshots you’re seeing—a lot of these instances are being traced back to an isolated social media post or a clinic that’s disreputable but exists—are out there on the Internet. It’s not simply making things up. But it’s also not returning what we would consider to be a high-quality result in formulating its response.

I saw that Google responded to some of the problems with a blog post saying that it is aware of these poor results and it’s trying to make improvements. And I can read you the one bullet point that addressed health. It said, “For topics like news and health, we already have strong guardrails in place. In the case of health, we launched additional triggering refinements to enhance our quality protections.” Do you know what that means?

DiResta: That blog posts is an explanation that [AI Overviews] isn’t simply hallucinating—the fact that it’s pointing to URLs is supposed to be a guardrail because that enables the user to go and follow the result to its source. This is a good thing. They should be including those sources for transparency and so that outsiders can review them. However, it is also a fair bit of onus to put on the audience, given the trust that Google has built up over time by returning high-quality results in its health information search rankings.

I know one topic that you’ve tracked over the years has been disinformation about vaccine safety. Have you seen any evidence of that kind of disinformation making its way into AI search?

DiResta: I haven’t, though I imagine outside research teams are now testing results to see what appears. Vaccines have been so much a focus of the conversation around health misinformation for quite some time, I imagine that Google has had people looking specifically at that topic in internal reviews, whereas some of these other topics might be less in the forefront of the minds of the quality teams that are tasked with checking if there are bad results being returned.

What do you think Google’s next moves should be to prevent medical misinformation in AI search?

DiResta: Google has a perfectly good policy to pursue. Your Money or Your Life is a solid ethical guideline to incorporate into this manifestation of the future of search. So it’s not that I think there’s a new and novel ethical grounding that needs to happen. I think it’s more ensuring that the ethical grounding that exists remains foundational to the new AI search tools.

For the first time, a small group of patients with amputations below the knee were able to control the movements of their prosthetic legs through neural signals—rather than relying on programmed cycles for all or part of a motion—and resume walking with a natural gait. The achievement required a specialized amputation surgery combined with a non-invasive surface electrode connection to a robotic prosthetic lower leg. A study describing the technologies was published today in the journal Nature Medicine.

“What happens then is quite miraculous. The patients that have this neural interface are able to walk at normal speeds; and up and down steps and slopes; and maneuver obstacles really without thinking about it. It’s natural. It’s involuntary,” said co-author Hugh Herr, who develops bionic prosthetics at the MIT Media Lab. “Even though their limb is made of titanium and silicone—all these various electromechanical components—the limb feels natural and it moves naturally, even without conscious thought.”

The approach relies on surgery at the amputation site to create what the researchers call an agonist-antagonist myoneural Interface, or AMI. The procedure involves connecting pairs of muscles (in the case of below-the-knee amputation, two pairs), as well as the introduction of proprietary synthetic elements.

The interface creates a two-way connection between body and machine. Muscle-sensing electrodes send signals to a small computer in the prosthetic limb that interprets them as angles and forces for joints at the ankle and ball of the foot. It also sends information back about the position of the artificial leg, restoring a sense of where the limb is in space, also known as proprioception.

Video 1 www.youtube.com

“The particular mode of control is far beyond what anybody else has come up with,” said Daniel Ferris, a neuromechanical engineer at the University of Florida; Ferris was not involved in the study, but has worked on neural interfaces for controlling lower limb prostheses. “It’s a really novel idea that they’ve built on over the last eight years that’s showing really positive outcomes for better bionic lower legs.” The latest publication is notable for a larger participant pool than previous studies, with seven treatment patients and seven control patients with amputations and typical prosthetic legs.

To test the bionic legs, patients were asked to walk on level ground at different speeds; up and down slopes and stairs; and to maneuver around obstacles. The AMI users had a more natural gait, more closely resembling movement by someone using a natural limb. More naturalistic motion can improve freedom of movement, particularly over challenging terrain, but in other studies researchers have also noted reduced energetic costs, reduced stress on the body, and even social benefits for some amputees.

