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For decades, the power of the placebo effect was thought to lie in patients’ belief that they were — or at least, could be — receiving a pharmacologically active treatment. A new study by physician-researchers at Beth Israel Deaconess Medical Center (BIDMC) suggests that patients don’t need to be deceived to receive benefit from treatment with placebo.
In a randomized clinical trial published in the journal PAIN, researchers found participants with moderate to severe irritable bowel syndrome (IBS) who were knowingly treated with a pharmacologically inactive pill — referred to as an honest or open-label placebo — reported clinically meaningful improvements in their IBS symptoms. People who received the open-label placebo experienced improvements that were significantly greater than those reported by participants assigned to a no-pill control group. There was no difference in symptom improvement between those who received open-label or double-blind placebos. The results build on the research team’s previous findings and challenge the long-held notion that concealment or deception are key elements in the placebo effect.
“The clinical response to open-label placebo in this six-week trial was high, with 69 percent of participants who received open-label placebo reporting a clinically meaningful improvement in their symptoms,” said first and corresponding author Anthony J. Lembo, MD, Professor of Medicine in the Division of Gastroenterology at BIDMC. “IBS is one of the most common reasons for healthcare consultations and absenteeism from work or school. Effective treatment options for IBS are limited, and we hypothesized it may be possible to ethically harness the placebo effect for clinical benefit.”
For the rigorously designed clinical trial, researchers enrolled 262 adult participants, 18 to 80 years old with at least moderately severe irritable bowel syndrome, as measured by the validated IBS-Severity Scoring System (IBS-SSS), which measures frequency and severity of abdominal pain and distention, quality of life and other relevant factors across a scale of 0-500. Participants were examined, filled out baseline questionnaires and were randomized into one of three study arms; open-label placebo; double-blind (which included double-blind placebo or double-blind peppermint oil); or no-pill control. During their examinations, all participants discussed the placebo effect, the trial and its aims with their physicians.
The open-label group received pill bottles labeled “open-label placebo,” and were told that the pills inside were pharmacologically inert, but could make them feel better through the placebo effect. The double-blind group received pill bottles labeled “double-blind placebo or peppermint oil.” Participants in the double-blind group received either a placebo or an identical pill containing peppermint oil, but neither they nor the research team knew which they received. All participants who received pills were instructed to take one pill three times a day, 30 minutes before meals. The no-pill control group received no pills but otherwise followed identical study protocol. During return visits three and six weeks into the study, all participants completed questionnaires, were verbally asked about adverse events and briefly met with a study physician.
Lembo and colleagues — including senior author, Ted J. Kaptchuk, Director of the Program in Placebo Studies and the Therapeutic Encounter at BIDMC — found that improvement in IBS-SSS scores from baseline to the six-week endpoint was significantly greater in the open-label placebo group compared to the no-pill control group. Additionally, participants in the double-blind placebo group also saw superior symptom improvement compared to the no-pill control group, but the double-blind and open-label groups were not different from each other.
Next, the researchers performed a post hoc analysis of the participants who experienced large clinical improvements — those who improved by at least 50 points and by at least 150 points, considered strong and very strong clinical responses, respectively. A greater percentage of participants in the open-label placebo and double-blind placebo groups reported a 50 point reduction in IBS severity score compared to the no-pill control group (approximately 70 percent in each placebo group compared to 54 percent in the no pill control group). Similarly, approximately 30 percent of open-label placebo and double-blind placebo participants reported a 150 point reduction in IBS symptoms, compared to only 12 percent of the no-pill group.
“If the presumption that deception is necessary for placebos to be effective is false, then many theories about the mechanisms that drive placebo effects may need modification,” said Kaptchuk, who with colleagues in 2010, published the results of the first randomized controlled trial to show that patients with IBS responded well to treatment with open-label placebo. Subsequent research has demonstrated similar findings in patients with what they call subjective symptoms, including low back pain, knee pain, cancer-related fatigue, migraine headaches, menopausal hot flashes, and allergic rhinitis. “Our finding that openly prescribed placebo may be as effective as double-blinded placebo has implications for clinical practice and for future research, especially in chronic visceral and somatic pain conditions.”

Washington State University researchers have discovered a protein that could be key to blocking the most common bacterial cause of human food poisoning in the United States.
