New data collected by University of Minnesota Medical School researchers demonstrate a clear connection between nicotine withdrawal and poor eating habits. Their findings point to the opioid system, the brain functions responsible for addiction and appetite regulation, as a possible cause for smoker preference of energy-dense, high-calorie food during nicotine withdrawal. This can lead to weight gain, for those who quit smoking, which, in turn, may increase the risk of relapse.
Mustafa al’Absi, PhD, a licensed psychologist and professor in the Department of Family Medicine and Biobehavioral Health at the U of M Medical School, Duluth Campus, is the principal investigator and the senior author of the study recently published in the Journal of Drug and Alcohol Dependence.
“We looked at whether or not acute nicotine withdrawal increases the intake of junk food — high in salt, fat and sugar — and how the stress-relieving receptors of the opioid system are involved,” al’Absi said. “Mitigating these challenges during the treatment process will help patients quit smoking while understanding their eating habits and encourage healthier decisions.”
The team studied a group of smoking and non-smoking participants between the ages of 18 and 75 during two laboratory sessions. All were randomly assigned to do a 24-hour withdrawal from nicotine products and administered either a placebo or 50 mg of naltrexone. At the end of each session, participants were given a tray of snack items that differed in high to low energy density and dimensions of salty, sweet and fat. The study found that: Smokers undergoing nicotine withdrawal consumed more calories than non-smokers. Participants were also less likely to select high-fat food after the naltrexone was administered than placebo. “The study’s findings may be related to the use of food, especially those high in calories, to cope with the negative affect and distress that characterizes the feelings people experience during smoking withdrawal,” al’Absi said. “Results from preclinical and clinical research support this and demonstrate that stress increases proclivity for high-fat and high-sugar foods.” Naltrexone normalized calorie intake to levels seen in non-smokers, suggesting that the opioid system may be a mechanism of withdrawal-induced intake of calories. “This is rather a novel finding in the context of nicotine addiction and has lots of implications for the development of future treatment,” al’Absi said. The choice and consumption of food items were impacted by the participants’ smoking backgrounds.al’Absi and his team are now focusing on the impact of appetite changes on weight gain post-cessation and the extent to which these changes hinder smoking cessation and increase the risk of relapse. Future work will be critical to identifying the mechanisms of these changes and could be targeted for therapeutic interventions.
“These findings extend earlier studies that indicate the impact of tobacco use on appetite and help identify the influence of an important biological link, the brain opioid system, on craving during nicotine withdrawal,” al’Absi said. “The fear of weight gain is a major concern among smokers who think about quitting. The key to removing these barriers is to better understand the factors that increase the urge for high-caloric foods.”
Co-authors include Justin J. Anker, PhD Nakajima Motohiro, PhD, Sharon Allen, MD, PhD, of the University of Minnesota Medical School, and Susan Raatz PhD, MPH, RD, in the Department of Food Science and Nutrition at the University of Minnesota.
This research was funded, in part by grants R01DA016351 and R01DA027232 awarded to al’Absi and the Stress and Resilience Research Laboratory by the National Institute on Drug Abuse. The grant K01AA024805 was awarded to Anker by the National Institute on Alcohol Abuse and Alcoholism.
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Materials provided by University of Minnesota Medical School. Original written by Alyssa Dindorf. Note: Content may be edited for style and length.

Can specific dietary guidelines help people living with bipolar disorders better manage their health? Maybe someday, according to a new study by Penn State College of Medicine researchers. Clinical trial results showed that a diet designed to alter levels of specific fatty acids consumed by participants may help patients have less variability in their mood.
Bipolar disorders, which affect up to 2.4% of the population, are mental health conditions where individuals experience cyclic and abnormally elevated and/or depressed mood states. During acute episodes, parts of the brain that regulate emotions are underactive, leading to either manic highs or depressive lows. Researchers are identifying ways to help patients with the symptoms they experience between episodes, which can include pain, anxiety, impulsivity and irritability.
“As clinicians, we understand that if we can help our patients better control these symptoms between episodes, it could help reduce the number of times they relapse into acute episodes,” said Dr. Erika Saunders, Shively-Tan Professor and chair of the Department of Psychiatry and Behavioral Health at Penn State Health Milton S. Hershey Medical Center. “Our goal with this trial was to see if specific dietary interventions could help patients with mood variability between episodes.”
