Publisher Health

Does dose reduction for patients on stable opioid therapy have long-term overdose and mental health risks?
Researchers from the UC Davis Center for Healthcare Policy and Research examined the potential long-term risks of opioid dose tapering. They found that patients on stable but higher-dose opioid therapy who had their doses tapered by at least 15% had significantly higher rates of overdose and mental health crisis in the second year after tapering compared to their pre-tapering period.
Their study was published June 13 in JAMA Network Open.
Opioid therapy and the push to reduce the dose of pain medication
Changes in prescribing guidelines and regulatory policies driven by the rise in opioid-related deaths have led many physicians to reduce daily doses for patients on stable opioid therapy for chronic pain. The dose reduction process — called tapering — has been linked to worsened pain, symptoms of opioid withdrawal and depressed mood among some patients.
Recently, a team of UC Davis Health researchers found an increased risk of overdose and mental health crisis up to one year following dose reduction. Their research suggested that patients undergoing tapering need significant support to safely reduce or discontinue their opioids.

Researchers at The University of Texas MD Anderson Cancer Center have developed a new approach to quantify tumor-specific total mRNA levels from patient tumor samples, which contain both cancer and non-cancer cells. Using this technique on tumors from more than 6,500 patients across 15 cancer types, the researchers demonstrated that higher mRNA levels in cancer cells were associated with reduced patient survival.
The study, published today in Nature Biotechnology, suggests this computational approach could permit large-scale analyses of tumor-specific total mRNA levels from tumor samples, which could serve as a prognostic biomarker for many types of cancers.
“Single-cell sequencing studies have shown us that total mRNA content in cancer cells is correlated with biological features of the tumor, but it’s not feasible to use single-cell approaches for analyzing large patient cohorts,” said corresponding author Wenyi Wang, Ph.D., professor of Bioinformatics & Computational Biology. “With this study, we propose a novel mathematical deconvolution technique to study this important biological feature of cancer at scale, using widely available bulk tumor sequencing data.”
Whereas single-cell sequencing approaches can profile thousands of individual cells from a sample, bulk sequencing generates an overall picture of the tumor across a larger number of cells. Because a tumor sample contains a diverse mixture of cancer and non-cancer cells, additional steps are required to isolate the cancer-specific information from bulk sequencing data.
Deconvolution is a computational technique designed to separate bulk sequencing data into its different components. This study is the first to report a deconvolution approach for quantifying total tumor-specific mRNA levels from bulk sequencing data, providing a scalable complement to single-cell analysis.
Together with Wang, the study was led by Shaolong Cao, Ph.D., former postdoctoral fellow, Jennifer R. Wang, M.D., assistant professor of Head & Neck Surgery, and Shuangxi Ji, Ph.D., postdoctoral fellow in Bioinformatics & Computational Biology.

A research team from the Hong Kong University of Science and Technology (HKUST) has demonstrated for the first time in-vivo imaging of fine neuronal structures in mouse cortex through the intact skull at an unprecedented depth of 750 µm below pia, making high-resolution microscopy in cortex near non-invasive and measurably facilitating the study of the living brain.
The direct and non-invasive visualization of neurons, glia, and microvasculature in the brain in vivo is critical for enhancing our understanding of how the brain functions. Over recent decades, great effort has been focused on developing novel techniques for in vivo imaging of the intact brain. However, none of the prevalent technologies, including ultrasound imaging (sonography), positron emission tomography (PET), and magnetic resonance imaging (MRI), provides sufficient spatial resolution to visualize biological structures at the subcellular level.
While optical microscopy such as three-photon microscopy (3PM) can provide structural and functional information in living specimens at high spatiotemporal resolution, optical aberration and scattering occur as light travels through and interacts with inhomogeneous biological tissues, fundamentally limiting the performance of optical microscopy in both resolution and depth.
Although adaptive optics (AO) is a possible solution to correct for the aberration and restore the rsolution of in vivo optical microscopy, it is not without shortcomings: the guide star signal for the conventional wavefront sensing fades away quickly when imaging depth increases.
