A new study investigated genetic changes that occur in a serious condition affecting scuba divers — ‘the bends’ — and found that inflammatory genes and white blood cell activity are upregulated. The findings could lead to biomarkers that will help doctors to diagnose the condition more precisely.
The bends, more formally known as decompression sickness, is a potentially lethal condition that can affect divers. Symptoms include joint pain, a skin rash, and visual disturbances. In some patients, the condition can be severe, potentially leading to paralysis and death. The bends can also affect people working in submarines, flying in unpressurised aircraft or in spacewalks.
It has been studied for a long time: a 1908 paper correctly hypothesised that it involves bubbles of gas forming in the blood and tissue due to pressure decrease. Yet even after a century the precise mechanisms underlying the condition are not well understood. Animal studies have suggested that inflammatory processes may have a role in decompression sickness, but no-one had studied this in humans.
Nowadays, getting ‘the bends’ is rare as divers have well-established methods to mitigate risk, such as controlled ascents from the depths. Nevertheless, doctors have no means to test for the condition, if they do encounter it, and instead rely on observing symptoms and seeing whether patients respond to hyperbaric oxygen therapy.
To investigate decompression sickness, the researchers sampled the blood of divers who had been diagnosed with decompression sickness and also divers who had completed a dive without it. The blood samples were drawn at two times: within 8 hours of the divers emerging from the water, and 48 hours afterwards, when those divers with decompression sickness had undergone hyperbaric oxygen treatment. RNA sequencing analysis was done to measure gene expression changes in white blood cells.
“We showed that decompression sickness activates genes involved in white blood cell activity, inflammation and the generation of inflammatory proteins called cytokines,” explained Dr Nikolai Pace of the University of Malta, a researcher involved in the study. “Basically, decompression sickness activates some of the most primitive body defense mechanisms that are carried out by certain white blood cells.”
These genetic changes had diminished in samples from 48 hours after the dive, after the patients had been treated with hyperbaric oxygen therapy — an interesting finding. The results provide a first step towards a diagnostic test for decompression sickness, and may also reveal new treatment targets.
“We hope that our findings can aid the development of a blood-based biomarker test for human decompression sickness that can facilitate diagnosis or monitoring of treatment response,” said Prof Ingrid Eftedal of the Norwegian University of Science and Technology, who was also involved in the project. “This will require further evaluation and replication in larger groups of patients.”
Journal information: “Acute effects on the human peripheral blood transcriptome of decompression sickness secondary to scuba diving” Frontiers in Physiology, DOI: 10.3389/fphys.2021.660402
Smokers needed their blocked arteries fixed nearly 10 years earlier than non-smokers, and patients with obesity underwent these procedures four years earlier than non-obese patients, according to a new US study.
Angioplasty is a nonsurgical procedure that opens clogged or narrow coronary arteries. The procedure involves inserting an inflatable balloon-tipped catheter through the skin in extremities and then inflating the balloon once it reaches the stenosed arterial site. The balloon pushes the atherosclerotic intraluminal plaque against the arterial wall and restores the luminal diameter, and so restores blood flow to the heart muscle.
The study included patients with no heart attack history, treated at hospitals across Michigan. The patients had all undergone angioplasty and/or stenting to widen or unblock their coronary arteries and restore blood flow. Nearly all of them had at least one traditional risk factor, including smoking, obesity, high blood pressure, high cholesterol and diabetes. Most patients had three or more.
Furthermore, compared to men, women generally had their first procedure at a later age. Over the past ten years, among patients undergoing their first angioplasty or stent procedure, obesity and diabetes rates have increased, while smoking and high cholesterol have decreased.
“Smoking is a completely preventable risk factor,” said senior author Devraj Sukul, MD, MSc, an interventional cardiologist and a clinical lecturer at the University of Michigan Health Frankel Cardiovascular Center. “If we direct additional efforts at preventing smoking and obesity we could significantly delay the onset of heart disease and the need for angioplasty and stenting.”
“In Michigan, we will work to help every smoker quit at the time of cardiac care because it is an unmatched teachable moment for patients,” said Michael Englesbe, M.D., a surgeon and professor at Michigan Medicine who serves as portfolio medical director for the Collaborative Quality Initiatives.
Journal information: Zoya Gurm et al, Prevalence of coronary risk factors in contemporary practice among patients undergoing their first percutaneous coronary intervention: Implications for primary prevention, PLOS ONE (2021). DOI: 10.1371/journal.pone.0250801
Researchers have demonstrated that normal breathing can transport viruses in saliva droplets up a distance of up to 2.2 metres in 90 seconds.
