'AMA: Some AI Use in Medicine Should Require Docs' Consent'

 The American Medical Association (AMA) this week called for requiring physician consent for some uses of artificial intelligence as it released its recommended principles for the use of AI in medicine.

"The AMA recognizes the immense potential of health care AI in enhancing diagnostic accuracy, treatment outcomes, and patient care," said AMA President Jesse M. Ehrenfeld, MD, MPH, in a statement. "However, this transformative power comes with ethical considerations and potential risks that demand a proactive and principled approach to the oversight and governance of health care AI."

The AMA said health plans should seek to use AI to simplify administrative tasks and reduce workflow burdens. There's potential for AI-enabled technologies to
cut down on paperwork, but they may "not be designed or supervised effectively, creating access barriers for patients and limiting essential benefits."

The AMA principles also noted that physicians could face increased risks for liability when they rely on AI-enabled tools and systems sold with little transparency about data and algorithms underpinning these products.

AMA said it will advocate to ensure that physician liability for the use of AI-enabled technologies is limited and adheres to current approaches to medical malpractice, even as legal theory about liability and accountability in this field evolves.

And the AMA's principles called for greater transparency about insurers' use of AI in automated decision-making systems that can "deny care more rapidly, often with little or no human review." Recent lawsuits against insurers have highlighted new concerns over insurers' use of AI in prior authorization to deny care.

Health plans using automated decision-making systems should be required to engage in regular audits to ensure use of these systems do not increase claims denials or coverage limitations, or otherwise decrease access to care, AMA said.

"In some instances, payors instantly reject claims on medical grounds without opening or reviewing the patient's medical record," the AMA said. "Rather than payors making determinations based on individualized patient care needs, reports show that decisions are based on algorithms developed using average or 'similar patients' pulled from a database."

Patient privacy remains a concern as "data hungry" AI tools gain greater access to patient records via interoperable systems, AMA said. In many cases, companies developing AI-enabled products create legal arrangements that bring them under the Health Insurance Portability and Accountability Act (HIPAA) rules.

"Yet even HIPAA cannot protect patients from the 'black box' nature of AI, which makes the use of data opaque," AMA said. "AI system outputs may also include inferences that reveal personal data or previously confidential details about individuals. This can result in a lack of accountability and trust and exacerbate data privacy concerns."

"Lagging" Oversight

In the principles, the AMA also highlighted the current gaps in US government oversight and regulation of AI in medicine. There's currently no national standard to guide the development and adoption of many applications of AI to medicine, AMA said.

Instead there's a patchwork.

For example, the Food and Drug Administration (FDA) regulates AI-enabled medical devices, but many other AI-enabled technologies fall outside the scope of the agency's oversight. The Federal Trade Commission and the Health and Human Services Office for Civil Rights have oversight over some aspects of AI, but their authorities "are limited and [are] not adequate to ensure appropriate development and deployment of AI," AMA said.

"With a lagging effort toward adoption of national governance policies or oversight of AI, it is critical that the physician community engage in development of policies to help inform physician and patient education, and guide engagement with these new technologies," the AMA said.

https://www.medscape.com/viewarticle/998961

Dark Side of GLP-1 Receptor Agonists

 The approval of the GLP-1 receptor agonist semaglutide for weight regulation in January 2023 ushered in a new era of obesity therapy. In recent months, however, drug regulatory authorities have also documented rare, occasionally severe side effects associated with the use of these agents in diabetes therapy that doctors may not necessarily have been aware of.

"When millions of people are treated with medications like semaglutide, even relatively rare side effects occur in a large number of individuals," said Susan Yanovski, MD, codirector of the Office of Obesity Research at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, in a JAMA news report.

Despite the low incidence of these adverse events and the likelihood that the benefits outweigh these risks in individuals with severe obesity, doctors and patients should be aware of these serious side effects, she added.

GLP-1 receptor agonists like semaglutide or liraglutide mimic certain intestinal hormones. Almost all their characteristic side effects involve the gastrointestinal tract: nausea, vomiting, constipation, and diarrhea. However, these are not the rare, severe side effects that are gaining increasing attention.

Severe Gastric Problems

A recent analysis published in JAMA shows that GLP-1 receptor agonists are associated with a ninefold higher risk of pancreatitis, compared with bupropion, an older weight-loss medication. Patients receiving GLP-1 receptor agonists also had four times more frequent intestinal obstruction and more than three times more frequent gastroparesis. The absolute risks for these complications, however, were less than 1% per year of use.

