Researchers took advantage of the fact that heat can affect the structure and immunoreactivity of peanuts, and tested out a peanut allergy therapy for children using sequential doses of boiled peanuts followed by roasted peanuts. Their trial, which is published in Clinical & Experimental Allergy, generated promising results, with 80% of participants experiencing desensitisation.
For this open-label, phase 2, single-arm clinical trial, 70 children aged 6–18 years old with peanut allergies received 12-hour boiled peanuts for 12 weeks, 2-hour boiled peanuts for 20 weeks, and roasted peanuts for 20 weeks, to a target maintenance dose of 12 roasted peanuts daily.
Fifty-six of the 70 (80%) participants became desensitised to peanuts. Treatment-related adverse events were reported in 43 (61%) participants, of whom three withdrew from the trial.
“Oral immunotherapy using boiled followed by roasted peanuts represents a pragmatic approach that appears effective in inducing desensitisation and is associated with a favourable safety profile,” the authors wrote.
A trapped mountaineer survived after enduring 16 frigid hours wedged in a crevasse on a mountain in Alaska. The difficult extraction and subsequent critical care are examined in the journal Wilderness & Environmental Medicine. This compelling case study highlights the distinguishing factors that led to the successful outcome, such as continuing even when survival from severe hypothermia seems impossible.
The mountaineer was wedged about 20 metres deep in the crevasse, waiting 4.5 hours for a rescue team to arrive, followed by an 11.5-hour extrication process. His condition deteriorated and he eventually lost consciousness. Even though the rescue team collectively felt there was little or no chance of survival, they continued rescue efforts until the victim was extricated from the crevasse. He was almost immediately placed in a hypothermia wrap with active warming, loaded onto a rescue helicopter, and transported to a hospital in Fairbanks, Alaska. He was released after 14 days and made a full recovery.
“This case documents the heroic, persistent and expert rescue efforts of a group of people dedicated to saving lives. After conferring with the chief rescuer and chief of medical personnel, we pulled together our collective insights about the challenges of extracting climbers from extremely confined spaces and providing medical care to those who have had extended cold exposure,” explained lead investigator Gordon G. Giesbrecht, PhD, professor at the University of Manitoba.
Their recommendations build on lessons learned from a previously published case study of a helicopter pilot who died after being trapped in an icy crevasse for only four hours. In that paper, Dr Giesbrecht identified the need to develop processes for search and rescue personnel to prevent circum-rescue collapse, which is a complex physiological response to extreme cold that is worsened by improper handling of the patient. He cautioned that rescuers should be trained with the principle that the colder the victim is, the more care is required to perform horizontal extrication as gently as possible. Adding a few minutes for gentle handling and to reposition will not significantly increase cold exposure, but will greatly minimise the chance of rescue collapse.
“Responders should be aware of the causes, symptoms, and prevention of rescue collapse. Training should include techniques for transitioning a victim gently from vertical to a horizontal supine or, for narrower passages, to a lateral decubitus position. Even if a victim has to be hauled up in a vertical position, a simple technique using a sling or rope under the knees allows a simple, gentle and horizontal extrication from the crevasse to the surface,” noted Dr Giesbrecht.
This case emphasised the need to continue extrication and treatment efforts for a cold patient even when survival with hypothermia seems impossible. It also underscored the need for rescue teams to pre-plan equipment and procedures specific to crevasse rescue of potentially cold patients.
This case highlights an important mix of preventive and resuscitative lessons and recommendations regarding crevasse rescue in an isolated location:
Urging climbers to rope up for glacier travel in areas with known and possible crevasses.
Making sure that any rescuers who descend into crevasses are continuously observed by someone who remains on the surface and has radio contact to call for immediate assistance.
Recognizing that respirations are often more easily detected than pulses.
Trying unorthodox extrication methods when necessary.
Rescue teams deployed for crevasse rescues should carry kits with a pneumatic hammer-chisel (important for extrication), a tripod and winch, a hypothermia wrap made of a sleeping bag and chemical heating blankets, onboard oxygen supply with an adapter that connects to nasal prongs or a patient’s mask, a mechanical chest compression device, an automated external defibrillator, and IV saline with a fluid warmer. The Denali National Park and Preserve mountaineering rangers now include such kits in their rescue aircraft.
The investigators plan to submit a standardised rescue process based on these recommendations for publication after completing field testing in the summer of 2023.
When asked about what he considered the most crucial factor for survival, Dr Giesbrecht stressed that rescuers should never give up even when the patient’s survival with hypothermia seems impossible.
