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Cancer has an obesity-related risk factor, and it depends on sex and cancer type

Source: Cell Press
Date: 6/12/2023
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Obesity has been previously linked to an increased risk of cancer, but most studies have not differentiated the risks between male and female patients. A new study published June 12 in the journal Cancer Cell takes a closer look at this connection. The investigators report that both overall fat accumulation and fat distribution in different parts of the body confer different cancer risks depending on sex. Additionally, the risks vary across cancer types, like colorectal, esophageal, and liver cancer.

“Doctors and scientists are aware that obesity increases cancer risk, but this connection is less well known to members of the public,” says first author Mathias Rask-Andersen, a researcher at Uppsala University in Sweden. “These observations are important for risk assessment and to gain a deeper understanding of adiposity-related disease risks.”

“An important aspect of obesity-associated disease risk is the distribution of fat in different compartments of the body,” says senior author Åsa Johansson, also of Uppsala University. “Fat stored in the abdomen is considered more pathogenic compared to subcutaneous fat. In addition, the amount of fat stored in different compartments, as well as the rates of most cancers, is known to differ between females and males. These facts motivated a careful sex-stratified analysis of adiposity-related cancer risk.”

The investigators used data from the UK Biobank, a cross-sectional cohort of 500,000 U.K. residents aged between 37 and 73 who were recruited between 2006 and 2010 and then followed for a mean time of 13.4 years. Among the data collected from participants in the database were details about the distribution of fat in their bodies and whether they developed cancer.

The researchers used Cox proportional hazards modeling to identify the associations between the levels and distribution of fat in the participants’ bodies at the time of the initial assessment and their later rates of cancer. The team found that all cancer types except brain, cervical, and testicular cancers are associated with at least one obesity-related trait.

In female patients, the strongest links between overall fat accumulation and cancer were in gallbladder cancer, endometrial cancer, and esophageal adenocarcinoma. In males, the strongest links between overall fat accumulation and cancer were in breast cancer, hepatocellular carcinoma, and renal cell carcinoma. In terms of fat accumulation and distribution, there were differential effects between sexes on colorectal, esophageal, and liver cancer. For instance, a larger proportion of fat stored in the abdomen was associated with esophageal squamous cell carcinoma in females, but not in males. Additionally, body fat accumulation was associated with a high risk for hepatocellular carcinoma in males, an effect that was not present in females.

“We were surprised to see that there appeared to be a difference in the effect of obesity on cancer risk, not only between males and females, but also between post- and pre-menopausal females,” Johansson says. “Most remarkable, obesity is only a risk factor for breast cancer after menopause, probably due to the change in estrogen production in association with menopause.”

The investigators note limitations to this study, especially that it was limited largely to British White participants, which make up almost 95% of the UK Biobank. They explain that their findings may differ from or may not be applicable to other ethnicities. They also say that because participants were older, the results are likely not directly transferable to younger populations.

They plan to do additional studies to help develop a complete understanding of the molecular mechanisms underlying these findings. Future work will also focus on genetic and environmental risk factors for cancer, which are not static but differ across a person’s lifespan. This includes taking a closer look at the variation in the effects of obesity before and after menopause.

“Given the rapidly increasing rates of obesity globally, obesity is now the fastest-growing risk factor for overall cancer risk,” Rask-Andersen says. “Measures to prevent and reduce the occurrence of obesity and being overweight are therefore highly motivated. However, it is important to consider that reducing weight does not eliminate the risk of cancer. There are still many individual risk factors that play a much larger impact on specific types of cancer, such as smoking for lung cancer and exposure to sun for skin cancer.”

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Researchers create embryo-like structures from monkey embryonic stem cells

Source: Cell Press
Date: 4/6/2023
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Human embryo development and early organ formation remain largely unexplored due to ethical issues surrounding the use of embryos for research as well as limited availability of materials to study. In a paper published April 6 in the journal Cell Stem Cell, a team of investigators from China report for the first time the creation of embryo-like structures from monkey embryonic stem cells. The investigators also transferred these embryo-like structures into the uteruses of female monkeys and determined that the structures were able to implant and elicit a hormonal response similar to pregnancy.

