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Wednesday, October 9, 2024

'About one in five heat-related deaths in recent years involved methamphetamine'

 On just 1 sweltering day during the hottest June on record in Phoenix, a 38-year-old man collapsed under a freeway bridge and a 41-year-old woman was found slumped outside a business. Both had used methamphetamine before dying from an increasingly dangerous mix of soaring temperatures and stimulants.

Meth is showing up more often as a factor in the deaths of people who died from heat-related causesopens in a new tab or window in the U.S., according to an Associated Press analysisopens in a new tab or window of data from the CDC. Death certificates show about one in five heat-related deaths in recent years involved methamphetamine. In Arizona, Texas, Nevada, and California, officials found the drug in nearly a third of heat deaths in 2023.

Meth is more common in heat-related deaths than the deadly opioid fentanyl. As a stimulant, it increases body temperature, impairs the brain's ability to regulate body heat, and makes it harder for the heart to compensate for extreme heat.

If hot weather has already raised someone's body temperature, consuming alcohol or opioids can exacerbate the physical effects, "but meth would be the one that you would be most concerned about," said Bob Anderson, PhD, chief of statistical analysis at the National Center for Health Statistics.

The trend has emerged as a synthetic drug manufactured south of the border by Mexican drug cartels has largely replaced the domestic version of meth fictionalized in the TV series "Breaking Bad." Typically smoked in a glass pipe, a single dose can cost as little as a few dollars.

At the same time, human-caused climate changeopens in a new tab or window has made it much easier to die from heat-related causes in places like Phoenix, Las Vegas, and California's southeastern desert. This has been Earth's hottest summer on record.

Phoenix baked in triple-digit heat for 113 straight daysopens in a new tab or window and hit 117 degrees Fahrenheit (47.2 Celsius) in late September -- uncharacteristic even for a city synonymous with heat. The triple digits have carried into October -- this week, the National Weather Service again warned of excessive heat.

"Putting on a jacket can increase body temperature in a cold room. If it's hot outside, we can take off the jacket," explained Rae Matsumoto, PhD, dean of the Daniel K. Inouye College of Pharmacy at the University of Hawaii in Hilo. But people using the stimulant in the outdoor heat "can't take off the meth jacket."

These fatalities are particularly prevalent in the Southwest, where meth overdoses overall have risen since the mid-2000s.

In Maricopa County, America's hottest major metropolitan area, substances including street drugs, alcohol, and certain prescription medicinesopens in a new tab or window for psychiatric conditions and blood pressure control were involved in about two-thirds, or 419 of the 645 heat-related deathsopens in a new tab or window documented last year. Meth was detected in about three-quarters of these drug cases and was often the primary cause of death, public health data show. Fentanyl was found in just under half of them.

In Pima County, home to Tucson, Arizona's second most populous city, methamphetamine was a factor in one-quarter of the 84 heat-related deaths reported so far this year, the medical examiner's office said.

In metro Las Vegas, heat was a factor in 294 deaths investigated last year by the Clark County coroner's officeopens in a new tab or window, and 39% involved illicit and prescription drugs and alcohol. Of those, meth was detected in three-fourths.

The U.S. Drug Enforcement Administration notes in its 2024 National Drug Threat Assessmentopens in a new tab or window that 31% of all drug-related deaths in the U.S. are now caused by stimulants that speed up the nervous system, primarily meth. More than 17,000 people in the U.S. died from fatal overdoses and poisonings related to stimulants in the first half of 2023, according to preliminary CDC data.

Although overdoses have been more associated with opiates like fentanyl, medical professionals say overdosing on meth is possible if a large amount is ingested. Higher blood pressure and a quickened heart rate can then provoke a heart attack or stroke.

"All of your normal physiological ways of coping with heat are compromised with the use of methamphetamines," said Aneesh Narang, MD, an emergency medicine physician at Banner University Medical Center in downtown Phoenix.

Narang, who sits on a board that reviews overdose fatalities, said the "vast majority" of the heat stroke patients seen in his hospital's emergency department this summer had used street drugs, most commonly methamphetamine.