Saunders and her colleagues designed a diet to alter the levels of specific polyunsaturated fatty acids — nutrients found in many foods — participants consumed while participating in usual care for bipolar disorders, including mood-stabilizing medication. Prior research showed that medications for treating bipolar disorders change the way bodies break down, or metabolize, fatty acids. The byproducts of this process activate different parts of the immune system and include other chemical processes that affect how the body perceives pain, a common symptom reported by people living with bipolar disorders.
The researchers hypothesized that by changing the type and amount of fatty acids consumed, the body would generate metabolites with specific purposes, such as reducing pain or inflammation. The experimental diet decreased omega-6 fatty acid consumption by limiting red meat, eggs and certain oils, and increased omega-3 fatty acid consumption by adding flax seed and fatty fishes like tuna and salmon. To keep participants unaware of which group they were in, the team gave participants specific meal plans with instructions on how to prepare their food as well as unlabeled cooking oils and specially prepared snack foods and baked products.
More than 80 people with bipolar disorders participated in diet counseling and were given specific foods to eat for a 12-week period. Twice a day they completed surveys on their mobile devices about their mood, pain and other symptoms. Throughout the study participants also had bloodwork taken so researchers could measure fatty acid levels and how the food was affecting their bodies. According to the researchers, the experimental diet improved mood variability in patients with bipolar disorders. The results were published in the journal Bipolar Disorders.
“At this time, we can’t yet recommend this type of diet for patients with bipolar disorders, although we found the diet to be safe,” said Saunders, noting that follow-up studies are needed. “This carefully constructed nutrition plan shows promise for regulating mood between manic and depressive episodes, but we’re not sure if this could be widely adopted since it would be challenging for patients to follow this rigorous program.”
In the future, the research team will continue to assess how fatty acid metabolites may affect pain in bipolar disorders. Saunders said that by replicating the study, they hope to make sound, scientific dietary recommendations for people with bipolar disorders that could be more easily implemented in their everyday lives.
“This diet isn’t meant to be a treatment for people with bipolar disorders who are experiencing acute, severe depression or mania,” Saunders said. “Rather, our goal is to develop solutions to help patients have better long-term management of their symptoms, including pain.”
Dahlia Mukherjee, Tiffany Myers, Emily Wasserman, Ahmad Hameed, Venkatesh Bassappa Krishnamurthy and Ming Wang of Penn State College of Medicine; Beth MacIntosh of University of North Carolina; and Anthony Domenichiello and Christopher Ramsden of the National Institute on Aging also contributed to this research. The authors report no conflicts of interest.
This project was funded by the Stanley Medical Research Institute (grant #13T-013). Additional support was provided by the National Institutes of Health through the National Institute on Aging, the National Institute on Alcohol Abuse and Alcoholism and the National Center for Advancing Translational Sciences through Penn State Clinical and Translational Science Institute (grant UL1 TR002014).
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Materials provided by Penn State. Original written by Zachary Sweger. Note: Content may be edited for style and length.

Engineers at MIT have developed a new approach to removing lead or other heavy-metal contaminants from water, in a process that they say is far more energy-efficient than any other currently used system, though there are others under development that come close. Ultimately, it might be used to treat lead-contaminated water supplies at the home level, or to treat contaminated water from some chemical or industrial processes.
The new system is the latest in a series of applications based on initial findings six years ago by members of the same research team, initially developed for desalination of seawater or brackish water, and later adapted for removing radioactive compounds from the cooling water of nuclear power plants. The new version is the first such method that might be applicable for treating household water supplies, as well as industrial uses.
The findings are published in the journal Environmental Science and Technology — Water, in a paper by MIT graduate students Huanhuan Tian, Mohammad Alkhadra, and Kameron Conforti, and professor of chemical engineering Martin Bazant.
“It’s notoriously difficult to remove toxic heavy metal that’s persistent and present in a lot of different water sources,” Alkhadra says. “Obviously there are competing methods today that do this function, so it’s a matter of which method can do it at lower cost and more reliably.”
The biggest challenge in trying to remove lead is that it is generally present in such tiny concentrations, vastly exceeded by other elements or compounds. For example, sodium is typically present in drinking water at a concentration of tens of parts per million, whereas lead can be highly toxic at just a few parts per billion. Most existing processes, such as reverse osmosis or distillation, remove everything at once, Alkhadra explains. This not only takes much more energy than would be needed for a selective removal, but it’s counterproductive since small amounts of elements such as sodium and magnesium are actually essential for healthy drinking water.
