A pair of new studies explains why babies get so many common respiratory infections and identifies a specialised cluster of immune cells found only in babies that help them better cope with new pathogens, helping explain why they were less vulnerable to COVID infection.
“We know little about how the immune system develops throughout life, and most of what we know about immune system development in children comes from animal studies,” says lead researcher Donna Farber, PhD, an expert in immune system development at Columbia University. “But mice develop much more quickly than humans and their immune systems are a bit different than ours.”
Using a trove of tissue samples from deceased paediatric organ donors, Farber’s team was able to pinpoint aspects of immune system development that distinguish babies from adults.
Immune cells in lungs and gut take time to mature
One study, published in Immunity, found that memory T cells, formed after first exposure to a pathogen, accumulate rapidly in the lungs and intestines through age three and more gradually in blood and lymph tissues. These cells enable older children and adults to mount an immediate and specific immune response during the next encounter with a pathogen.
But there’s a hitch.
“We found that memory T cells in young children are not functionally mature and only begin to have the capacity for protective immunity at around ages four to six years,” Farber says. “This explains why babies and young children are more vulnerable to recurrent respiratory infections and other infectious diseases compared with adults.”
The findings also may explain why introducing foods to children during the first year of life could prevent severe food allergies. “Early memory T cells are more tolerant than mature memory cells, so they’re not going to create an immune response against new foods,” Farber says.
‘Secret weapon’ protects babies from new pathogens
But while babies are highly susceptible to recurrent infections, a second study, published in Nature Immunology, found that babies have a unique way of coping with new pathogens. The researchers found clusters of antibody-producing B cells surrounded by T cells in the infants’ lungs. This bronchus-associated lymphoid tissue, or BALT, is formed between six and 12 months of age and disappears after age three.
“BALT enables the lung to make antibodies to respiratory pathogens well before T cell memory has developed but fall apart in later childhood when they are no longer needed,” says Farber. “This mechanism helps young children respond to the many different respiratory pathogens they encounter early in life.”
It also may explain why young children are more resilient to new respiratory infections compared to adults, as seen with SARS-CoV-2.
“With SARS-CoV-2, a virus no one had ever encountered before, we saw that people in their 50s and 60s were very susceptible to severe COVID, but most kids exposed to SARS-CoV-2 were fine, and many didn’t even have symptoms,” Farber says. “That told us that the babies and young children must have some adaptations to respond to new pathogens that adults don’t have.”
BALT also may be a reason why some children develop chronic asthma and allergies. “It’s possible that these diseases may be caused in part by the abnormal persistence of BALT well into childhood, which could trigger an overreaction to certain antigens,” says Farber.
Farber adds that the study may provide clues about why early trials of intranasal COVID vaccines have not shown promise in adults, whereas intranasal influenza vaccine tends to work better in children. “It could be that this type of vaccine works better in children because they have BALT structures that can initiate new antibodies in the lungs.”
“BALT provides some protection but clearly does not protect young children from everything,” Farber continues. “We have to remember that before vaccines, a third of children died of infectious diseases during infancy. So childhood vaccines are really important for protecting us.”
Research team led by Joshua Pearce has developed a new 3-D printed, completely open-source autoinjector for a tenth of the cost of a commercially purchased product. (Photo by Anjutha Selvaraj)
A new study published in PLOS One describes the development of a spring-driven autoinjector for the delivery of insulin and other medications. This device, made from a combination of 3D-printed and commercially available parts, could cost less than $7 to make while a store-bought version is closer to $70.
Sir Frederick Banting was an inspiration for a new open source self-administering drug delivery device. Long before open source was an option or even a concept, the now-celebrated former University of Western Ontario lecturer refused to patent insulin because he wanted it to be inexpensive and widely available for the betterment of all.
A century after Banting won the Nobel Prize for his discovery, Western researchers led by engineering and Ivey Business School professor Joshua Pearce has developed a new 3D printed, completely open-source autoinjector – a device designed to deliver a single dose of medicine – for a tenth of the cost of a commercially purchased product.
“I think of this device, like so much of what we’re doing here at Western, very much as following the golden rule: do unto others as you would have them do unto you,” said Pearce. “It makes the world slightly better to have an open-source version of an autoinjector, especially for people who don’t have access or the financial means to purchase a proprietary one.”