Because of its proximity to the U.S.-Mexico border, Phoenix is considered a "source city" where large amounts of newly smuggled meth are stored and packaged into relatively tiny doses for distribution, said Det. Matt Shay, a seasoned narcotics investigator with the Maricopa County Sheriff's Office.

"It's an amazing amount that comes in constantly every day," Shay said. "It's also very cheap."

U.S. Customs and Border Protection seized about 164,000 pounds (about 74,000 kilograms) of meth at the U.S.-Mexico border this last fiscal year ending September 30, up from the 140,000 pounds (about 63,500 kilograms) captured in the previous 12 months.

And sellers often target homeless people, Shay said.

"It's a customer base that is easy to find and exploit," Shay said. "If you're an enterprising young drug dealer, all you need is some type of transportation and you just cruise around and they swarm your car."

Jason Elliott, a 51-year-old unemployed machinist, said he's heard of several heat-related deaths involving meth during his 3 years on the streets in Phoenix.

"It's pretty typical," said Elliot, noting that stimulants enable people to stay awake and alert to prevent being robbed in shelters or outdoors. "What else can you do? You have stuff; you go to sleep, you wake up and your stuff is gone."

Nick Staab, MD, MSPH, assistant medical director of the Maricopa County Department of Public Health, said brochures were printed this summer and distributed in cooling centers to spread the word about the risk of using stimulants and certain prescription medicines in extreme heat.

But it's unclear how many are being reached. People who use drugs may not be welcomed at some cooling centers. A better solution, according to Stacey Cope, capacity building and education director for the harm reduction nonprofit Sonoran Prevention Works, is to lower barriers to entry so that people most at risk "are not expected to be absent from drugs, or they're not expected to leave during the hottest part of the day."

https://www.medpagetoday.com/psychiatry/addictions/112319

'One Way to Spot Early Cognitive Decline? Medicare Wellness Visits'

 A Medicare annual wellness visit (AWV) was associated with greater recognition of mild cognitive impairment in older adults, a population-based cohort study in Texas showed.

Compared with those who didn't have an annual visit, AWV recipients had a 21% increase in mild cognitive impairment diagnoses (HR 1.21, 95% CI 1.16-1.27) and a 4% increase in diagnoses of Alzheimer's disease or dementia (HR 1.04, 95% CI 1.02-1.06) after propensity score matching, reported Huey-Ming Tzeng, PhD, of the University of Texas Medical Branch at Galveston, and co-authors in JAMA Network Openopens in a new tab or window.

AWV recipients had a diagnosis of mild cognitive impairment 76 days earlier than those who did not receive AWVs. A sensitivity analysis that treated AWV as a time-dependent variable showed a higher association of AWV with a mild cognitive impairment diagnosis (HR 1.40, 95% CI 1.32-1.49), but a nonsignificant association with dementia diagnoses.

The findings indicate that AWV recipients had timelier first mild cognitive impairment diagnoses, but first dementia diagnoses differed little, Tzeng and colleagues said. "This study suggests that the Medicare AWV health policy may increase mild cognitive impairment identification, prompting more specialized care," they wrote.

"Early recognition of cognitive impairment is key to optimal dementia care," the researchers noted. "Patient access to dementia assessment often limits timely diagnosis of cognitive impairment."

Medicare AWVs, introduced under the Affordable Care Act, offer comprehensive health evaluationsopens in a new tab or window that include a review of a patient's medical history and risk factors, plus a cognitive assessment. This assessment often includes brief tests like the Mini-Cog, Memory Impairment Screen, or General Practitioner Assessment of Cognition to identify mild cognitive impairment or early dementia.

"The debate over cognitive impairment screening, whether to use a broad or targeted approach, is crucial given the complexities of early dementia detection," observed Márlon Juliano Romero Aliberti, MD, PhD, of the University of Sao Paulo in Brazil, and co-authors in an accompanying editorialopens in a new tab or window.