The new approach uses a process called shock electrodialysis, in which an electric field is used to produce a shockwave inside an electrically charged porous material carrying the contaminated water. The shock wave propagates from one side to the other as the voltage increases, leaving behind a zone where the metal ions are depleted, and separating the feed stream into a brine and a fresh stream. The process results in a 95 percent reduction of lead from the outgoing fresh stream.

Rift Valley fever virus causes economically devastating outbreaks of hemorrhagic fever in livestock such as sheep, goats and cattle. These mosquito-borne outbreaks lead to infection in people working with dead or dying animals, sometimes causing hundreds of human cases and dozens of deaths.
Rift Valley fever, for which there is no specific treatment, has been limited to Africa and the Arabian Peninsula. But mosquitoes capable of transmitting the virus can be found all over the world, necessitating a need to understand and control the virus.
Researchers at Washington University School of Medicine in St. Louis and the University of Pittsburgh Center for Vaccine Research and School of Public Health have discovered that the virus gets inside cells by taking advantage of a protein normally involved in taking up low-density lipoproteins (LDL, the carriers of so-called bad cholesterol) from the blood. The discovery, published Sept. 23 in the journal Cell, could lead to therapies that prevent Rift Valley fever or reduce its impact by interfering with the ability of the virus to get into cells.
“For people in areas where Rift Valley fever is endemic, an outbreak threatens not only their livelihood but their health,” said co-senior author Gaya K. Amarasinghe, PhD, a professor of pathology & immunology and of biochemistry & molecular biophysics at Washington University. “People have a 1% to 2% chance of death if they get infected with this virus, which doesn’t sound like much, but it’s about the same as COVID-19. The disease is much more severe in domesticated animals, especially young animals, which get very ill and die in large numbers. This virus has been flying under the radar, but given that it’s transmitted by mosquitoes that are found everywhere, it could spread into other parts of the world and become a serious issue.”
The World Health Organization has listed Rift Valley fever as a prioritized disease likely to cause epidemics in the near future. The virus spreads easily among domesticated animals via mosquito bite. People also can be infected by mosquito bite, but most people who become infected are workers exposed to infected animal body fluids as they care for sick animals or dispose of their remains.
To find out how the virus invades cells, first author Safder Ganaie, PhD, a postdoctoral researcher who works with Amarasinghe, grew the virus on mouse cells in a dish. By systematically disrupting normal mouse genes, Ganaie and colleagues found that the virus failed to infect mouse cells that lacked certain genes, notably the gene for LDL receptor-related protein 1 (Lrp1). Further experiments showed that the virus needs LRP1 to infect mouse, hamster, cow, monkey and human cells, indicating that the virus uses the same protein across distantly related species.
The finding constitutes an opportunity. If the virus needs LRP1 to infect cells, then temporarily taking LRP1 out of commission may limit its ability to spread in the body, thereby reducing disease. The researchers used a protein that effectively does this. Called RAP, the protein attaches to LRP1 and fends off anything else that tries to attach.
The researchers infected a group of mice with the virus and simultaneously treated them with RAP. A second group of mice also was infected but was left untreated for comparison. Most of the treated mice survived, while all of the untreated mice died. Further, the treated mice had lower levels of virus throughout their bodies on the third day after infection compared with the untreated mice.
RAP itself is not a good prospect for drug development, since it’s a normal mammalian protein that plays a role in many important biological processes. But the results suggest that targeting LRP1 may lead to therapeutics for Rift Valley fever.
“This finding is the key to understanding how Rift Valley fever virus spreads not only throughout the human body but also how it is able to infect mosquitoes and different species of mammals. Knowing how the virus spreads will help us develop targeted therapies, which currently do not exist for Rift Valley fever,” said co-senior author Amy Hartman, PhD, an associate professor of infectious diseases & microbiology at the University of Pittsburgh. “This discovery opens up new opportunities to study virus-host interactions at the cellular and organismal level and enriches our understanding of the basic biology of mosquito-transmitted emerging viruses.”