Autoinjectors are used all over the world by health care practitioners, patients and parents (for children under 12) to inject insulin into people with diabetes. Other chronic conditions such as psoriasis, multiple sclerosis and rheumatoid arthritis can also be treated using an autoinjector. The device is also essential during emergency conditions for migraine, anaphylaxis and status epilepticus patients, as well.
Pearce, along with research assistant Anjutha Selvaraj and post-doctoral associate Apoorv Kulkarni, have created the new open-source autoinjector to make the device – considered more reliable and easier to operate than a simple syringe for self-administering medications into the body – an equitable alternative to the more expensive options.
Studies show self-administration of medications by patients improves compliance and comfort and empowers patients as they are actively involved in their personal care. It also allows patients to avoid time-consuming and costly visits to the hospital, which is a bonus for overburdened health care systems.
And, as with all open-source hardware, there is money to be made as the digitally replicable device enables low-cost distributed manufacturing. All materials, designs and assembly instructions are also detailed in the new study, and the effectiveness of the autoinjector is tested against the current standard (ISO 11608-1:2022) for needle-based injection systems. It is released with an open source hardware license. Companies wishing to commercialise the device will still need to meet their own local regulatory requirements.
“Does this design make it possible for other people to commercialise it anywhere in the world? Yes, it does,” said Pearce. “But more importantly, it means we can really target isolated communities, whether they’re in northern Canada, Africa or anywhere in else in the world, and improve health care access for everyone.”
In what is likely one of the largest treatment rollouts in South African history, well over four million people living with HIV have started taking the antiretroviral dolutegravir since its introduction around four years ago. Now, according to a recent study published in the Lancet medical journal, use of dolutegravir in South Africa is associated with more people staying on treatment and higher rates of viral suppression.
The use of a three-in-one combination of the antiretroviral drugs tenofovir, lamivudine and dolutegravir (TLD for short) for the treatment of HIV was first recommended by the World Health Organization (WHO) in 2018. A year later it was recommended in the South African treatment guidelines as first line treatment for HIV and a three-year tender was awarded. Since then, dolutegravir has largely replaced another antiretroviral called efavirenz.
Today, TLD is the recommended treatment option for most people living with HIV in the country. The 2023 National antiretroviral (ARV) guidelines also include recommendations for the use of child-friendly formulations of dolutegravir and dolutegravir containing regimens in kids. Spotlight reported on these here.
Around 4.7m people in SA taking dolutegravir
According to Foster Mohale, spokesperson for the National Department of Health, in 2019 the HIV clinical guidelines were revised to include a fixed combination dose of TLD “for all eligible people for use as the first line regimen.”
Based on this, the department set a goal that 90% of those eligible for it should receive TLD as a first line regimen. In terms of meeting this goal, Mohale says that by March 2023, just over four million (4 127 427) people were on TLD. Additionally, about 650 000 (653 884) people were on other dolutegravir based regimens. Altogether, there are thus now over 4.7 million people in the country on treatment combinations that include dolutegravir.
“Based on the March 2023 data, 90% of clients on first line regimen were on TLD. However, performance varies by province,” he says.
Of the total number of people on ART in the public health sector, 75.8% are on TLD, according to Mohale.
Trends in the roll out
While on paper the country’s transition from efavirenz to dolutegravir-based regimens seems to have been smooth, the reality on the ground has been more complex. A study published in the Lancet earlier this year looked at real-world rollout data from 2019 to 2022. The study was conducted in 59 clinics across the country and collected data from two cohorts-one cohort were first time initiators of ART and the other were transitioning from regimens that did not include dolutegravir to ones that did.
In the initiator cohort, just over 45 000 people were initiated on ART between December 2019 and February 2022. Of those, 68.9% were initiated on dolutegravir-based regimens, 31.1% on efavirenz-based regimens, and 0.1% on nevirapine-based regimens.
Those initiated on dolutegravir-based regimens were more likely to still be on treatment a year later and were also more likely to be virally suppressed than those who were initiated on the other regimens.