"Most dementia cases go undiagnosed, with symptoms often subtle, unreported, or mistaken for normal aging," they added. "The U.S. Preventive Services Task Forceopens in a new tab or window and the National Institute for Health and Care Excellence both recommend targeted strategies rather than broad screening."

Early identification allows for proactive strategies that may slow the progression of mild cognitive impairment, Aliberti and colleagues emphasized. "Patients who receive a diagnosis early can benefit from personalized care plans addressing modifiable risk factors such as hypertension, diabetes, and lifestyle choices," they noted.

It also "opens the door for crucial conversations about goals of care and advance care planning, allowing patients and families to make informed decisions about future care preferences and end-of- life care," they added.

But widespread early detection can place a strain on healthcare systems, upping the need for specialist referrals, diagnostic testing, and ongoing management, the editorialists pointed out. New Alzheimer's drugs -- lecanemab (Leqembi)opens in a new tab or window and donanemab (Kisunla)opens in a new tab or window -- also have increased pressure on physicians to evaluate cognitive changes so eligible patients can be diagnosed sooner.

Tzeng and colleagues examined records of 549,516 Medicare beneficiaries in Texas with no diagnosis of mild cognitive impairment or dementia from 2015 to 2017. Mean age was about 77 years; 52.8% of beneficiaries were women and 73.6% were white.

A total of 66,433 people (12.1%) had an AWV in 2018. The primary outcome was the first mild cognitive impairment or dementia diagnosis from the 2018 AWV index date through the end of 2022.

Adults who had an AWV were more likely to be women and white than those without an AWV. They had more education, were more likely to live in a metropolitan area, had more comorbidities, and were more likely to have a primary care provider in the 12 months before the AWV date. To control for differences between beneficiaries with and without an AWV, the researchers used propensity score matching with demographic and health information as covariates.

Annual wellness visits have a patient self-selection bias, Tzeng and colleagues acknowledged. The analyses in this study were limited to Medicare billing data, and details about AWVs or referrals to neurologists or psychiatrists were not available.

Disclosures

This work was supported by the National Institute on Aging of the National Institutes of Health.

Tzeng and co-authors had no conflicts of interest.

Aliberti reported relationships with the Alzheimer's Association and the Maria Emília Foundation. No other editorialists had disclosures.

Primary Source

JAMA Network Open

Source Reference: opens in a new tab or windowTzeng H, et al "Annual wellness visits and early dementia diagnosis among Medicare beneficiaries" JAMA Netw Open 2024; DOI: 10.1001/jamanetworkopen.2024.37247.

Secondary Source

JAMA Network Open

Source Reference: opens in a new tab or windowAliberti MJR, et al "Maximizing early dementia detection through Medicare annual wellness visits" JAMA Netw Open 2024; DOI: 10.1001/jamanetworkopen.2024.37162.


https://www.medpagetoday.com/neurology/dementia/112320

Russia Blasts Kamala Harris For 'Outrageous, Boorish' Remarks On Putin

 Russia has blasted the "outrageous" remarks of US Vice President Kamala Harris when talking about President Vladimir Putin during a Howard Stern interview aired live on SiriusXM radio.

In the Tuesday show she called Putin a "murderous dictator". If she's elected the remarks are unlikely to ever be forgotten by the Russian side, making the possibility of improved diplomacy extremely difficult, and perhaps that's the point.

Getty Images

The Russian Embassy in Washington has issued official statement Wednesday: "The recent unacceptable statements made by US Vice-President Kamala Harris towards Russian President Vladimir Putin are outrageous. However, we have to admit that such a boorish language has become a habit among the current so-called American statesmen," it reads.

"It only shows the frustration and impotence of the ruling circles in Washington. Due to their inability to deal with the Russian Federation and inflicting 'a strategic defeat,' their speech apparatus channels anger and offensive rhetoric," the embassy continued.

"The US authorities should come to terms with the fact that Russia is pursuing a policy based on its national interests. Such US escapades insult the entire Russian people, who demonstrate unwavering unity around the leader of our country," the statement underscored.