The discovery that Rift Valley fever virus uses LRP1 to get inside cells is interesting because the protein is better known for its role in cholesterol metabolism. It also is thought to play a role in Alzheimer’s disease and possibly in infections by the intestinal bacterium C. difficile. It’s not clear why these disparate biological processes are linked, but Amarasinghe, Hartman and their collaborators already have several projects underway to explore these connections.

Scientists have identified two subtypes of metastatic prostate cancer that respond differently to treatment, information that could one day guide physicians in treating patients with the therapies best suited to their disease.
Building off of earlier studies that discovered clinically relevant subtypes of breast cancer and non-metastatic prostate cancer, researchers identified genetic signatures that can divide metastatic prostate tumors into two types known as luminal and basal.
Luminal tumors responded better to testosterone-blocking treatments, while basal tumors did not benefit as much from this hormone treatment. Basal tumors also included the particularly aggressive form of metastatic disease known as small cell neuroendocrine prostate cancer. Further clinical trials will be required before any new diagnostic-based treatment selection is available.
“The reason why these subtypes are important is they respond to hormone therapy very differently,” says Shuang Zhao, a professor of oncology in the University of Wisconsin School of Medicine and Public Health who helped direct the research. “In localized prostate cancer, we’ve shown that luminal tumors had a bigger benefit from anti-testosterone therapy. We wanted to know if the same pattern extended to metastatic disease.”
With colleagues at the University of California, San Francisco and other institutions, Zhao published his findings Sept. 23 in the journal JAMA Oncology. The work was co-led by Rahul Aggarwal of UCSF and Nicholas Rydzewski in the Department of Human Oncology at SMPH.
About 20 years ago, scientists discovered luminal and basal subtypes of breast cancer and found that each responds better to different therapies. This has given doctors greater precision in treating their breast cancer patients.

Traumatic brain injury (TBI) and other injuries to blood vessels in the brain, like stroke, are a leading cause of long-term disability or death. Researchers at the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health, have found a possible explanation for why some patients recover much more poorly from brain injury if they later become infected. The findings were published in Nature Immunology.
Making use of a mouse model for mild TBI (mTBI) that they had developed previously, the team of researchers led by NINDS scientist Dorian McGavern, Ph.D., discovered that viral, fungal, or a mimic for bacterial infections all impacted blood vessel repair within the meninges, the protective covering of the brain. When they looked closer, they observed that some cells of the immune system no longer moved into the site of the injury, which occurred in the uninfected animals, suggesting they were responding to systemic infection. The study also looked in a second injury model affecting the blood vessels in the brain, called a cerebrovascular injury (CVI), and saw a similar effect on repair.
“Evolution prioritizes mobilizing the immune system to fight off infection over repair,” said Dr. McGavern. “Because the body is dealing with a greater threat, cells that would normally repair the damaged blood vessels in or around the brain are needed elsewhere.”
This change in priority for the immune system is not permanent, as infected mice were able to eventually repair the blood vessel damage at a later time compared to uninfected mice, unless a second infection was encountered. This timing is especially critical in the case of CVI mice, because the delay in response produced by infection led to permanent cognitive dysfunction and damage to the brain tissue. The repaired brain blood vessels, which are normally very well sealed, remained permanently leaky.
“The presence of infection causes the immune system to take a break from repair while it fights off the virus,” said Dr. McGavern. “In the case of mild TBI, this seems to be ok, but when you have a large vascular injury in the brain itself, like a stroke, every minute counts. These findings highlight the utmost importance in quickly identifying and treating infections in patients.”
Although the presence of infection was affecting the immune system’s ability to respond to mTBI, the exact cause remained unknown. When cells in the body become infected, they call for help by releasing proteins that signal the immune system. One group of proteins released after viral infection are called type I interferons (IFN-I), which turn on a variety of genes that affect the immune response. Following mTBI, the researchers saw a large increase in IFN-I-related genes in infected compared to non-infected mice.
Additional experiments confirmed the importance of IFN-I in shifting the focus of the immune system away from blood vessel repair. Mice that have had their genome altered so that their immune cells cannot sense the presence of IFN-1 showed similar rates of repair after mTBI regardless of whether they had a viral infection. Deleting the IFN-I sensor only in one type of immune cell known to be important for repairing blood vessels after mTBI also eliminated the defect produced by infection. Finally, directly applying one of the IFN-I proteins directly to the injury site prevented blood vessel repair without the presence of infection. IFN-I signaling also appeared to play a critical role in the repair delay seen in CVI mice.
