Day: 01/27/2024

Measles outbreaks a wake-up call for the unvaccinated.

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Measles viruses. 3D illustration showing structure of measles virus with surface glycoprotein spikes heamagglutinin-neuraminidase and fusion protein

The United Kingdom is facing a measles outbreak, while cases have also popped up in a few U.S. states in recent weeks, leading to health authorities on both sides of the pond to issue urgent warnings. 

The virus, which was declared eliminated in the U.S. in 2000, is a wake-up call for the importance of vaccination to personal and public health. The U.K. only recently reachieved measles elimination status in 2021 after having lost the distinction in 2018. 

Unlike COVID-19 vaccines, which help prevent serious illness but don’t prevent infection, the measles vaccine is almost 100 percent effective in preventing infection. And almost everyone who has been recently infected in the U.K. and U.S. is not vaccinated against measles. 

The Centers for Disease Control and Prevention (CDC) on Thursday advised health care providers to be alert for potential measles symptoms, which include a rash; cough; sore or swollen eyes; and flu-like symptoms. Providers should also be aware of patients who have recently traveled abroad. 

“Measles cases often originate from unvaccinated or undervaccinated U.S. residents who travel internationally and then transmit the disease to people who are not vaccinated against measles,” the CDC’s alert stated. 

“The increased number of measles importations seen in recent weeks is reflective of a rise in global measles cases and a growing global threat from the disease.” 

In the U.K., more than 300 probable cases — 216 of which are confirmed — have been detected since October, with the majority centered around the city of Birmingham.  

Since December, the CDC has received notice of at least 23 measles cases in the U.S., with seven having been imported by international travelers. States that have reported measles cases include Delaware, Georgia, New Jersey, Pennsylvania, Virginia, and Washington state. 

Jenny Harries, chief executive of the U.K. Health Security Agency, recently warned the infections in her country would continue to spread without urgent action — and vaccinations. 

“Immediate action is needed to boost MMR uptake across communities where vaccine uptake is low,” Harries said during a visit to Birmingham. 

In the U.K. and the U.S., MMR (measles, mumps and rubella) vaccinations remain high but have fallen away from the ideal 95 percent rate, which is the target countries aim to reach by 2030, as well as the coverage the World Health Organization recommends to prevent measles outbreaks. 

As KFF noted last summer, MMR vaccination rates in the U.S. have seen a slight decline in recent years, reaching 93 percent among kindergartners during the 2022-23 school year, the lowest this figure has been in almost a decade. The U.K. mirrored this trend, with MMR vaccination rates at the age of 5 falling to 92.5 percent, the lowest since 2010-11. 

“We’ve started to lose our herd immunity,” Keri Cohn, physician and partnership chair for the American Academy of Pediatrics, told The Hill.

“So, you really need to have 95 percent of the population vaccinated in order to have good herd immunity for measles. That number is less for other organisms, but because measles is so contagious, you really have to have such a high number,” Cohn explained.

Like many health issues occurring in the world today, experts see a link between measles outbreaks and the COVID-19 pandemic. 

“Generally, we certainly saw a real slide in the provision of essential health services like childhood vaccines during COVID. And that’s continued,” said Elisha Dunn-Georgiou, president and CEO of the Global Health Council. 

According to the CDC, more than 61 million measles vaccine doses were postponed or missed globally from 2020 to 2022, increasing the risk of outbreaks both in the U.S. and abroad. While measles is still considered endemic in countries like Yemen and India, Dunn-Georgiou said high-income like the U.S. and the U.K. shouldn’t be seeing outbreaks. 

Vaccine hesitancy and disinformation are likely contributing factors to waning immunization rates, but Dunn-Georgiou also opined that recent measles outbreaks may be a sign the U.S. is falling victim to its success in combating the disease. 

“I think there’s another piece around infectious disease that is not so much hesitancy but complacency. Like if you don’t see how terrible it is, you don’t realize how terrible it is until it happens,” she said. “When diseases get completely under control, I think there’s a little bit of amnesia.” 

Measles cases could potentially snowball in the U.K. Andrew Pollard, chair of the British government’s Joint Committee on Vaccination and Immunization, recently told The Guardian there is “a very large susceptible population of children” in the country. 

Despite the potential for spread, Dunn-Georgiou was doubtful that travel restrictions between the U.S. and the U.K. would be necessary. 

“Travel bans have not proven to be that effective of a public health control,” Dunn-Georgiou said, noting the virus appears to so far be contained in one region of the U.K., the West Midlands. 

“And measles is one of those diseases where if you are vaccinated, you won’t get it,” she added. “It would necessitate … a child under the age of seven getting on to a plane with measles and traveling to a community nobody’s vaccinated.” 

And measles always carries the risk of becoming a serious infection. Cohn noted children who get infected “are not infrequently needing hospitalization.”

“About 25 [percent] to 30 percent of them end up having complications that can range from otitis media to pneumonia to even death,” Cohn said, though she also noted that treating measles shouldn’t be a challenge for most hospitals. The real challenge when it comes to measles is identifying and isolating cases before they can spread.

A breakthrough in DNA sequencing hints at why most smokers don’t get lung cancer

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lung cancer

Some people could have “very proficient systems for repairing DNA damage or detoxifying cigarette smoke.”

Cigarettes contain dozens of chemicals that cause changes to DNA in lung cells.Rattankun Thongbun/iStock (left), Shutter2u/iStock (right)

If you’re worried about lung cancer, then smoking is incredibly dangerous. The chance of a non-smoker developing the disease is roughly one in 6,000. For someone who smokes regularly, the chances skyrocket to one in five or ten.