“The molecular mechanisms of human embryogenesis and organogenesis are largely unclear,” says co-corresponding author Zhen Liu of the Chinese Academy of Sciences (CAS) in Shanghai. “Because monkeys are closely related to humans evolutionarily, we hope the study of these models will deepen our understanding of human embryonic development, including shedding light on some of the causes of early miscarriages.”

“This research has created an embryo-like system that can be induced and cultured indefinitely,” says co-corresponding author Qiang Sun, also of CAS. “It provides new tools and perspectives for the subsequent exploration of primate embryos and reproductive medical health.”

The investigators started with macaque embryonic stem cells, which they exposed to a number of growth factors in cell culture. These factors induced the stem cells to form embryo-like structures for the first time using non-human primate cells.

When studied under a microscope, the embryo-like structures, also called blastoids, were found to have similar morphology to natural blastocysts. As they further developed in vitro, they formed arrangements that looked like the amnion and yolk sac. The blastoids also started to form the types of cells that eventually make up the three germ layers of the body. Single-cell RNA sequencing revealed that the different types of cells found within the structures had similar gene expression patterns to cells found in natural blastocysts or post-implantation embryos.

The blastoids were then transferred into the uteruses of 8 female monkeys; in 3 of the 8, the structures implanted. This implantation resulted in the release of progesterone and chorionic gonadotropin, hormones normally associated with pregnancy. The blastoids also formed early gestation sacs, fluid-filled structures that develop early in pregnancy to enclose an embryo and amniotic fluid. However, they did not form fetuses and the structures disappeared after about a week.

In future work, the investigators plan to focus on further developing the system of culturing embryo-like structures from monkey cells. “This will provide us with a useful model for future study,” says co-corresponding author Fan Zhou of Tsinghua University. “Further application of monkey blastoids can help to dissect the molecular mechanisms of primate embryonic development.”

The researchers acknowledge the ethical concerns surrounding this type of research but emphasize that there are still many differences between these embryo-like structures and natural blastocysts. Importantly, the embryo-like structures do not have full developmental potential. They note that for this field to advance it’s important to have discussions between the scientific community and the public.

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Activating adult-born neurons through deep brain stimulation alleviates Alzheimer’s symptoms in rodent models

Source: Cell Press
Date: 4/6/2023
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People with Alzheimer’s disease develop defects in cognitive functions like memory as well as problems with noncognitive functions that can lead to anxiety and depression. In a paper published April 6 in the journal Cell Stem Cell, investigators used mice to study a process through which new neurons are generated in adulthood, called adult hippocampus neurogenesis (AHN). The research showed that deep brain stimulation of new neurons helped restore both cognitive and noncognitive functions in mouse models of Alzheimer’s disease.

“We were surprised to find that activating only a small population of adult-born new neurons was enough to make a significant contribution to these brain functions,” says senior author Juan Song, an associate professor at the University of North Carolina at Chapel Hill. The neurons were modified by deep brain stimulation of the suprammamillary nucleus (SuM), which is located in the hypothalamus. “We are eager to find out the mechanisms that underlie these beneficial effects,” Song says.

This research used two distinct mouse models of Alzheimer’s. The investigators used optogenetics to stimulate the SuM and enhance AHN in Alzheimer’s mice. Their earlier research had shown that stimulation of the SuM could increase the production of new neurons and improve their qualities in normal adult mice. In the new study, the investigators showed that this strategy was also effective in the Alzheimer’s mice, leading to the generation of new neurons that made better connections with other parts of the brain.

However, having more improved new neurons is not enough to improve memory and mood. Behavioral improvement in Alzheimer’s mice were seen only when these improved new neurons were activated by chemogenetics. The researchers used memory tests as well as established assessments to look for anxiety-like and depression-like behavior to confirm these improvements. The results suggested that multi-level enhancement of new neurons — enhancement in number, properties, and activity — is required for behavioral restoration in Alzheimer’s brains.

To further understand the mechanism, they also analyzed the protein changes in the hippocampus of Alzheimer’s mice in response to activation of SuM-modified adult-born new neurons. They found several well-known protein pathways activated inside cells, including those known to be important for improved memory performance, as well as those that allow clearance of the plaques related to Alzheimer’s.