Systemic infections are common among patients hospitalized for TBI and CVI, and they have been linked to poorer outcomes. The findings in this study highlight the importance of controlling those infections (whether bacterial or viral) as quickly as possible. This is especially true for CVI patients, as a delay in repair can lead to permanent damage to the brain.

The last case of smallpox worldwide occurred in Somalia in October 1977. In 1980, the World Health Organization (WHO) declared the eradication of the smallpox. According to official sources, the virus continues to exist today only in two high-security laboratories in Russia and the USA, where it is used for research purposes.
But although this means that poxviruses are no longer an immediate threat to humans, this virus family is still of great interest to scientists. On the one hand, modified strains are used in the treatment of cancer, and on the other hand, they possess highly intriguing multiplication properties.
Smallpox viruses build their own multiplication machine
While many viruses draw largely on the biochemical resources of the host cell for their multiplication, poxviruses encode their own molecular machinery in their genome for that purpose. The important components of this machinery are two enzymes: DNA polymerase to multiply the viral genes, and RNA polymerase to transcribe the viral genes into mRNA. The RNA polymerase of the vaccinia poxvirus strain, for example, is a large complex comprising 15 different protein subunits with different biochemical functions.
A team of researchers from the Biocenter of the Julius-Maximilian’s University of Würzburg (JMU) has now for the first time been able to watch the polymerase of vaccinia viruses doing their work at an atomic level. Before that, the team had already reported on three-dimensional structure of the RNA polymerase at atomic resolution. The group in charge of the work is led by Utz Fischer, who holds the JMU’s Chair of the Department of Biochemistry I. The results of their work have now been presented in a publication in the journal Nature Structure and Molecular Biology.
Three-dimensional structures on an atomic scale
“We have mixed isolated RNA polymerase with a piece of DNA containing the promoter, i.e. the start signal for the transcription of viral genes. The enzyme recognized precisely this DNA element and started producing mRNA,” explains Julia Bartuli, in charge of the biochemical work of the study. In a next step, the samples were examined in the cryo-electron microscope, in cooperation with Bettina Böttcher from the Department of Biochemistry II. On the basis of the data collected, the scientists were able to reconstruct the three-dimensional structure of the sample down to the atomic scale, using modern computerized methods.

SharecloseShare pageCopy linkAbout sharingimage source, AFPThe head of Africa’s health agency has warned that the UK’s policy of not accepting Covid-19 vaccine certificates from the continent could increase vaccine hesitancy.Dr John Nkegasong said the UK’s stance was confusing and had far-reaching implications for vaccination campaigns. “We do not understand why the UK has taken this position,” he told a virtual news briefing. Many Africans are furious, and have called the policy discriminatory.Last week the UK government removed several countries from its so-called “red list”, from where travellers would need to quarantine if they visited England. However, it said those who have had their vaccines in most countries outside the EU and the US would still need to quarantine because the UK would not accept the certificates. The other UK nations – Scotland, Wales and Northern Ireland – set their own health policies.Dr Nkegasong, head of the Africa Centres for Disease Control and Prevention (Africa CDC), said some people in Africa would ask why they should take these vaccines if they were not recognised internationally.He said it was “a message that creates confusion within our population… creating more reticence, reluctance for people to receive vaccines”.”This message doesn’t really speak to solidarity and co-operation that we all believe are the cornerstone and ingredients for us to emerge from this pandemic together,” he addedDr Richard Mihigo from the World Health Organization’s Africa region says countries should now find a way of coming up with a mutual system that will recognise vaccine certificates by different countries. Less than 4% of people in Africa are fully vaccinated against Covid-19, compared to around 54% in the US and 65% in the UK.A shortage of vaccines is a problem in most African countries but in some, such as the Democratic Republic of Congo, vaccine hesitancy is a major issue and the government is trying to persuade more people to get jabs.You may also be interested in:Africa Live: For more on this and other storiesHow short of vaccines is Africa?UK recognises India’s Covishield jab after outcry

Researchers at the University of Surrey have released a new online tool to help schools, hospitals and residents understand and reduce the impact of traffic-related air pollution.