The World Health Organization and the Centers for Disease Controlrecommend social distancing to prevent the spread of COVID. The distances are estimated from various studies, but there is a need for further research into how viruses are transported from one person to another. Previous studies considered aerosol transport after coughing or sneezing, while this study focused on normal human breathing, using computer simulations with a more realistic model than prior studies. A normal breath produces periodic jet flows that contain saliva droplets, but those jets’ velocity is less than a tenth that of a cough or sneeze.
Wearing a face mask greatly reduces the distance which these droplets can travel. Saliva droplets restricted by a mask had travelled only 0.72 metres after two minutes, far short of the distance of 1.8 metres suggested by the CDC.
The investigators found even normal breathing produces a complex field of vortices that can move saliva droplets away from the person’s mouth. The role of these vortices has not previously been understood.
Study author, Ali Khosronejad, American Institute of Physics said: “Our results show that normal breathing without a facial mask generates periodic trailing jets and leading circular vortex rings that propagate forward and interact with the vortical flow structures produced in prior breathing cycles.”
This complex vorticity field can enable the transport of aerosol droplets over long distances despite the slow speeds. A face mask serves to dissipate the kinetic energy of the jet produced by an exhaled breath, thereby disrupting the vortices and limiting the travel of virus-laden droplets.
The researchers also took into account evaporation of the saliva droplets. With no mask, they found the saliva droplets near the front of the plume of exhaled breath had partially evaporated, reaching a size of only one-tenth of a micrometre. In stagnant indoor air, it would take days for droplets this small to settle to the ground.
Masks partially redirect the exhaled breath downward, significantly restricting forward motion of the plume, so the risk of suspended droplets remaining in the air is substantially reduced.
“To simplify the breathing process, we did not consider the flow of air-saliva mixture through the nose and solely accounted for the flow through the mouth,” Khosronejad said. “In future studies, we will explore the effect of normal breathing via both the nose and mouth.”
Journal reference: Khosronejad, A., et al. (2021) A computational study of expiratory particle transport and vortex dynamics during breathing with and without face masks. Physics of Fluids. doi.org/10.1063/5.0054204.
Underage youth consumed $17.5 billion worth, or 8.6 percent, of the alcoholic drinks sold in 2016 in the US. Nearly half of youth consumption was made up of products from three alcohol companies: AB Inbev, MillerCoors and Diageo. The study findings were published in the Journal of Studies on Alcohol and Drugs.
In a landmark study of youth alcohol consumption by brand, the authors collected large amounts of data to estimate, for the first time in two decades, the monetary value of youth alcohol consumption. And for the first time, they were able to attribute those revenues to specific companies.
“The alcohol industry has said they don’t want minors to drink, but when we counted up the drinks, it was clear that they were making billions of dollars from these sales,” said co-lead author Pamela J. Trangenstein, PhD, assistant professor of health behaviour at the University of North Carolina Gillings School of Global Public Health. “There is a clear disconnect when an industry advocates prevention but then makes billions of dollars from prevention’s failure.”
Alcohol is the number one substance used among people ages 12 to 20. Although underage drinking has fallen in recent years, alcohol is still responsible for approximately 3500 deaths annually for under 21s, according to the Centers for Disease Control and Prevention.
In the US, the minimum drinking age is 21, although before 1984 states set their own drinking age. According to the CDC, raising the drinking age to 21 saw a 16% reduction in motor vehicle accident deaths, and there is evidence that this limit protects drinkers from alcohol and other drug dependence, adverse birth outcomes, and suicide and homicide.
“Our prior studies have repeatedly shown that youth are exposed to and influenced by alcohol marketing,” commented co-author David H Jernigan, PhD, professor at Boston University. “If alcohol companies are truly committed to preventing youth drinking, they should be willing to put these revenues into an independent agency able to address underage drinking without a conflict of interest.”
The Institute of Medicine and National Research Council, the science advisory body for the US Congress, made that recommendation in their 2003 report on underage drinking. In 2006, the legislation was passed entirely devoted to curbing underage drinking. While that legislation authorised $18 million in spending, the full amount has never been used.
“Community coalitions in North Carolina and across the country are constantly begging for dollars to support their work on underage drinking,” said Prof Trangenstein. “Our study identifies a clear source for that badly needed funding. Families and communities are paying the price, while big alcohol companies are reaping all the benefits.”
More information: Eck, R. H., Trangenstein, P. J., Siegel, M., & Jernigan, D. H. (2021). Company-specific revenues from underage drinking. Journal of Studies on Alcohol and Drugs, 82, 368–376. DOI: 10.15288/jsad.2021.82.368
In addition to traditional subcutaneous administration for the vaccine candidate, the trial will measure immune responses generated by sublingual and nasal administration routes. Photo by Gustavo Fring from Pexels
The Phase I clinical trial of ImmunityBio’s experimental COVID vaccine, designed to be effective against COVID variants, is about to be expanded to include different administration routes as well as effectiveness in people who previously had COVID.