Chances are, if you’ve eaten undercooked poultry or cross contaminated food by washing raw chicken, you may be familiar with the food-borne pathogen.
“Many people that get sick think, ‘oh, that’s probably Salmonella,’ but it is even more likely it’s Campylobacter,” said Nick Negretti (’20 Ph.D.), a lead member of the research team in Michael Konkel’s Laboratory in WSU’s School of Molecular Biosciences.
According to a study on the research recently published in Nature Communications, a secreted protein known as CiaD facilitates cell entry by Campylobacter and takes control of important cell processes by changing the composition of a protein complex inside the cell.
By gaining insight into the infection process and the specific actions of the Campylobacter secreted proteins, the work gives the WSU team and the rest of the field a foundation to understanding why infections occur and persist.
Until the Konkel Lab’s latest finding, the functions of the bacterium’s proteins and how they infect the cell were largely unknown.

A mechanism has been identified that explains how physical exercise in pregnancy confers metabolic health benefits in offspring. According to researchers, the key lies with a protein called SOD3, vitamin D and adequate exercise, with the outcomes possibly forming the first steps to designing rational diet and exercise programs to use during pregnancy and particularly when mothers may also be overweight or obese.
The study, which was led by authors from the Joslin Diabetes Center at the Harvard Medical School and colleagues from Japan, the US, Canada and Denmark, has been published online by Cell Metabolism.
“We’ve known for a while that risks for obesity and type 2 diabetes can originate in the critical prenatal developmental period,” said senior author Laurie Goodyear. “In particular, there is real concern that the increasing levels of obesity seen in women of reproductive age will transmit disease risk to subsequent generations. It’s important to understand that if this is not alleviated, rates of diabetes and obesity will only continue to grow in the coming years.”
Many previous studies have linked increased maternal body weight and unhealthy diets to poorer metabolic outcomes in offspring, often many years later. Understanding the mechanisms of how maternal exercise can reverse these effects might lead to interventions that prevent these diseases transmitting across generations, say the authors of the study.
“The findings offer an explanation as to why physical exercise during pregnancy may have metabolic benefits for offspring as they get older,” said Goodyear. “We show how physical exercise during pregnancy, in combination with adequate vitamin D levels, enhances levels of a placenta-derived protein called SOD3 (superoxide dismutase 3), and that via a number of intermediate steps, this improves glucose tolerance in offspring.”
The findings come from a series of investigations with pregnant mice, comparing groups exposed to voluntary wheel running (i.e., exercise) and groups that were sedentary. Using various techniques, the authors carefully investigated the effects of exercise on parameters such as DNA methylation, cell signaling and gene expression, particularly in relation to glucose metabolism.

When variants of SARS-CoV-2 (the virus that causes COVID-19) emerged in late 2020, concern arose that they might elude protective immune responses generated by prior infection or vaccination, potentially making re-infection more likely or vaccination less effective. To investigate this possibility, researchers from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and colleagues analyzed blood cell samples from 30 people who had contracted and recovered from COVID-19 prior to the emergence of virus variants. They found that one key player in the immune response to SARS-CoV-2 — the CD8+ T cell — remained active against the virus.
The research team was led by NIAID’s Andrew Redd, Ph.D., and included scientists from Johns Hopkins University School of Medicine, Johns Hopkins Bloomberg School of Public Health and the immunomics-focused company, ImmunoScape.
The investigators asked whether CD8+ T cells in the blood of recovered COVID-19 patients, infected with the initial virus, could still recognize three SARS-CoV-2 variants: B.1.1.7, which was first detected in the United Kingdom; B.1.351, originally found in the Republic of South Africa; and B.1.1.248, first seen in Brazil. Each variant has mutations throughout the virus, and, in particular, in the region of the virus’ spike protein that it uses to attach to and enter cells. Mutations in this spike protein region could make it less recognizable to T cells and neutralizing antibodies, which are made by the immune system’s B cells following infection or vaccination.
Although details about the exact levels and composition of antibody and T-cell responses needed to achieve immunity to SARS-CoV-2 are still unknown, scientists assume that strong and broad responses from both antibodies and T cells are required to mount an effective immune response. CD8+ T cells limit infection by recognizing parts of the virus protein presented on the surface of infected cells and killing those cells.