The Hedge Design for the Abatement of Traffic Emissions (HedgeDATE) — online tool allows users to describe their environment — such as a road with buildings on one side — and then recommends actions citizens can take to improve its air quality.
For example, HedgeDATE advises that a resident living in a shallow street canyon should install hedges and a green wall; the tool can also give more detailed information on the species of plants suitable for different locations.
The development of HedgeDATE builds on years of research and public engagement work by the University of Surrey’s Global Centre for Clean Air Research (GCARE). HedgeDATE grew out of workshops on air pollution mitigation conducted with local communities as part of Guildford Living Lab.
Professor Prashant Kumar, founding director of GCARE and founder of the Guildford Living Lab at the University of Surrey, said: “The best use of research is for public benefit. However, this poses the challenge of translating complex science into simple, evidence-based actions. At GCARE, we proactively engage with the community and produce co-designed solutions such as HedgeDATE. Soon, when the world is back on its feet after the pandemic, we will need to come to terms with the air pollution and climate change crisis.
“HedgeDATE is about giving ordinary people — our schools, hospitals and councils — easy-to-use tools that can inspire them to make a real difference to the quality of the air they breathe.”
Justine Fuller, co-author of the paper on HedgeDATE from Guildford Borough Council, said: “We have been collaborating with Professor Kumar’s team for many years. The HedgeDATE tool is an excellent means of engaging the public on air pollution issues. It has been a pleasure to support this project and will look forward to sharing this with the interested user groups.”
Dr Stuart Cole, another co-author from Oxfordshire County Council, said: “We’re proud to be collaborators on the HedgeDATE project. HedgeDATE will be a useful educational tool for councils, schools, other organisations and members of the public to consult when planning green areas for improved air quality.”
Professor Stephen Holgate, UK Research and Innovation and Met Office Clean Air Champion, and Special Advisor to the Royal College of Physicians on Air Quality, said: “HedgeDATE is another excellent outcome of the work undertaken by Professor Kumar’s team to communicate complex science via practical and accessible means. Like their earlier work on guidance for schools, this tool will help to improve and protect public health. There is an urgent need for a joined-up approach to communication, which is one of the next important tasks for us in our role as UKRI/Met Office Clean Air Champions.”
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Materials provided by University of Surrey. Note: Content may be edited for style and length.

New research in the September 2021 issue of JNCCN — Journal of the National Comprehensive Cancer Network finds that more than 80% of therapies tested in Phase III oncology trials did not achieve meaningful clinical benefit in prolonging survival. The researchers analyzed 362 industry-sponsored Phase III randomized trials in oncology from 2008 to 2017, and found that 87% were either false-positive or true-negative for meeting overall survival goals. More than half of the initially reported positive trials were found to be false-positive (58.4%) for overall survival, while the overwhelming majority of negative results were determined to be true-negative (with only 0.9% false-negative).
Dr. Shen continued: “Our study shows that reducing false positive errors by imposing more stringent statistical threshold in Phase III trials is not likely to be practically feasible. A better strategy is to rethink the process that leads to the decision of moving a new therapy to Phase III testing to begin with. More research is needed in this regard.””Our study highlights the need to more efficiently identify which new therapies merit Phase III testing,” said lead researcher Changyu Shen, PhD, Associate Professor at Harvard Medical School at the time this study was conducted. “In order to sustain the rate of innovation in cancer therapeutics and ensure that our patients have access to effective yet affordable therapies, the clinical trial pipeline in oncology must be efficient and accurate. Our work shows that in the past ten years, this has not been the case.”
Most of the trials in this novel study focused on lung, breast, gastrointestinal, and hematologic cancers; trials with fewer than 100 participants were excluded, meaning rare cancer types were less likely to be included. The Phase III trials were predominately two-arm studies of an interventional regimen compared with a control treatment.
“This paper shows that a lot of drugs with ‘positive’ Phase III trials may have a smaller ultimate benefit than was expected, and that changing the threshold for statistical significance is not a quick fix,” said Elizabeth A. Handorf, PhD, Associate Research Professor, Fox Chase Cancer Center, who was not involved in this research. “I think it highlights the need for more efficient study designs, like adaptive trials, and clear definitions of what makes an effect clinically meaningful.”
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Materials provided by National Comprehensive Cancer Network. Note: Content may be edited for style and length.