“It was striking that multilevel enhancement of such a small number of adult-born new neurons made such a profound functional contribution to the animals’ diseased brains,” Song says. “We were also surprised to find that activation of SuM-enhanced neurons promoted the process that can potentially remove plaques.”

Future efforts of the team will focus on developing potential therapeutics that mimic the beneficial effects mediated by activation of SuM-modified new neurons. “We are hoping these drugs could exert therapeutic effects in patients with low or no hippocampal neurogenesis,” Song says. “Ultimately, the hope is to develop first-in-class, highly targeted therapies to treat Alzheimer’s and related dementia.”

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Machine learning identifies “heart roundness” as a new tool for diagnosing cardiovascular conditions

Source: Cell Press
Date: 3/29/2023
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Physicians currently use assessments like heart chamber size and systolic function to diagnose and monitor cardiomyopathy and other related heart conditions. A paper publishing in the journal Med on March 29 suggests that another measurement—cardiac sphericity, or roundness of the heart—may one day be a useful implement to add to the diagnostic toolkit.

“Roundness of the heart isn’t necessarily the problem per se—it’s a marker of the problem,” says co-corresponding author Shoa L. Clarke (@ShoaClarke), a preventive cardiologist and an instructor at Stanford University School of Medicine. “People with rounder hearts may have underlying cardiomyopathy or underlying dysfunction with the molecular and cellular functions of the heart muscle. It could be reasonable to ask whether there is any utility in incorporating measurements of sphericity into clinical decision-making.”

This proof-of-concept study used big data and machine learning to look at whether other anatomical changes in the heart could improve the understanding of cardiovascular risk and pathophysiology. The investigators chose to focus on sphericity because clinical experience had suggested it is associated with heart problems. Prior research had primarily focused on sphericity after the onset of heart disease, and they hypothesized that sphericity may increase even before the onset of clinical heart disease.

“We have established traditional ways of evaluating the heart, which have been important for how we diagnose and treat heart disease,” Clarke says. “Now with the ability to use deep-learning techniques to look at medical images at scale, we have the opportunity to identify new ways of evaluating the heart that maybe we haven’t considered much in the past.”

“They say a picture is worth a thousand words, and we show that this is very true for medical imaging,” says co-corresponding author David Ouyang (@David_Ouyang), a cardiologist and researcher at the Smidt Heart Institute of Cedars-Sinai. “There’s a lot more information available than what physicians are currently using. And just as we’ve previously known that a bigger heart isn’t always better, we’re learning that a rounder heart is also not better.”

This research employed data from the UK Biobank, which includes genetic and clinical information on 500,000 people. As part of that study, a subset of volunteers had MRI imaging of their hearts performed. The California-based team used data from a subset of about 38,000 UK Biobank study participants who had MRIs that were considered normal at the time of the scans. Subsequent medical records from the volunteers indicated which of them later went on to develop diseases like cardiomyopathy, atrial fibrillation, or heart failure and which did not.

The researchers then used deep-learning techniques to automate the measurement of sphericity. Increased cardiac sphericity appeared to be linked to future heart troubles.

The investigators also looked at genetic drivers for cardiac sphericity and found overlap with the genetic drivers for cardiomyopathy. Using Mendelian randomization, they were able to infer that intrinsic disease of the heart muscle—meaning defects not caused by heart attacks—caused cardiac sphericity.

“There are two ways that these findings could add value,” Ouyang says. “First, they might allow physicians to gain greater clinical intuition on how patients are likely to do at a very rapid glance. In the broader picture, this research suggests there are probably many useful measurements that clinicians still don’t understand or haven’t discovered. We hope to identify other ways to use imaging to help us predict what will happen next.”

The researchers emphasize that much more research is needed before the findings from this study can be translated to clinical practice. For one thing, the connection is still speculative and would need to be confirmed with additional data. If the link is confirmed, a threshold would need to be established to indicate what degree of sphericity might suggest that clinical interventions are needed. The team is sharing all the data from this work and making them available to other investigators to begin answering some of these questions.