In their study of recovered COVID-19 patients, the researchers determined that SARS-CoV-2-specific CD8+ T-cell responses remained largely intact and could recognize virtually all mutations in the variants studied. While larger studies are needed, the researchers note that their findings suggest that the T cell response in convalescent individuals, and most likely in vaccinees, are largely not affected by the mutations found in these three variants, and should offer protection against emerging variants.
Optimal immunity to SARS-Cov-2 likely requires strong multivalent T-cell responses in addition to neutralizing antibodies and other responses to protect against current SARS-CoV-2 strains and emerging variants, the authors indicate. They stress the importance of monitoring the breadth, magnitude and durability of the anti-SARS-CoV-2 T-cell responses in recovered and vaccinated individuals as part of any assessment to determine if booster vaccinations are needed.
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Primary sclerosing cholangitis (PSC) is a rare, chronic, inflammatory disease of the bile ducts and is difficult to treat, since its causes have not yet been adequately researched. Using RNA sequencing, an international research consortium led by Michael Trauner, Head of MedUni Vienna’s Division of Gastroenterology and Hepatology (Department of Medicine III), has now succeeded in identifying a new prognostic factor for PSC from liver biopsies. This is so-called cellular ER stress. ER stress is the name given to a complex cellular response to stress caused by the build-up of misfolded proteins in the endoplasmic reticulum (ER).
PSC is a rare disease with a poor prognosis and can lead to cirrhosis of the liver or bile duct cancer. It affects 0.01% of the population but, even though it is rare, PSC is responsible for more than 10% of all liver transplants, making it the third most common indication on liver transplant waiting lists in Europe.
In the recent study, which has now been published in the leading journal Hepatology, the researchers were able to identify a molecular signature for ER stress both in the liver cells (hepatocytes) and also in the bile duct epithelium — and notably as a stand-alone factor that is independent of the disease stage or degree of liver fibrosis (laying down of scar tissue) as a precursor to possible liver cirrhosis. “Using transcriptional analysis, we were able to identify a personalised molecular signature of primary sclerosing cholangitis, which shows that patients with an impaired response to ER stress have a poorer prognosis with a higher incidence of complications,” explains Trauner. “This discovery also opens up new treatment options, since ER stress can be counteracted with drugs.”
Since the build-up of potentially toxic bile acids in cholestasis results in ER stress, it is now being attempted to restore this balance pharmacologically using the new bile acid therapeutics that are available. Beneficial effects can reportedly be expected from drugs already in clinically testing — however, more research has already been initiated to explore this further.
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Researchers have mapped the distribution of SARS-CoV-2, the virus that causes COVID-19, in deceased patients with the disease, and shed new light on how viral load relates to tissue damage.
Their study of 11 autopsy cases, published today in eLife, may contribute to our understanding of how COVID-19 develops in the body following infection.
More than 24 million SARS-CoV-2 infections have been reported to date, and the number of deaths attributed to COVID-19 has exceeded 828,000 worldwide. COVID-19 occurs with varying degrees of severity. While most patients have mild symptoms, some experience more severe symptoms and may need to be hospitalised. A minority of those in hospital may enter a critical condition, with respiratory failure, blood vessel complications, or multiple organ dysfunction.
“Clinical observations suggest that COVID-19 is a systemic disease, meaning that it affects the entire body rather than just a single organ such as the lungs,” explains co-first author Stefanie Deinhardt-Emmer, Resident in Medical Microbiology, Jena University Hospital, Jena, Germany. “But we don’t currently have a clear understanding of disease development in humans and other organisms, due to the lack of appropriate experimental models. Investigating the viral distribution of SARS-CoV-2 within the human body and how this relates to tissue damage would help us address this gap.”
To do this, Deinhardt-Emmer and colleagues studied 11 autopsy cases of patients with COVID-19. They performed the autopsies at the early postmortem stage to minimise bias due to the degradation of tissues and viral ribonucleic acid (RNA — a molecule similar to DNA).
Their analysis revealed high viral loads in most of the patients’ lungs, which had caused significant damage to those organs. Using an imaging technique called transmission electron microscopy, the team also visualised intact viral particles in the lung tissue.
