Experimental Drug Has Potential Against Alzheimer’s Disease

The drug reversed Alzheimer’s in mice through removing garbage from their brain cells. The research seems like a notable milestone against Alzheimer’s disease.

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Researchers at Albert Einstein College of Medicine have designed an experimental drug that reversed key symptoms of Alzheimer’s disease in mice. The drug works by reinvigorating a cellular cleaning mechanism that gets rid of unwanted proteins by digesting and recycling them. The study was published online today in the journal Cell.

“Discoveries in mice don’t always translate to humans, especially in Alzheimer’s disease,” said co-study leader Ana Maria Cuervo, M.D., Ph.D., the Robert and Renée Belfer Chair for the Study of Neurodegenerative Diseases, professor of developmental and molecular biology, and co-director of the Institute for Aging Research at Einstein. “But we were encouraged to find in our study that the drop-off in cellular cleaning that contributes to Alzheimer’s in mice also occurs in people with the disease, suggesting that our drug may also work in humans.” In the 1990s, Dr. Cuervo discovered the existence of this cell-cleaning process, known as chaperone-mediated autophagy (CMA) and has published 200 papers on its role in health and disease.

CMA becomes less efficient as people age, increasing the risk that unwanted proteins will accumulate into insoluble clumps that damage cells. In fact, Alzheimer’s and all other neurodegenerative diseases are characterized by the presence of toxic protein aggregates in patients’ brains. The Cell paper reveals a dynamic interplay between CMA and Alzheimer’s disease, with loss of CMA in neurons contributing to Alzheimer’s and vice versa. The findings suggest that drugs for revving up CMA may offer hope for treating neurodegenerative diseases.

Establishing CMA’s Link to Alzheimer’s

Dr. Cuervo’s team first looked at whether impaired CMA contributes to Alzheimer’s. To do so, they genetically engineered a mouse to have excitatory brain neurons that lacked CMA. The absence of CMA in one type of brain cell was enough to cause short-term memory loss, impaired walking, and other problems often found in rodent models of Alzheimer’s disease. In addition, the absence of CMA profoundly disrupted proteostasis — the cells’ ability to regulate the proteins they contain. Normally soluble proteins had shifted to being insoluble and at risk for clumping into toxic aggregates.

Dr. Cuervo suspected the converse was also true: that early Alzheimer’s impairs CMA. So she and her colleagues studied a mouse model of early Alzheimer’s in which brain neurons were made to produce defective copies of the protein tau. Evidence indicates that abnormal copies of tau clump together to form neurofibrillary tangles that contribute to Alzheimer’s. The research team focused on CMA activity within neurons of the hippocampus — the brain region crucial for memory and learning. They found that CMA activity in those neurons was significantly reduced compared to control animals.

What about early Alzheimer’s in people — does it block CMA too? To find out, the researchers looked at single-cell RNA-sequencing data from neurons obtained postmortem from the brains of Alzheimer’s patients and from a comparison group of healthy individuals. The sequencing data revealed CMA’s activity level in patients’ brain tissue. Sure enough, CMA activity was somewhat inhibited in people who had been in the early stages of Alzheimer’s, followed by much greater CMA inhibition in the brains of people with advanced Alzheimer’s.

“By the time people reach the age of 70 or 80, CMA activity has usually decreased by about 30% compared to when they were younger,” said Dr. Cuervo. “Most peoples’ brains can compensate for this decline. But if you add neurodegenerative disease to the mix, the effect on the normal protein makeup of brain neurons can be devastating. Our study shows that CMA deficiency interacts synergistically with Alzheimer’s pathology to greatly accelerate disease progression.”

A New Drug Cleans Neurons and Reverses Symptoms

In an encouraging finding, Dr. Cuervo and her team developed a novel drug that shows potential for treating Alzheimer’s. “We know that CMA is capable of digesting defective tau and other proteins,” said Dr. Cuervo. “But the sheer amount of defective protein in Alzheimer’s and other neurodegenerative diseases overwhelms CMA and essentially cripples it. Our drug revitalizes CMA efficiency by boosting levels of a key CMA component.”

In CMA, proteins called chaperones bind to damaged or defective proteins in cells of the body. The chaperones ferry their cargo to the cells’ lysosomes — membrane-bound organelles filled with enzymes, which digest and recycle waste material. To successfully get their cargo into lysosomes, however, chaperones must first “dock” the material onto a protein receptor called LAMP2A that sprouts from the membranes of lysosomes. The more LAMP2A receptors on lysosomes, the greater the level of CMA activity possible. The new drug, called CA, works by increasing the number of those LAMP2A receptors.

“You produce the same amount of LAMP2A receptors throughout life,” said Dr. Cuervo. “But those receptors deteriorate more quickly as you age, so older people tend to have less of them available for delivering unwanted proteins into lysosomes. CA restores LAMP2A to youthful levels, enabling CMA to get rid of tau and other defective proteins so they can’t form those toxic protein clumps.” (Also this month, Dr. Cuervo’s team reported in Nature Communications that, for the first time, they had isolated lysosomes from the brains of Alzheimer’s disease patients and observed that reduction in the number of LAMP2 receptors causes loss of CMA in humans, just as it does in animal models of Alzheimer’s.)

The researchers tested CA in two different mouse models of Alzheimer’s disease. In both disease mouse models, oral doses of CA administered over 4 to 6 months led to improvements in memory, depression, and anxiety that made the treated animals resemble or closely resemble healthy, control mice. Walking ability significantly improved in the animal model in which it was a problem. And in brain neurons of both animal models, the drug significantly reduced levels of tau protein and protein clumps compared with untreated animals.

“Importantly, animals in both models were already showing symptoms of disease, and their neurons were clogged with toxic proteins before the drugs were administered,” said Dr. Cuervo. “This means that the drug may help preserve neuron function even in the later stages of disease. We were also very excited that the drug significantly reduced gliosis — the inflammation and scarring of cells surrounding brain neurons. Gliosis is associated with toxic proteins and is known to play a major role in perpetuating and worsening neurodegenerative diseases.”