And yet, most people who smoke won’t develop lung cancer.

A team of researchers has begun to figure out why. In a small study published Monday in the peer-reviewed journal Nature Genetics, they report that smoking appears to drive a predictable increase in the number of cancer-causing mutations in lung cells — but only up to a point. Once someone had smoked the equivalent of a pack of cigarettes per day for 23 years, the number of mutations stopped rising.

“Our data suggest that these individuals may have survived for so long in spite of their heavy smoking because they managed to suppress further mutation accumulation,” says pulmonologist and genetics researcher Simon Spivack, a co-author on the study. “This leveling off of mutations could stem from these people having very proficient systems for repairing DNA damage or detoxifying cigarette smoke.”

A genomics breakthrough brings mutations into focus

Researchers who study the health effects of cigarette smoke have used all kinds of methods — from giving lab animals high doses of chemicals found in tobacco to combing through archives to determine which diseases smokers get more often — to figure out how the habit affects the body. Those studies have made it clear that cigarettes contain hundreds of harmful chemicals, including dozens of carcinogens.

For decades, researchers didn’t have any way to measure the mutations in lung cells that actually cause lung cancer. Five years ago, researchers at Albert Einstein College of Medicine in New York found a way to overcome technical limitations that had made it impossible to sequence the genome. That is, they figured out how to determine the exact order of the A, T, C, and G molecules of the DNA within a single cell without introducing too many errors in the process.

In this new study, many of the same researchers used that technique to compare lung cells from people who’d never smoked and from people who smoked for years.

Smoking causes mutations to build — but only up to a point

This relatively small study involved just 33 participants, ranging in age from 11 to 86 years old. Roughly half of them were smokers. The rest had never smoked. Doctors collected cells from the linings of their lungs during medically necessary bronchoscopies.

​​“These lung cells survive for years, even decades, and thus can accumulate mutations with both age and smoking,” says Dr. Spivack. “Of all the lung’s cell types, these are among the most likely to become cancerous.”

The researchers used their new technique to identify the number of mutations in those cells for each person. Then they compared that information to data about how much each participant had smoked over their lifetime, as measured in a unit called “pack years.” One pack year is equivalent to smoking one pack of cigarettes per day for one year. The heaviest smoker in the study had smoked for 116 pack years.

Unsurprisingly, they found that smoking for more pack years tended to correlate with more DNA mutations in lung cells. “This experimentally confirms that smoking increases lung cancer risk by increasing the frequency of mutations,” just as researchers have believed for decades, Spivack says.

But there was a surprise in their data. That close correlation between the number of pack years and the number of mutations disappeared at 23 pack years. After that point, the number of mutations stopped increasing.

“The heaviest smokers did not have the highest mutation burden,” Spivack says. In other words, the participant who’d smoked 116 pack years didn’t have five times the number of mutations as someone else who’d smoked a couple of dozen pack years. “Our data suggest that these individuals may have survived for so long in spite of their heavy smoking because they managed to suppress further mutation accumulation,” Spivack says.

More findings like these could revolutionize how doctors prevent lung cancer

While this is an early finding from a small study, it’s a remarkable fact that might offer insight into why some people get cancer while others don’t.

“This leveling off of mutations could stem from these people having very proficient systems for repairing DNA damage or detoxifying cigarette smoke,” Spivack says.

If researchers can figure out how to identify those people before it’s too late, they can offer targeted help — and give the people most likely to suffer an even better reason not to smoke.

“This may prove to be an important step toward the prevention and early detection of lung cancer risk and away from the current herculean efforts needed to battle late-stage disease, where the majority of health expenditures and misery occur,” Spivack says.

Kids With Autism May Benefit From Rare Bacteria

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A new study adds to research showing the benefits of L. reuteri for improving social functioning in children with autism. 

New evidence is adding to previous research showing that Limosilactobacillus reuteri (L. reuteri) improves the social function of children with autism.

Published in Cell Host and Microbe, the study found that the bacteria—formerly called Lactobacillus reuteri—improved some social function markers related to autistic behavior. Though it involved a small cohort of 43 children, the study was a randomized, double-blind, placebo-controlled trial, considered the gold standard for quality research.

The study builds on previous research showing that oxytocin—often called the “love hormone” that helps with human bonding—delivered intranasally to children with autism may help with social deficits. Manipulating the microbiome specifically by increasing levels of L. reuteri has been shown to be another way to increase oxytocin and improve mental health.

The number of children diagnosed with autism spectrum disorder (ASD) has grown dramatically in the last few decades—up to 2.8 percent of children—and the cost associated with care for autism is expected to reach $461 billion by 2025. Difficulties with social interaction is a defining symptom of autism—and is exceptionally challenging to address, though there is a wide array of interventions targeting it.

Those difficulties include establishing and maintaining relationships, reciprocating social interaction, and communicating with others, according to a 2017 article in Patient Related Outcome Measures.

“Lack of social skills may have lifelong implications for children with ASD, affecting their family/community interactions, academic skills, self-worth, and independence,” noted the article.

“Reports on social skills in ASD indicate that these skills are extremely difficult to learn and that educational objectives should be focused on developing social skills because they have lifelong implications.”

This problem calls for effective interventions that can help these children improve their social capabilities, noted the article.

The Overall Effect of L. Reuteri

In addition to looking at social behaviors in children with autism, the new study examined repetitive behaviors, overall microbiome compositions, and the immune profiles of the children. It measured parameters before and after six months of taking either the placebo or two probiotic tablets containing 200 million colony-forming units (CFU). CFU is the number of viable bacteria.