Research on fungi has helped transform tough-to-recycle plastic waste from the Pacific Ocean into key components for making pharmaceuticals, using a genetically altered version of an everyday soil fungus, Aspergillus nidulans. The researchers described their chemical-biological approach in Angewandte Chemie, a journal of the German Chemical Society.
“What we’ve done in this paper is to first digest polyethylenes using oxygen and some metal catalysts – things that are not particularly harmful or expensive – and this breaks the plastics into diacids,” said co-author Berl Oakley, professor at the University of Kansas.
Next, long chains of carbon atoms resulting from the decomposed plastics were fed to genetically modified Aspergillus fungi. The fungi, as designed, metabolised them into an array of pharmacologically active compounds, including commercially viable yields of asperbenzaldehyde, citreoviridin and mutilin.
Unlike previous approaches, Oakley said the fungi digested the plastic products quickly, like “fast food.”
“The thing that’s different about this approach is it’s two things – it’s chemical, and it’s fungal,” he said. “But it’s also relatively fast. With a lot of these attempts, the fungus can digest the material, but it takes months because the plastics are so hard to break down. But this breaks the plastics down fast. Within a week you can have the final product.”
The KU researcher added the new approach was “bizarrely” efficient.
“Of the mass of diacids that goes into the culture, 42% comes back as the final compound,” he said. “If our technique was a car, it would be doing 200 miles per hour, getting 60 miles per gallon, and would run on reclaimed cooking oil.”
Previously, Oakley has worked with corresponding author Clay Wang of the University of Southern California to produce about a hundred secondary metabolites of fungi for a variety of purposes.
“It turns out that fungi make a lot of chemical compounds, and they are useful to the fungus in that they inhibit the growth of other organisms – penicillin is the canonical example,” Oakley said. “These compounds aren’t required for the growth of the organism, but they help either protect it from, or compete with, other organisms.”
Oakley’s lab at KU has honed gene-targeting procedures to change the expression of genes in Aspergillus nidulans and other fungi, producing new compounds.
The researchers focused on developing secondary metabolites to digest polyethylene plastics because those plastics are so hard to recycle. For this project, they harvested polyethylenes from the Pacific Ocean that had collected in Catalina Harbor on Santa Catalina Island, California.
“There’ve been a lot of attempts to recycle plastic, and some of it is recycled,” Oakley said. “A lot of it is basically melted and spun into fabric and goes into various other plastic things. Polyethylenes are not recycled so much, even though they’re a major plastic.”
The KU investigator said the long-term goal of the research is to develop procedures to break down all plastics into products that can be used as food by fungi, eliminating the need to sort them during recycling.
“I think everybody knows that plastics are a problem,” Oakley said. “They’re accumulating in our environment. There’s a big area in the North Pacific where they tend to accumulate. But also you see plastic bags blowing around – they’re in the rivers and stuck in the trees. The squirrels around my house have even learned to line their nest with plastic bags. One thing that’s needed is to somehow get rid of the plastic economically, and if one can make something useful from it at a reasonable price, then that makes it more economically viable.”
This image shows pancreatic cancer cells (nuclei in blue) growing as a sphere encased in membranes (red). Credit: NIH
Researchers at have discovered a molecular pathway critical to the initiation of pancreatic tumours, which could partly explain the disease’s high resistance to chemotherapy and its propensity for metastasis.
The study, published in Nature Cell Biology, found that pancreatic tumour-initiating cells must first overcome local ‘isolation stress’ by creating their own tumour-promoting microenvironment, and then recruit surrounding cells into this network. By targeting this tumour-initiating pathway, new therapeutics could limit the progression, relapse and spread of pancreatic cancer.
Pancreatic cancer is one of the most lethal cancers, notoriously resistant to treatment. Almost all patients experience cancer recurrence or metastasis.
In the early stages of tumour formation, cancer cells (those with cancerous mutations, called oncogenes) experience a loss of adhesion to other cells and the extracellular matrix. This isolation leads to a local lack of oxygen and nutrients. Most cells do not survive such isolation stress, but a certain group of cells can.
Tumour-initiating cells (TIC) play a major role in the formation, recurrence and metastatic spread of tumours. What sets them apart from other cancer cells is their resilience to these early substandard conditions. Like cacti in a desert, they can adapt to the harsh environment and set the scene for further tumour progression.
“Our goal was to understand what special properties these tumour-initiating cells have and whether we can control the growth and spread of cancer by disrupting them,” said senior study author David Cheresh, PhD.