Treatment with CA did not appear to harm other organs even when given daily for extended periods of time. The drug was designed by Evripidis Gavathiotis, Ph.D.,, professor of biochemistry and of medicine and a co-leader of the study.

Drs. Cuervo and Gavathiotis have teamed up with Life Biosciences of Boston, Mass., to found Selphagy Therapeutics, which is currently developing CA and related compounds for treating Alzheimer’s and other neurodegenerative diseases.

The study is titled, “Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome.” The study’s other co-leader and first author is Mathieu Bourdenx, Ph.D., a postdoctoral fellow in Dr. Cuervo’s lab and also a junior researcher at the Institute of Neurodegenerative Diseases, University of Bordeaux, France. Additional Einstein authors include: Adrián Martín-Segura, Aurora Scrivo, Susmita Kaushik, Ph.D., Inmaculada Tasset, Ph.D., Antonio Diaz and Yves R. Juste.

Study Shows Electrolytes Effective at Preventing Muscle Cramping

The study found that electrolyte-infused water is more effective than plain water.

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If you reach for water when a muscle cramp strikes, you might want to think again. New research from Edith Cowan University (ECU) has revealed drinking electrolytes instead of pure water can help prevent muscle cramps.

The study, published in the Journal of the International Society of Sports Nutrition, found that people who drank electrolyte enhanced water during and after exercise were less susceptible to muscle cramps than those who drank pure water.

Muscle cramps are a common painful condition affecting many people, including around 39 per cent of marathon runners, 52 per cent of rugby players and 60 per cent of cyclists.

Dilution solution

Lead researcher Professor Ken Nosaka, from ECU’s School of Medical and Health Sciences, said the study builds on the evidence that a lack of electrolytes contributes to muscle cramps, not dehydration.

“Many people think dehydration causes muscle cramps and will drink pure water while exercising to prevent cramping,” he said.

“We found that people who solely drink plain water before and after exercise could in fact be making them more prone to cramps.

“This is likely because pure water dilutes the electrolyte concentration in our bodies and doesn’t replace what is lost during sweating.”

When cramp strikes

Professor Nosaka began researching the causes of muscle cramps after regularly suffering from them while playing tennis.

The study involved 10 men who ran on a downhill treadmill in a hot (35ºC) room for 40 to 60 minutes to lose 1.5 to 2 per cent of their body weight through sweat in two conditions.

They drank plain water during and after exercise for one condition and took a water solution containing electrolytes in the other condition.

The participants were given an electrical stimulation on their calves to induce muscle cramp. The lower the frequency of the electrical stimulation required, the more the participant is prone to muscle cramp.

“We found that the electrical frequency required to induce cramp increased when people drank the electrolyte water, but decreased when they consumed plain water,” said Professor Nosaka.

“This indicates that muscles become more prone to cramp by drinking plain water, but more immune to muscle cramp by drinking the electrolyte water.”

Not all water is equal

Electrolytes are minerals including sodium, potassium, magnesium and chloride. They are essential for muscle health and help the body to absorb water.

Oral rehydration solutions contain electrolytes in specific proportions and can be made with water, salt and sugar. They are commonly found in supermarkets and pharmacies.

Professor Nosaka said electrolytes have many benefits for both athletes and the general population.

“Electrolytes are vital to good health — they help the body to absorb water more effectively than plain water and replace essential minerals lost through sweat or illness,” he said.

“People should consider drinking oral rehydration fluids instead of plain water during moderate to intense exercise, when it’s very hot or when you are sick from diarrhoea or vomiting.”

Professor Nosaka is planning further research to find out the optimal amount of electrolytes to prevent muscle cramps as well as how they could help the elderly and pregnant women.

Study of 670,450 American Women Shows Almost Half of Them Are Receiving the Wrong UTI Treatment

Many American healthcare professionals are still prescribing incorrect antibiotics treatments for too long of a duration.

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Across the United States, in both rural and urban settings, most women with private health insurance are receiving inappropriate treatment for their urinary tract infections (UTIs), according to a new study. 

Of the 670,450 women included in this research, all of whom had been diagnosed with uncomplicated UTIs between the ages of 18 and 44, nearly half received the wrong antibiotics and over three quarters were prescribed the medicine for too long. (A UTI is declared ‘uncomplicated’ when the patient has no abnormality or disease that could predispose them to more frequent infections.)

The results are largely consistent from location to location, although patients in more rural settings were more likely to be prescribed antibiotics for longer. 

Over the course of the study, from 2011 to 2015, there was only a slight improvement in proper antibiotic prescriptions based on current clinical guidelines.

“Inappropriate antibiotic prescriptions for uncomplicated urinary tract infections are prevalent and come with serious patient- and society-level consequences,” says epidemiologist Anne Mobley Butler from the Washington University School of Medicine, St. Louis.

“Our study findings underscore the need for antimicrobial stewardship interventions to improve outpatient antibiotic prescribing, particularly in rural settings.” 

The research was funded in part by several pharmaceutical companies, including Sanofi Pasteur, Pfizer, and Merck. The results were peer-reviewed and fall largely in line with the findings of previous studies, which suggest up to 60 percent of antibiotics prescribed in intensive care units are “unnecessary, inappropriate, or suboptimal”.

Nor is this just a problem in the US. Around the world, UTIs are one of the most common infections leading to emergency room visits. In the United Kingdom, it’s the second most common reason for prescribing antibiotics. 

Not only does taking the wrong antibiotic have worse outcomes for the individual patient, longer prescriptions are not necessarily better and can cause bacteria to grow resistant, making recurrence more likely and future infections harder to treat. 