There were no indications of an increased risk for gallbladder diseases. Acute pancreatitis and acute gallbladder diseases are known complications of GLP-1 receptor agonists.

These results "reinforce that these are effective medications, and all medications have side effects," said Yanovski. She emphasized that despite a significant increase in relative risk, however, the absolute risk remains very low.

Anesthetic Complications

In the spring of 2023, reports of patients taking GLP-1 receptor agonists and vomiting or aspirating food during anesthesia surfaced in some scientific journals. It was particularly noticeable that some of these patients vomited unusually large amounts of stomach contents, even though they had not eaten anything, as directed by the doctor before the operation.

Experts believe that the slowed gastric emptying intentionally caused by GLP-1 receptor agonists could be responsible for these problems.

The American Society of Anesthesiologists now recommends that patients do not take GLP-1 receptor agonists on the day of surgery and discontinue weekly administered agents like Wegovy 7 days before the procedure.

Increased Suicidality Risk?

In July, case reports of depression and suicidal ideation led the European Medicines Agency to investigate about 150 cases of potential self-harm and suicidal thoughts in patients who had received liraglutide or semaglutide. The review now also includes other GLP-1 receptor agonists. Results of the review process are expected this month.

Yanovski noted that it is unclear whether these incidents are caused by the drugs, but suicidal thoughts and suicidal behavior have also been observed with other medications for obesity treatment (eg, rimonabant). "It is certainly a good idea to use these medications cautiously in patients with a history of suicidality and monitor the patients accordingly," she said.

Long-Term Safety

GLP-1 receptor agonists likely need to be used long term, potentially for life, for the effects on body weight to persist. Whether there are side effects and complications that only become apparent over time is currently unknown — especially when these medications are used for weight reduction.

Studies in rodents have suggested an increased risk of medullary thyroid carcinomas. Whether a similar signal exists in humans may only become apparent in many years. In patients who have had medullary thyroid carcinoma themselves or in the family, dulaglutide, liraglutide, semaglutide, and tirzepatide, a dual GLP-1/GIP receptor agonist, are contraindicated.

With dual agonists like tirzepatide or even triple agonists like retatrutide (GLP-1/GIP/glucagon), patients can lose significantly more weight than with the monoagonist semaglutide. Gastrointestinal events were also frequent in studies of dual agonists.

Awaiting Guideline Updates

Guidelines for using these new medications are still scarce. "There are clinical guidelines for obesity therapy, but they were all written before the GLP-1 receptor agonists came on the market," said Yanovski. "Medical societies are currently working intensively to develop new guidelines to help doctors use these medications safely and effectively in clinical practice."

https://www.medscape.com/viewarticle/998986

Rude Awakening on Trying to Keep Donor Hearts Usable With Common Hormone Infusions

 Giving unstable brain-dead heart donors intravenous levothyroxine did not lead to more hearts being transplanted, a randomized trial showed.

In hemodynamically unstable potential donors, administering the thyroid hormone supplement after brain death did not significantly improve donor heart utilization compared with saline placebo, with transplantation rates of 54.9% and 53.2%, respectively (adjusted risk ratio 1.01, 95% CI 0.97-1.07), reported Rajat Dhar, MD, of Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, and colleagues.

The prespecified recipient safety outcome -- graft survival at 30 days after transplantation -- occurred in 97.4% of transplanted hearts in the levothyroxine group and 95.5% in the saline group (P<0.001 for noninferiority). However, severe hypertension and tachycardia occurred in excess in the levothyroxine group, Dhar and colleagues noted in the New England Journal of Medicineopens in a new tab or window.

"Neither weaning from vasopressor therapy nor ejection fraction on echocardiography was better with levothyroxine than with normal saline, findings that suggest a lack of physiological benefit of levothyroxine on donor cardiovascular function," they wrote. "These results provide evidence that thyroid hormone administration does not improve donor stability or organ-transplantation rates."

In the trial, 12 of the 15 participating organ-procurement organizations (OPOs) had been using levothyroxine as part of their standard protocols for years. With the present results, several organizations have stopped using thyroid hormone in this setting, Dhar said in a statement.

Intravenous levothyroxine has been widely used in deceased donor care due to the theory that neurohormonal insufficiency after brain death leads to myocardial energy depletion and shock, and hormone supplementation should widen the net of usable organs. However, this was supported only by observational data.