To answer these questions, first author Chengsheng Wu, PhD, a postdoctoral fellow in Cheresh’s lab, subjected pancreatic cell lines to various forms of stress, including low oxygen and sugar levels. He then identified which cells could adapt to the harsh conditions and observed which genes and molecules were modified in these cells.
The stress-tolerant tumour-initiating cells showed reduced levels of a tumour-suppressive microRNA, miR-139-5p. This in turn led to the upregulation of lysophosphatidic acid receptor 4 (LPAR4), a G-protein-coupled receptor on the cell surface.
“LPAR4 is not normally found on happy cells, but it gets turned on in stressful environments to help the cells survive, which is particularly advantageous for tumor-initiating cells,” said Cheresh.
The researchers found that LPAR4 expression promoted the production of new extracellular matrix proteins, allowing the solitary cancer cells to start building their own tumour-supporting microenvironment.
The new extracellular matrix was particularly rich in fibronectin, a protein that binds to transmembrane receptors called integrins on surrounding cells. Once the integrins on these cells sensed the fibronectin, they began signalling the cells to express their own tumour-initiating genes. Eventually, these other cells were recruited into the fibronectin matrix laid by the tumour-initiating cells and a tumour started to form.
“Our findings establish a critical role for LPAR4 in pancreatic tumour initiation, and a likely role in other epithelial cancers, such as lung cancer,” said Cheresh. “It is central to tumour-initiating cells’ ability to overcome isolation stress and build their own niche in which tumours can form.”
Chemotherapy drugs are also designed to put cancer cells under stress, and may use this pathway. Indeed, Cheresh’s team found that treating cultured tumour cells and pancreatic tumours in mice with standard-of-care chemotherapeutics also led to the upregulation of LPAR4. The researchers said this might explain how such tumour cells could develop a stress tolerance and resistance to the drugs.
Further experiments also showed that using integrin antagonists to block cells’ ability to utilise the fibronectin matrix reversed the stress tolerance benefit of LPAR4 expression. Thus, the authors suggest targeting the LPAR4 pathway or disrupting the fibronectin/integrin interaction could be effective in preventing the growth, spread and drug resistance of pancreatic tumours.
“We can think of tumour-initiating cells as being in a transient state that can be induced by different stressors, so our clinical goal would be to prevent oncogenic cells from ever entering this state,” said Cheresh. “Now that we’ve identified the pathway, we can assess all the different ways we can intervene.”
The researchers suggested a new drug targeting this pathway could be used as a prophylactic in patients at high risk of developing the disease, or to prevent new tumours from forming in cancer cases with a high likelihood of metastasis.
Pairing the new drug with existing chemotherapeutics that put stress on mature tumour cells could also mitigate the effects of drug resistance and make cancer treatments more effective, authors said.
“Treating cancer can feel a little like whack-a-mole,” said Cheresh, “but if we have two or three hammers and we know where the moles are going to pop up next, we can beat the game.”
For people with paralysis caused by neurologic injury or disease, brain-computer interfaces (BCIs) can potentially restore mobility and function by transmitting neural data to external devices such as mobility aids, which have already shown promise in trials.
Although implanted brain sensors, the core component of many brain-computer interfaces, have been used in neuroscientific studies with animals for decades and have been approved for short term use (< 30 days) in humans, the long-term safety of this technology in humans is unknown.
New results published in Neurology from the BrainGate feasibility study, the largest and longest-running clinical trial of an implanted BCI, suggest that these sensors’ safety is similar to other chronically implanted neurologic devices, with skin irritation around the implant interface.
This new report from a Massachusetts General Hospital (MGH)-led team, examined data from 14 adults with quadriparesis from spinal cord injury, brainstem stroke, or ALS who were enrolled in the BrainGate trial from 2004 to 2021 through seven clinical sites in the United States.
Participants underwent surgical implantation of one or two microelectrode arrays in a part of the brain responsible for generating the electrical signals that control limb movement. With these “Utah” microelectrode arrays, the brain signals associated with the intent to move a limb can then be sent to a nearby computer that decodes the signal in real-time and allows the user to control an external device simply by thinking about moving a part of their body.
The authors of the study report that across the 14 enrolled research participants, the average duration of device implantation was 872 days, yielding a total of 12 203 days for safety analyses. There were 68 device-related adverse events, including 6 device-related serious adverse events.
The most common device-related adverse event was skin irritation around the portion of the device that connects the implanted sensor to the external computer system. Importantly, they report that there were no safety events that required removal of the device, no infections of the brain or nervous system, and no adverse events resulting in permanently increased disability related to the investigational device.