Co-author Hyungeun Song, a postdoctoral researcher at MIT, says the group was surprised by the efficiency of the bionic setup. The prosthetic interface sent just 18 percent of the typical amount of information that’s sent from a limb to the spine, yet it was enough to allow patients to walk with what was considered a normal gait.

Next Steps for the Bionic Leg

AMI amputations have now become the standard at Brigham and Women’s Hospital in Massachusetts, where co-author Matthew Carty works. And because of patient benefits in terms of pain and ease of using even passive (or non-robotic) prosthetics, this technique—or something similar—could spread well beyond the current research setting. To date, roughly 60 people worldwide have received AMI surgery above or below either an elbow or knee.

In principle, Herr said, someone with a previously amputated limb, such as himself, could undergo AMI rehabilitation, and he is strongly considering the procedure. More than 2 million Americans are currently living with a lost limb, according to the Amputee Coalition, and nearly 200,000 lower legs are amputated each year in the United States.

On the robotics side, there are already commercial leg prosthetics that could be made compatible with the neural interface. The area in greatest need of development is the connection between amputation site and prosthesis. Herr says commercialization of that interface might be around five years away.

Herr says his long-term goal is neural integration and embodiment: the sense that a prosthetic is part of the body, rather than a tool. The new study “is a critical step forward—pun intended.”

In the United States alone, more than 100,000 people currently need a lifesaving organ transplant. Instead of waiting for donors, one way to solve this crisis in the future is to assemble replacement organs with bio-printing—3D printing that uses inks containing living cells. Scientists in Israel have found that origami techniques could help fold sensors into bio-printed materials to help determine whether they are behaving safely and properly.

Although bio-printing something as complex as a human organ is still a distant possibility, there are a host of near-term applications for the technique. For example, in drug research, scientists can bio-print living, three-dimensional tissues with which to examine the effects of various compounds.

Ideally, researchers would like to embed sensors within bio-printed items to keep track of how well they are behaving. However, the three-dimensional nature of bio-printed objects makes it difficult to lodge sensors within them in a way that can monitor every part of the structures.

“It will, hopefully in the future, allow us to monitor and assess 3D biostructures before we would like to transplant them.” —Ben Maoz, Tel Aviv University

Now scientists have developed a 3D platform inspired by origami that can help embed sensors in bio-printed objects in precise locations. “It will, hopefully in the future, allow us to monitor and assess 3D biostructures before we would like to transplant them,” says Ben Maoz, a professor of biomedical engineering at Tel Aviv University in Israel.

The new platform is a silicone rubber device that can fold around a bio-printed structure. The prototype holds a commercial array of 3D electrodes to capture electrical signals. It also possesses other electrodes that can measure electrical resistance, which can reveal how permeable cells are to various medications. A custom 3D software model can tailor the design of the origami and all the electrodes so that the sensors can be placed in specific locations in the bio-printed object.

The scientists tested their device on bio-printed clumps of brain cells. The research team also grew a layer of cells onto the origami that mimicked the blood-brain barrier, a cell layer that protects the brain from undesirable substances that the body’s blood might be carrying. By folding this combination of origami and cells onto the bio-printed structures, Maoz and his colleagues were able to monitor neural activity within the brain cells and see how their synthetic blood-brain barrier might interfere with medications intended to treat brain diseases.

Maoz says the new device can incorporate many types of sensors beyond electrodes, such as temperature or acidity sensors. It can also incorporate flowing liquid to supply oxygen and nutrients to cells, the researchers note.

Currently, this device “will mainly be used for research and not for clinical use,” Maoz says. Still, it could “significantly contribute to drug development—assessing drugs that are relevant to the brain.”

The researchers say they can use their origami device with any type of 3D tissue. For example, Maoz says they can use it on bio-printed structures made from patient cells “to help with personalized medicine and drug development.”

The origami platform could also help embed devices that can modify bio-printed objects. For instance, many artificially grown tissues function better if they are placed under the kinds of physical stresses they might normally experience within the body, and the origami platform could integrate gadgets that can exert such mechanical forces on bio-printed structures. “This can assist in accelerating tissue maturation, which might be relevant to clinical applications,” Maoz says.