Additionally, ultrasound is more commonly used than MRI to image the heart. To further advance this research, replicating these findings using ultrasound images will be useful, they note.

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Myalgic encephalomyelitis/chronic fatigue syndrome is associated with distinct changes in the microbiome and gut metabolites

Source: Cell Press
Date: 2/8/2023
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Over the past three years, the emergence of long-term effects associated with COVID-19 has led to increased focus on a disease with similar hallmarks and symptoms—myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Two studies publishing February 8 in the journal Cell Host & Microbe are taking a closer look at ME/CFS as it relates to the microbiome and the metabolites that microbial species produce. Both studies found that ME/CFS is associated with reduced levels in the gastrointestinal microbiome of microbes known to produce the fatty acid butyrate. These microbiome disruptions could explain in part how the immune system becomes disrupted in people with ME/CFS.

“It’s important to note that this research shows correlation, not causation, between these microbiome changes and ME/CFS,” says Julia Oh (@jjsso0), an associate professor at the Jackson Laboratory and senior author of one of the two papers. “But these findings are the prelude to many other mechanistic experiments that we hope to do to understand more about ME/CFS and its underlying causes.”

“This research demonstrates that there are robust bacterial signatures of gut dysbiosis in individuals with ME/CFS,” says Brent L. Williams, an assistant professor at Columbia University and senior author of the other paper. “It helps to expand on this growing field of research by pinpointing the structural and functional disturbances in the microbiome in a chronic disease that affects the quality of life of millions of people.”

ME/CFS is a chronic, complex, and systemic disease associated with neurological, immunological, autonomic, and energy metabolism dysfunctions. It has been recognized for decades, but its causes remain poorly understood. Like long COVID, it is believed in most cases to be triggered by exposure to viruses or other infectious agents. One thing that’s made ME/CFS difficult to study is that it tends to be heterogenous—not all people with the disease have the same medical history or symptoms. Both research teams say that’s why it’s important to do studies like these that analyze data from a large number of patients. The microbiome has recently emerged as a potential contributor to and biomarker for ME/CFS, making it important to study.

Oh’s study used shotgun metagenomics to compare microbiome samples from people with both short-term ME/CFS (defined as those diagnosed in the previous four years; 74 patients) and long-term ME/CFS (defined as those who have had symptoms for more than 10 years; 75 patients) as well as 79 age- and sex-matched healthy controls. The investigators also looked at plasma samples from the participants. The patients were being treated at the Bateman Horne Center in Salt Lake City, Utah, which has a longstanding collaboration with members of the Jackson Laboratory.

The analysis showed that patients with short-term disease had a number of changes to their microbiomes with regard to diversity. Most notably, they had a depletion of microbes known to be butyrate producers. Butyrate is important for protecting the integrity of the gut barrier and is also known to play an important role in modulating the immune system.

In contrast, those with long-term disease had gut microbiomes that had reestablished and were more similar to the healthy controls. However, those participants had accumulated a number of changes in the metabolites in their blood plasma, including many of those related to the immune system. They also had differences in levels of certain types of immune cells compared with the healthy controls.

Williams’s study used shotgun metagenomic sequencing to look at the microbiomes of 106 people with ME/CFS and 91 healthy controls that were matched for age, sex, geography, and socioeconomic status. This study was undertaken by an interdisciplinary, multi-institutional research group, the Center for Solutions for ME/CFS, and recruited patients from five different sites across the United States, which helped to control for microbiome differences that may be present in different geographic regions.

This study also looked at levels of microbial species in the stool. It didn’t include analysis of plasma, though this group has already published plasma metabolomics analyses from their cohort elsewhere. It did look at metabolites in the stool, which demonstrated reduced levels of butyrate metabolites in ME/CFS.

The study from the Columbia team found significant relationships between the severity of fatigue symptoms and levels of specific species of gut bacteria—in particular the butyrate-producing bacterium Faecalibacterium prausnitzii. It also revealed a higher overall load of bacteria in the stool and disturbances in the interactions among bacterial species in patients with ME/CFS.

More research is needed before these findings can be applied directly to new treatments, but the researchers say these findings will aid in the development of new diagnostic tools and could help with the development of better animal models.