The microbiome is the collection of bacteria, viruses, fungi, and other microorganisms that live in the gastrointestinal tract.

The study found that L. reuteri did not improve overall symptom severity, nor did it change the microbiome or the immune profile. There were no reported changes to gastrointestinal symptoms from the intervention.

However, the aim of the study was primarily to test the hypothesis that L. reuteri could work as a therapeutic intervention for autism, particularly for social skills. A 2021 meta-analysis published in the National Autistic Society looked at 31 studies and concluded that oxytocin levels were “significantly lower in autistic people.”

A 2021 study published in Cell noted that treating mice with L. reuteri at various developmental stages was able to improve social deficits.

The new study reported improvements in communication but not social motivation or mental state understanding. However, there were significant improvements in adaptive social functioning, which refers to developmentally appropriate skills and abilities necessary to communicate and function in daily living.

‘Still a Success’

Dr. William Davis, cardiologist and author of “Super Gut,” who has researched L. reuteri, told The Epoch Times the study is an important piece of the autism puzzle.

“I applaud what these people did. They did the study I wanted to do but just didn’t have the funding for it,” he said. “I didn’t expect it to be a cure-all. People want to hear, ‘They cured autism.’ If L. reuteri improves some aspect of social behavior, that’s still a success.”

It’s more likely that there will be a collection of several microbes that will prove beneficial for autism. In the meantime, Dr. Davis has witnessed many anecdotes of L. reuteri leading to improvement with autism among his own clients.

One is a mother whose adult daughter with autism was barely functional. Though she was physically capable of working, her social deficits didn’t allow her to hold down a job or engage socially. She began taking L. reuteri and now has a job and friends. It didn’t cure anything, but she became a different person, Dr. Davis explained.

One thing he pointed out was that probiotic manufacturers often have too small of a dose in their products. He teaches clients to culture the bacteria in yogurt to increase a 400 million CFU dose to one with 300 billion CFUs.

“Four hundred million sounds like a lot, but in microbes, it’s a drop in the bucket. My suspicion is you’d see bigger effects in higher doses. In the real world, I see that happen, and I see dramatic improvements,” Dr. Davis said.

Eventually, he said, research will catch up to include more precise dosing. He compares the dosing in many studies to taking half milligrams of aspirin and expecting it to work for a headache when the proper dose is 600 milligrams.

Where Has All the L. Reuteri Gone?

When it was discovered, L. reuteri was found in about 30 percent to 40 percent of the population. A Science Daily article in 2010 noted its presence had shrunk to 10 percent to 20 percent by then. While specific data are hard to come by, Dr. Davis believes its level is now around 4 percent.

As with many other bacteria that are disappearing from the human microbiome, L. reuteri’s extinction is connected to antibiotic overuse, glyphosate, emulsifiers in processed food, and stomach acid blockers.

“Nearly everybody has lost this gut microbe L. reuteri … because it’s very susceptible to common antibiotics like amoxicillin and penicillin. We’ve nearly knocked off the reuterin in modern populations,” Dr. Davis said.

CRISPR-edited crops break new ground in Africa

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Scientists in the global south use the popular technique to protect local crops against local threats.

A field of Sorghum plants in Botswana.
A field of sorghum in Botswana. Gene editing has created sorghum plants that are resistant to a destructive parasite called witchweed.

Molecular biologist Steven Runo once thought that his team would make history as the first to plant gene-edited seeds in African soil. The competition turned out to be stiffer than he’d anticipated.

A research group working on maize “beat us by two or three months”, says Runo, who works at Kenyatta University in Nairobi and whose gene-editing project focuses on sorghum. “But that’s good — African countries will see that this is actually possible.”

The friendly rivalry is a sign of progress. Researchers have long hoped that the relative ease and low cost of CRISPR gene-editing systems would make it possible for scientists in low- and middle-income countries to produce crops with traits tailored to the needs of local farmers — rather than relying on seeds developed in foreign countries. Now scientists are overseeing at least a dozen efforts to develop such gene-edited crops.

Among those projects is Runo’s effort to engineer sorghum to be resistant to Striga hermonthica, a troublesome species of a parasitic plant known as witchweed. Field trials of the new variety are scheduled for later this year, Runo said at the Plant and Animal Genome Conference in San Diego, California, on 16 January.

“It’s not as easy as people make it out to be to do gene editing, but it is pretty accessible,” says Kevin Pixley, a research director at the International Maize and Wheat Improvement Center in Texcoco, Mexico. “Runo is a perfect example of that.”

CRISPR takes on a witchy weed

Sorghum is a hardy crop that is used widely in Africa for food, building materials and feedstock. But more than 60% of African farmland is contaminated with species of Striga, a parasitic plant that attaches itself to sorghum roots and siphons away nutrients and water. A witchweed infestation can wipe out an entire crop.

Some wild varieties of sorghum are resistant to Striga because they carry mutations that alter the crop’s production of compounds called strigolactones, which promote germination of Striga seeds. Runo and his collaborators have used CRISPR–Cas9 to mimic these mutations.

Close up of the purple flowers of giant witchweed.
Witchweed, which infests a large proportion of farmland in Africa, can devastate a crop.

Under Kenya’s 2022 regulations governing gene-edited crops, such plants are treated like conventionally bred crops because they do not contain DNA from another species. This means that these gene-edited plants can bypass some of the heavy testing and requirements imposed on genetically modified crops that contain foreign DNA. Nigeria and Malawi have similar policies, and other African countries, including Ethiopia and Uganda, are expected to follow suit, Runo says.