The scientists detailed their findings in the 26 June issue of Advanced Science.

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.

Tech startups are stepping up to meet the needs of 60 million people worldwide who use opioids, representing about 1 percent of the world’s adult population. In the United States, deaths involving synthetic opioids have risen 1,040 percent from 2013 to 2019. The COVID-19 pandemic and continued prevalence of fentanyl have since worsened the toll, with an estimated 81,083 fatal overdoses in 2023 alone.

Innovations include biometric monitoring systems that help doctors determine proper medication dosages, nerve stimulators that relieve withdrawal symptoms, wearable and ingestible systems that watch for signs of an overdose, and autonomous drug delivery systems that could prevent overdose deaths.

Helping Patients Get the Dosage They Need

For decades, opioid blockers and other medications that suppress cravings have been the primary treatment tool for opioid addiction. However, despite its clinical dominance, this approach remains underutilized. In the United States, only about 22 percent of the 2.5 million adults with opioid use disorder receive medication-assisted therapy such as methadone, Suboxone, and similar drugs.

Determining patients’ ideal dosage during the early stages of treatment is crucial for keeping them in recovery programs. The shift from heroin to potent synthetic opioids, like fentanyl, has complicated this process, as the typical recommended medication doses can be too low for those with a high fentanyl tolerance.

A North Carolina-based startup is developing a predictive algorithm to help clinicians tailor these protocols and track real-time progress with biometric data. OpiAID, which is currently working with 1,000 patients across three clinical sites, recently launched a research pilot with virtual treatment provider Bicycle Health. Patients taking Suboxone will wear a Samsung Galaxy Watch6 to measure their heart rate, body movements, and skin temperature. OpiAID CEO David Reeser says clinicians can derive unique stress indications from this data, particularly during withdrawal. (He declined to share specifics on how the algorithm works.)

“Identifying stress biometrically plays a role in how resilient someone will be,” Reeser adds. “For instance, poor heart rate variability during sleep could indicate that a patient may be more susceptible that day. In the presence of measurable amounts of withdrawal, the potential for relapse on illicit medications may be more likely.”

Nerve Stimulators Provide Opioid Withdrawal Relief

While OpiAID’s software solution relies on monitoring patients, electrical nerve stimulation devices take direct action. These behind-the-ear wearables distribute electrodes at nerve endings around the ear and send electrical pulses to block pain signals and relieve withdrawal symptoms like anxiety and nausea.

The U.S. Food and Drug Administration (FDA) has cleared several nerve stimulator devices, such as DyAnsys’ Drug Relief, which periodically administers low-level electrical pulses to the ear’s cranial nerves. Others include Spark Biomedical’s Sparrow system and NET Recovery’s NETNeuro device.

Masimo’s behind-the-ear Bridge device costs US $595 for treatment providers.Masimo

Similarly, Masimo’s Bridge relieves withdrawal symptoms by stimulating the brain and spinal cord via electrodes. The device is intended to help patients initiating, transitioning into, or tapering off medication-assisted treatment. In a clinical trial, Bridge reduced symptom severity by 85 percent in the first hour and 97 percent by the fifth day. A Masimo spokesperson said the company’s typical customers are treatment providers and correctional facilities, though it’s also seeing interest from emergency room physicians.

Devices Monitor Blood Oxygen to Prevent Overdose Deaths

In 2023, the FDA cleared Masimo’s Opioid Halo device to monitor blood oxygen levels and alert emergency contacts if it detects opioid-induced respiratory depression, the leading cause of overdose deaths. The product includes a pulse oximeter cable and disposable sensors connected to a mobile app.

Opioid Halo utilizes Masimo’s signal extraction technology, first developed in the 1990s, which improves upon conventional oxygen monitoring techniques by filtering out artifacts caused by blood movement. Masimo employs four signal-processing engines to distinguish the true signal from noise that can lead to false alarms; for example, they distinguish between arterial blood and low-oxygen venous blood.