In December 2019, in the transition cohort, just over 180 000 people were on a non-dolutegravir first line regimen. By February 2022, 67% of them had transitioned to a dolutegravir-based regimen. These people were also more likely to be retained in care at 12 months and be virologically suppressed than those who had not switched to a dolutegravir-based regimen.
“That’s good for a number of reasons. It means that the treatment’s working, people are less likely to get unwell and also, they can’t transmit the virus onto other people,” explains Dr Jienchi Dorward, one of the study authors and an academic clinical lecturer at the University of Oxford and honorary associate scientist at the Centre for the AIDS Programme of Research in South Africa (CAPRISA).
‘Bumpy transition’
Dr Yukteshwar Sookrajh, a Senior Medical Practitioner at the eThekwini Municipality Health Unit who was also involved in the study, tells Spotlight that the rollout quickly gathered momentum.
“But initially there were some issues to navigate around drug interactions; concurrent TB infection and the use of dolutegravir in women of childbearing potential,” he says. “Once those concerns were addressed, the comfort of switching to dolutegravir was increased and we find that the majority of our patients have now safely transitioned across to dolutegravir-based regimens.”
In many ways South Africa was slow in rolling out dolutegravir compared to other African countries, according to Professor Francois Venter, the head of Ezintsha at Wits University. Reasons for this, he says, include an initial concern around the safety of dolutegravir use among pregnant women, and disruption in training due to the COVID-19 pandemic.
He says that the South African Clinicians society was alerted during the COVID-19 pandemic that many patients in the public health sector had still not been transitioned to dolutegravir. An education campaign was then launched to encourage clinicians to start or switch patients to dolutegravir.
However, as it stands now the rollout of the drug in the public sector has been a huge success, despite what Venter calls a “bumpy transition”.
Initial safety concerns
One important reason to conduct the study reported in the Lancet, according to Dorward, was a safety concern regarding the use of dolutegravir by pregnant women. An earlier study conducted in Botswana called Tsepamo found a higher prevalence of neural-tube defects (a type of birth defect) associated with dolutegravir exposure at conception than with other types of antiretroviral exposure. As more data has been gathered since, it has however become clear that dolutegravir does not in fact increase the risk of neural-tube defects.
But the Tsepamo scare did impact who was initiated and transitioned onto dolutegravir in first two years of the rollout.
“The initial concerns around neural-tube defects and the use of dolutegravir in women of childbearing potential clearly hampered rollout of dolutegravir in women – and this has been clearly demonstrated in this study,” says Sookrajh.
The Lancet study found that pregnant women and non-pregnant women were less likely to be initiated on dolutegravir than men early in the rollout, with the biggest difference between women and men aged 15 to 24 years old. This difference decreased with age and by age 55 there was no difference between men and women receiving dolutegravir.
But this changed over time and by September 2021 women were as likely to get initiated on dolutegravir as men. Spotlight previously reported that the rollout was done in two stages. In the first stage men, adolescent boys, women on reliable contraception, and older women were prioritised.
Of those who started treatment during the study period, 46.9% of the pregnant women in the cohort were initiated on dolutegravir-based regimens, while 63.9% of the non-pregnant women and 82.3% of the men in the cohort were initiated on dolutegravir-based regimens.
“In both those groups [cohorts] we found that women were less likely than men to get dolutegravir, but interestingly, this was particularly in younger women,” Dorward explains. “As time went on, the difference between men and women became much less…around June to September 2021 was a time period where we found that women and men pretty much began to equally get dolutegravir.”
Dorward says the data showed an uptick in women in the study being given dolutegravir once the South African guidelines changed to reflect that there was no longer a concern around neural-tube defects. It is thus likely that the safety concern was responsible for the lower initial uptake among young women.
He adds that the messaging around this potential risk was based on the evidence available at the time and was clearly outlined in the guideline document and training for dolutegravir use, but these did not appear to adequately allay these concerns among healthcare workers.
“The risks versus benefits needed to be messaged in a more effective way such that healthcare workers were more comfortable and confident in offering dolutegravir to women,” he says. Based on this experience Sookrajh adds that in future there needs to be more engagement with “practitioners on the ground to determine what type of messaging and supportive materials are required to facilitate better understanding of guidelines at the coal face.”