Last year, Kenyan authorities gave Runo and his collaborators permission to grow the gene-edited seeds under those regulations, and he plans to launch field studies later this year. It is a significant step, Runo said at the conference, because Striga is not a problem in wealthier regions — meaning that large, multinational corporations have little incentive to develop solutions for it.

Seeking cattle that can beat the heat

Other gene-editing projects are underway to improve African agricultural products. Pixley and his collaborators, including researchers at the Kenya Agricultural and Livestock Research Organization in Nairobi, have developed ways to edit maize (corn) to make it resistant to maize lethal necrosis disease. They are also editing pearl millet to make its flour less prone to becoming rancid soon after milling, and groundnuts to make them more resistant to infection by the fungus that produces cancer-causing aflatoxins

African livestock are also being edited. At the Plant and Animal Genome Conference, Dan Carlson, chief scientific officer at Recombinetics in Eagan, Minnesota, described a project in which African breeds of cattle are being edited improve their milk yields and tolerance to heat and disease.

Although gene editing is relatively cheap to perform in the laboratory, there are still significant hurdles to bringing edited crops to the farm, says Klara Fischer, who studies rural development at the Swedish University of Agricultural Sciences in Uppsala.

“Sometimes the discourse around this technology is overly enthusiastic,” she says. And because the market is unlikely to provide for poor small-scale farmers with limited purchasing power, government involvement would probably still be needed for the gene-edited products to benefit them.

Markets and money

Runo has relied on funding from the US Agency for International Development and has collaborated with Corteva Agriscience, an agricultural company in Indianapolis, Indiana. Pixley and his team have received funds from the Bill & Melinda Gates Foundation in Seattle, Washington, and have also gotten technical assistance from Corteva.

Runo is mindful that this support might not always be available. He and his team are working on cutting the cost of lab supplies and equipment and finding alternative funding sources.

Also unknown, says Pixley, is how intellectual-property battles over CRISPR gene editing will ultimately affect efforts in Africa, and whether foreign markets — particularly in Europe — will be open to African-grown gene-edited crops.

But as for local acceptance of the crops, Runo says the farmers he has spoken to feel more comfortable with crops developed by a local researcher than with seeds developed abroad. “This is not a multinational company. The people using the technology are people you have grown up with,” he says. “The narrative is very different.”

Leptin Reduction as a Required Component for Weight Loss. 

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Partial leptin reduction can induce significant weight loss, while weight loss contributes to partial leptin reduction. The cause-and-effect relationship between leptin reduction and weight loss remains to be further elucidated. Here, we show that FGF21 and the glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide rapidly induced a reduction in leptin. This leptin reduction contributed to the beneficial effects of GLP-1R agonism in metabolic health, as transgenically maintaining leptin levels during treatment partially curtailed the beneficial effects seen with these agonists. Moreover, a higher degree of leptin reduction during treatment, induced by including a leptin neutralizing antibody with either FGF21 or liraglutide, synergistically induced greater weight loss and better glucose tolerance in diet-induced obese mice. Furthermore, upon cessation of either liraglutide or FGF21 treatment, the expected immediate weight regain was observed, associated with a rapid increase in circulating leptin levels. Prevention of this leptin surge with leptin neutralizing antibodies slowed down weight gain and preserved better glucose tolerance. Mechanistically, a significant reduction in leptin induced a higher degree of leptin sensitivity in hypothalamic neurons. Our observations support a model that postulates that a reduction of leptin levels is a necessary prerequisite for substantial weight loss, and partial leptin reduction is a viable strategy to treat obesity and its associated insulin resistance.

Article Highlights

  • Weight loss agents in the glucagon-like peptide 1 receptor and FGF21 group induced a rapid suppression of leptin immediately upon agonist exposure.
  • This leptin suppression significantly contributed to the weight loss.
  • Further leptin suppression with a leptin neutralizing antibody enhanced weight loss and further improved insulin sensitivity.
  • Enhanced leptin reduction leads to further reduction in hepatic steatosis and fibrosis.

New Insights Into the Genetics of Glycemic Response to Metformin 

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Metformin is one of the most commonly prescribed medications in the world, with 25 million prescriptions in England in the last year alone (data are from https://openprescribing.net) for a population of 56 million people. Metformin has been in clinical use for >60 years, yet despite this, or probably because of this, the mechanism(s) for how metformin lowers glucose remains unclear. Population genetic studies have transformed our understanding of the etiology of most common and rare diseases. It follows that population pharmacogenetic studies should provide insight into variation in glycemic response to metformin, which can be attributed to variation in pharmacokinetics and pharmacodynamics of the medication. This might allow us to better understand how metformin works, enabling more targeted drug treatments or the identification of who is likely to respond or not respond.

Unlike common disease and trait genetics, where it is now not uncommon to see genetic studies of more than 1 million people, pharmacogenetic studies in general are much smaller, are less powered, and have had limited success when considering common diseases and medications. It should be noted that this is not the case for genetics of rare disease, severe adverse drug reactions, drug metabolism, and anticancer treatments, where pharmacogenetics is increasingly making its way into clinical care. For metformin, there have been three genome-wide association studies (GWAS) published to date reporting on HbA1c change in people with type 2 diabetes (1–3), with additional GWAS reporting on the genetic interaction with metformin and diabetes prevention (4) and acute response to metformin in people without diabetes (5). Of these, only the loci at NPAT/ATM and SCL2A2 have been replicated.