Today, it’s estimated one in three uncomplicated UTIs in women are resistant to the popular combined antibiotic drug Bactrim (sulfamethoxazole and trimethoprim), and one in five are resistant to five other common antibiotics. 

An estimate of the number of deaths related to antibiotic-resistant UTIs is hard to establish due to a lack of research and monitoring, but some studies suggest that in US hospitals alone it could be around 13,000 lives lost per year. And some people suffer recurrent, resistant infections for years on end with little to no relief.

In light of these emerging concerns, in 2010 the Infectious Diseases Society of America (IDSA) and the European Society for Microbiology and Infectious Diseases updated their clinical practice guidelines. Based on results from various studies, they now recommend several first-line antibiotic agents and durations to best treat UTIs while minimizing the risk of antibiotic resistance.

That advice, however, is clearly not getting through to physicians and healthcare professionals. Many are still prescribing non-recommended antibiotics for improper durations.

Figuring out where the most inappropriate prescriptions are happening could help us target areas where we need to improve adherence to antibiotic guidelines. In the US, rural areas experience numerous health disparities compared to more urban areas, and yet this is the first large-scale study to evaluate how that impacts UTI treatment.

The authors are not sure why longer antibiotic treatments for UTIs are especially prevalent in rural areas, but suggest it could have to do with access to care and physician awareness. In rural areas, women may be given longer prescriptions to avoid future travel if that treatment fails.

Studies also show late-career physicians are more prevalent in rural locations and are more likely to prescribe antibiotics for longer, possibly because they have not heard of updated guidelines. 

“Accumulating evidence suggests that patients have better outcomes when we change prescribing from broad-acting to narrow-spectrum antibiotics and from longer to shorter durations,” explains Butler.

“Promoting optimal antimicrobial use benefits the patient and society by preventing avoidable adverse events, microbiome disruption, and antibiotic-resistant infections.”

When up to 60 percent of women can suffer from a UTI at some point in their life, it’s clearly vital that guidelines for treatment are better enforced, especially as antibiotic resistance increases.

This particular study was only based on commercially insured individuals, which means those who are uninsured or who receive public insurance were not considered. Rural areas were also loosely defined, including small towns as well as ‘exurbs’ on the edges of urban areas, and men, who also suffer from UTIs (albeit at a lower rate), were not included. 

Future research should focus on filling these gaps, but in the meantime, the trend reinforces the idea that clinicians need to periodically review clinical practice guidelines, even for common conditions that they have been treating for years.

“In recent years, little effective progress has been achieved to reduce inappropriate antibiotic prescribing for uncomplicated UTI,” the new paper concludes

“Given the large quantity of inappropriate prescriptions annually in the United States, as well as the negative patient- and society-level consequences of unnecessary exposure to antibiotics, antimicrobial stewardship interventions are needed to improve outpatient UTI antibiotic prescribing, particularly in rural settings.”

The study was published in Infection Control & Hospital Epidemiology.

Don’t Take Ibuprofen or Acetaminophen Before Receiving a COVID-19 Vaccine

Regardless of what one thinks about the COVID-19 vaccines and the current amount of data on them, everyone reading this will probably know someone that will receive a COVID-19 vaccine. The current evidence suggests that taking drugs such as ibuprofen or acetaminophen is one of the worst things people can do before receiving one of the COVID-19 vaccines. The human body needs a proper immune response to develop immunity to the virus and the drugs will plausibly interfere with that immune response, very possibly leading to a reduced level of immunity. That reduced level of immunity may lead to a susceptibility to COVID-19 later on.

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Taking OTC pain medications ahead of your shot to try and decrease symptoms is not recommended by the CDC, because it’s not clear how that could affect the vaccine’s effectiveness.

The concern is that pre-treating with pain medications that reduce fevers and inflammation (like acetaminophen and ibuprofen) could dampen your immune system’s response to the vaccine.

That’s because your immune system responds to vaccines through a process called “controlled inflammation,” Dr. Colleen Kelley, an associate professor of medicine at Emory University School of Medicine, told USA Today in January.

Covid messenger RNA vaccines work by giving cells genetic material that tells them how to make a non-infectious piece of the virus. The immune system then creates antibodies against it — which is controlled inflammation — and can remember how to trigger an immune response if exposed to the virus in the future.

But OTC pain-relieving medications “reduce the production of inflammatory mediators,” Kelley said. That’s why it’s important to wait until after you’ve gotten the vaccine (and have started creating an inflammatory response already) to take pain medication.

Research on children has shown that those who take acetaminophen before getting vaccines have a lower immune response than those who didn’t. And a recent study out of Yale found that giving mice nonsteroidal anti-inflammatory drugs (aka “NSAIDS”) before being exposed to SARS-CoV-2 led to fewer protective antibodies from the virus.

The exception is for people who normally take these types of OTC pain medications as part of their routine to manage another medical condition. Those individuals should […] check with their doctor for additional guidance.

New “Obesity Fighting” Drug That Claims to Cut Body Weight by Up to 20 Percent

People have been looking for weight loss in a pill for ages. The issue is whether this drug will have any major side effects on certain people, and if it does, whether those side effects are worth the benefits of weight loss. The natural way to lose weight is to simply burn more calories than you consume, thus entering what’s known as a caloric deficit. The importance of “calories in, calories out,” is not emphasized enough in our systems of education, and it is a massive detriment to the population that that’s the case. In the trial, one of the people began gaining weight after the administration of the drug stopped, and that shows how losing weight remains an issue to address outside of medically-supervised drug usage. Additionally, I have to question how much of the weight loss was from the drug when the participants of the trial were also supposedly eating less and doing more exercise.

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The drug – semaglutide – hijacks the body’s appetite regulating system in the brain, leading to reduced hunger and calorie intake.

Rachel Batterham, professor of obesity, diabetes and endocrinology who leads the Centre for Obesity Research at UCL and the UCLH Centre for Weight Management, said: “The findings of this study represent a major breakthrough for improving the health of people with obesity.