"The few randomized trials that have evaluated administration of thyroid hormone to donors have focused on intermediate outcomes such as donor hemodynamics and were underpowered to evaluate organ utilization," Dhar and team wrote. "Despite little high-quality evidence, consensus guidelines continue to recommend thyroid hormone in hemodynamically unstable or heart-eligible donors."

"We found good evidence that this intervention we've been using for 40 years doesn't work," Dhar said in a press releaseopens in a new tab or window. "It's vital that we explore questions like this to ensure we are doing all we can for patients who need organs -- and to ensure that they receive the most benefit possible from the generous people who choose to donate organs."

Dhar and colleagues acknowledged that blinding was not feasible in their trial. Open-label use of levothyroxine was allowed after 12 hours and used in a minority of the control group. Moreover, they noted their trial did not test the more active thyroid hormone (T3 or triiodothyronine).

In an accompanying editorialopens in a new tab or window, Kiran Khush, MD, MAS, of Stanford University School of Medicine in California, noted that "even so, [this study] provides the most definitive data to date about donor thyroid hormone replacement therapy. The results have major clinical implications for OPOs around the country."

Khush cited data from the United Network for Organ Sharing suggesting that 48% of all potential organ donors and 55% of donors with left ventricular dysfunction were treated with levothyroxine from 2015 to 2022. Nearly half the OPOs nationwide routinely administer thyroid hormone during donor care, he added.

The present study included 852 hemodynamically unstable potential heart donors (mean age 36 years, over 30% women). Participants were randomly assigned to open-label infusion of IV levothyroxine (30 μg/hour for 12+ hours) or saline placebo within 24 hours of death according to neurologic criteria. The median time from declaration of brain death to levothyroxine or saline administration was 8 hours.

In addition to the main results of the trial, there were no differences between the levothyroxine and saline groups in terms of vasopressor requirements, donor ejection fraction, and number of organs transplanted (four per donor in both groups).

"It is very unusual to have a study of deceased organ donors of this size and with such sufficient rigor, but we believed the 4-year, multicenter research was critical to definitively answer this key question to enable better organ donor management," said study co-author Gary Marklin, MD, also of Washington University School of Medicine, in the press release.

The researchers said their patient sample was representative of the target population, and their findings may be generalizable to hemodynamically unstable heart donors.

Disclosures

The trial was supported by Mid-America Transplant with internal support from each organ procurement organization.

Dhar disclosed consulting to Marinus Pharmaceuticals and Mid-America Transplant.

Khush reported receiving research funding from the NIH and consulting to the Scientific Registry for Transplant Recipients.

Primary Source

New England Journal of Medicine

Source Reference: opens in a new tab or windowDhar R, et al "Intravenous levothyroxine for unstable brain-dead heart donors" N Engl J Med 2023; DOI: 10.1056/NEJMoa2305969.

Secondary Source

New England Journal of Medicine

Source Reference: opens in a new tab or windowKhush KK "The importance of randomized, controlled trials in the care of organ donors" N Engl J Med 2023; DOI: 10.1056/NEJMe2311964.

https://www.medpagetoday.com/transplantation/hearttransplantation/107620

'Rare Syndrome After COVID Vaccines Described'

 People who experienced rare long-term adverse events after COVID-19 vaccination often had neurologic symptoms, survey data showed.

Among 241 people who self-reported a post-vaccination syndrome (PVS), the five most common symptoms were exercise intolerance (71%), excessive fatigue (69%), numbness (63%), brain fog (63%), and neuropathy (63%), reported Harlan Krumholz, MD, of Yale School of Medicine in New Haven, Connecticut, and co-authors in a paper posted on the preprint server medRxivopens in a new tab or window. The paper has not been peer-reviewed.

"The study is the largest investigation of the experience of people reporting a chronic, debilitating condition that began soon after a COVID-19 vaccination," Krumholz told MedPage Today.

"It raises awareness about what these individuals are experiencing and points attention to the need for more studies to understand what is underlying this condition and how to relieve suffering," he continued. "These people are not anti-vaxxers -- they were all vaccinated -- but because of politics, many have had the experience of being dismissed and ignored."

Ongoing symptoms after COVID vaccines are rarely studied. "Even the definition of post-vaccination syndrome is in flux, but a working definition could be symptoms that begin with a week of a vaccination and persist for at least 2 months," Krumholz said.