In this issue of Diabetes Care, Wu et al. (6) report a further GWAS of glycemic response to metformin. The discovery GWAS used data from 447 African Americans, with replication undertaken in 353 African Americans and 466 European Americans. A genome-wide variant, rs143276236, in gene ARFGEF3, replicated in the African American cohort but not in the European American population. This is the first GWAS to focus discovery on an African American population, with previous metformin GWAS being predominantly in populations of White European or mixed ethnicity. This, of course, is important to ensure precision medicine findings are not limited to the European population and may identify ancestry-specific variants that would not be detected in a White European population. The variant identified is an intronic single nucleotide polymorphism (SNP) in a gene, ARFGEF3, that has a plausible connection to glucose metabolism, as it is expressed in α-cells and β-cells and its knockout in mice is associated with increased insulin granule content and increased insulin secretion. The mechanism whereby rs143276236 alters metformin response is unclear and follow-on mechanistic studies are needed, but this study, like the previous GWAS, provides potential novel insights into how metformin works to lower glucose in humans.

One area highlighted by this study that has important implications for pharmacogenetic studies is the challenge of defining a phenotype of drug response in diabetes studies. The focus here is specifically on glycemic response in patients with type 2 diabetes rather than acute response or prevention of diabetes. As outlined in Fig. 1, the U.K. Prospective Diabetes Study (UKPDS) and subsequent studies, like A Diabetes Outcome Progression Trial (ADOPT) (7) and Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) (8), show that when a new medication is started there is a reduction in HbA1c to a nadir between 6 and 12 months and then an inexorable deterioration in glycemic control that reflects the underlying diabetes disease progression, resulting in what is commonly referred to as the “Nike tick.” The most-used measure of drug response is to simply measure the change from a pretreatment value to an on-treatment value measured at or close to the HbA1c nadir (∼6–12 months) and to adjust for the baseline HbA1c in a regression model. This method has merit because it captures the short-term response, which is only minimally confounded by underlying disease progression, and it is a simple definition that can be applied across populations. However, it is far from perfect: it will be confounded by lifestyle change at the time of medication initiation, which may well be marked for metformin, because it is often started at or close to diabetes diagnosis and will be affected by regression to the mean (9). Another approach would be to model time to failure of a medication, although it is difficult to disentangle drug effect from underlying disease progression. Probably the best approach, if sufficient data are available longitudinally, is to use a linear mixed model with many HbA1c measures before and after medication initiation, as used by McGurnaghan et al. (10) for modeling dapagliflozin response. In the study by Wu et al. (6), two on-treatment HbA1c measures are used at least 120 days apart, and the closest such pair to metformin initiation was used. This definition was largely determined by the lack of pretreatment HbA1c measures but does show how, even without pretreatment measures, a measure of drug response can be derived from observational data. Supplementary Fig. 9 in their article nicely demonstrates how, as the window used to define metformin response shifts away from the initiation of metformin, the drug effect is attenuated, with much of the informative data coming from those patients with the first HbA1c measure before 146 days after starting metformin, which explains why the overall HbA1c reduction seen with metformin is low. The potential merits of this approach are that it may be less affected by regression to the mean caused by a randomly increased baseline measure. Importantly, Wu et al. (6) go on to investigate the interaction between drug dose (exposure) and HbA1c change and report a significant interaction for rs143276236 and metformin exposure; the SNP effect was only observed in those receiving >425 mg/day of metformin. The use of such an interaction analysis provides strong support that the SNP is working to alter metformin response, and its effect is not independent of metformin.

An illustration of how HbA1c changes over time with initiation of new treatment. Each letter depicts different definitions of drug response: A, difference between pretreatment HbA1c and on-treatment HbA1c at 6–12 months; B, the approach used by Wu et al. (6), which relied on the difference between two on-treatment HbA1c values at least 120 days apart and closest to initiation of medication; C, time to failure of medication, defined as initiation of next medication or a threshold HbA1c reached; and D, a linear mixed model allowing for within-person slope prior to medication initiation.

The challenges of defining drug response are largely overcome by randomized controlled trials (RCTs), where the randomization removes the baseline differences and the ability to assess the genetic effect in an interaction with treatment allocation ensures that findings truly reflect a pharmacogenetic effect. To date, limited RCT trial data with genotyping have been made available to researchers, but this is changing. A recent pharmacogenetic study of glycemic response to glucagon-like peptide 1 receptor agonists included data from the Harmony trials (albiglutide) and the Assessment of Weekly Administration of LY2189265 (dulaglutide) in Diabetes (AWARD) studies (11), and the pharmacogenetic study of GRADE (8) is ongoing. These open the possibility of undertaking metanalysis of GWAS for RCTs of newer medications where genetic data are available, but these are likely to still be underpowered (only tens of thousands of individuals) and do not help us with older medications like metformin and sulfonylureas. With increasing availability of large biobanks, we should be able to supplement RCTs with large cohorts (potentially reaching up to 100,000 individuals) where drug response is defined from electronic medical record data that capture longitudinal drug exposure, HbA1c, BMI, and other covariates. Hopefully the complementary meta-analyses of RCTs and large real-world data from biobanks will allow us to move diabetes pharmacogenetics closer to diabetes disease genetics, finding many robust replicated variants that inform on drug mechanisms and support a precision approach to diabetes care.