“Three quarters (75%) of people who received semaglutide 2.4mg lost more than 10% of their body weight and more than one-third lost more than 20%.

The professor, who is one of the principal authors on the paper, added: “No other drug has come close to producing this level of weight loss – this really is a game-changer.

“For the first time, people can achieve through drugs what was only possible through weight-loss surgery.”

The drug will soon be submitted for regulatory approval as a treatment for obesity to the National Institute of Clinical Excellence (NICE), the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA).

As well as the drug, participants received individual face-to-face or phone counselling sessions from registered dietitians every four weeks to help them adhere to the reduced-calorie diet and increased physical activity.

They also received incentives such as kettle bells or food scales to mark progress and milestones.

A placebo group observed an average weight loss of 2.6kg (0.4 stone) with a reduction in BMI of minus 0.92.

Semaglutide is clinically approved to be used for patients with type 2 diabetes, but they are prescribed a lower dose.

A New Tool In Improving Mental Health — Building Design

Buildings can be designed in ways that allow for more of the interior to be exposed to sunlight and nature. In the time of the pandemic, more sunlight in rooms can act as a natural disinfectant, and one study found that people had better mental health after taking walks through nature.

For decades, psychiatric hospitals were grim settings where patients were crowded into common rooms by day and dorms at night. But new research into the health effects of our surroundings is spurring the development of facilities that feel more residential, with welcoming entrances, smaller living units within larger buildings and a variety of gathering spaces. Nature plays a big role: Windows provide views of greenery, landscapes decorate walls, and outdoor areas give patients and staff access to fresh air and sunlight.

The new approach, promoted as healing and therapeutic, has produced environments that are more calming and supportive. And it feels particularly timely, given the surge in mental health issues created by the pandemic.

“We’ve been talking about this for a really long time,” said Mardelle McCuskey Shepley, chair of the department of design and environmental analysis in Cornell University’s College of Human Ecology in New York. “It’s only now that it’s gaining momentum.”

Even before the pandemic, the number of Americans affected by mental illness was at a new high. One in five adults was experiencing depression, bipolar disorder, schizophrenia, post-traumatic stress or some other malady, according to the National Institute of Mental Health. The rates were significantly higher for adolescents (about 50%) and young adults (about 30%).

Nearly a year into the pandemic, more people are suffering. Young adults and Black and Latino people of all ages are reporting increased levels of anxiety, depression and substance abuse, according to a survey from the Centers for Disease Control and Prevention. A recent Gallup poll showed that Americans felt their mental health was “worse than it has been at any point in the last two decades.”

Demand for treatment has soared, and the construction of mental health facilities has been outpacing that of other specialty hospitals. Last year, 40% of the specialty hospitals under construction were psychiatric hospitals and behavioural health centres, according to the American Society for Health Care Engineering.

Architecture and interior design firms with expertise in health care buildings have reported an increase in activity. At design firm Architecture+ in Troy, New York, one or two major mental health facilities are typically in the pipeline, with total construction costs for those projects at about $250 million a year, said Francis Murdock Pitts, a principal and founding partner. Last year, the firm was working on 16 large mental health projects totalling about $1.9 billion.

His firm and others like it have medical planners on staff who help translate research into “evidence-based” designs. “This isn’t just about being warm and fuzzy,” Pitts said.

For instance, exposure to nature has been shown to lower cortisol levels, a measure of stress. Adding healing gardens and other greenery can help soothe agitated patients and give staff a place to decompress.

Research specific to mental health care settings is also coming into play. Studies have shown that reducing crowding by providing private rooms and multiple communal spaces may lessen patient and employee stress and aggression. Lowering noise — eliminating unnecessary beeping of medical equipment, for example — can also help. If patients are less stressed, they may make faster and more lasting progress during treatment, experts say.

But because mental health issues vary widely, there is no one-size-fits-all design solution. And safety — for both patients and staff — remains paramount.

Codes and guidelines fine-tuned over many years have sought to eliminate room features that patients have used to harm themselves and others. Window glazing is made of polycarbonate compounds to reduce breaking. Doors are hung on quick-release hinges to allow staff to enter a room if a patient is barricaded in. Plumbing and other fixtures have been designed to prevent the possibility of hanging or strangulation.

Such safety measures are crucial, but “you don’t want it to get to the point where it looks prisonlike,” said Shary Adams, a principal at HGA, a national design firm. At the same time that the built environment must be engineered to ensure safety, there is also a move to give patients some control over their surroundings. Manual thermostats allow patients to adjust the temperature in their rooms, for example, and dimmer switches let them modulate the lights.

The location of mental health facilities is changing, too. Psychiatric institutions used to be tucked away, but today they are likely to be part of hospital campuses or otherwise conveniently situated. They often combine inpatient rooms for those who need round-the-clock monitoring and areas for outpatient services, allowing patients to shift to less intensive care in the same building.

Lifelong Exercise Shown to Slow Aging

The benefits of exercise are underrated much too often.

Researchers at the University of Birmingham and King’s College London have found that staying active keeps the body young and healthy.

The researchers set out to assess the health of older adults who had exercised most of their adult lives to see if this could slow down ageing.

The study recruited 125 amateur cyclists aged 55 to 79, 84 of which were male and 41 were female. The men had to be able to cycle 100 km in under 6.5 hours, while the women had to be able to cycle 60 km in 5.5 hours. Smokers, heavy drinkers and those with high blood pressure or other health conditions were excluded from the study.

The participants underwent a series of tests in the laboratory and were compared to a group of adults who do not partake in regular physical activity. This group consisted of 75 healthy people aged 57 to 80 and 55 healthy young adults aged 20 to 36.

The study showed that loss of muscle mass and strength did not occur in those who exercise regularly. The cyclists also did not increase their body fat or cholesterol levels with age and the men’s testosterone levels also remained high, suggesting that they may have avoided most of the male menopause.