“Interestingly, we also detected SARS-CoV-2 RNA throughout various other tissues and organs unrelated to the lungs that did not cause visible tissue damage,” says co-first author Daniel Wittschieber, Senior Forensic Pathologist at Jena University Hospital. The researchers say that this distribution of viral RNA throughout the body supports the idea that our immune system is unable to respond adequately to the virus’ presence in the blood.
“We show that COVID-19 is a systemic disease as determined by the presence of virus RNA, and yet unrelated to tissue damage outside the lungs,” says co-senior author Bettina Löffler, Director of the Institute for Medical Microbiology, Jena University Hospital. “To our knowledge, this study is the only one to date that has measured viral loads in a wide variety of organs and tissues, with more than 60 samples studied per patient.”
“The insights gathered from our work may add to our understanding of how COVID-19 develops in the body following infection,” concludes co-senior author Gita Mall, Head of the Institute of Forensic Medicine, Jena University Hospital.
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Recent studies indicate a link between children’s cardiorespiratory fitness and their school performance: the more athletic they are, the better their marks in the main subjects — French and mathematics. Similarly, cardiorespiratory fitness is known to benefit cognitive abilities, such as memory and attention. But what is the real influence of such fitness on school results? To answer this question, researchers at the University of Geneva (UNIGE), Switzerland tested pupils from eight Geneva schools. Their results, published in the journal Medicine & Science in Sport & Exercise, show that there is an indirect link with cardiorespiratory fitness influencing cognitive abilities, which in turn, influence school results.
Charles Hillman, a professor at Northeastern University in Boston and co-author of this study, has suggested in previous research that there is a link between children’s cardiorespiratory fitness and their academic performance, as well as a beneficial effect of cardiorespiratory fitness on executive functions. “There are three main executive functions,” explains Marc Yangüez, a researcher at the UNIGE’s Faculty of Psychology and Educational Sciences (FPSE) and first author of the study. “The first is inhibition, i.e., our ability to inhibit intrusive or irrelevant behaviour or thoughts. The second is cognitive flexibility, which often called multitasking, and refers to our ability to flexibility move between tasks or responses based on task demands. Finally, the third is working memory, which is our ability to maintain information in our minds and manipulate it.”
However, the link between fitness and academic skills does not seem obvious at first sight. This is why researchers at the UNIGE wanted to analyze it and observe how one influences the other and whether a specific cognitive process plays a predominant role.
Testing the physical and cognitive abilities of Geneva students
The Geneva investigators teamed up with eight schools in the canton of Geneva to conduct cognitive and physical tests on 193 pupils aged 8 to 12. First of all, children took a physical test known as the “shuttle run test”: the children had to run back and forth between two lines 20 meters apart at an increasingly fast pace. “Combined with height, weight, age and sex, this test allows us to assess the child’s cardiovascular fitness,” says Marc Yangüez. “Following this, we used nine tasks that allow us to assess children’s abilities in the three main executive functions — inhibition, cognitive flexibility and working memory — and we measured different indicators such as the precision and speed of their responses,” explains Julien Chanal, researcher at the FPSE of the UNIGE. For example, one of the tests of inhibition presents students with images of fish swimming. The central fish can either swim in the same direction as the others or in the opposite direction. The students have to indicate as quickly and accurately as possible the direction in which the central fish is swimming when they are only shown the picture for 200 milliseconds. To measure cognitive flexibility, the students took three tests as well, one of the tests asked the students to connect in ascending order numbers and letters (1-A-2-B-3-C, etc.). In one of the working memory tests, the students had to memorize a sequence of numbers, such as 2 6 4 9 7, and then repeat them in the reverse order. In addition, at the end of the year, the teachers, with the parents’ consent, transmitted the students’ marks for the three terms of the year in mathematics, French 1 (comprehension and expression of text) and French 2 (grammar, spelling and vocabulary).
An indirect link between cardiorespiratory fitness and school results
By combining the data obtained, the psychologists found that there was a link between better cardiorespiratory fitness and higher marks in mathematics and French 2. “French 1 is probably less directly concerned, because the evaluation of the text and the writing depend more on subjective factors, which is less the case for mathematics or grammar, for which there is little subjectivity in the right or wrong answers,” explains Marc Yangüez. In addition to the existence of a link between cardiorespiratory fitness and school results, the data obtained also confirm a link between cardiorespiratory fitness and executive functions. But does good cardiorespiratory fitness affect academic performance directly or indirectly through executive functions?