Harris during the Stern interview was responding to questions raised about journalist Bob Woodward's new book, which bizarrely alleges that during the height of the Covid pandemic then President Trump secretly sent coronavirus tests to Putin as a gesture of good will.

This action, even if true (the Trump campaign has slammed it as a falsehood), hardly rises to the level of a national scandal. But of course, the Democrats are trying to spin the allegations, or what essentially appears meager Trump efforts to improve diplomacy with Moscow, into big headlines.

"He admires strongmen, and he gets played by them because he thinks that they’re his friends," Harris said. "And they are manipulating him full time."

Screengrab of Tuesday's Howard Stern show

"[This is] just the most recent, stark example of who Donald Trump is," Harris continued in response to the Woodward book. "People were dying by the hundreds. Everybody was scrambling to get these kits, the COVID test kits. Couldn’t get them, couldn’t get them anywhere.

But that's when she said in reference to Putin, "And this guy who was president of the United States is sending them to Russia, to a murderous dictator, for his personal use."

https://www.zerohedge.com/geopolitical/russia-blasts-kamala-harris-outrageous-boorish-remarks-putin

Astellas places $2bn+ bet on AviadoBio dementia gene therapy

 Astellas has added another gene therapy to its pipeline, taking an option on a clinical-stage candidate for a rare genetic form of dementia from UK biotech AviadoBio for around $50 million.

The deal is focusing on AVBV-101, AviadoBio's lead gene therapy candidate, which is the phase 1/2 ASPIRE-FTD study in frontotemporal dementia with progranulin mutations (FTD-GRN), currently enrolling subjects in Europe and the US.

Most forms of dementia don't have a genetic component that can be targeted by gene therapy, but those that do tend to be fairly devastating and FTD-GRN is no exception. It progresses at a terrible speed, leading to rapid declines in cognitive ability and typically leading to death within a few years.

It is hard to diagnose, typically causing changes in personality, behaviour, and language that can be confused with other conditions, and is often seen in a younger, sub-65 age bracket than other forms of dementia.

Astellas is making a $20 million equity investment in London-based AviadoBio – which was first set up in 2019 – along with up to $30 million in upfront payments. The total value of the deal could be around $2.2 billion, plus royalties, if the Japanese drugmaker exercises its option and brings AVB-101 to market.

AVB-101 delivers the GRN gene by infusion directly into the thalamus of the brain, boosting the production of the GRN protein human progranulin (hPGRN), a protein that helps control the growth, division, and survival of cells in the body, including neurons and support cells in the brain called microglia.

ASPIRE-FTD trial is said to be the first intrathalamic gene therapy to be tested in humans for any adult neurodegenerative disease.

The UK biotech's chief executive, Lisa Deschamps, said the alliance with Astellas will "accelerate delivering this investigational medicine to families around the world who so desperately need treatment options for FTD-GRN and other neurological diseases."

AviadoBio is developing gene therapy candidates for other diseases, including amyotrophic lateral sclerosis (ALS), also known as motor neuron disease. Like AVB-101, the ALS candidate is designed to deliver PGRN, but has a different route of administration, given via an injection under the spinal cord's subpial membrane, which allows lower doses to be used and is less invasive.

Gene therapy is a key focus for Astellas, although it has run into some problems with some of its early programmes, including a series of Duchenne muscular dystrophy (DMD) therapies that were discontinued in 2022 and a candidate for X-linked myotubular myopathy (XLMTM).

https://pharmaphorum.com/news/astellas-places-2bn-bet-aviadobio-dementia-gene-therapy

FDA knocks back Zealand's dasiglucagon once again

 Zealand Pharma has suffered another setback in its bid to bring glucagon receptor agonist dasiglucagon for ultra-rare disease congenital hyperinsulinism (CHI) to the US market.

For the second time in less than a year, the FDA has issued a complete response letter to the company, citing the need for data on a third-party manufacturing site that had failed an earlier inspection by the agency.

The company said the second CRL was due to the timing of a reinspection of the facility, which was completed a few weeks ago, but not processed in time for the FDA's review deadline for the application. The earlier deficiencies – which did not involve dasiglucagon – were resolved as of the reinspection, it added.