More surprisingly, the study also revealed that the benefits of exercise extend beyond muscle as the cyclists also had an immune system that did not seem to have aged either.

An organ called the thymus, which makes immune cells called T cells, starts to shrink from the age of 20 and makes less T cells. In this study, however, the cyclists’ thymuses were making as many T cells as those of a young person.

The findings come as figures show that less than half of over 65s do enough exercise to stay healthy and more than half of those aged over 65 suffer from at least two diseases.* Professor Janet Lord, Director of the Institute of Inflammation and Ageing at the University of Birmingham, said: “Hippocrates in 400 BC said that exercise is man’s best medicine, but his message has been lost over time and we are an increasingly sedentary society.

“However, importantly, our findings debunk the assumption that ageing automatically makes us more frail.

“Our research means we now have strong evidence that encouraging people to commit to regular exercise throughout their lives is a viable solution to the problem that we are living longer but not healthier.”

Dr Niharika Arora Duggal, also of the University of Birmingham, said: “We hope these findings prevent the danger that, as a society, we accept that old age and disease are normal bedfellows and that the third age of man is something to be endured and not enjoyed.”

Professor Stephen Harridge, Director of the Centre of Human & Aerospace Physiological Sciences at King’s College London, said: “The findings emphasise the fact that the cyclists do not exercise because they are healthy, but that they are healthy because they have been exercising for such a large proportion of their lives.

“Their bodies have been allowed to age optimally, free from the problems usually caused by inactivity. Remove the activity and their health would likely deteriorate.”

Norman Lazarus, Emeritus Professor at King’s College London and also a master cyclist and Dr Ross Pollock, who undertook the muscle study, both agreed that: “Most of us who exercise have nowhere near the physiological capacities of elite athletes.

“We exercise mainly to enjoy ourselves. Nearly everybody can partake in an exercise that is in keeping with their own physiological capabilities.

“Find an exercise that you enjoy in whatever environment that suits you and make a habit of physical activity. You will reap the rewards in later life by enjoying an independent and productive old age.”

Important COVID-19 Antibody Drugs Aren’t Being Used Enough

“Antibody drugs from Regeneron and Eli Lilly could reduce hospitalizations from Covid-19 by 50-70%,” as the article says.

When President Donald Trump got sick with Covid-19 in October, he credited an antibody drug from Regeneron with making him feel better “immediately.”

“I felt as good three days ago as I do now,” he said in a video shot in front of the White House after he left Walter Reed National Military Medical Center, promising medicines from Regeneron and Eli Lilly would soon be available to the American public to help stop the terrible effects of Covid-19.

The concern, as these drugs were cleared through the FDA and made it to market last month, was that there wouldn’t be enough supply. They’re complicated to manufacture, and Regeneron said there were only enough doses for 80,000 Americans by the end of November. Lilly has 250,000 doses available.

An average of more than 200,000 Americans are currently getting diagnosed with Covid-19 every day, according to data compiled by Johns Hopkins University. Policymakers expected to need to ration the antibody drugs.

But a month into their distribution, the opposite problem has emerged: the drugs are not getting used.

“We have a surplus of these monoclonal antibodies right now,” Health Secretary Alex Azar told CNBC’s Shepard Smith Tuesday night. “What’s happening is people are waiting too long to seek out the treatments.”

Moncef Slaoui, chief scientific adviser to the U.S. government’s Operation Warp Speed, told CNBC Tuesday that the federal government is distributing about 65,000 doses of the antibody drugs every week to states.

But, he said, only 5% to 20% of the doses are getting administered to patients.

“It should be used much more,” Slaoui said in a telephone interview, noting the drugs — which are indicated for patients at high risk for severe Covid-19 — could cut down on hospitalizations by 50% to 70%.

The drugs are not simple to administer. For one thing, they’re given by intravenous infusion, so patients must go to health centers where this can be done. But since they’re likely contagious, existing IV facilities, like where patients receive chemotherapy, can’t be used.

Another issue is that the drugs need to be given early in the course of the disease. The FDA’s guidance for health-care providers says they should be administered as soon as possible after diagnosis, and within 10 days of symptom onset. It recommends against use of the drugs once patients are so sick they’re hospitalized.

But many patients don’t feel sick right away, so the idea of an IV-infused drug doesn’t occur to them immediately after diagnosis, Slaoui and Azar suggested.

“If you are over 65 or at risk of serious complications or hospitalization due to co-morbidities, what have you, and you test positive, you need to seek out and get the Lilly or Regeneron monoclonal antibody,” Azar said on the “News With Shepard Smith.” “It can dramatically reduce the risk for us of hospitalizations at a time when hospitals are getting very crowded with people with Covid.”

But it’s a challenge for some health systems to set up the infrastructure to deliver these drugs. Some states are using 100% of their allocation, Slaoui said. Others, like in Georgia and Illinois, may not be using any, according to former FDA Commissioner Dr. Scott Gottlieb.

Georgia’s public health department didn’t immediately respond to questions about their antibody usage. A spokeswoman for Illinois’ Department of Public Health said providers aren’t yet required to report use of monoclonal antibodies, but that the U.S. Department of Health and Human Services will require hospitals to report the information starting Jan. 8.

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He noted the data behind the medicines suggest “the number needed to treat in terms of keeping one patient out of the hospital … is 10.” Lilly has said it will have 950,000 doses available by the end of January, Gottlieb cited the effects if 900,000 doses were used: “That means if all of the drugs got distributed, we could avoid 90,000 hospitalizations or emergency room visits. That would be substantial.”

Lilly noted the IV administration of the antibody drugs “presents unique challenges to the healthcare system,” and said it’s working to address the challenges to ensure patients who need the drug can get it. The company is running a number of pilot programs through Operation Warp Speed, including one with CVS for in-home infusions, a company spokeswoman said.