Another concern for some healthcare workers has been that dolutegravir-based regimens have been associated with greater weight gain than efavirenz-based regimens. But, as argued in a recent editorial in the Southern African Journal of HIV medicine, association is not the same as causation and it may well be that efavirenz inhibits weight gain rather than dolutegravir promoting it. People living with HIV who start taking antiretroviral medicines often gain weight as their health recovers.
New guidelines should further boost uptake
Sookrajh says that the National Department of Health’s antiretroviral (ARV) 2023 guidelines will further improve the uptake of dolutegravir in the public healthcare system.
“With the April 2023 National Department of Health ARV Guidelines, we actually find that further barriers to switching to dolutegravir have been removed and dolutegravir is clearly placed as the preferred drug of choice in almost all scenarios for both first- and second-line antiretrovirals,” he says.
“I think the new [ARV] guidelines hopefully will be a big improvement for people who are on treatment, and part of that is possible because we’re using the drug that is better. You’re less likely to get resistance with dolutegravir so we’re less worried if people don’t take treatment properly that they might get drug resistance, although we still need more research to be sure about that,” Dorward says. “And it’s still very important for people to take treatment consistently to suppress the virus and maintain their own health and prevent onward transmission.”
According to Venter, there needs to be proper resistance surveillance to detect potential dolutegravir resistance.
“We can’t take for granted we’ll never have resistance [to dolutegravir]…eventually there will be the occasional patient that does have resistance, but we need proper surveillance there,” he says. “And then we need to keep an eye on things. There are still patients getting HIV…there’s still a lot of new infections…we need to make that stop…we’ve got amazing PrEP and way too few people getting it. So, we do need to start addressing that.” (PrEP, or pre-exposure prophylaxis, refers to antiretrovirals taken to prevent HIV infection.)
Venter adds that while successful in the public health sector, the uptake of dolutegravir has been extremely slow in the private health sector for reasons unknown to him.
Penicillin allergy affects up to 1 in 10 Americans yet most penicillin allergy labels are in fact incorrectly applied. In addition to limiting the choice of antibiotics to prescribe, the widespread mislabelling contributes to the growing threat of antibiotic resistance. A new procedure developed by researchers at Vanderbilt University Medical Center aims to fix that.
Some 75% of penicillin allergy labels come on by age 3 due to, for example, confusion with a viral rash. The majority of these rashes were never allergic, but the labels ‘stick’ into adulthood and carry many adverse consequences.
Many low-risk patients with a penicillin allergy were able to have their penicillin allergy label removed through a simple procedure known as “direct oral challenge” as part of a world-first multi-centre randomised control trial known as the Penicillin Allergy Clinical Decision Rule (PALACE) study, the results of which were published in JAMA Internal Medicine.
In the PALACE study, investigators randomised low-risk penicillin allergic patients to two different approaches to remove their allergy label. They either underwent the current standard of care to have skin testing followed if negative by oral challenge with a penicillin or they went straight to oral challenge (“direct oral challenge”) without preceding skin testing.
“The majority of patients labelled as penicillin allergic, more than 90%, have low-risk histories, meaning they did not have a history to suggest a severe or more recent reaction to a penicillin,” said PALACE study protocol member and Vanderbilt University Medical Center principal investigator Elizabeth Phillips, MD. “We would expect more than 95% of these patients to have negative testing and be able to take penicillin in the future.”
The study, undertaken by a team of researchers from specialised centres in North America and Australia, enrolled 382 adults who were assessed using a specialized risk assessment tool called PEN-FAST. Participants were randomly assigned to receive either a direct oral penicillin challenge or the standard approach (penicillin skin testing followed by an oral challenge). The primary goal was to determine if the direct oral penicillin challenge was no worse than the standard method of skin testing followed by oral challenge which needs to be performed in an allergist’s office.
Only one patient (0.5%) in each group experienced a positive reaction to the penicillin challenge, demonstrating that the direct oral penicillin challenge performs just as well as the standard method. Importantly, there were no significant differences in adverse events between the two groups, and no serious adverse events were reported.