Incarcerated Obturator Hernia

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An 84-year-old woman with a history of six vaginal deliveries presented to the gastroenterology department with a 12-hour history of left lower abdominal pain, nausea, and vomiting. Her body-mass index (the weight in kilograms divided by the square of the height in meters) was 16, indicating underweight status. On physical examination, the patient had tenderness to palpation in the left inguinal region. Computed tomography of the abdomen revealed a loop of small bowel protruding through the left obturator canal, between the pectineus muscle anteriorly and the obturator external muscle posteriorly (Panels A [axial view] and B [coronal view], asterisk). Small-bowel dilatation with fluid accumulation proximal to the herniated bowel was also observed. A diagnosis of an incarcerated obturator hernia was made. Emergency laparotomy was performed, during which a part of the ileum located 80 cm from the ileocecal region was found embedded in the left obturator canal. The ileum was manually returned to the peritoneum, and the hernia was repaired. An obturator hernia is a rare type of hernia most commonly identified in thin, multiparous, older women. Owing to the lack of overt findings associated with this pelvic hernia on physical examination, diagnosis may be delayed. The patient recovered well and was discharged home 7 days after surgery.

Brain Network for Thirst and Salt Regulation Revealed

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Summary: Researchers made a significant breakthrough in understanding how the brain regulates thirst and salt appetite. Their study utilized optogenetic and chemogenetic techniques on mice to explore the parabrachial nucleus (PBN), a key brain region in processing ingestion signals.

They identified two specific neuron populations in the lateral PBN that respond to water and salt intake, revealing how these neurons help modulate consumption behavior and prevent excessive intake. This research provides crucial insights into brain mechanisms controlling fluid balance and related disorders.

Key Facts:

  1. Two distinct neuron populations in the lateral PBN respond to water and salt intake, regulating thirst and salt appetite.
  2. Optogenetic activation of these neurons reduces water and salt consumption, even in deprived conditions.
  3. The findings offer significant insights into neurological control of fluid intake and have implications for understanding disorders caused by excessive water and salt consumption.

Source: Tokyo Institute of Technology

Staying hydrated and consuming appropriate amounts of salt is essential for the survival of terrestrial animals, including humans. The human brain has several regions constituting neural circuits that regulate thirst and salt appetite, in intriguing ways.

Previous studies suggested that water or salt ingestion quickly suppresses thirst and salt appetite before the digestive system absorbs the ingested substances, indicating the presence of sensing and feedback mechanisms in digestive organs that help real-time thirst and salt appetite modulation in response to drinking and feeding. Unfortunately, despite extensive research on this subject, the details of these underlying mechanisms remained elusive.

This shows a head and neurons made of water.
During the experiments, the researchers offered the mice—either in regular or water- or salt-depleted conditions—water and/or salt water, and monitored neural activities along with the corresponding drinking behaviors.

To shed light on this matter, a research team from Japan has recently conducted an in-depth study on the parabrachial nucleus (PBN), the brain’s relay center for ingestion signals coming from digestive organs.

Their latest paper, whose first author is Assistant Professor Takashi Matsuda from Tokyo Institute of Technology, was published in Cell Reports on January 23, 2024.

The researchers conducted a series of in vivo experiments using genetically engineered mice. They introduced optogenetic (and chemogenetic) modifications and in vivo calcium imaging techniques into these mice, enabling them to visualize and control the activation or inhibition of specific neurons in the lateral PBN (LPBN) using light (and chemicals).

During the experiments, the researchers offered the mice—either in regular or water- or salt-depleted conditions—water and/or salt water, and monitored neural activities along with the corresponding drinking behaviors.

In this way, the team identified two distinct subpopulations of cholecystokinin mRNA-positive neurons in the LPBN, which underwent activation during water and salt intake. The neuronal population that responds to water intake projects from the LPBN to the median preoptic nucleus (MnPO), whereas the one that responds to salt intake projects to the ventral bed nucleus of the stria terminalis (vBNST).

Interestingly, if the researchers artificially activated these neuronal populations through optogenetic (genetic control using light) experiments, the mice drank substantially less water and ingested less salt, even if they were previously water- or salt-deprived. Similarly, when the researchers chemically inhibited these neurons, the mice consumed more water and salt than usual.

Therefore, these neuronal populations in the LPBN are involved in feedback mechanisms that reduce thirst and salt appetite upon water or salt ingestion, possibly helping prevent excessive water or salt intake.

These results, alongside their previous neurological studies, also reveal that MnPO and vBNST are the control centers for thirst and salt appetite, integrating promotion and suppression signals from several other brain regions.

“Understanding brain mechanisms controlling water and salt intake behaviors is not only a significant discovery in the fields of neuroscience and physiology, but also contributes valuable insights to understand the mechanisms underlying diseases induced by excessive water and salt intake, such as water intoxication, polydipsia, and salt-sensitive hypertension,” remarks Dr. Matsuda.

Prof. Noda mentions, “Many neural mechanisms governing fluid homeostasis remain undiscovered. We still need to unravel how the signals for inducing and suppressing water and salt intake, accumulated in the MnPO and vBNST, are integrated and function to control intake behaviors.”

Abstract

Two parabrachial Cck neurons involved in the feedback control of thirst or salt appetite

Highlights

  • Thirst and salt appetite are temporarily suppressed after water and salt ingestion, respectively
  • Two distinct subpopulations of LPBN Cck neurons are activated by water or salt ingestion
  • One population stimulates GABA neurons in the MnPO and the other those in the vBNST
  • These two pathways are involved in the suppression of thirst or salt appetite

Summary

Thirst and salt appetite are temporarily suppressed after water and salt ingestion, respectively, before absorption; however, the underlying neural mechanisms remain unclear. The parabrachial nucleus (PBN) is the relay center of ingestion signals from the digestive organs.