Experimental Drug Quickly Reduces Age-Related Mental Decline

The compound, known as ISRIB, holds potential for reversing numerous cognitive problems in humans. Mice are used in scientific studies due to having genes that are approximately 85 percent similar to the genes of humans.

Just a few doses of an experimental drug can reverse age-related declines in memory and mental flexibility in mice, according to a new study by UC San Francisco scientists. The drug, called ISRIB, has already been shown in laboratory studies to restore memory function months after traumatic brain injury (TBI), reverse cognitive impairments in Down Syndrome, prevent noise-related hearing loss, fight certain types of prostate cancer, and even enhance cognition in healthy animals.

In the new study, published December 1, 2020 in the open-access journal eLife, researchers showed rapid restoration of youthful cognitive abilities in aged mice, accompanied by a rejuvenation of brain and immune cells that could help explain improvements in brain function.

“ISRIB’s extremely rapid effects show for the first time that a significant component of age-related cognitive losses may be caused by a kind of reversible physiological ‘blockage’ rather than more permanent degradation,” said Susanna Rosi, PhD, Lewis and Ruth Cozen Chair II and professor in the departments of Neurological Surgery and of Physical Therapy and Rehabilitation Science.

“The data suggest that the aged brain has not permanently lost essential cognitive capacities, as was commonly assumed, but rather that these cognitive resources are still there but have been somehow blocked, trapped by a vicious cycle of cellular stress,” added Peter Walter, PhD, a professor in the UCSF Department of Biochemistry and Biophysics and a Howard Hughes Medical Institute investigator. “Our work with ISRIB demonstrates a way to break that cycle and restore cognitive abilities that had become walled off over time.”

Could Rebooting Cellular Protein Production Hold the Key to Aging and Other Diseases?

Walter has won numerous scientific awards, including the Breakthrough, Lasker and Shaw prizes, for his decades-long studies of cellular stress responses. ISRIB, discovered in 2013 in Walter’s lab, works by rebooting cells’ protein production machinery after it gets throttled by one of these stress responses — a cellular quality control mechanism called the integrated stress response (ISR; ISRIB stands for ISR InhiBitor).

The ISR normally detects problems with protein production in a cell — a potential sign of viral infection or cancer-promoting gene mutations — and responds by putting the brakes on cell’s protein-synthesis machinery. This safety mechanism is critical for weeding out misbehaving cells, but if stuck in the on position in a tissue like the brain, it can lead to serious problems, as cells lose the ability to perform their normal activities, Walter and colleagues have found.

In particular, recent animal studies by Walter and Rosi, made possible by early philanthropic support from The Rogers Family Foundation, have implicated chronic ISR activation in the persistent cognitive and behavioral deficits seen in patients after TBI, by showing that, in mice, brief ISRIB treatment can reboot the ISR and restore normal brain function almost overnight.

The cognitive deficits in TBI patients are often likened to premature aging, which led Rosi and Walter to wonder if the ISR could also underlie purely age-related cognitive decline. Aging is well known to compromise cellular protein production across the body, as life’s many insults pile up and stressors like chronic inflammation wear away at cells, potentially leading to widespread activation of the ISR.

“We’ve seen how ISRIB restores cognition in animals with traumatic brain injury, which in many ways is like a sped-up version of age-related cognitive decline,” said Rosi, who is director of neurocognitive research in the UCSF Brain and Spinal Injury Center and a member of the UCSF Weill Institute for Neurosciences. “It may seem like a crazy idea, but asking whether the drug could reverse symptoms of aging itself was just a logical next step.”

ISRIB Improves Cognition, Boosts Neuron and Immune Cell Function

In the new study, researchers led by Rosi lab postdoc Karen Krukowski, PhD, trained aged animals to escape from a watery maze by finding a hidden platform, a task that is typically hard for older animals to learn. But animals who received small daily doses of ISRIB during the three-day training process were able to accomplish the task as well as youthful mice, much better than animals of the same age who didn’t receive the drug.

The researchers then tested how long this cognitive rejuvenation lasted and whether it could generalize to other cognitive skills. Several weeks after the initial ISRIB treatment, they trained the same mice to find their way out of a maze whose exit changed daily — a test of mental flexibility for aged mice who, like humans, tend to get increasingly stuck in their ways. The mice who had received brief ISRIB treatment three weeks before still performed at youthful levels, while untreated mice continued to struggle.

To understand how ISRIB might be improving brain function, the researchers studied the activity and anatomy of cells in the hippocampus, a brain region with a key role in learning and memory, just one day after giving animals a single dose of ISRIB. They found that common signatures of neuronal aging disappeared literally overnight: neurons’ electrical activity became more sprightly and responsive to stimulation, and cells showed more robust connectivity with cells around them while also showing an ability to form stable connections with one another usually only seen in younger mice.

The researchers are continuing to study exactly how the ISR disrupts cognition in aging and other conditions and to understand how long ISRIB’s cognitive benefits may last. Among other puzzles raised by the new findings is the discovery that ISRIB also alters the function of the immune system’s T cells, which also are prone to age-related dysfunction. The findings suggest another path by which the drug could be improving cognition in aged animals, and could have implications for diseases from Alzheimer’s to diabetes that have been linked to heightened inflammation caused by an aging immune system.

“This was very exciting to me because we know that aging has a profound and persistent effect on T cells and that these changes can affect brain function in the hippocampus,” said Rosi. “At the moment, this is just an interesting observation, but it gives us a very exciting set of biological puzzles to solve.