“While these findings don’t unequivocally demonstrate causative relationships between disturbances in the microbiome and symptoms, these microbiome-symptom relationships present potentially actionable, manipulatable targets for future therapeutic trials,” Williams says. “These trials could perhaps focus on dietary, probiotic, prebiotic, or synbiotic interventions and could provide direct evidence that gut bacteria influence chronic symptom presentation.”

Oh notes that her future studies will help to further subdivide patients by the features of their disease, including those with conditions frequently associated with ME/CFS—like irritable bowel syndrome and neuroinflammatory disorders. “This will help us pinpoint specific microbial and metabolomic factors that are associated with this disease,” she says.

Williams plans to further investigate his findings in animal models. “A tractable mouse model to study the gut microbiome disturbances found in ME/CFS would provide an important tool to evaluate causal hypotheses, mechanisms, and treatments,” he says.  

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Combining time-restricted eating and HIIT improves health measures in women with obesity

Source: Cell Press
Date: 10/4/2022
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Both time-restricted eating (TRE) and high-intensity interval training (HIIT) have been shown to improve cardiometabolic health in people who are overweight and at risk of serious disease. Now a randomized, controlled trial has tested whether combining these two approaches is more effective than either of them on their own. The results, publishing in the journal Cell Metabolism on October 4, show that the combination improved the average long-term glycemic control compared to a no-intervention control group and induced 2-fold greater reductions in fat mass and visceral fat area compared with each intervention in isolation.

“Isolated TRE and HIIT have received increasing attention for being effective and feasible strategies for at-risk populations,” says senior author Trine Moholdt, head of the Exercise, Cardiometabolic Health, and Reproduction Research Group at Norwegian University of Science and Technology (NTNU). “We wanted to compare the effects of the combination of TRE and HIIT with their isolated effects and to determine whether TRE and HIIT would act synergistically in improving health in individuals with risk for cardiometabolic disease. This finding highlights the importance of changing both dietary and physical activity habits for individuals who wish to rapidly improve their health and lower their disease risk.”

The trial had four arms: HIT alone, TRE alone, the TRE-HIIT combination, and a control group. A total of 131 women were enrolled, with 32 or 33 in each arm. All of them had overweight or obesity and had risk factors for cardiometabolic diseases like type 2 diabetes and cardiovascular disease. TRE was defined as consuming all daily calories within a 10-hour time window. HIIT was defined as exercise done at 90% of maximum heart rate for 35 minutes, three times per week. The exercise sessions were supervised by the investigators, and the participants were asked to log their first and last calories every day.

The interventions lasted for 7 weeks. Several measures were taken both before and after the study, including the participants’ blood pressure, body mass index, fat and cholesterol levels in the blood, and several measures of blood glucose and insulin levels.

The researchers found that the participants who combined TRE and HIIT were able to improve their average long-term glycemic control measured as HbA1c. They were also able to effectively reduce fat mass and visceral fat and increase their cardiorespiratory fitness measured as peak oxygen uptake. However, there were no statistically significant differences in blood lipids, appetite hormones, or vital signs after any of the interventions compared with the control group.

Another important finding from the study was that adherence to the study was high. “High adherence rates are important,” says first author Kamilla La Haganes, a PhD student at NTNU. “Adherence rates to general lifestyle recommendations are low, and our diet-exercise strategies may serve as an alternative.” After the study was completed, 18 participants from the control group also chose to try one of the study interventions.

“We recommend this kind of program for people who wish to have a relatively simple way of changing diet and exercise habits and improving their health,” Moholdt says. “TRE is a less tedious and time-efficient method to lose weight compared with daily calorie counting, and HIIT is tolerable and safe for previously sedentary individuals and can be completed within 30-40 minutes.”

A limitation of the study was that the intervention period was only 7 weeks; longer-term investigations are needed to determine effects and feasibility for longer periods of time. The study also took place during COVID-19 lockdowns, which affected the participants’ lifestyles and could have influenced the results.