The findings have wide-ranging implications for patients. By accurately identifying low-risk penicillin allergy patients, health care providers can ensure appropriate antibiotic prescriptions. Patients with a documented penicillin allergy are more likely to be prescribed alternative antibiotics, known as second-line antibiotics, which are often not as effective against certain infections and may have more side effects.
“Patients with penicillin allergy are more likely to get second-line or broader spectrum antibiotics that lead to risk of antibiotic resistance and serious infections such as antibiotic-associated diarrhoea due to Clostridioides difficile, which can spread through hospitals and become a major public health problem.” Phillips said. “In the US increasingly we also have a major problem with other antibiotic-resistant ‘superbugs’ such as multi-resistant gram-negative infections, Candida auris and even a resurgence of syphilis for which penicillin is the best treatment and the only treatment that should be used in pregnancy to prevent transmission to an unborn child.
“The evidence provided by the PALACE study will change clinical practice. Many patients in the United States do not have direct access to an allergist to provide specialised testing such as skin testing. Therefore, the ability to go to direct oral challenge with a penicillin in low-risk patients which can be carried out in any observed setting will make it easier for patients in the United States to access health care to safely and effectively remove the label of penicillin allergy,” she said.
3D structure of a melanoma cell derived by ion abrasion scanning electron microscopy. Credit: Sriram Subramaniam/ National Cancer Institute
New research has helped explain how melanoma evades the immune system and may guide the discovery of future therapies for the disease. The study found that a protein known to be active in immune cells is also active inside melanoma cells, helping promote tumour growth. The findings, published in the journal Science Advances, suggest that targeting this protein with new drugs may deliver a powerful double hit to melanoma tumours.
“The immune system’s control of a tumour is influenced by both internal factors within tumour cells, as well as factors from the tumour’s surroundings,” says first author Hyungsoo Kim, PhD, a research assistant professor at Sanford Burnham Prebys in the lab of senior author Ze’ev Ronai, PhD. “We found that the protein we’re studying is involved in both, which makes it an ideal target for new cancer therapies.”
“Immunotherapy is the first-line therapy for several cancers now, but the success of immunotherapy is limited because many cancers either don’t respond to it or become resistant over time,” says Kim. “An important goal remains to improve the effectiveness of immunotherapy.”
To find ways to boost immunotherapy in melanoma, the research team analysed data from patient tumours to identify genes that may coincide with patients’ responsiveness to immunotherapy. This led to the identification of a protein that helps tumours evade the immune system – called NR2F6 – which was found not only in tumour cells, but also in the surrounding noncancerous cells.
“Often we find that a protein has the opposite effect outside of tumours compared to what it does within a tumour, which is less effective for therapy,” says Kim. “In the case of NR2F6, we found that it elicits the same change in the tumour and in its surrounding tissues, pointing to a synergistic effect. This means that treatments that block this protein’s activity could be twice as effective.”
In a mouse model, the researchers then deleted the NR2F6 protein in both melanoma tumours and in the tumours’ environment. This inhibited melanoma growth more strongly, compared to when this effect occurs in either the tumour or its microenvironment alone. The cancer’s response to immunotherapy was also enhanced upon loss of NR2F6 in both tumours and their microenvironment.
“This tells us that NR2F6 helps melanoma evade the immune system, and without it, the immune system can more readily suppress tumour growth,” adds Kim.
To help advance their discovery further, the team is working with the Institute’s Conrad Prebys Center for Chemical Genomics to identify new drugs that can target NR2F6.
“Discovering drugs that can target this protein are expected to offer a new way to treat melanomas, and possibly other tumours, that would otherwise resist immunotherapy,” says Kim.
After implementation of a multidisciplinary quality improvement project, the percentage of infants from the neonatal intensive care unit (NICU) experiencing hypothermia upon operating room (OR) arrival and at any point during the operation decreased from 48.7% to 6.4% and 67.5% to 37.4%, respectively. Conducted at Ann & Robert H. Lurie Children’s Hospital of Chicago, the successful project and was featured in the journal Pediatric Quality and Safety.