Zealand is trying to secure approval of dasiglucagon for the prevention and treatment of hypoglycaemia in paediatric patients seven days of age and older with CHI for up to three weeks of dosing.

The company is also seeking approval for the drug beyond three weeks in CHI, and the FDA has also sought additional continuous glucose monitoring (CGM) information from Zealand's phase 3 trials that it reckons it will be able to file before the end of the year.

In CHI, the beta cells in the pancreas do not function properly and secrete too much insulin, leading to frequent, recurrent, and often severe episodes of hypoglycaemia. It mainly affects infants and children – putting them at risk of seizures, brain damage, and death – and, according to Zealand, is diagnosed in between 180 and 300 newborns each year in the US and Europe.

Glucagon is a recognised therapy for the disorder, but to date no formulations of the drug have been approved by the FDA.

Older injectable formulations need to be prepared in a multi-step mixing and reconstitution process, but dasiglucagon is given by pen injector and is a fast-acting water-soluble analogue, with trials showing that a single dose can restore normal glucose levels in the blood within 10-15 minutes.

Another drugs that may be used off-label for GHI include Xeris' Gvoke brand of glucagon in pre-filled syringe and pen injector formulations, which was approved in 2019 as a hypoglycaemia rescue therapy for diabetics. Eli Lilly's nasal spray Baqsimi was also approved in 2019 for a similar indication.

"We at Zealand Pharma are acutely aware of the significant unmet medical need for newborns and children with congenital hyperinsulinism who have either no or very limited treatment options today," said David Kendall, the Danish company's chief medical officer.

"We are committed to working with the FDA and our third-party manufacturing partner to bring dasiglucagon to patients living with this devastating disease in the months ahead."

Survodutide advances for MASH

In more positive news for Zealand, its Boehringer Ingelheim-partnered dual glucagon/GLP-1 receptor agonist survodutide has been awarded breakthrough status by the FDA for the treatment of adults with non-cirrhotic metabolic dysfunction-associated steatohepatitis (MASH) and moderate or advanced fibrosis, based on promising phase 2 data.

Boehringer has also started a pair of phase 3 MASH trials of the drug, which is already in late-stage development for obesity. The two studies are LIVERAGE in adults with MASH and moderate or advanced fibrosis, and LIVERAGE-Cirrhosis in those with MASH and cirrhosis.

https://pharmaphorum.com/news/fda-knocks-back-zealands-dasiglucagon-once-again

Disney Resort In Direct Path Of Hurricane Milton, Faces $200 Million Hit

 Walt Disney World Resort is in Hurricane Milton's forecasted path. Analysts from Goldman expect closures and disruptions from the storm could cost the entertainment company between $150 million and $200 million this quarter. 

Milton is expected to make landfall in Central Florida late Wednseday night or early Thursday as a powerful Cat. 4 hurricane. Disney shuttered park operations today, and all parks will remain closed on Thursday. 

"Specifically, we estimate a $150 mn - $200 mn adverse impact to F1Q25E Parks & Experiences EBIT driven by a 4 pp adverse impact to domestic attendance growth in F1Q25E based on historical headwinds from hurricanes due to closure and disruption times. For instance, Hurricane Irma in 2017 was a $100 mn headwind to DIS EBIT and a 3 pp headwind to domestic parks attendance with 2 days of closure at Walt Disney World and some cruise ship itinerary disruptions," the team of Goldman analysts led by Michael Ng and Shelby Spencer wrote in a note to clients on Tuesday.

Ng and Spencer said their F4Q24E estimates (published 9/24/2024) remain unchanged and forecast Disney to deliver F4Q24E EPS of $1.16 (v. Visible Alpha Consensus Data of $1.10) and segment OI of $3.8 bn (in-line with consensus). However, they reduced their F1Q25E Parks and Experience EBIT from the estimated hurricane impact, pushing down the F2025E EPS estimate to $5.14 (v. $5.22 prior and $5.13 consensus), adding, "Our F2026/27 EPS are essentially unchanged on average at $5.96/$7.10." 