We herein identify two distinct neuronal populations expressing cholecystokinin (Cck) mRNA in the lateral PBN that are activated in response to water and salt intake, respectively. The two Cck neurons in the dorsal-lateral compartment of the PBN project to the median preoptic nucleus and ventral part of the bed nucleus of the stria terminalis, respectively.

The optogenetic stimulation of respective Cck neurons suppresses thirst or salt appetite under water- or salt-depleted conditions. The combination of optogenetics and in vivo Ca2+ imaging during ingestion reveals that both Cck neurons control GABAergic neurons in their target nuclei.

These findings provide the feedback mechanisms for the suppression of thirst and salt appetite after ingestion.

Breathing’s Crucial Role in Memory Enhancement During Sleep

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Summary: A new study uncovered a crucial link between breathing and the consolidation of memories during sleep.

Through a detailed analysis of EEG and respiratory patterns in human participants, the researchers discovered that peaks in inhalation are closely associated with an increase in slow oscillations and spindle activity in the brain. These specific brain rhythms are known to play a critical role in the process of memory consolidation.

This pivotal finding emphasizes the significant role of respiration in modulating brain activity during sleep. It opens up new avenues for understanding the complex mechanisms underlying sleep-related memory processes and disorders, potentially reshaping our approach to improving cognitive health and treating sleep-related memory impairments.

Key Facts:

  1. The study demonstrates that respiration significantly influences the emergence of slow oscillations and spindles during sleep, two key brain rhythms involved in memory consolidation.
  2. The strength of the coupling between respiration and these sleep oscillations correlates with the extent of memory reactivation, indicating a functional link between breathing patterns and memory processing during sleep.
  3. The research provides evidence for the role of breathing as a potential underlying pacemaker orchestrating sleep-related brain rhythms, opening new avenues for understanding and enhancing memory consolidation during sleep.

Source: Neuroscience News

Sleep, often seen as a passive state, is a hive of brain activity where vital processes for our well-being and cognitive functions take place. One such process is memory consolidation – the transformation of experiences into lasting memories.

Recent research has taken a significant leap in understanding this phenomenon, revealing an intricate dance between our breathing and brain rhythms during sleep.

For decades, scientists have known that certain brain wave patterns during non-rapid eye movement (NREM) sleep, particularly slow oscillations and spindles, are essential for memory consolidation. However, a groundbreaking study has now established a direct link between these brain rhythms and respiration.

This shows a woman sleeping.
This study represents a paradigm shift in sleep science. It challenges existing models of memory consolidation by introducing an entirely new factor – breathing.

The study in question re-analyzed data from 20 participants, where both scalp electroencephalography (EEG) and respiration were recorded as participants learned associative memories before taking a nap. This analysis has opened a new window into our understanding of the sleep-memory nexus, particularly the role of breathing in this intricate process.

The Interplay of Breath and Brain

The researchers found that the emergence of slow oscillations and spindles – key players in memory processing – is modulated by respiration during sleep. Specifically, these brain rhythms increased around the peaks of inhalation. This modulation suggests that our breathing pattern could be acting as a conductor, orchestrating the brain’s memory consolidation process.

Memory Consolidation: A Respiration-Driven Process?

The study went a step further to link these findings to memory reactivation. The strength of the coupling between respiration and the brain’s oscillatory activities correlated with the extent of memory reactivation. Simply put, the better the coordination between breathing and brain waves, the more effective the memory consolidation.

Implications for Neuroscience and Beyond

These findings are revolutionary, not just for our basic understanding of sleep and memory but also for potential therapeutic applications. They suggest that modulating breathing patterns could be a new frontier for enhancing memory consolidation during sleep. This could have profound implications for conditions like sleep apnea, where disrupted breathing might be impairing memory processes.

The Methodology: A Fusion of Technologies

The study’s methodology, combining EEG and respiratory recordings, was crucial in uncovering these insights. By re-analyzing existing datasets with a fresh perspective on the interplay between respiration and brain waves, the researchers could unravel a hidden layer of the sleep-memory relationship.

Bridging the Gap in Sleep Research

This research bridges a significant gap in our understanding of sleep-related memory consolidation. Previous studies have highlighted the importance of slow oscillations and spindles but did not clarify what governs their occurrence. The discovery of respiration’s role provides a missing piece in this complex puzzle.

Beyond the Brain: A Holistic View

The study underscores a holistic view of bodily functions, showing how processes like breathing, often considered in isolation, are deeply intertwined with cognitive functions. This perspective opens new avenues in neuroscience, emphasizing the need to consider the body as a whole in understanding brain functions.

Future Directions: From Research to Applications

Looking ahead, this research paves the way for innovative sleep therapies aimed at enhancing memory. It also raises questions about the impact of breathing disorders on cognitive health and memory, potentially leading to new treatments for such conditions.

Challenges and Limitations

While the study is a significant step forward, it is not without limitations. The sample size was relatively small, and the study design was correlational, making it difficult to infer causation. Future research with larger and more diverse samples, perhaps using interventions to alter breathing patterns, could provide more definitive answers.

A New Paradigm in Sleep Science

This study represents a paradigm shift in sleep science. It challenges existing models of memory consolidation by introducing an entirely new factor – breathing. As we continue to unravel the mysteries of sleep, this research points us toward a more integrated understanding of how our bodies and brains work together in this fundamental state.

Conclusion

In conclusion, the discovery of breathing’s role in memory consolidation during sleep marks a significant advance in our understanding of the sleep-memory connection. It opens new pathways for research and potential therapies, bringing us closer to unlocking the full potential of our sleep for cognitive health and well-being.