The researchers are currently inviting the participants back for follow-up testing 2 years after they completed the study to find out if they have continued with the interventions. They also plan to determine whether the combination of TRE and HIT will induce the same health benefits and have equally good adherence rates in a completely home-based setting. That study will include both men and women. “Together, these two new studies will tell us more about the long-term feasibility and also the possibility for implementation in a real-world setting,” Haganes says. “Additionally, we can investigate if there are any sex differences in response to these interventions.”

This research is supported by the Liaison Committee for Education, Research and Innovation in Central Norway, the EFSD/Novo Nordisk Foundation Future Leaders Awards Programme, the Norwegian University of Science and Technology (NTNU), and by a Novo Nordisk Foundation Challenge Grant.

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Time-restricted eating reduces cardiovascular health risks associated with shift work for firefighters

Source: Cell Press
Date: 10/4/2022
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Shift work has been linked to a number of health problems, including higher rates of diabetes, heart attacks, and other cardiometabolic diseases. But despite the known risks, little research has been done to identify lifestyle interventions that could help prevent these concerns. A new randomized, controlled clinical trial, published October 4 in Cell Metabolism, found that time-restricted eating (TRE) could be safely practiced in shift workers. Additionally, the researchers found that TRE provided benefits to participants who had indications of cardiometabolic disease. Called the Healthy Heroes Study, the intervention focused on San Diego firefighters.

“Shift work is much more common than many people think, affecting workers in a range of different fields as well as parents of newborn babies,” says co-corresponding author Satchidananda Panda, a professor at the Salk Institute and holder of the Rita and Richard Atkinson Chair. “Not only does shift work contribute to an increased burden of disease in our society, but it makes it hard for people with existing conditions like diabetes and cardiovascular disease to manage them.”

“Within the confines of shift work, there are many lifestyle interventions that can potentially optimize the health of shift workers,” says co-corresponding author Pam Taub, a cardiologist and professor in the University of California San Diego School of Medicine’s Division of Cardiovascular Medicine. “However, there are very few research studies on this population. Our study sheds light on one way that we can help this population.”

Panda and Taub have collaborated on research into TRE for several years. In January 2020, they published a study in Cell Metabolism that found that restricting the time of eating to 10 hours a day reduced body weight and improved blood pressure and cholesterol levels in people with metabolic syndrome. In the current study, they focused on TRE in shift workers. The trial recruited San Diego firefighters, who work 24-hour shifts. There were 137 firefighters ultimately enrolled in the study; 70 followed TRE, eating all of their meals within a 10-hour time window, and 67 were in the control group. All participants were encouraged to follow a Mediterranean diet that was rich in fruits, vegetables, whole grains, and healthy fats. The subjects were followed for 12 weeks.

One barrier to conducting research studies with shift workers has been the subjects’ inability to come to the lab during regular business hours. The researchers got around this by going to the fire stations to apply wearable devices on the participants to collect their activity, sleep, and blood glucose levels. They also customized an app that allowed the firefighters to log their food and sleep and answer study surveys; the app also enabled the researchers to send study materials and to guide the participants on following the recommended lifestyle.

The investigators found that for the firefighters, following a time-restricted eating pattern was both safe and feasible. The subjects didn’t report any problems with concentration, reaction times, or other issues. Their quality of life generally improved.

“Overall, firefighters are a pretty healthy group of people, but we found that for those who had underlying cardiometabolic risk factors like high blood pressure, high cholesterol, and hyperglycemia, there was some benefit to TRE, especially in terms of improvement in glucose levels and blood pressure,” Taub says. “Even those who were healthy with no underlying cardiomeatabolic risk factors had improvements in quality of life and in VLDL, which is a form of bad cholesterol.”

Taub and Panda say they would like to conduct similar research on other shift workers, especially healthcare workers, but it’s difficult to get funding for such studies.

“Humans have been living with circadian rhythms for at least 200,000 years, and these rhythms clearly have a profound effect on us,” Panda says. “Shift workers, whether they are astronauts or custodians, are vital to our society. It’s time to think about how we might help them improve their health.”