Now, co-led by Prof. QU Jianan, professor in Department of Electronic and Computer Engineering, and Prof. Nancy IP, chair professor in Division of Life Science, an HKUST research team developed a microscope that combines 3PM with two forms of AO, demonstrating fast measurements and the correction of both low-order and high-order aberrations in tissue at great depth.
The technology makes use of two AO techniques: direct focus sensing with phase-sensitive detection and conjugate adaptive optics (CAO) with remote focusing. The guide star signal is coded and then decoded in the aberration measurement to achieve AO correction of aberrations. These enable the accurate measurement of the aberrant electric-field point-spread function of a laser in tissue and the fast correction of the aberration over a large imaging volume in the brain.
The team validated the imaging performance of the AO-3PM system using a wavelength of 1300 nm, imaging through intact skull both in vivo and on in vitro preparations. The results showed that AO-3PM achieved high spatial resolution with a drastically improved fluorescence signal over a large depth, and high-resolution in vivo structural and functional imaging of mouse cortices through the intact skull up to 750 µm below the pia mater.
Further, by using a pupil AO-3PM, the team achieved high-resolution imaging of subcortical structures up to 1.1 mm below the pia mater within the intact brain. Taking advantage of the tight focus provided by their unique AO technique, the team went on to demonstrate the capability of AO-3PM to guide precise laser microsurgery and investigate post-operative microglial dynamics in the cortex through the intact skull.
“It is absolutely fun to exploit the marriage of electronics and optics to bring a new tool for experimental biology,” Prof. Qu said. “Overall, our results demonstrate that AO-3PM technology holds great potential to advance in vivo imaging techniques and facilitate study of living brain.”
“It is truly remarkable what this state-of-the-art AO-3PM system can achieve,” Prof. Ip explained, “the high performance and unparalleled accuracy of this advanced deep-brain imaging technology will substantially widen our understanding of living brain with optimal physiological representation.”

A newly published study by University of Calgary researchers reveals a potential new way to treat chronic pain using anti-cancer drugs rather than opioid-based pain medication.
By analysing a large number of genes important in the transmission of pain information to the brain, principal investigator Dr. Christophe Altier, PhD, who holds a Canada Research Chair in Inflammatory Pain, and his team have identified the existence of a molecule in the nervous system that enhances sensitivity to pain.
This molecule had previously been thought to play a role in cancer growth but had never been reported in the nervous system. It may now be possible to use already existing anti-cancer drugs to block pain.
“The most exciting part of this discovery is that we don’t need to develop a new drug,” says Dr. Christophe Altier, PhD, associate professor at the Cumming School of Medicine (CSM) and member of the Snyder Institute for Chronic Diseases at the CSM. “We’ve shown that an existing drug, approved in the treatment of cancer, can be repurposed to treat pain.”
In the study on mice, Altier’s team showed drugs commonly used for treating lung cancer and a type of brain cancer could be effective in controlling pain. The researchers specifically tested for pain resulting from nerve injury and inflammation and found the cancer drugs worked very well. The next step is to secure funding for clinical trials to see whether the same positive results will be experienced by people suffering from chronic conditions including abdominal pain and post surgery pain.
Because the drugs being used already exist and have been proven safe, the timeline for this treatment to become a reality will be shorter than if they had to develop new medications. Altier has already filed a patent application for this novel treatment with study co-author Dr. Gerald Zamponi, PhD, professor at the CSM and member of the Hotchkiss Brain Institute.
The discovery will be welcome news for chronic pain sufferers who in the future might have the option to stop taking potentially addictive opioids that require increases in doses over time to remain effective.
“With these anti-cancer drugs, there is no effect on tolerance,” says Dr. Manon Defaye, PhD, first author on the paper. “We don’t need to increase the dose of the drug to obtain pain relief.”
Funding for this research came from the Canadian Institutes of Health Research and the Alberta Children’s Hospital Research Institute.