Masimo’s Opioid Halo system is available over-the-counter without a prescription. Masimo

Opioid Halo is available over-the-counter for US $250. A spokesperson says sales have continued to show promise as more healthcare providers recommend it to high-risk patients.

An Ingestible Sensor to Watch Over Patients

Last year, in a first-in-human clinical study, doctors used an ingestible sensor to monitor vital signs from patients’ stomachs. Researchers analyzed the breathing patterns and heart rates of 10 sleep study patients at West Virginia University. Some participants had episodes of central sleep apnea, which can be a proxy for opioid-induced respiratory depression. The capsule transmitted this data wirelessly to external equipment linked to the cloud.

Celero’s Rescue-Rx capsule would reside in a user’s stomach for one week.Benjamin Pless/Celero Systems

“To our knowledge, this is the first time anyone has demonstrated the ability to accurately monitor human cardiac and respiratory signals from an ingestible device,” says Benjamin Pless, one of the study’s co-authors. “This was done using very low-power circuitry including a radio, microprocessor, and accelerometer along with software for distinguishing various physiological signals.”

Pless and colleagues from MIT and Harvard Medical School started Celero Systems to commercialize a modified version of that capsule, one that will also release an opioid antagonist after detecting respiratory depression. Pless, Celero’s CEO, says the team has successfully demonstrated the delivery of nalmefene, an opioid antagonist similar to Narcan, to rapidly reverse overdoses.

Celero’s next step is integrating the vitals-monitoring feature for human trials. The company’s final device, Rescue-Rx, is intended to stay in the stomach for one week before passing naturally. Pless says Rescue-Rx’s ingestible format will make the therapy cheaper and more accessible than wearable autoinjectors or implants.

Celero’s capsule can detect vital signs from within the stomach. www.youtube.com

Autonomous Delivery of Overdose Medication

Rescue-Rx isn’t the only autonomous drug-delivery project under development. A recent IEEE Transactions on Biomedical Circuits and Systems paper introduced a wrist-worn near-infrared spectroscopy sensor to detect low blood oxygen levels related to an overdose.

Purdue University biomedical engineering professor Hugh Lee and graduate student Juan Mesa, who both co-authored the study, say that while additional human experiments are necessary, the findings represent a valuable tool in counteracting the epidemic. “Our wearable device consistently detected low-oxygenation events, triggered alarms, and activated the circuitry designed to release the antidote through the implantable capsule,” they wrote in an email.

Lee and Purdue colleagues founded Rescue Biomedical to commercialize the A2D2 system, which includes a wristband and an implanted naloxone capsule that releases the drug if oxygen levels drop below 90 percent. Next, the team will evaluate the closed-loop system in mice.

This story was updated on 27 August 2024 to correct the name of Masimo’s Opioid Halo device.

Manu Prakash spoke with IEEE Spectrum shortly after returning to Stanford University from a month aboard a research vessel off the coast of California, where he was testing tools to monitor oceanic carbon sequestration. The associate professor conducts fieldwork around the world to better understand the problems he’s working on, as well as the communities that will be using his inventions.

Prakash develops imaging instruments and diagnostic tools, often for use in global health and environmental sciences. His devices typically cost radically less than conventional equipment—he aims for reductions of two or more orders of magnitude. Whether he’s working on pocketable microscopes, mosquito or plankton monitors, or an autonomous malaria diagnostic platform, Prakash always includes cost and access as key aspects of his engineering. He calls this philosophy “frugal science.”

Why should we think about science frugally?

Manu Prakash: To me, when we are trying to ask and solve problems and puzzles, it becomes important: In whose hands are we putting these solutions? A frugal approach to solving the problem is the difference between 1 percent of the population or billions of people having access to that solution.

Lack of access creates these kinds of barriers in people’s minds, where they think they can or cannot approach a kind of problem. It’s important that we as scientists or just citizens of this world create an environment that feels that anybody has a chance to make important inventions and discoveries if they put their heart to it. The entrance to all that is dependent on tools, but those tools are just inaccessible.

How did you first encounter the idea of “frugal science”?