About one-third of infants admitted to children’s hospitals’ NICUs require surgery and are at increased risk for intraoperative hypothermia due to environmental heat loss, anaesthesia, and inconsistent temperature monitoring. Hypothermic infants are at risk for infection, excessive bleeding, increased oxygen consumption, the need for cardiorespiratory support, and mortality.
Upon return to the NICU, the percentage of infants experiencing postoperative hypothermia decreased from 5.8% to 2.1% while postoperative hyperthermia increased from 0.8% to 2.6%.
“Intraoperative hypothermia is more prevalent than postoperative hypothermia, yet the problem appears to be recognized less. Several improvement projects have addressed postoperative hypothermia, however, few have focused on reducing intraoperative hypothermia,” said senior author Gustave Falciglia, MD, MSCI, MSHQPS, neonatologist at Lurie Children’s. “The strengths of our project were the large cohort of infants and the use of continuous, secure and automated data to ensure normal temperature for infants before, during and after an operation. Using our current approach, however, further decreasing intraoperative and postoperative hypothermia may not be possible without further increasing postoperative hyperthermia.”
Dr Falciglia and colleagues from Lurie Children’s Center for Quality and Safety, anaesthesiology, NICU and OR nursing, surgery, neonatology and Data Analytics and Reporting succeeded in reducing rates of intraoperative hypothermia by standardising temperature monitoring, the transport process to the OR and intraoperative warming.
“In this project, we used improvement science methodology to understand the barriers to maintaining normal temperature in NICU infants before, during and after surgery, and then to design and implement solutions,” said lead author Abbey Studer from the Center for Quality and Safety at Lurie Children’s. “We found variation in processes that contributed to intraoperative hypothermia, so we focused on standardizing temperature monitoring and thermal support during the infant’s transport and operation. Automated monitoring using a preoperatively placed continuous temperature probe enhanced providers’ situational awareness of infant temperature and guided clinical adjustments.”
For this improvement project, the hospital’s Center for Quality and Safety coordinated care and resources between multiple departments. It achieved consensus and buy-in from providers despite competing factors such as perspiring surgeons and busy anaesthesia providers transporting all infants to the OR. It identified key participants who were vested in revising processes and facilitated adoption with their colleagues, following up on missed opportunities and gaps in the processes identified through observation and surveys. The centre provided data analysts who worked iteratively with providers to generate valid, actionable, and real-time data.
“Although medicine prizes specialisation, our success relied upon individuals with various talents sharing their skills and knowledge,” said Dr Falciglia. “Working together we can continue to improve the care of infants in the NICU who need surgery.”
University of Virginia School of Medicine researchers have discovered a lipid biomarker to identify pregnant women at risk of preeclampsia, complications from which are the second-leading cause of maternal death around the world. Their findings are published in the Journal of Lipid Research.
The UVA scientists, led by Charles E. Chalfant, PhD, say that their finding opens the door to simple blood tests to screen patients. Further, the approach worked regardless of whether the women were on aspirin therapy, which is commonly prescribed to women thought to be at risk.
“Clinicians have been seeking simple tests to predict risk of preeclampsia before symptoms appear. Although alterations in some blood lipid levels have been known to occur in preeclampsia, they have not been endorsed as useful biomarkers. Our study presents the first comprehensive analysis of lipid species, yielding a distinctive profile associated with the development of preeclampsia,” said Chalfant. “The lipid ‘signature’ we described could significantly improve the ability to identify patients needing preventative treatment, like aspirin, or more careful monitoring for early signs of disease so that treatment could be initiated in a timely fashion.”
Preeclampsia affects up to 7% of all pregnancies. Symptoms typically appear after 20 weeks and include high blood pressure, kidney problems and abnormalties in blood clotting. The condition is associated with dangerous complications such as kidney and liver dysfunction and seizures, as well as a lifelong increased risk of heart disease for the mothers. An estimated 70 000 women around the world die from preeclampsia and its complications each year.
Doctors commonly recommend low-dose aspirin for at-risk women, but it works for only about half of patients, and it needs to be started within the first 16 weeks of pregnancy – well before symptoms appear. That makes it all the more important to identify women at risk early on, and to better understand preeclampsia in general.