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Front-loading calories early in the day reduces hunger but does not affect weight loss

Source: Cell Press
Date: 9/9/2022
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There’s the old saying in dieting that one must “breakfast like a king, lunch like a prince, and dine like a pauper,” based on the belief that consuming the bulk of daily calories in the morning optimizes weight loss by burning calories more efficiently and quickly. But according to a new study publishing September 9 in Cell Metabolism, whether a person eats their largest meal early or late in the day does not affect the way their body metabolizes calories. However, people who ate their largest meal in the morning did report feeling less hungry later in the day, which could foster easier weight loss in the real world.

“There are a lot of myths surrounding the timing of eating and how it might influence either body weight or health,” says senior author Professor Alexandra Johnstone, a researcher in the field of appetite control at the Rowett Institute, University of Aberdeen, Scotland. “This has been driven largely by the circadian rhythm field. But we in the nutrition field have wondered how this could be possible. Where would the energy go? We decided to take a closer look at how time of day interacts with metabolism.”

In this study, the investigators recruited healthy subjects who were overweight or obese to have their diets controlled and their metabolisms measured over a period of time; 16 men and 14 women completed the study. Each participant was randomly assigned to eat either a morning-loaded or an evening-loaded diet for four weeks. The diets were isocaloric, with a balance of 30% protein, 35% carbohydrate, and 35% fat. After a washout period of one week in which calories were balanced throughout the day, each participant crossed over to the opposite diet for four weeks. In that way, each participant acted as their own study control.

Throughout the study, the subjects’ total daily energy expenditures were measured using the doubly labelled water method, an isotope-based technique that looks at the difference between the turnover rates of the hydrogen and oxygen of body water as a function of carbon dioxide production. The primary endpoint of the study was energy balance measured by body weight. Overall, the researchers found that energy expenditures and total weight loss were the same for the morning-loaded and evening-loaded diets. The subjects lost an average of just over 3 kg (about 7 pounds) during each of the four-week periods.

The secondary end points were subjective appetite control, glycemic control, and body composition. “The participants reported that their appetites were better controlled on the days they ate a bigger breakfast and that they felt satiated throughout the rest of the day,” Johnstone says. “This could be quite useful in the real-world environment, versus in the research setting that we were working in.”

One limitation of the study is that it was conducted under free-living conditions rather than in the lab. Additionally, certain metabolic measurements were available only after breakfast and not after dinner.

Johnstone notes that this type of experiment could be applied to the study of intermittent fasting (also called time-restricted eating), to help determine the best time of day for people following this type of diet to consume their calories.

The group plans to expand its research into how the time of day affects metabolism by conducting studies similar to the one described here in subjects who do shift work. It’s possible these individuals could have different metabolic responses due to the disruption of their circadian rhythms. “One thing that’s important to note is that when it comes to timing and dieting, there is not likely going to be one diet that fits all,” Johnstone concludes. “Figuring this out is going to be the future of diet studies, but it’s something that’s very difficult to measure.”

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Research reveals how common online health marketing practices may violate patient privacy

Source: Cell Press
Date: 8/15/2022
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Newswise — The Health Insurance Portability and Accountability Act (HIPAA) was passed in 1996 to protect sensitive protected health information (PHI) from being disclosed without patient consent. But a study published August 15 in the journal Patterns shows that some PHI is not as secure as expected. Researchers reviewed the tactics of five digital medicine companies and the actions of cross-site tracking software to demonstrate how browsing data related to health topics is shared with Facebook for lead generation and advertising purposes.

“We started doing this research because we want to make sure people understand how they are targeted and followed across different digital platforms, including online health services and social media apps like Facebook,” says co-author Andrea Downing, an independent security researcher and co-founder of the Light Collective, a group created to study cybersecurity risks in the realm of patient privacy. “In my opinion, data gathering and predictive algorithms that are used for advertising and other purposes are one of the biggest threats to online patient communities.”

To conduct the analysis, the investigators recruited ten patient advocates and asked them to share data on how some of their online activities were being tracked. The investigators focused on patient advocates working in the hereditary cancer community space, particularly moderators of Facebook-based support groups. The participants were asked to download and share their JavaScript Object Notation (JSON) files. These files reveal how data are shared between web servers and web apps. The investigators used these files to determine how information flows from health-related websites and apps to Facebook for the purposes of targeted advertising.