ISRIB May Have Wide-Ranging Implications for Neurological Disease

It turns out that chronic ISR activation and resulting blockage of cellular protein production may play a role in a surprisingly wide array of neurological conditions. Below is a partial list of these conditions, based on a recent review by Walter and colleague Mauro Costa-Mattioli of Baylor College of Medicine, which could potentially be treated with an ISR-resetting agent like ISRIB:

  • Frontotemporal Dementia
  • Alzheimer’s Disease
  • Amyotrophic Lateral Sclerosis (ALS)
  • Age-related Cognitive Decline
  • Multiple Sclerosis
  • Traumatic Brain Injury
  • Parkinson’s Disease
  • Down Syndrome
  • Vanishing White Matter Disorder
  • Prion Disease

ISRIB has been licensed by Calico, a South San Francisco, Calif. company exploring the biology of aging, and the idea of targeting the ISR to treat disease has been picked up by other pharmaceutical companies, Walter says.

One might think that interfering with the ISR, a critical cellular safety mechanism, would be sure to have serious side effects, but so far in all their studies, the researchers have observed none. This is likely due to two factors, Walter says. First, it takes just a few doses of ISRIB to reset unhealthy, chronic ISR activation back to a healthier state, after which it can still respond normally to problems in individual cells. Second, ISRIB has virtually no effect when applied to cells actively employing the ISR in its most powerful form — against an aggressive viral infection, for example.

Naturally, both of these factors make the molecule much less likely to have negative side effects — and more attractive as a potential therapeutic. According to Walter: “It almost seems too good to be true, but with ISRIB we seem to have hit a sweet spot for manipulating the ISR with an ideal therapeutic window.

Researchers Claim Oral Drug Blocks COVID-19 Transmission Within 24 Hours

This drug (MK-4482) is notable because it has the distinction of “MK,” as in, it was developed in part by the Merck pharmaceutical company. I’m one to often disparage the pharmaceutical companies but Merck has done notable things in its past drug research. The Merck development of MK-677 — an experimental growth hormone secretagogue that has been shown to increase hunger, increase bone density in the frail, and improve healing in humans — has shown significant potential in medicine. A former Head of the US Biomedical Advanced Research and Development Authority has said that drugs similar to MK-4482 cause birth defects, but the study authors claim that toxicity studies on MK-4482 have already been done, with the results already approved by regulators as a sign to continue with research into the drug in people.


Treatment of SARS-CoV-2 infection with a new antiviral drug, MK-4482/EIDD-2801 or Molnupiravir, completely suppresses virus transmission within 24 hours, researchers in the Institute for Biomedical Sciences at Georgia State University have discovered.

The group led by Dr. Richard Plemper, Distinguished University Professor at Georgia State, originally discovered that the drug is potent against influenza viruses.

“This is the first demonstration of an orally available drug to rapidly block SARS-CoV-2 transmission,” said Plemper. “MK-4482/EIDD-2801 could be game-changing.”

Interrupting widespread community transmission of SARS-CoV-2 until mass vaccination is available is paramount to managing COVID-19 and mitigating the catastrophic consequences of the pandemic.

Because the drug can be taken by mouth, treatment can be started early for a potentially three-fold benefit: inhibit patients’ progress to severe disease, shorten the infectious phase to ease the emotional and socioeconomic toll of prolonged patient isolation and rapidly silence local outbreaks.

“We noted early on that MK-4482/EIDD-2801 has broad-spectrum activity against respiratory RNA viruses and that treating infected animals by mouth with the drug lowers the amount of shed viral particles by several orders of magnitude, dramatically reducing transmission,” said Plemper. “These properties made MK-4482/EIDD/2801 a powerful candidate for pharmacologic control of COVID-19.”

In the study published in Nature Microbiology, Plemper’s team repurposed MK-4482/EIDD-2801 against SARS-CoV-2 and used a ferret model to test the effect of the drug on halting virus spread.

“We believe ferrets are a relevant transmission model because they readily spread SARS-CoV-2, but mostly do not develop severe disease, which closely resembles SARS-CoV-2 spread in young adults,” said Dr. Robert Cox, a postdoctoral fellow in the Plemper group and a co-lead author of the study.

The researchers infected ferrets with SARS-CoV-2 and initiated treatment with MK-4482/EIDD-2801 when the animals started to shed virus from the nose.

“When we co-housed those infected and then treated source animals with untreated contact ferrets in the same cage, none of the contacts became infected,” said Josef Wolf, a doctoral student in the Plemper lab and co-lead author of the study. By comparison, all contacts of source ferrets that had received placebo became infected.

If these ferret-based data translate to humans, COVID-19 patients treated with the drug could become non-infectious within 24 hours after the beginning of treatment.

MK-4482/EIDD-2801 is in advanced phase II/III clinical trials against SARS-CoV-2 infection.

U.S. Hospitals Charging Patients Up to 1800% More for Services Than They Cost

The American system has produced some incredible medical advances, but it is reasons like these absurdly high costs that make it largely such a catastrophe.

Hospitals in the United States charge patients as much as 1,800% more than their costs amid the coronavirus pandemic, according to a new study.

The 100 most expensive hospitals in the United States charge between $1,129 and $1,808 for every $100 of their costs, according to a study by National Nurses United, the largest nurses union in the country.

Overall, hospitals across the US charge an average of $417 for every $100 of their costs. The average markup has more than doubled over the past two decades, according to the report.

The markups have resulted in hospital profits skyrocketing by 411% from 1999 to 2017, hitting a record $88 billion.

“The rise in charges coincides with growing hospital mergers and acquisitions by large systems,” the union said in a news release. “The result is increased market consolidation, which leads to higher profits and increased charges, not savings for patients as hospital systems often claim.”

Medical workers worry that high costs will increase the number of people avoiding medical care.

“There is no excuse for these scandalous prices. These are not markups for luxury condo views, they are for the most basic necessity of your life: your health,” nurse Jean Ross, the president of the union, said in a statement. “Unpayable charges are a calamity for our patients, too many of whom avoid— at great risk to their health — the medical care they need due to the high cost, or they become burdened by devastating debt, hounded by bill collectors or driven into bankruptcy.”

The union warned that “high hospital charges also drive up Covid-19 treatment costs.”