Co-investigator Prof Graeme Meintjes, second chair in the Department of Medicine at UCT, said that the Phase I trial has started and is still ongoing at the Wellcome Centre for Infectious Diseases Research in Africa’s (CIDRI-Africa) Khayelitsha clinical research site.
He said that the first two cohorts of ten participants each both received two subcutaneous injections of the vaccine, three weeks apart, with one cohort receiving a higher dose.
“The purpose of that was to assess safety, so participants were followed up very carefully for side effects and for reactions to the vaccine. And the review of that suggests no major safety concerns,” he explained. He added that the Phase I trial design has since been adapted to include four more cohorts, which is going through the approval process. These four additional cohorts will include people who have had COVID because the researchers want to look at the effect the vaccine will have on boosting existing immunity against COVID. Each cohort will have ten participants, bringing the expected total number of participants for Phase I to 60 people.
New administration routes
To see whether different administration routes produce a sufficient immune response, each participant in these new cohorts will receive one dose of the vaccine through one of four routes. These would be either a subcutaneous injection, a sublingual route, a combination of subcutaneous injection and sublingual method, or an intranasal route.
“We’ll be measuring the antibody responses as well as the T-cell responses to the vaccine, but we do not have results yet,” said Meintjes. He added that enrolment should be complete in the next two months, pending the outcome of the approval process.
Phase II/III trial plans
Phase II and Phase III trials in South Africa are being planned, which will be headed by the South African Medical Research Council (SAMRC), Mentjes confirmed.
Details will be made available once the trial has been approved by SAHPRA. It is unlikely that placebos will be used, now that vaccines are shown to be effective; rather different vaccines will be compared.
Broader immune response with two-pronged defence
The vaccine has been designed to potentially offer a broader, long-lasting immune response, Mentjes noted. In this way it should also provide improved protection against COVID variants.
Currently, most of the COVID vaccines are designed to produce an immune response against the spike protein of the virus, but it mutates rapidly, allowing certain variants to partially or fully escape vaccines.
The ImmunityBio vaccine aims to offer a two-pronged or dual defence, Meintjes said, with the vaccine containing two proteins from the SARS-CoV-2 virus: the spike protein along with the more stable nucleocapsid protein. The nucleocapsid is an RNA-binding protein which is critical for viral replication and genome packaging.
He explains that targeting nucleocapsid could potentially provide more durable and long-term protection against different variants of the SARS-CoV-2 virus because the immune system will recognise the nucleocapsid even when the spike protein changes.
“The hope is that by including the nucleocapsid you would generate a vaccine response that covers emerging variants, those that have emerged and those that might emerge in the future,” he says.
Human-adenovirus based vaccine carrier
The ImmunityBio vaccine will use an adenovirus vector to deliver the antigens. Director of the Africa Health Research Institute (AHRI), Professor Willem Hanekom, explained that a vector is needed in order to stimulate the immune system’s response, and a viral vector is effective since it is foreign to the immune system, helping provoke an immune response. The virus is designed to simply carry the antigens into the body.
The AstraZeneca vaccine uses a modified chimpanzee adenovirus while Johnson & Johnson’s uses the human adenovirus Ad26, which has been used before in a number of vaccines including HIV. ImmunityBio’s vaccine uses the human adenovirus hAd5, which was initially used in failed gene therapy trials — but which proved to be an excellent vaccine delivery system. However, its development over the past two decades has been halting.
According to Prof Hanekom, if there is previous immunity against the adenovirus being used in a vaccine, the immune system will destroy it before the antigens inside are released. This has been circumvented with the ImmunityBio vaccine so that the immune system doesn’t immediately recognise the hAd5 vector. There was concern that the Johnson & Johnson vaccine would have limited efficacy in sub-Saharan Africa due to the fact that about half the population have immunity to Ad26.
“They’ve modified the adenovirus so it will still work and still be seen by the immune system even if there is pre-existing immunity because they’ve taken out the parts that the pre-existing immunity sees,” Prof Hanekom said.
Enhanced T-cell response
The vaccine is specifically designed to elicit strong T-cell responses to the nucleocapsid, and this has been seen in animal studies, Mentjes noted.
“Obviously one purpose of these studies is to see whether this design element generates those strong T-cell responses in humans as well,” he says. “All COVID vaccines elicit T and B cell responses, it’s not one or the other. But this (vaccine) is specifically designed to enhance those T-cell responses.”
B-cells and T-cells form part of the body’s adaptive immune response. B-cells form the antibodies to respond to a pathogen, and when the virus is introduced again, memory B-cells provide the antibodies to respond quickly.