Last year, an NIH-funded study on medRxiv evaluated new neuropathic symptomsopens in a new tab or window in 23 people that started soon after they received a COVID vaccine. About half (52%) of the 23 participants had objective evidence of small-fiber peripheral neuropathy; of those, 58% who were treated with oral corticosteroids had complete or near-complete improvement after 2 weeks. Some participants improved without immunotherapy.

Case reports suggested post-vaccine neuropathy and tinnitusopens in a new tab or window may be treated with plasma exchange. Postural orthostatic tachycardia syndrome (POTS) also has been diagnosedopens in a new tab or window after COVID vaccines.

Reports to the Vaccine Adverse Event Reporting Systemopens in a new tab or window (VAERS) after COVID vaccination include a variety of neurologic and systemic manifestations, Krumholz and co-authors noted. These symptoms may share mechanisms with post-COVID complications, they observed.

"Importantly, immune-mediated neurological adverse events post-vaccination are rare and often less severe than those that follow actual infection," they wrote.

Krumholz and colleagues surveyed 241 adults who self-reported PVS after COVID-19 vaccination and who joined the online LISTENopens in a new tab or window study from May 2022 to July 2023. People with long COVID were excluded from the study.

Median participant age was 46. Most were women (80%), white (87%), and from the U.S. (88%). About half (55%) received the Pfizer-BioNTech (Comirnaty) vaccine and 37% had the Moderna (Spikevax) shot. A third (34%) said they had SARS-CoV-2 infection at least once.

PVS symptom onset occurred within a median of 3 days of the index vaccination. Symptoms began after the first, second, third, and fourth (or more) vaccinations for 44%, 33%, 14%, and 9% of participants, respectively.

Participants completed surveys from November 2022 and July 2023, a median of 595 days after vaccination. From a list of 96 symptoms, they were asked to identify health conditions they had as a result of vaccine injury. They also reported their self-perceived health status on a 5-point scale of excellent, very good, good, fair, or poor.

In addition, participants rated their quality of life with the Euro-QoL visual analogue scale (EQ-VASopens in a new tab or window; a score of 100 represented the best), and reported symptom severity by rating symptoms on their worst days, with 0 meaning trivial illness and 100 being unbearable.

The median number of symptoms attributed to PVS was 22. Overall, 44% rated their current health as fair or poor. The median EQ-VAS score was 50; in people without previous comorbidities, it was 52. Participants reported a median symptom severity of 80 on their worst days.

The median number of treatments tried was 20. The most common prescription therapies were oral steroids (48%), gabapentin (25%), low-dose naltrexone (20%), ivermectin (18%), propranolol (11%), and bronchodilators (11%).

The most common non-drug treatments included limiting exercise or exertion (51% of participants), quitting alcohol or caffeine (44%), hydration and increasing salt intake (44%), and intermittent fasting (39%).

In the week before completing the survey, most participants said they felt unease (93%), fearfulness (82%), or overwhelmed by worries (81%), and reported feelings of helplessness (80%), anxiety (76%), depression (76%), or hopelessness (72%) at least once.

This report is a step toward acknowledging the effects of PVS, Krumholz noted. "The next step is to correlate what these people are experiencing with deep investigations of immune function," he said. The LISTEN study continues to recruit participants, he added.

The study had limitations; participants were self-referred and symptoms were self-reported. "The participants are not representative, so it is not possible to estimate the incidence or who might be most susceptible to this condition," the researchers acknowledged.

Disclosures

This project was in part supported by the Howard Hughes Medical Institute Collaborative COVID-19 Initiative and in part from a grant from the National Center for Advancing Translational Science of the NIH.

Krumholz received expenses and/or personal fees from Element Science, Eyedentify, and F-Prime in the past 3 years. He is a co-founder of Refactor Health and Ensight-AI. He and his spouse are co-founders of, and have equity in, Hugo Health, the personalized health data platform company that developed the Hugo Kindred platform. The Yale Conflict of Interest Committee oversees his involvement in this study. He is the editor of Journal Watch: Cardiology of the Massachusetts Medical Society and a section editor for UpToDate. He is associated with contracts through Yale New Haven Hospital from CMS, and through Yale University from Janssen, Johnson & Johnson Consumer, and Pfizer.

Co-authors reported relationships with RIGImmune, Xanadu Bio, PanV, Paratus Sciences, InvisiShield Technologies, Roche Holding Ltd., the NIH, the Patient-Centered Outcomes Research Institute, Sentara Research Foundation, the American Heart Association, the Agency for Healthcare Research and Quality, CMS, Pfizer, and the Yale-Mayo Clinic Center of Excellence in Regulatory Science and Innovation.