A study by the health care data nonprofit FAIR Health in the spring found that uninsured coronavirus patients or those that receive care considered out-of-network by their insurer face costs ranging from $42,486 to $74,310 if they require inpatient hospital treatment.

A survey by the health care research group the Commonwealth Fund also found that more than two-thirds of Americans say that “potential out-of-pocket costs would be very or somewhat important in their decision to seek care if they had symptoms of the coronavirus.”

While insurers often negotiate prices with hospitals, uninsured patients have little recourse. And as with other health care and coronavirus-related disparities, people of color are disproportionately impacted. Latinos are nearly three times as likely and Black people are nearly twice as likely to be uninsured than white Americans, according to a study from the Kaiser Family Foundation.

The National Nurses United report argued that the findings further make the case for a Medicare for All system because Medicare is the “most effective” system to limit price gouging.

“The most viable solution to slowing the growth in hospital charges and the continued inflation of hospital prices, is to bring all health care purchasers together, under a public, nationwide single-payer plan,” the report said.

The RAND Corporation, a nonprofit think tank, found that hospitals charged private insurers an average of 2.4 times more than Medicare rates.

“Nurses know that the best way to rein in these outrageous charges that create such grievous harm for our patients is with Medicare for All, as other countries have proven,” said Ross, the union president. “Medicare for All will not only guarantee health care coverage for every person in the United States, it will end medical bankruptcies, medical debt lawsuits, and the health insecurity faced by millions who make painful choices every day about whether to seek the care they desperately need.”

[…]

A study published in the Annals of Internal Medicine earlier this year found that 34% of health care expenditures go toward administrative costs alone. The US spent about $2,497 per person on administrative costs in 2017, compared to $551 per person in Canada, which has a single-payer system. Switching to a single-payer system would drive down health care costs by $600 billion on administrative costs alone, according to the analysis.

“Americans spend twice as much per person as Canadians on health care. But instead of buying better care, that extra spending buys us sky-high profits and useless paperwork,” lead author Dr. David Himmelstein, a professor at the CUNY School of Public Health at Hunter College, said in a statement.

Another study published in The Lancet earlier this year found that Medicare for All would save the country about $450 billion per year while preventing more than 68,000 unnecessary deaths annually.

Lead researcher Dr. Alison Galvani, an epidemiologist and director of the Center for Infectious Disease Modeling and Analysis at Yale University, argued that Biden’s proposal to essentially expand Obamacare could actually increase costs compared to the Medicare for All plan that the president-elect decried during the primaries as too costly.

“Without the savings to overhead, pharmaceutical costs, hospital/clinical fees, and fraud detection, ‘Medicare for all who want it’ could annually cost $175 billion dollars more than status quo,” she told Newsweek. “That’s over $600 billion more than Medicare for all.”

An analysis published in PLOS Medicine of 22 single-payer studies showed that 19 of them “predicted net savings … in the first year of program operation and 20 … predicted savings over several years; anticipated growth rates would result in long-term net savings for all plans.”

Critics have argued that reducing costs by switching to a single-payer system would result in doctor shortages and the rationing of health care. But data shows that fewer than 1% of doctors have opted out of the existing Medicare and Medicaid programs, with nearly half of those being psychiatrists. Single-payer proponents also dismiss rationing claims, arguing that Americans are already effectively self-rationing due to sky-high costs, even for those with private insurance.

A Federal Reserve survey published last year found that about 25% of American “adults skipped necessary medical care in 2018 because they were unable to afford the cost.” Another survey found that 26% of Americans with diabetes have rationed their insulin, primarily due to the cost.

“It would be a missed opportunity for America to ignore lessons about universal coverage from other countries out of a fear that they ration health care more than we do,” researchers at the Commonwealth Fund warned in a report last year. “In reality, more people in the U.S. forgo needed health care because access to care is rationed through lack of access to adequate insurance or unaffordable services and treatments.”

Honey Has Been Shown to Treat Upper Respiratory Infections Better Than Traditional Remedies

Honey is unique in that its a bacteria-killing agent that hasn’t been shown to trigger antibiotic resistance due to how it naturally contains hydrogen peroxide.

A trio of researchers at Oxford University has found that honey is a better treatment for upper respiratory tract infections (URTIs) than traditional remedies. In their paper published in BMJ Evidence-based Medicine, Hibatullah Abuelgasim, Charlotte Albury, and Joseph Lee describe their study of the results of multiple clinical trials that involved testing of treatments for upper respiratory tract infections (URTIs) and what they learned from the data.

Over the past several years, the medical community has grown alarmed as bacteria have developed resistance to antibacterial agents. Some studies have found that over-prescription of such remedies is hastening the pace. Of particular concern are antibacterial prescriptions written for maladies that they are not likely to help, simply due to demands from patients. One such case is often URTIs, the vast majority of which are caused by viruses, not bacteria. Because of such cases, scientists have been looking for other remedies for these infections, and one therapy in particular has begun to stand out: honey.

Anecdotal evidence has suggested that honey can be used to treat colds in general and coughs in particular—people have been using it as a therapy for thousands of years. In this new effort, the researchers looked at the results of multiple clinical trials testing the effectiveness of therapies against URTIs. In all, the team looked at data from 14 clinical trials involving 1,761 patients.

In analyzing the data from all of the trials combined, the researchers found that the trials had included studies of virtually all of the traditional remedies such as over-the-counter cold and sinus medicines as well as antibiotics—and honey. They found that honey proved to be the best therapy among all of those tested. In addition to proving more effective in treating coughing (36 percent better at reducing the amount of coughing and 44 percent better at reducing coughing severity), it also led to a reduction in average duration of infection by two days.

The researchers note that the reason honey works as a treatment for URTIs is because it contains hydrogen peroxide—a known bacteria killer—which also makes it useful as a topical treatment for cuts and scrapes. Honey is also of the right consistency—its thickness works to coat the mouth and throat, soothing irritation.