They note prior storms, including Hurricanes Ian (F4Q22), Dorian (F4Q19), Irma (F4Q17) and Matthew (F1Q17), forced Disney to shutter resorts for 1-2 days on average. 

The analysts shifted down their F2025 EBIT estimate by 1% due to Milton's likely impacts in the next 12 to 24 hours. They added that estimates in F2024, F2026, and F2027 remain unchanged. 

Despite Milton's current forecast directly impacting Disney's resort, the analysts told clients: "We are Buy rated on shares of Walt Disney Co. Our 12-month price target of $120 (unchanged)..." 

Shares are currently trading at a 26.5% discount versus Goldman's price target.

Furthermore, the analysts noted non-weather-related downside risks for Disney, which include "intensified cord-cutting, sports rights cost inflation, streaming competition, economic slowdown impacting consumer spending, weak theatrical slate, M&A, unfavorable regulatory or policy reforms, higher than expected interest rates and FX." 

Given Milton's strength and trajectory and many meteorologists claiming this storm is one for the history books, the probability that Disney's resort could be shuttered for longer than the projected 1-2 days continues to rise.

https://www.zerohedge.com/markets/disney-parks-direct-path-hurricane-milton-face-200-million-hit

Lilly, Insitro Ink Unique AI Deal, Eye Novel Treatments for Metabolic Diseases

 

In a departure from most deals, startup insitro will in-license Lilly’s delivery technology for its investigational liver-targeted siRNA therapies. The pharma will be eligible for milestones and royalties down the line.

Eli Lilly and AI startup insitro on Wednesday announced they have entered into three strategic agreements to advance new therapies for metabolic diseases, particularly metabolic dysfunction-associated steatotic liver disease.

Unlike other AI-driven drug development deals, the flow of assets under Wednesday’s contracts is reversed. As per the first two agreements, insitro will have the option to in-license a clinical-stage ternary N-acetylgalactosamine (GalNAc) delivery method from Lilly. The biotech intends to use this technology with two of its investigational siRNA therapies, each directed against a liver target.

In the third contract, Lilly and insitro will work collaboratively to discover and develop an antibody therapy for a “novel target” for another metabolic disease. The partners will work together through the preclinical stage and until candidate nomination, after which insitro will take over clinical development and commercialization.

The companies did not specify what disease each agreement will focus on, only revealing that all three contracts are geared toward developing novel treatments for metabolic diseases, particularly metabolic dysfunction-associated steatotic liver disease (MASLD). No upfront payment was disclosed, but across all three agreements, Lilly will be entitled to milestone payments and royalties.

Insitro CEO Daphne Koller said in a statement that the partnership with Lilly will help the biotech “accelerate our therapeutic programs toward the clinic.”

The therapeutic core of Wednesday’s deal is insitro’s proprietary machine learning platform, which according to Koller leverages “multimodal data at scale, computational power, and genetics.”

According to its website, insitro’s platform draws from human genetics to identify “causal intervention points” in diseases and combines that with human and cellular phenotypic data to yield effective potential therapies. Insitro’s overall approach “brings nebulous human biology into focus” and leads to a clearer understanding of diseases, opening up better therapeutic options.

With Wednesday’s Lilly deal, insitro joins the growing number of AI startups that have partnered with big pharma to produce better drugs.

In June 2024, for instance, Lilly signed a partnership with OpenAI, specifically designed to address drug-resistant infections. Terms of the deal were scant, but Lilly said at the time that it plans to use the AI technology to produce novel microbial agents for pathogens that have evolved multiple resistances to existing treatments.

Meanwhile, Flagship Pioneering’s Generate:Biomedicines last month bagged $65 million upfront from pharma powerhouse Novartis—alongside the promise of performance-based milestones and royalties—for an agreement of up to $1 billion in value. The partners have yet to disclose what their priority targets are or their therapeutic area of focus.

https://www.biospace.com/business/lilly-insitro-ink-unique-ai-deal-eye-novel-treatments-for-metabolic-diseases