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A novel artificial intelligence method can be used to generate high-quality “PET/CT” images and subsequently decrease radiation exposure to the patient. Developed by the National Cancer Institute, the method bypasses the need for CT-based attenuation correction, potentially allowing for more frequent PET imaging to monitor disease and treatment progression without radiation exposure from CT acquisition. This research was presented at the Society of Nuclear Medicine and Molecular Imaging 2022 Annual Meeting.
Cancer patients often undergo several imaging studies throughout diagnosis and treatment, potentially including multiple PET/CT scans in close succession. The CT portion of the exam contributes to a patient’s overall radiation exposure yet is largely redundant. In this study, researchers sought to reduce or eliminate the need for low-dose CT in PET/CT by using an artificial intelligence model to generate virtual attenuation-corrected PET scans.
The data cohort for artificial intelligence model development included 305 18F-DCFPyL PSMA PET/CT studies. Each study contained three scans: non-attenuation-corrected PET, attenuation-corrected PET, and low-dose CT. Studies were broken down into three sets for training (185), validation (60) and testing (60). A 2D Pix2Pix generator was then used to generate synthetic attenuation-corrected PET scans (gen-PET) from the original non-attenuation-corrected PET.
For qualitative evaluation, two nuclear medicine physicians reviewed 40 PET/CT studies in a randomized order, blinded to whether the image was from original attenuation-corrected PET or gen-PET. Each expert recorded the number and locations of PET-positive lesions and qualitatively reviewed overall noise and image quality. The readers were able to successfully detect lesions on the gen-PET images with reasonable sensitivity values.
“High-quality artificial intelligence-generated images preserve vital information from raw PET images without the additional radiation exposure from CT scans,” said Kevin Ma, PhD, a post-doctoral researcher at the National Cancer Institute in Bethesda, Maryland. “This opens opportunities for increasing the frequency and number of PET scans per patient per year, which could provide more accurate assessment for lesion detection, treatment efficacy, radiotracer effectivity, and other measures in research and patient care.”
Abstract 151. “Artificial Intelligence-generated PET images for PSMA-PET/CT studies: Quantitative and Qualitative Assessment,” Kevin Ma, National Cancer Institute, National Institutes of Health, College Park, Maryland; Esther Mena, Liza Lindenberg, Deborah Citrin, William Dahut, James Gulley, Peter Choyke, Baris Turkbey, and Stephanie Harmon, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; Peter Pinto, Urologic Oncology Branch, National Cancer Insititute, National Insitutes of Health, Bethesda, Maryland; Bradford Wood, Radiology and Imaging Sciences, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and Ravi Madan, Genitourinary Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

New research has revealed that humans moderate the size of energy-rich meals they eat, suggesting people are smarter eaters than previously thought.
The findings, led by the University of Bristol, revisit the long-held belief that humans are insensitive to the energy content of the foods they consume and are therefore prone to eating the same amount of food (in weight) regardless of whether it is energy-rich or energy-poor.
The study, published today in The American Journal of Clinical Nutrition, is especially significant as it challenges a common view among researchers that people are apt to overconsume high-energy foods.
This idea stems from previous studies which manipulated the energy content of foods or meals to create low- and high-energy versions. In those studies, people were not told whether they were eating a low- or a high-energy version, and findings showed they tended to eat meals of the same weight, resulting in greater calorie intake with the high-energy version.
“For years we’ve believed that humans mindlessly overeat energy-rich meals. Remarkably, this study indicates a degree of nutritional intelligence whereby humans manage to adjust the amount they consume of high-energy density options,” said lead author Annika Flynn, Doctoral Researcher in Nutrition and Behaviour at the University of Bristol.
Rather than artificially manipulating the calories in single foods, this study looked at data from a trial using a normal, everyday meals with different energy densities, such as a chicken salad sandwich with fig roll biscuits or porridge with blueberries and almonds. The trial involved 20 healthy adults who temporarily lived in a hospital ward where they were served a variety of meals for four weeks.