The investigators focused on five clinical services used by the participants. They reviewed the companies’ websites for third-party ad trackers and looked at whether use of these ad trackers complied with the companies’ own privacy policies. They also looked at Facebook’s ad library for each participant to determine whether health data obtained through these companies influenced the types of ads that the participants were seeing.

“We constantly get bombarded by these ads,” Downing says. “Our question is, why they are being served up to us, and what information do these third parties have in order to serve up these ads?”

The five companies included in the analysis provide information or services (including genetic testing) related to inherited cancer risk. The investigators determined that two of the companies targeted ads but were consistent with their own privacy policies. The other three did not comply with their own policies and claims of privacy. “This loss of privacy can cause harm in the wrong hands, from people who want to scam the patient community or target them with misinformation,” Downing says.

This is the first peer-reviewed study from the Light Collective, which was founded in 2019 to study issues around patient privacy and digital media. Earlier this summer, the Light Collective brought their research to the Markup, a nonprofit news organization focused on the intersection of technology and society. The Markup published a related study about how hospitals share sensitive medical information collected on their websites with advertisers.

“We recognize that this is a small sampling that only scratched the surface, and clearly much more research is needed here,” Downing says. “We want to put this study in the hands of data scientists and to partner with researchers who can expand upon it. There is clearly a much-needed dialogue in this country about the state of health privacy and how it affects all patient populations.”

Eric Perakslis, Executive Director at the Center for Biomedical Informatics at Duke University, was the other co-author of the Patterns paper.

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A Study Finds That People With Low BMI Aren’t More Active

Source: Cell Press
Date: 8/27/2022
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The majority of obesity research to date has concentrated on examining people with high body mass indexes (BMI), but a Chinese research team is using a different strategy. In a study that was published in the journal Cell Metabolism, the researchers focused on those with very low BMIs. Contrary to the belief that they have a metabolism that makes them inherently more active, their data show that these individuals are really much less active than those with a BMI in the usual range. They also consume less food than those with a normal BMI.

“We expected to find that these people are really active and to have high activity metabolic rates matched by high food intakes,” says corresponding author John Speakman, a professor at the Shenzhen Institutes of Advanced Technology in China and the University of Aberdeen in the UK. “It turns out that something rather different is going on. They had lower food intakes and lower activity, as well as surprisingly higher-than-expected resting metabolic rates linked to elevated levels of their thyroid hormones.”

150 participants who were “healthy underweight” (with a BMI below 18.5) and 173 people with normal BMIs (range 21.5 to 25) were recruited by the researchers. They screened out individuals with eating problems, those who claimed to have purposefully restricted their eating, and those who were HIV-positive. Additionally, they disqualified those who had lost weight recently that may have been caused by an illness or who were using any form of medicine. Only 4 out of 150 people claimed to “exercise in a driven way,” but they did not exclude them.The participants were observed for two weeks. Their food intake was determined using the doubly-labeled water method, an isotope-based approach that gauges energy expenditure by comparing the turnover rates of hydrogen and oxygen in body water as a function of carbon dioxide production. Their physical activity was tracked using an accelerometry-based motion detector.

The investigators found that compared with a control group that had normal BMIs, the healthy underweight individuals consumed 12% less food. They were also considerably less active, by 23%. At the same time, these individuals had higher resting metabolic rates, including elevated resting energy expenditure and elevated thyroid activity.

“Although these very lean people had low levels of activity, their markers of heart health, including cholesterol and blood pressure, were very good,” says first author Sumei Hu, currently at the Beijing Technology and Business University. “This suggests that low body fat may trump physical activity when it comes to downstream consequences.”

The investigators acknowledge some limitations of this research, including the fact that although they measured food intake, they didn’t measure what the participants were actually eating or their feelings of satiation or satiety.

The team is now expanding its research, including studies that include these measures. They also plan to look at genetic differences between normal weight and healthy underweight individuals. Preliminary analysis suggests single nucleotide polymorphisms in certain genes that might play a role. When these genetic changes were replicated in mice, the animals had some aspects of the phenotype that was observed in human subjects.

“The next stage is to understand more about the phenotype itself and understand the mechanisms that generate it more clearly,” says Speakman.