Primary Source

medRxiv

Source Reference: opens in a new tab or windowKrumholz HM, et al "Post-vaccination syndrome: a descriptive analysis of reported symptoms and patient experiences after COVID-19 immunization" medRxiv 2023; DOI: 10.1101/2023.11.09.23298266.

https://www.medpagetoday.com/neurology/generalneurology/107644

Prone Positioning Falls Flat for Weaning COVID Patients Off ECMO

 Early application of prone positioning did not help patients with severe acute respiratory distress syndrome (ARDS) -- mostly from COVID -- get off venovenous extracorporeal membrane oxygenation (VV-ECMO) any faster compared to supine positioning, a randomized trial found.

Among ARDS patients receiving ECMO, an identical 44% of patients were successfully weaned off ECMO after 60 days whether they were placed in sessions of prone positioning or simply kept supine (P=0.64), reported Matthieu Schmidt, MD, of the Hôpital de la Pitié-Salpêtrière in Paris, and colleagues.

Within 90 days, there was no significant difference seen in ECMO duration between prone and supine groups (28 vs 32 days, P=0.13). Also no different were 90-day mortality rates between positions (51% vs 48%, P=0.62), according to the French PRONECMO study published in JAMAopens in a new tab or window.

"Despite promising findings in observational studies, prone positioning of patients undergoing ECMO failed to reduce ECMO duration or mortality in this randomized trial," Schmidt and coauthors concluded.

Prone positioning has been shown to reduce mortality in ARDSopens in a new tab or window, and promotes "better overall ventilation/perfusion matching through a more homogeneous distribution of gas-tissue ratios along the dependent-nondependent axis in addition to decreased levels of lung stress and strain," the investigators explained in their introduction.

But whether the benefit extended to ARDS patients on VV-ECMO was unclear. One recent meta-analysis of 13 observational studiesopens in a new tab or window had found prone positioning during ECMO for ARDS -- COVID-19 or not -- to be associated with a significant improvement in ventilator-free days and intensive care unit (ICU) survival, Schmidt's group noted.

Prone positioning is strongly recommended in current clinical practice guidelines, noted Ricardo Teijeiro-Paradis, MD, and Niall Ferguson, MD, MSc, both of the University of Toronto, in an accompanying editorialopens in a new tab or window.

"Based on these results, routine prone positioning during VV-ECMO does not facilitate earlier liberation from ECMO or improve outcomes. This suggests that on average, prone positioning does not facilitate further lung protection than that already provided with an ultraprotective ventilation strategy facilitated by VV-ECMO," Teijeiro-Paradis and Ferguson wrote.

"Results of the PRONECMO trial may lead us to turn our backs on routine prone-position ventilation during VV-ECMO and face forward toward novel group-specific interventions targeting lung and diaphragm-protective ventilation, early awakening, and patient mobility," the duo commented.

Study authors and editorialists posed several factors that may explain PRONECMO's neutral results for prone positioning.

"First, the majority of enrolled patients were placed in prone position before ECMO, compared with widely variable proportions of patients in previous cohorts. Second, the majority of patients had COVID-19-related ARDS, perhaps with a greater severity of pulmonary injury," Schmidt and colleagues wrote.

They added that a person's response to prone positioning may depend on his or her specific etiology or severity of respiratory illness. "The COVID-19 variant may also contribute to prone positioning response, as less favorable pandemic outcomes were observed in late 2020, and the Delta variant was predominant in France during part of the trial. This contrasts with early reports of prone positioning benefit in COVID-19 patients receiving ECMO during predominance of the wild-type SARS-CoV-2 strain," they wrote.

Additionally, Teijeiro-Paradis and Ferguson suggested that sedation may have played a role in prone positioning's lack of benefit in the trial.

"Not infrequently, our patients develop complete lung collapse/consolidation with resulting tidal volumes far below anatomical dead space," the pair wrote. "Such derecruitment is exacerbated by the lack of respiratory effort due to deep sedation and paralysis often needed to maintain adequate ECMO flow and safe inspiratory pressures. A similar phenomenon may explain the progressive decrease in respiratory system compliance observed in both groups in the PRONECMO study."