The team of international researchers, including leading experts in diet and metabolism from the National Institutes of Health (NIH) in the United States, calculated the calories, grams, and energy density (calories per gram) for every meal each participant consumed. The results demonstrated that meal calorie intake increased with energy density in energy-poor meals as previous observations with artificially manipulated foods also found. However, surprisingly, with greater energy density a turning point was observed whereby people start to respond to increases in calories by reducing the size of the meals they consume. This suggests a previously unrecognised sensitivity to the energy content of the meals people were eating.
As this finding was based on data from a small, highly-controlled trial, the researchers went on to see if this pattern remained when participants lived freely, choosing their own meals. Using data from the UK National Diet and Nutrition Survey, researchers again found meal calorie intake increased with energy density in meals which were energy-poor and then decreased in energy-rich meals. Importantly, for this turning point pattern to occur, participants would have needed to consume smaller meals, by weight, of the more energy-rich meals.
Annika said: “For instance, people ate smaller portions of a creamy cheese pasta dish, which is an energy-rich meal, than a salad with lots of different vegetables which is relatively energy-poor.”
This research sheds new light on human eating behaviour, specifically an apparent subtle sensitivity to calories in energy-rich meals.
Co-author Jeff Brunstrom, Professor of Experimental Psychology, said: “This research gives added weight to the idea humans aren’t passive overeaters after all, but show the discerning ability to moderate how much of an energy-rich meal they consume.
“This work is particularly exciting as it reveals a hidden complexity to how humans interact with modern energy-rich foods, something we’ve been referring to as ‘nutritional intelligence’. What this tells us is we don’t seem to passively overconsume these foods and so the reason why they are associated with obesity is more nuanced than previously thought. For now, at least this offers a new perspective on a longstanding issue and it opens the door to a range of important new questions and avenues for future research.”
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New research has shown that normal human brain temperature varies much more than we thought, and this could be a sign of healthy brain function. In healthy men and women, where oral temperature is typically less than 37°C, average brain temperature is 38.5°C, with deeper brain regions often exceeding 40°C, particularly in women during the daytime.
Previously, human brain temperature studies have relied upon data capture from brain-injured patients in intensive care, where direct brain monitoring is often needed. More recently, a brain scanning technique, called magnetic resonance spectroscopy (MRS), has enabled researchers to measure brain temperature non-invasively in healthy people. Until now, however, MRS had not been used to explore how brain temperature varies throughout the day, or to consider how an individual’s ‘body clock’ influences this.
The new study, led by researchers at the Medical Research Council (MRC) Laboratory for Molecular Biology, in Cambridge, UK, has produced the first 4D map of healthy human brain temperature. This map overturns several previous assumptions and shows the remarkable extent to which brain temperature varies by brain region, age, sex, and time of day. Importantly, these findings also challenge a widely held belief that human brain and body temperature are the same.
The research, published in the journal Brain, also included analysis of data from patients with traumatic brain injury, showing that the presence of daily brain temperature cycles strongly correlates with survival. These findings could be used to improve understanding, prognosis, and treatment of brain injury.
Striking brain temperature variation in health
To study the healthy brain, the researchers recruited 40 volunteers, aged 20-40 years, to be scanned in the morning, afternoon, and late evening over one day, at the Edinburgh Imaging Facility, Royal Infirmary of Edinburgh.

Researchers at Karolinska Institutet in Sweden might have found an explanation for why people with self-injury behaviour generally feel less pain than others. The key seems to be a more effective pain-modulation system, a discovery that can benefit people seeking help for their self-harm. The findings are published in the journal Molecular Psychiatry.
Most people try to avoid pain, but some, especially adolescents and young adults, can sometimes subject themselves to physical injury. Self-harming is strongly associated with other mental health issues, such as anxiety and depression, but far from everyone with such a condition engages in self-injury.