Prakash: I grew up in India and lived with very little access to things. And I got my Ph.D. at MIT. I was thinking about this stark difference in worlds that I had seen and lived in, so when I started my lab, it was almost a commitment to [asking]: What does it mean when we make access one of the critical dimensions of exploration? So, I think a lot of the work I do is primarily driven by curiosity, but access brings another layer of intellectual curiosity.

How do you identify a problem that might benefit from frugal science?

Prakash: Frankly, it’s hard to find a problem that would not benefit from access. The question to ask is “Where are the neglected problems that we as a society have failed to tackle?” We do a lot of work in diagnostics. A lot [of our solutions] beat the conventional methods that are neither cost effective nor any good. It’s not about cutting corners; it’s about deeply understanding the problem—better solutions at a fraction of the cost. It does require invention. For that order of magnitude change, you really have to start fresh.

Where does your involvement with an invention end?

Prakash: Inventions are part of our soul. Your involvement never ends. I just designed the 415th version of Foldscope [a low-cost “origami” microscope]. People only know it as version 3. We created Foldscope a long time ago; then I realized that nobody was going to provide access to it. So we went back and invented the manufacturing process for Foldscope to scale it. We made the first 100,000 Foldscopes in the lab, which led to millions of Foldscopes being deployed.

So it’s continuous. If people are scared of this, they should never invent anything [laughs], because once you invent something, it’s a lifelong project. You don’t put it aside; the project doesn’t put you aside. You can try to, but that’s not really possible if your heart is in it. You always see problems. Nothing is ever perfect. That can be ever consuming. It’s hard. I don’t want to minimize this process in any way or form.

When it comes to the effects that the upcoming Trump presidency will have on healthcare, attendees’ attitudes ranged from cautiously optimistic to fairly anxious. Some of the issues they highlighted included mental health parity, telehealth prescribing flexibilities, and the role of Robert F. Kennedy Jr.

The post How Did Attendees at a Behavioral Health Conference React to Trump’s Victory? appeared first on MedCity News.

Navigating the regulatory and ethical requirements of different medical data providers across many different countries, as well as safeguarding patient privacy, is a mammoth task that requires extra resources and expertise.  

The post AI is Revolutionizing Healthcare, But Are We Ready for the Ethical Challenges?  appeared first on MedCity News.

CDMO Avid Bioservices is being acquired by the private equity firms GHO Capital Partners and Ampersand Capital Partners. Avid specializes in manufacturing biologic products for companies at all stages of development.

The post Private Equity Is Picking Up Biologics CDMO Avid Bioservices in $1.1B Acquisition appeared first on MedCity News.

Value-based care contracting is especially difficult for behavioral health providers, Taft Parsons III, chief psychiatric officer at CVS Health/Aetna, pointed out during a conference this week.

The post CVS Health Exec: Payers Need to Stop Making Behavioral Health Providers Jump Through Hoops In Order to Participate in Value-Based Care appeared first on MedCity News.

The vast majority of older adults want to age at home. To support that goal, doctors should encourage them to consider their care options — long before they need assistance.

The post Through Early Discussions About Elder Care, Doctors Can Empower Seniors to Age in Place appeared first on MedCity News.

By fostering collaboration and seamless data integration into healthcare systems, the industry is laying the groundwork for a future in which “personalized medicine” is so commonplace within clinical practice that we will just start calling it “medicine.”

The post Driving Genetic Testing Adoption and Improved Patient Care through Health Data Intelligence appeared first on MedCity News.

Access to care isn’t enough. Healthcare organizations need to build trust in order to reach underserved communities, experts said on a recent panel.

The post How Can Healthcare Organizations Earn Trust with Marginalized Communities? appeared first on MedCity News.

As radiopharmaceuticals enter a new phase, industry leaders must rethink external services and internal capabilities to master the complexities of delivering advanced therapies.

The post Unlocking the Future of Radioligand Therapy: From Discovery to Delivering at Scale appeared first on MedCity News.

Experts agree that the incoming Trump administration will likely shake things up in the prescription drug world — most notably when it comes to research and development, drug pricing and PBM reform.