Chalfant and his team wanted to find ‘biomarkers’ in the blood of pregnant women that could reveal their risk of developing preeclampsia. They examined blood plasma samples collected from 57 women in their first 24 weeks of pregnancy, then looked at whether the women went on to develop preeclampsia. The researchers found significant differences in ‘bioactive’ lipids in the blood of women who developed preeclampsia and those who did not.
This, the researchers say, should allow doctors to stratify women’s risk of developing preeclampsia by measuring lipid changes in their blood. The changes represent an important ‘lipid fingerprint’, the scientists say, that could be a useful tool for identifying, preventing and better treating preeclampsia.
“The application of our comprehensive lipid profiling method to routine obstetrical care could significantly reduce maternal and neonatal morbidity and mortality,” Chalfant said. “It represents an example of how personalised medicine could address a significant public health challenge.”
A low-cost version of ketamine to treat severe depression has performed strongly in a placebo-controlled double-blind trial. Results published in the British Journal of Psychiatry showed that more than one in five participants achieved total remission from their symptoms after a month of bi-weekly injections, while a third had their symptoms improve by at least 50%.
“For people with treatment-resistant depression – so those who have not benefitted from different modes of talk-therapy, commonly prescribed antidepressants, or electroconvulsive therapy – 20 per cent remission is actually quite good,” lead researcher Professor Colleen Loo says.
“We found that in this trial, ketamine was clearly better than the placebo – with 20 per cent reporting they no longer had clinical depression compared with only 2 per cent in the placebo group. This is a huge and very obvious difference and brings definitive evidence to the field which only had past smaller trials that compared ketamine with placebo.”
How the trial worked
The researchers, led by UNSW Sydney and the affiliated Black Dog Institute, recruited 179 people with treatment-resistant depression. All were given an injection of either a generic form of ketamine that is already widely available in Australia as a drug for anaesthesia and sedation – or placebo. Participants received two injections a week in a clinic where they were monitored for around two hours while acute dissociative and sedative effects wore off, usually within the first hour. The treatment ran for a month and participants were asked to assess their mood at the end of the trial and one month later.
In this double-blind trial, a placebo was chosen that also causes sedation, to improve treatment masking. Midazolam is a sedative normally administered before a general anaesthetic, while in many previous studies the placebo was saline.
“Because there are no subjective effects from the saline, in previous studies it became obvious which people were receiving the ketamine and which people received placebo,” Prof Loo says.
“In using midazolam – which is not a treatment for depression, but does make you feel a bit woozy and out of it – you have much less chance of knowing whether you have received ketamine, which has similar acute effects.”
Other features of the recent trial that set it apart from past studies included accepting people into the trial who had previously received electroconvulsive therapy (ECT).
“People are recommended ECT treatment for their depression when all other treatments have been ineffective,” Prof. Loo says.
“Most studies exclude people who have had ECT because it is very hard for a new treatment to work where ECT has not.”
Another difference about this trial was that the drug was delivered subcutaneously (injected into the skin) rather than by drip, thus greatly reducing time and medical complexity. The study is also the largest in the world to date that compares generic ketamine with placebo in treating severe depression.
Much more affordable
Apart from the positive results, one of the standout benefits of using generic ketamine for treatment-resistant depression is that it is much cheaper than the patented S-ketamine nasal spray currently in use in Australia. Where S-ketamine costs about AUS$800 (R9 600) per dose, the generic ketamine is a mere fraction of that, costing as little as AUS$5 (R60), depending on the supplier and whether the hospital buys it wholesale. On top of the cost for the drug, patients need to pay for the medical care they receive to ensure their experience is safe – which at Black Dog Institute clinics, comes to AUS$350 (R4200) per session.
“With the S-ketamine nasal spray, you are out of pocket by about AUS$1200 for every treatment by the time you pay for the drug and the procedure, whereas for generic ketamine, you’re paying around AUS$300-350 for the treatment including the drug cost,” Prof Loo says.
She adds that for both S-ketamine and generic ketamine treatments, the positive effects often wear off after a few days to weeks, so ongoing treatment may be required, depending on someone’s clinical situation. But the prohibitive costs of the drug and procedure make this an unsustainable proposition for most.
The researchers will next be looking at larger trials of generic ketamine over longer periods, and refining the safety monitoring of treatment.