“We have long tried to understand how people who display self-injury behaviour differ from others and why the pain itself isn’t a sufficient deterrent,” says Karin Jensen, researcher and group leader at the Department of Clinical Neuroscience, Karolinska Institutet, and the study’s corresponding author. “Previous studies how shown that people who self-harm are generally less sensitive to pain, but the mechanisms behind it are not fully understood.”
Tolerated more pain
In this present study, the researchers examined these mechanisms by comparing pain modulation in 41 women who had engaged in self-injury at least five times in the past year with 40 matched women without self-injury behaviour. The women, who were aged between 18 and 35, underwent laboratory pain tests at Karolinska University Hospital on two occasions in 2019-2020 during which they were asked to rate the pain they experienced from transient pressure and heat stimulations. Their brain activity during pain was also measured using MRI scans.
The researchers found that on average the self-harming women tolerated higher levels of pain than the controls. The brain scans also revealed differences in activation between the groups. Compared with the controls, the brain activity of the women with self-injury behaviour displayed more connections between brain areas directly involved in the perception of pain and those linked to the modulation of pain.
Another finding was that the difference in pain modulation was not determined by how long, how often or in what way the participants had engaged in self-injury.
Clinically useful knowledge
“Our study suggests that effective pain modulation is a risk factor for self-injury behaviour,” says Maria Lalouni, researcher at the Department of Clinical Neuroscience, Karolinska Institutet, and the study’s joint first author with Jens Fust, who recently earned his PhD on the project. “It also tells us more about differences in the brains of people who engage in self-injury, knowledge that can be used for improving the support provided to people seeking care for their behaviour as well as in conversations with patients to help them understand their self-injury and the need for treatment.”
Limitations to the study include the fact that women with self-injury behaviour tended to report more psychiatric comorbidities than the controls. They also took more drugs, such as antidepressants, which the researchers factored into their analysis.
The study was supported by grants from the Swedish Research Council and the Strategic Research Area Neuroscience (StratNeuro) at Karolinska Institutet, and by a donation from Leif Lundblad to pain research.
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Blood vessels are the body’s essential architecture that exists in order to nurture cells with sufficient nutrients and oxygen. Angiogenesis, or the formation of new blood vessels, is of great research interest in cancer medicine. As tumors need to generate new blood vessels to grow, inhibiting angiogenesis has been suggested as a promising approach to treating cancer.
Sprouting angiogenesis is the process where new sprouts are formed from pre-existing vessels. The key biological process in sprouting angiogenesis involves balancing the formation of ‘tip’ and ‘stalk’ endothelial cells (ECs). This is a process called tip-stalk specification. Tip ECs are highly motile with many long and dynamic filopodia, whereas stalk ECs are highly proliferative with fewer filopodia. These functionally distinct tip and stalk cells coordinate into a branched network of vessels for sprouting angiogenesis.
Morphologically, tip EC induction is the foremost step for sprouting angiogenesis. The formation of the tip ECs is induced by a pathway called vascular endothelial growth factor (VEGF)-A (given as VEGF hereafter) signaling. Molecularly, intracellular activation of VEGFR2 signaling is initiated by ligand-induced, clathrin-dependent VEGFR2 internalization. Scientists have long been curious how one particular EC ends up possessing higher VEGFR2 signaling activity than its neighbors and is thus fated to become a tip EC during sprouting angiogenesis.
Led by Dr. BAE Jung Hyun and Professor KOH Gou Young, researchers at the Center for Vascular Research within the Institute for Basic Science (IBS) in Daejeon, South Korea discovered that a protein called Merlin is indispensable for tip EC induction by regulating intracellular VEGFR2 downstream signaling during sprouting angiogenesis.
Merlin, encoded by the neurofibromatosis type-2 gene NF2, has been known for quite a while to function as a tumor suppressor. It is ubiquitously expressed in all types of cells and acts as a membrane-associated protein, which plays a gatekeeping role in signal transduction from membrane receptors in a cell density-dependent manner. Nevertheless, it has not been investigated whether endothelial Merlin is essential in sprouting angiogenesis and, in detail, which intracellular signaling is regulated by endothelial Merlin.