Looking Ahead

As science continues to explore this fascinating connection, the dream of enhancing memory consolidation through controlled breathing during sleep inches closer to reality. This study not only expands our knowledge of sleep’s complexities but also reminds us of the wonders that lie within the most ordinary aspects of our daily lives – like taking a breath.

Abstract

Respiration modulates sleep oscillations and memory reactivation in humans

The beneficial effect of sleep on memory consolidation relies on the precise interplay of slow oscillations and spindles. However, whether these rhythms are orchestrated by an underlying pacemaker has remained elusive.

Here, we tested the relationship between respiration, which has been shown to impact brain rhythms and cognition during wake, sleep-related oscillations and memory reactivation in humans.

We re-analysed an existing dataset, where scalp electroencephalography and respiration were recorded throughout an experiment in which participants (N = 20) acquired associative memories before taking a nap. Our results reveal that respiration modulates the emergence of sleep oscillations.

Specifically, slow oscillations, spindles as well as their interplay (i.e., slow-oscillation_spindle complexes) systematically increase towards inhalation peaks. Moreover, the strength of respiration – slow-oscillation_spindle coupling is linked to the extent of memory reactivation (i.e., classifier evidence in favour of the previously learned stimulus category) during slow-oscillation_spindles.

Our results identify a clear association between respiration and memory consolidation in humans and highlight the role of brain-body interactions during sleep.

HPV vaccine study finds zero cases of cervical cancer among women vaccinated before age 14

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Ahistoric new study out of Scotland shows the real-world impact of vaccines against the human papillomavirus: The country has detected no cases of cervical cancer in women born between 1988-1996 who were fully vaccinated against HPV between the ages of 12 and 13.

Many previous studies have shown that HPV vaccines are extremely effective in preventing cervical cancer. But the study, published on Monday in the Journal of the National Cancer Institute, is the first to monitor a national cohort of women over such a long time period and find no occurrence of cervical cancer.

“The study is super exciting. It shows that the vaccine is extremely effective,” said Kathleen Schmeler, a professor of gynecologic oncology at the University of Texas MD Anderson Cancer Center, who was not involved in the research. “It’s obviously early. We’re just starting to see the first data of the impact of the vaccine because it takes so long from the time of the vaccine to the effects.”

The results underscore the importance of working to increase uptake of the HPV vaccine in the U.S., said Schmeler. Scotland, for example, introduced routine immunization in schools in 2008, and close to 90% of students in their fourth year of secondary school (equivalent to 10th grade in the U.S.) in the 2022-2023 school year had received at least one dose of the vaccine. In the U.S., where HPV vaccines are not administered in school, uptake among adolescents ages 13 to 17 is a little over 60%.

The study also points to how crucial the timing of vaccination is. “The girls that didn’t develop any cancer were vaccinated before becoming sexually active,” said Schlemer. “So we should not wait to vaccinate folks and really do it, for the guidelines, prior to becoming sexually active.”

The benefits of receiving the HPV vaccine before age 14

The authors of the Scotland study monitored the records of all women born between 1988 and 1996 who were eligible for cancer screening, about 450,000 women. Of that group, 40,000 were vaccinated between the ages of 12 and 13, and 124,000 received the vaccines at or after 14 years of age. The remaining women, nearly 300,000, were not vaccinated.

No cases of cervical cancer were found among the women who were vaccinated before they turned 14, even if they had only received one or two doses of the vaccine rather than the full, three-dose protocol. Also noteworthy is that women who received the three-dose protocol between the ages of 14 and 22 also benefited significantly. While some cases of cervical cancer were recorded in this group, the incidence (3.2 cases per 100,000 women) was two and a half times lower than among unvaccinated women (8.4 cases per 100,000 women).

“I was very surprised that there were no cases” of cancer in the group who received vaccines before 14, said Tim Palmer, the former clinical lead for cervical screening in Scotland and an HPV immunization consultant at Public Health Scotland, who was a lead author of the study. “In that age group, I expected about 15 to 17 a year in Scotland — and we have had none.”

The types of vaccine administered to the cohorts monitored in the study changed as newer ones became available, covering more types of HPV. Until 2012, the vaccine in use was the bivalent Cervarix, targeting HPV 16 and 18. Then the quadrivalent Gardasil was administered until 2023, when the nonavalent Gardasil 9 was introduced.

This is why it’s still possible that cervical cancers may still arise even in vaccinated women, caused by the HPV strains not targeted by the earlier vaccines. “There are obviously other HPV types that cause cancer,” Palmer said, noting that the current results don’t mean cases of cervical cancers, caused by less high-risk strains of HPV, won’t emerge in the analyzed cohort in the future.

The study’s findings don’t diminish the need for continued screenings for early detection of cervical cancers caused by HPV types that were not targeted in the original bivalent vaccine, said Palmer, but the vaccines effectively targeted the more aggressive strains of HPV (16 and 18).

The impact of the vaccination was also greater among women of lower socioeconomic status, who otherwise reported higher occurrences of cancer, said Palmer.

Ville Pimenoff, a senior researcher at the Karolinska Institutet and professor at the University of Oulu in Finland, published the results of a large cohort study in Finland in November 2023, which showed the effectiveness of cohort vaccination in creating herd immunity against HPV. He said the results from Scotland confirm his findings. “When you vaccinate in a cohort way, there seems to be very strong, protective immunity in those communities,” said Pimenoff, who was not involved in the Scottish study.