Vardas says that with the ImmunityBio vaccine, B-cells and memory B-Cells will be formed that will remember the spike protein and the nucleocapsid and how to attack it. She likens this to a sniper attack. She explains that when a memory B-cell detects the spike or nucleocapsid protein, it signals for the production of B-cell antibodies. These antibodies then coat the outside of the virus, which signals the T-cells to attack and essentially “eat up” the virus-infected cells.
There are two types of T-cells, explains Vardas – CD4 cells which attack the virus, and CD8 cells, which also form a memory cell as the B-cell does. “You’ll have groups of CD4 and CD8 cells that are spike protein-specific and groups that are nucleocapsid specific, so improving that kind of attack to two sides of the war,” said Vardas.
A small dose of nitrous oxide may be able to relive the symptoms of medication-resistant depression. Photo by Mockup Graphics on Unsplash
A new study at the University of Chicago Medicine and Washington University found that inhaling low doses of nitrous oxide gas rapidly relieved symptoms of treatment-resistant depression, with few adverse side effects. They found that this was as effective as higher doses of the gas, with fewer unpleasant side effects.
These findings add to the growing body of evidence of non-traditional treatments that may be a viable option for patients with depression that is unresponsive to typical antidepressant medications. It may also be a fast-acting and effective treatment option for patients in crisis.
Often called ‘laughing gas’, nitrous oxide is widely used as an anaesthetic, providing short-term pain relief in dentistry, emergency response and surgery.
A previous study tested a one-hour inhalation session with 50% nitrous oxide gas, which resulted in rapid improvements in depressive symptoms that lasted for at least 24 hours. However, several patients reported negative side effects, including nausea, vomiting and headaches.
“This investigation was motivated by observations from research on ketamine and depression,” said Peter Nagele, MD, Chair of Anesthesia and Critical Care at UChicago Medicine. “Like nitrous oxide, ketamine is an anaesthetic, and there has been promising work using ketamine at a sub-anesthetic dose for treating depression. We wondered if our past concentration of 50% had been too high. Maybe by lowering the dose, we could find the ‘Goldilocks spot’ that would maximize clinical benefit and minimize negative side effects.”
The new study used a similar protocol with 20 patients, this time adding an additional inhalation session with 25% nitrous oxide. They found that the halved-concentration treatment was nearly as effective as 50% nitrous oxide, but there were only one quarter of the negative side effects.
Additionally, researchers tested the patients’ depression scores following treatment over a longer period of up to two weeks compared to 24 hours in the previous protocol. Surprisingly, they found that after only a single administration, some patients had improvements that lasted for the entire follow-up period.
“The reduction in side effects was unexpected and quite drastic, but even more excitingly, the effects after a single administration lasted for a whole two weeks,” said Dr Nagele. “This has never been shown before. It’s a very cool finding.”
These findings point to nitrous oxide being a promising, rapid and effective treatment for those suffering from severe depression which is unresponsive to the usual medication such as SSRIs.
“A significant percentage — we think around 15% — of people who suffer from depression don’t respond to standard antidepressant treatment,” said Charles Conway, MD, Professor of Psychiatry and Director of the Treatment Resistant Depression and Neurostimulation Clinic at Washington University School of Medicine. “These ‘treatment-resistant depression’ patients often suffer for years, even decades, with life-debilitating depression. We don’t really know why standard treatments don’t work for them, though we suspect that they may have different brain network disruptions than non-resistant depressed patients. Identifying novel treatments, such as nitrous oxide, that target alternative pathways is critical to treating these individuals.”
Despite its ‘laughing gas’ name, patients actually fall asleep after such a low dose.
“They’re not getting high or euphoric, they get sedated,” Dr Nagele said.
Non-traditional treatments for depression faces an uphill battle for acceptance in the mainstream, though researchers hope that the findings from this and similar studies will help open physicians’ minds towards these other possible solutions.
“These have just been pilot studies,” said Dr Nagele. “But we need acceptance by the larger medical community for this to become a treatment that’s actually available to patients in the real world. Most psychiatrists are not familiar with nitrous oxide or how to administer it, so we’ll have to show the community how to deliver this treatment safely and effectively. I think there will be a lot of interest in getting this into clinical practice.”
With broader public acceptance, Dr Nagele hopes that these results help those patients who are struggling to find adequate therapies for their depression.
“There is a huge unmet need,” he said. “There are millions of depressed patients who don’t have good treatment options, especially those who are dealing with suicidality. If we develop effective, rapid treatments that can really help someone navigate their suicidal thinking and come out on the other side — that’s a very gratifying line of research.”
Journal information: P. Nagele et al., “A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression,” Science Translational Medicine (2021).