The researchers showed that the density of the EC in the environment was the key factor. When the localization and density of Merlin in the cells under low or high culture density were compared, Merlin in the high cell density culture was able to better form complex with VEGFR2. The researchers showed that this is due to the fact that the presence of VE-cadherin, a cell-to-cell junction protein, is required for Merlin and VEGFR2 to form a complex with one another. This formation of the Merlin-VEGFR2 complex suppresses VEGFR2 internalization, thereby suppressing the pathway. In contrast, Merlin in a low-density ECs environment with relatively low VE-cadherin density allows a high level of VEGFR2 signaling and ERK activation, which leads to tip EC induction.
The researchers investigated the importance of cell density on Merlin-VEGFR2 complex formation by studying Merlin in its normal form, inactive phosphorylated form (pMerlin (S518), short for phosphorylated Merlin at Serine 518), and a variant that cannot be phosphorylated. It was shown that Merlin engages in physical interaction with VEGFR2 and VE-cadherin in dense culture, which has a low pMerlin (S518), but Merlin does not engage in this interaction in sparse culture, with a high pMerlin (S518) in cultured ECs. Thus, the interaction between Merlin and VEGFR2 depends on pMerlin (S518), which is regulated by cell density.
“The role of Merlin in EC fulfills the missing piece for sprouting angiogenesis. Sprouting angiogenesis should be regulated by the coordinated balance of promotion and inhibition of signaling through Merlin,” explains the first author, BAE Jung Hyun.
The researchers further demonstrated that Merlin also plays a gatekeeping role in maintaining capillary integrity and proper angiogenesis by suppressing the unnecessary formation of filopodia and sprouting from the adult vessels in normal tissues and tumors. When the Merlin was depleted in the EC, the researchers found that an excessive amount of non-functional vessels are formed in the tumor model, which enhances tumor necrosis and reduces tumor growth. Merlin-deficient mice implanted with human lung cancer showed an impressive 80.6% reduction in tumor growth after 3 weeks in comparison to regular mice. Likewise, adult vessels in the thyroid gland and small intestine showed an increased number of filopodia in Merlin-deleted mice in comparison to wild-type mice.
Director KOH Gou Young of the Center for Vascular Research summarized, “Our study showed that Merlin is mainly localized at the cell membrane in vascular ECs, interacts with VEGFR2 and VE-cadherin, and plays a negative role in VEGFR2 intracellular downstream signaling by suppressing VEGFR2 internalization. As a consequence, endothelial Merlin can be seen as a gatekeeping regulator for tip EC induction in retinal sprouting angiogenesis during postnatal development, for formations of filopodia and sprouts in matured and established capillary ECs of adults, and for tip cell formation and proper tumor vessel construction in tumor vessels.”

Medical equipment that can be manufactured at low cost, is simple to use and can be easily maintained will help extend surgery to the 5 billion people worldwide who currently cannot get access to it, say researchers.
Writing in the IEEE Journal of Translational Engineering in Health and Medicine, they argue that surgical technology is often developed for well-resourced healthcare systems — and is of little or no use in poorer settings where hospitals lack sophisticated support infrastructure or appropriately trained staff.
Without access to medical equipment they can use, hospitals and clinics in low-to-middle income countries cannot offer surgical treatment to nine out of ten patients.
An international research team led by the University of Leeds is calling for a focus on creating medical devices specifically for use in low-to-middle income countries. They have pioneered a development approach based on “participatory design,” where the users of the technology are closely involved in its design — and where functionality of the device is pared back to key essentials.
To demonstrate their approach, the researchers describe how they designed a simplified surgical tool for performing laparoscopic — or keyhole surgery — in low resource settings. The result is that laparoscopic surgery can now be carried out in clinics and hospitals where it was not possible before.
Dr Pete Culmer, Associate Professor in Healthcare Technologies at Leeds, who supervised the research, said: “Laparoscopic surgery has benefits for patients. People recover more quickly, and the risks of cross infection are lower.