The post What Might the Future of Prescription Drugs Look Like Under Trump? appeared first on MedCity News.

The Pew Charitable Trusts joined dozens of research, health care, and nonprofit stakeholders in urging President-elect Joe Biden to prioritize and strengthen the national response to antibiotic resistance.

In 2018, opioid overdoses in the United States caused one death every 11 minutes, resulting in nearly 47,000 fatalities. The most effective treatments for opioid use disorder (OUD) are three medications approved by the Food and Drug Administration (FDA): methadone, buprenorphine, and naltrexone.

Few correctional facilities in the United States have treatment programs for individuals with opioid use disorder (OUD), despite clear evidence that certain medications reduce the risk of overdose and death. Even in facilities where treatment is available, the COVID-19 pandemic has complicated efforts to provide such care.

The Pew Charitable Trusts sent comments Jan. 4 to the Office of the National Coordinator for Health Information Technology (ONC) and the Centers for Medicare & Medicaid Services (CMS) urging them to support the easy exchange of individuals’ health records through a pair of regulations.

Faulty diagnostic tests can compromise both patient care and the nation’s response to infectious diseases—as made all too clear earlier this month when the Food and Drug Administration issued a safety alert about a COVID-19 test that carries a high risk of false negative results.

Dr. Cassandra Quave’s path to her work as a leader in antibiotic drug discovery research initiatives at Emory University in Atlanta started when she was a child and she and her family dealt with her own serious health issues that have had life-long repercussions.

Between 1999 and 2014, opioid use disorder (OUD) among pregnant women more than quadrupled, risking the health of the women—before and after giving birth—and their infants. As states grapple with COVID-19’s exacerbation of the opioid crisis, several are taking innovative steps to address the needs of high-risk groups, including low-income, postpartum patients with OUD.

Over the past year, COVID-19 has taken a grave toll in lives as well as on medical and health care systems worldwide. The pandemic has laid bare the importance of public health readiness and the myriad consequences when such a crisis strikes an unprepared population.

The Pew Charitable Trusts today commended Michigan Governor Gretchen Whitmer (D), state Senate Majority Leader Mike Shirkey (R), and Lee Chatfield (R)—whose term as state House Speaker ended last month—for passing and signing a bipartisan package of bills aimed at protecting public safety while reducing the number of people in county jails.

As the coronavirus pandemic grips the world, the opioid epidemic continues to affect millions of Americans. Several states are developing innovative ways to tackle this public health issue. In this episode, we speak with Beth Connolly, who leads Pew’s research on substance use disorders, and Louisiana Representative Paula Davis, who helped ensure effective treatment in her state.

Sales of medically important antibiotics for use in food-producing animals increased 3% in 2019, according to recent data from the U.S. Food and Drug Administration. This is the second year in a row that the quantities of antibiotics sold for animal use have risen, underscoring the need for further FDA action to ensure judicious use of these lifesaving drugs.

The United States is grappling with two severe health crises: the COVID-19 pandemic and an opioid epidemic that appears to be worsening as more people deal with stress and isolation as they face increased barriers to medical care. Preliminary numbers for 2020 show that overdose deaths were outpacing the record-setting number of more than 71,000 fatalities in 2019.

Technology has revolutionized the way people live their lives. Individuals can use smartphones to access their bank account, shop from almost any store, and connect with friends and family around the globe. In fact, these personal devices have tethered communities together during the coronavirus pandemic, allowing many people to maintain much of their lives remotely.

The Food and Drug Administration published a concept paper in early January that describes a preliminary proposal for how the agency will ensure that companies developing antibiotics for administration to animals establish defined, evidence-based durations of use for all medically important antibiotics.

Pharmaceutical and biotech companies breathed a sigh of relief Monday when the Federal Circuit unanimously ruled in a precedential opinion that the mere sale of manufacturing services to create embodiments of a patented product is not a “commercial sale” of the invention that triggers the on-sale bar of 35 U.S.C. § 102(b) (pre-AIA).[1]  The en banc opinion...… Continue Reading

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