“By decomposing these effects via a statistical mediation model, we established that the link between cardiorespiratory fitness and academic performance was indirect. In fact, physical fitness is related to better executive functions, and it is indeed executive functions that influences school performance, more specifically cognitive flexibility,” emphasizes Julien Chanal.
Important results for the planning of physical education in schools
The results of this study are important for the organization of school planning. “By demonstrating the link between physical capacities, such as cardiorespiratory capacity, cognitive abilities and grades, it underlines the importance of not reducing physical activity (and in particular physical education hours) in favour of other subjects, as this could ultimately have a negative impact on the development of the child as a whole,” says Marc Yangüez. This study also challenges the idea of forcing children to study more and spend more time at their desks in order to succeed at school, depriving them of physical exercise. Finally, and all the more so in times of a pandemic, the Geneva psychologists stress the importance of not depriving children of movement, which would be detrimental to both their physical health and their cognitive health. “We would now like to carry out an intervention study into schools in different regions of Switzerland, in order to demonstrate on a large scale that when children’s weekly physical activity increases, it has a positive impact on the development of executive functions, leading to a significant improvement in school results,” concludes Julien Chanal.

Humans are creating or exacerbating the environmental conditions that could lead to further pandemics, new University of Sydney research finds.
Modelling from the Sydney School of Veterinary Science suggests pressure on ecosystems, climate change and economic development are key factors associated with the diversification of pathogens (disease-causing agents, like viruses and bacteria). This has potential to lead to disease outbreaks.
The research, by Dr Balbir B Singh, Professor Michael Ward, and Associate Professor Navneet Dhand, is published in the international journal, Transboundary and Emerging Diseases.
They found a greater diversity of zoonotic diseases (diseases transmitted between animals and humans) in higher income countries with larger land areas, more dense human populations, and greater forest coverage.
The study also confirms increasing population growth and density are major drivers in the emergence of zoonotic diseases. The global human population has increased from about 1.6 billion in 1900 to about 7.8 billion today, putting pressure on ecosystems.
Associate Professor Dhand said: “As the human population increases, so does the demand for housing. To meet this demand, humans are encroaching on wild habitats. This increases interactions between wildlife, domestic animals and human beings which increases the potential for bugs to jump from animals to humans.”
“To date, such disease models have been limited, and we continue to be frustrated in understanding why diseases continue to emerge,” said Professor Ward, an infectious diseases expert.

Working with fruit flies, scientists at Johns Hopkins Medicine say they have identified a new molecular pathway that helps steer moving cells in specific directions. The set of interconnected proteins and enzymes in the pathway act as steering and rudder components that drive cells toward an “intended” rather than random destination, they say.
In a report on the work, published March 2 in Cell Reports, these same molecular pathways, say the scientists, may drive cancer cells to metastasize or travel to distant areas of the body and may also be important for understanding how cells assemble and migrate in an embryo to form organs and other structures.
The team of scientists was led by Deborah Andrew, Ph.D., professor of cell biology and associate director for faculty development for the Institute for Basic Biomedical Sciences at the Johns Hopkins University School of Medicine.
Andrew and her colleagues began this research while studying a gene called Tre1 and its role in the development of salivary glands in fruit flies. The tools to study the effects of turning the gene on and off weren’t ideal, she says. So, two of the team members, Caitlin Hanlon, Ph.D., of Quinnipiac University and JiHoon Kim, Ph.D., of Johns Hopkins, generated fruit flies that lack the protein-coding portion of the Tre1 gene. The pair also put a fluorescent tag on the Tre1 protein to learn where it localized during key steps in development.
In experiments with fruit fly embryos carrying an intact Tre1 gene, cells that produce future generations of the organism, called germ cells, migrate correctly to the sex organ, known as the gonad.
“Without the Tre1 gene, however, most of the germ cells failed to meet up with other nongerm cells, or somatic cells, of the gonad,” says Andrew. “Correct navigation of germ cells is important to ensure that future generations of the organism will happen.”
This is not the first time that scientists noted Tre1’s importance in germ cell navigation. Two research teams from Indiana University and the Massachusetts Institute of Technology had previously made the link. However, says Andrew, questions remained about what happens inside germ cells to get cells to the right place once Tre1 activates.