The randomized trial was conducted at 14 ICUs in France with clinicians having the experience and capability to perform prone positioning during ECMO. Study participants were patients undergoing ECMO for severe ARDS. From March to December 2021, adult patients were enrolled if they were undergoing invasive mechanical ventilation and were supported by VV-ECMO for less than 48 hours.

The study cohort included 170 patients (median age 51, 35% women). Approximately 93% of the cohort presented with COVID-19-related ARDS, the remainder having bacterial pneumonia or another etiology.

Those assigned to prone positioning underwent at least four prone position sessions of 16 hours during the first 4 days (unless a patient met predefined criteria for early stopping of the prone intervention), whereas the supine ECMO group was not allowed to be put in prone before day 60.

All individuals in the prone group were placed in this position immediately after randomization. Overall, 80% received at least four prone sessions, with discontinuation most commonly due to respiratory system compliance and improvements in oxygenation.

Among the study's limitations were its small sample size and unblinded trial methods. A caveat to the study's generalizability was the observation that approximately 40% of study participants had been enrolled from a single very experienced center, Schmidt and colleagues cautioned.

Disclosures

This study was supported by funding from the Programme Hospitalier de Recherche Clinique-PHRC 2018 (French Ministry of Health).

Schmidt reported relationships with Getinge, Dräger, Baxter, and Fresenius Medical Care.

Teijeiro-Paradis and Ferguson reported no disclosures.

Primary Source

JAMA

Source Reference: opens in a new tab or windowSchmidt M, et al "Prone positioning during extracorporeal membrane oxygenation in patients with severe ARDS: The PRONECMO randomized clinical trial" JAMA 2023; DOI: 10.1001/jama.2023.24491.

Secondary Source

JAMA

Source Reference: opens in a new tab or windowTeijeiro-Paradis R, Ferguson ND "Prone positioning during venovenous ECMO for severe ARDS" JAMA 2023; DOI: 10.1001/jama.2023.22456.

https://www.medpagetoday.com/criticalcare/generalcriticalcare/107645

ADC and GLP-1 Rocket Ride Continues as 2023 Comes to Close

 With just a month left in what has been a challenging year for biopharma, two product categories that remain rock steady are antibody-drug conjugates and glucagon-like peptide 1 agonists. Targeted toward the cancer and diabetes/weight loss markets, respectively, ADCs and GLP-1 drugs are not new technologies—the first FDA approval of an ADC came in 2000 and GLP-1s were first introduced in 2010—but subsequent advancements and regulatory green lights have cemented their place in the industry.

The rise of ADCs with their targeted and potent cytotoxic payloads are transforming cancer treatment. Last year, BioSpace took a look at how, amid waves of biotech layoffs, ADC developers such as ImmunoGen were thriving. This week, ImmunoGen’s ship came in as AbbVie agreed to acquire the Waltham, Mass.-based company for $10.1 billion. AbbVie gains access to ImmunoGen’s FDA-approved Elahere ADC for platinum-resistant ovarian cancer and a pipeline of promising next-generation ADCs.

The multibillion-dollar deal comes the same week AbbVie scored a Phase II win for its investigational c-Met protein directed ADC in patients with previously treated non-small cell lung cancer. While AbbVie’s Teliso-V is not approved by any regulatory authority and its safety and efficacy have not been established, it could become the first ADC targeting c-Met to be approved by the FDA. AbbVie will discuss with global health authorities the potential to support an accelerated approval.

So, where does ADC technology go from here? Despite their payload targeting, these novel agents come with their share of challenges. “Even very, very stable ADCs have toxicity problems,” according to Nathan Tumey, associate professor at the School of Pharmacy and Pharmaceutical Sciences at Binghamton University. BioSpace this week examined the next-generation of ADCs that are striving to overcome these toxicities and payload problems.    

If the ADC market is red hot in cancer, then the GLP-1 market is a full-fledged weight loss drug craze fueled by the FDA’s approval of Eli Lilly’s obesity drug Zepbound (tirzepatide) earlier this month and Novo Nordisk’s phenomenal success with Wegovy (semaglutide).

While there are currently no head-to-head randomized clinical studies pitting these two therapies against each other, a comparative analysis of electronic health records by healthcare data and analytics firm Truveta found that tirzepatide might be a better choice than semaglutide. These are interesting real-world data. The caveat is that the research, its methods, results, analysis and conclusions have yet to be peer reviewed.