“This interim report demonstrates that the investigational BrainGate Neural Interface system, which is still in ongoing clinical trials, thus far has a safety profile comparable to that of many approved implanted neurologic devices, such as deep brain stimulators and responsive neurostimulators,” says lead author Daniel Rubin, MD, PhD.
“Given the rapid recent advances in this technology and continued performance gains, these data suggest a favorable risk/benefit ratio in appropriately selected individuals to support ongoing research and development,.” said Rubin.
Leigh Hochberg, MD, PhD, director of the BrainGate consortium and clinical trials and the article’s senior author emphasised the importance of ongoing safety analyses as surgically placed brain-computer interfaces advance through clinical studies.
“While our consortium has published more than 60 articles detailing the ever-advancing ability to harness neural signals for the intuitive control of devices for communication and mobility, safety is the sine qua non of any potentially useful medical technology,” says Hochberg.
“The extraordinary people who enroll in our ongoing BrainGate clinical trials, and in early trials of any neurotechnology, deserve tremendous credit. They are enrolling not to gain personal benefit, but because they want to help,” said Hochberg.
Researchers have found new evidence that vitamin D may be metabolised differently in people with high body mass index (BMI), who don’t benefit as greatly from supplements of the nutrient. The study, published in JAMA Network Open, is a new analysis of data from the large-scale VITAL trial, which investigated the effect of vitamin D or marine omega-3 supplements on reducing the risk of developing cancer, heart disease, or stroke.
“The analysis of the original VITAL data found that vitamin D supplementation correlated with positive effects on several health outcomes, but only among people with a BMI under 25,” said first author Deirdre K. Tobias, ScD, an associate epidemiologist in Brigham’s Division of Preventive Medicine. “There seems to be something different happening with vitamin D metabolism at higher body weights, and this study may help explain diminished outcomes of supplementation for individuals with an elevated BMI.”
Vitamin D is an essential nutrient involved in many biological processes, most notably for mineral absorption. While some vitamin D is generated in the body from sunlight, vitamin D deficiencies are often treated with supplementation. Evidence from laboratory studies, epidemiologic research and clinical research has also suggested that vitamin D may play a role in the incidence and progression of cancer and cardiovascular disease, and it was this evidence that prompted the original VITAL trial.
The VITAL trial was a randomised, double-blind, placebo-controlled trial in 25,871 U.S. participants, which included men over the age of 50 and women over the age of 55. All participants were free of cancer and cardiovascular disease at the time of enrolment. While the trial found little benefit of vitamin D supplementation for preventing cancer, heart attack, or stroke in the overall cohort, there was a statistical correlation between BMI and cancer incidence, cancer mortality, and autoimmune disease incidence. Other studies suggest similar results for type 2 diabetes.
The new study aimed to investigate this correlation. The researchers analysed data from 16 515 participants from the original trial who provided blood samples at baseline, as well as 2742 with a follow-up blood sample taken after two years. The researchers measured the levels of total and free vitamin D, as well as many other novel biomarkers for vitamin D, such as its metabolites, calcium, and parathyroid hormone, which helps the body utilise vitamin D.
“Most studies like this focus on the total vitamin D blood level,” said senior author JoAnn E. Manson, MD, DrPH, chief of the Division of Preventive Medicine at the Brigham and principal investigator of VITAL. “The fact that we were able to look at this expanded profile of vitamin D metabolites and novel biomarkers gave us unique insights into vitamin D availability and activity, and whether vitamin D metabolism might be disrupted in some people but not in others.”
The researchers found that vitamin D supplementation increased most of the biomarkers associated with vitamin D metabolism in people, regardless of their weight. However, these increases were significantly smaller in people with elevated BMIs.
“We observed striking differences after two years, indicating a blunted response to vitamin D supplementation with higher BMI,” Tobias said. “This may have implications clinically and potentially explain some of the observed differences in the effectiveness of vitamin D supplementation by obesity status.”
“This study sheds light on why we’re seeing 30–40 percent reductions in cancer deaths, autoimmune diseases, and other outcomes with vitamin D supplementation among those with lower BMIs but minimal benefit in those with higher BMIs, suggesting it may be possible to achieve benefits across the population with more personalised dosing of vitamin D,” said Manson. “These nuances make it clear that there’s more to the vitamin D story.”
The authors conclude that the VITAL findings are a call to action for the research community to continue exploring the potential benefits of vitamin D supplementation for preventing cancer and other diseases and to take BMI into account when evaluating the supplement’s health impacts.