The Charlotte Maxeke Johannesburg Academic Hospital (CMJAH) would like to dismiss the misleading information shared by Mr Jack Bloom regarding cancelled operations.
CMJAH would like to put it on record that there were no “more than 50 elective cases cancelled due to the cold weather conditions”. The statement by Mr Bloom creates the impression that all elective cases were cancelled, which is not true.
There were 53 operations scheduled for Monday, 10 July 2023, and 26 cases were done, while only 15 were cancelled due to low temperatures at theatres and 12 were cancelled for reasons not related to low temperatures.
Out of the 15 cancelled cases, 3 were for Thoracic, 6 were for Trauma Orthopaedic, 2 were for Paeds Orthopaedic, 1 was for Paeds plastics, and 3 were for Ear, Nose, & Throat.
The problem of temperature control has been a challenge for the facility for years, but it became worse in the last two years due to the copper theft which took place during the period when the facility was evacuated for months after the fire incident. This affected the central heating system of the facility, which regulates the level of acceptable temperatures in the entire hospital, but mostly in the theatres.
To remedy the situation, the process of installing Schedule 40 pipes, which are less susceptible to theft as they do not have an attractive market value as copper does, has started. During the installation process, the theatres and intensive care units (ICU) were prioritised. From the date of appointment, 28 June 2023, to date, the contractor has completed the installation of schedule 40 pipes for Blocks 2, 3 and 4. The installation process at Block 5 has already started and the work is progressing well, ahead of schedule.
The water system is currently running, with close monitoring, at all three blocks where the schedule 40 pipes were installed to check for any possible leaks as the system has not been running for the past two years.
The facility would like to apologise to the public for any inconvenience this might have caused. The installation of the schedule 40 pipes is a necessary project that would address the issue of copper theft and the central heating system.
The facility would further like to assure the public that this matter is getting the urgency it deserves, and cancelled cases are being attended to.
Scanning electron micrograph of a human T lymphocyte (also called a T cell) from the immune system of a healthy donor. Credit: NIAID
One of the adaptive immune system’s most intriguing abilities of the is its memory: upon first contact with antigens, it takes around two weeks to respond, but responses afterwards are much faster, as if the cells ‘remembered’ the antigen. But how is this memory attained? In a recent publication in Science Immunology, a team of researchers examined epigenetic and the structure of DNA for possible clues.
In their research paper, first author Anne Onrust-van Schoonhoven and colleagues compared the response of immune cells that had never been in contact with an antigen (called naïve cells) with cells previously exposed to antigen (memory cells) and sort of knew it. They focused on the differences in the epigenetic control of the cellular machinery and the nuclear architecture of the cells, two mechanisms that could explain the quick activation pattern of memory cells.
While all the cells in an individual have the same genetic information, different cell types access to different parts of the DNA. The term ‘epigenetics’ encompasses the mechanisms that dynamically control this access. The results revealed a particular epigenetic signature in memory T helper (TH)2 cells, resulting in the rapid activation of a crucial set of genes compared to naïve cells. These genes were much more accessible to the cellular machinery, in particular to a family of transcription factors called AP-1. Like athletes before a race, these genes had essentially been ‘warming up’ ever since the cell’s first contact with the antigen.
However, this epigenetic signature was just the tip of the iceberg. It is known that the position of the DNA in the nucleus is not random and reflects the cell’s activation state. The researchers found that, indeed, the 3D distribution of DNA in the nucleus is different between naïve and memory immune cells. Key genes for the early immune response are grouped together and under the influence of the same regulatory regions, called enhancers. Keeping with the racing metaphor, the genes are not only warmed-up, but also gathered together at the starting line.
Although most of the research has focused on healthy cells, the scientific team wondered whether any of the mechanisms found could, when altered, explain actual diseases in which the immune system plays an important role. To address this question, they analysed immune cells from chronic asthma patients and found that the circuits identified as key for an early and strong immune response were overactivated.
The epigenetic control of the immune system is a blossoming field and discoveries like the ones by Dr Stik and colleagues are setting the stage for the next generation of epigenetic drugs and treatments, targeting autoimmune diseases and cancer.