Among the most common side effects of Novo’s Wegovy and Lilly’s Zepbound injections are nausea, diarrhea, abdominal pain, vomiting and constipation. Apparently, these are problems also shared by oral GLP-1 drugs.

Pfizer announced Friday that while its twice-daily oral GLP-1 candidate met its primary endpoint in a Phase IIb obesity trial, danuglipron resulted in high rates of adverse events including nausea, vomiting and diarrhea. The company said the twice-daily danuglipron formulation “will not advance into Phase III studies.” Future drug development will focus on a once-daily form, with data coming in the first half of 2024.

Finally, Altimmune this week scored a Phase II win showing that its investigational GLP-1/glucagon dual receptor agonist pemvidutide induced strong weight loss in adults with overweight or obesity. Patients treated with Altimmune’s pemvidutide saw up to 15.6% weight loss, and nearly a third of those taking the highest dose lost at least 20% of their body weight.

https://www.biospace.com/article/adc-and-glp-1-mania-continue-as-2023-comes-to-close/

The Urgency Of Strengthening America’s Electric Grid Cybersecurity

 by Paul Steidler via RealClear Wire,

The U.S. electric grid continues to face a bevy of foreign and domestic cyberattack threats. Therefore, it makes more sense than ever before for utilities and transmission operators to aggressively fortify their cyber defenses. In fact, failure to do so is a classic case of being penny wise and pound foolish. 

The evidence includes the following: 

• On November 16, following two days of cybersecurity scenario testing by more than 250 organizations, Manny Cancel, Senior Vice President of the North American Electric Reliability Corporation (NERC) said, “The threat landscape in which we are operating is unprecedented – we are facing challenges that are increasingly difficult to detect and protect against.”
• NERC added that evolving cyber threats to the grid are “guided by geopolitical events, new vulnerabilities, changes in technologies, and increasingly bold cyber criminals and hackers.”
• China, Russia, and other countries continue to impose cybersecurity threats to the U.S. electric grid, as discussed in the Office of the Director of National Intelligence’s Annual Threat Assessment.
• Cybersecurity insurance premiums continue to rise sharply, making preventative actions more compelling from a cost-benefit standpoint. 
• The shift to renewable energy and distributed resources opens additional vulnerabilities for electric utilities. As Bruce Walker, President and Chief Executive Officer of the Alliance for Critical Infrastructure Security said in July 18 Congressional testimony, “Importantly, the risk associated with cyber is exacerbated by the rapid transformational changes happening in the electric sector. The transition away from a centralized generation and command and control model to a decentralized model, has increased the surface area for cyber penetration.  

The grid’s Operational Technology (OT) vulnerabilities are particularly notable. OT refers to the remote monitoring and control of components in the electric system. This encompasses supervisory control and data acquisition (SCADA) and industrial control systems (ICS) networks. 

An October 2022 U.S. Department of Energy study found, “Another industry trend is increased attacker experimentation and exploitation targeting OT systems.” 

The U.S. Government Accountability Office has issued a similar warning: “Grid distribution systems – which carry electricity from transmission systems to consumers – have grown more vulnerable, in part because their operational technology increasingly allows remote access and connections to business networks.”

One way to simplify critical infrastructure protection and keep OT secure is to place a device that only allows pre-defined, legitimate signals to be sent to the OT on a network. This reduces the costs of more holistic network changes. It also prevents non-specific commands from passing through a protected device. 

One such system, Binary Armor, places an in-line barrier to cyber intrusion, while monitoring all communications to a piece of OT. The device is small, approximately five by three inches, and weighs less than a pound. It can be deployed throughout the distribution grid, including on main substation data lines and within substations. 

Legitimate commands can pass through. Those that would cause the device to behave in dangerous, destructive ways are thwarted. 

Binary Amor cannot be modified or reconfigured without physical access to the system, thereby providing robust security for remote facilities and critical infrastructure. The system allows the system operator to define the rules for SCADA/ICS traffic and to inspect every byte of information. 

The scope of threats that the U.S. electric grid will continue to face are likely to rise in complexity and severity. Rather than waiting for dictates from regulators, utilities and transmission grid operators should identify important areas for cybersecurity protection, especially where there are efficient, cost-effective solutions. In this environment, OT protection is especially important and likely to be even more so soon. 

Paul Steidler is a senior fellow of the Lexington Institute who researches, studies, and discusses logistics and energy issues.

https://www.zerohedge.com/energy/urgency-strengthening-americas-electric-grid-cybersecurity