Researchers have found that a novel therapy for the bone marrow cancer myelofibrosis to be safe and well-tolerated, and is associated with modest improvements in patients in an early clinical trial. They shared their findings during an oral presentation at the American Society of Hematology annual meeting in December.
The therapy AVID200 showed improvements in patients’ symptom burden, anaemia, and spleen enlargement. The results from the Phase 1b clinical trial showed that the therapy was safe and displayed some evidence of efficacy (although safety and finding optimal dosage was the main goal) and researchers concluded that the therapy would need to be combined with other drugs to optimise effectiveness in patients.
“This is a real testament to cutting-edge translational research at The Tisch Cancer Institute,” said John Mascarenhas, MD, Director of the Institute’s newly launched Center of Excellence for Blood Cancer and Myeloid Disorders. “Our scientists tested this therapy in the lab, physician-scientists conducted a successful phase 1 trial, and now the optimal combination therapy approach is the subject of ongoing laboratory studies at Mount Sinai. The most interesting finding in this trial was that a subset of patients had a lasting improvement in their platelet counts – including three whose counts were normalised – supporting the preclinical studies conducted.”
Myelofibrosis is a bone marrow cancer type that disrupts normal blood cell production, causing an enlarged spleen, extensive scarring in the bone marrow, and low levels of red blood cells and platelets, increasing bleeding risk. Myelofibrosis patients who have failed the available first-line therapy face a well-documented poor prognosis, so additional therapies are urgently needed to help these patients.
Twenty-one patients enrolled in this multicenter trial were given AVID200, and while this trial’s main purpose was to test safety, some patients had an increase in platelets and there was a decrease in the size of their enlarged spleens. However, in spite of the other clinical benefits seen. patients’ bone marrow scarring did not decline, indicating that AVID200 would need to be combined with other rational therapies in the future.
If you’re stuck for gift ideas for a certain healthcare worker, or you are one yourself and looking to leave hints for someone stuck for ideas, this list could help.
1: A Good Pair of Scrubs This one may seem obvious, but not all scrubs are identical or of high quality, and healthcare providers can never have enough high-quality scrubs. Ones that are soft, flexible, and moisture-resistant are ideal. For the fashion-conscious healthcare worker, go for jogger style.
2: A Massage Gun The healthcare working environment is a physically demanding one. With long shifts, sometimes up to 24 hours or even longer, much of the time is spent standing. A massage gun can work wonders for sore muscles, aches, and pains.
3: Good Moisturiser or Hand Cream Healthcare workers wash their hands and use hand sanitiser all day long, which can cause the skin to dry out and lead to painful cracking. A good moisturiser can go a long way. However, avoid those that are heavily scented since some patients may be sensitive to the chemicals. Another great option is hydrating single-use hand masks.
4: Quick Meal Solutions Gift cards for food delivery services like Uber Eats or Mr D are a great way for healthcare workers to get an easy meal – and can offer healthy alternatives to junk food. Cooking most likely is not at the top of their priority list either on shift or coming off of it, so this can be a practical way to be supportive and make their lives a little easier.
5: Custom Tailored Lab CoatThe long white lab coat is a symbol of office for physicians, a representation of all the long years of hard work they’ve put into their career as well as a reassuring sight for patients. A custom-tailored and embroidered white lab coat would make the perfect gift for any physician.
6: Spa DayTwo years into the pandemic with the constant threat of burnout, there’s nothing quite like having an indulgent spa day for your healthcare worker friend or family member to relax. A good massage to ease stiff muscles and a sauna session is a fantastic way to help unwind, lease the burden and de-stress.
7: Smartwatch A smartwatch that can track health data and perform other functions can make a great gift for a healthcare worker if they don’t have one already. Smartwatches are of course convenient for checking the time, but they can also monitor activity and exercise levels and overall well-being and sync with mobile phones for calls, alerts, and many apps – some of which can warn if healthcare workers are falling ill.
8: Travel Mug People who are on the go for their job can always use a travel mug, especially paramedics who spend long nights on shift on the road. This will keep coffee (or tea, hot chocolate, or soup) at just the right temperature for extended periods of time.
9: Compression Socks Working in a field that requires a great deal of time spent on their feet, most healthcare workers likely know about the benefits of compression socks. They prevent muscle soreness and stiffness in the legs, and just like regular socks (and scrubs), you can never have too many.
10: Blue Light Blocking Glasses Hours spent sitting at a computer, inputting patient charts can cause some serious eyestrain. This can purportedly be reduced by wearing blue light glasses (which can be either prescription or non-prescription) which filter out blue light, supposedly reducing strain. Evidence for the glasses are mixed, but many swear by them.
Why patients with asthma find their condition worsens at night has remained largely unknown, but now researchers have found that the sleep hormone melatonin may be the culprit.
In ‘nocturnal asthma’ , patients with asthma often experience a worsening of asthmatic symptoms at night. More than 50% of asthma deaths occur at night, showing a link between nocturnal asthma symptoms and asthma deaths. Though numerous triggers that explain the pathogenesis of nocturnal asthma have been described, the precise mechanisms regulating this asthma phenotype remain obscured until now. Now, a study published in the American Journal of Physiology Lung Cellular and Molecular Physiology may have explained the relationship via melatonin.
Asthma patients suffer from bronchoconstriction which may be eased with a bronchodilator. However, melatonin, which is often prescribed for insomnia, favours a state of bronchoconstriction and weakens the relaxing effect of a bronchodilator through the activation of the melatonin MT2 receptor.
To elucidate this, the research group identified the expression of the melatonin MT2 receptor in human airway smooth muscle. They observed that the activation of the melatonin MT2 receptor with higher doses of melatonin or melatonin receptor agonist ramelteon greatly potentiated the bronchoconstriction. In addition, melatonin attenuated the relaxing effects of the widely used bronchodilator β-adrenoceptor agonist.
“Although serum concentration of melatonin did not significantly induce the airway constriction, greater doses of melatonin, which is clinically used to treat insomnia, jet lag, or cancer, worsened asthma symptoms and impaired the therapeutic effect of bronchodilators,” said study leader Kentaro Mizuta from Tohoku University Graduate School of Dentistry .
First author Haruka Sasaki added, “The pharmacological therapy that blocks the melatonin MT2 receptor could inhibit the detrimental effects of melatonin on airways.”
A report in Nature examines why Omicron was such a surprise, and how the possible evolutionary pathways available to SARS-CoV-2 shape future scenarios of the COVID pandemic.
Currently, Delta and its descendants still dominate worldwide, and they were expected to eventually outcompete the last holdouts. But Omicron has undermined those predictions. “A lot of us were expecting the next weird variant to be a child of Delta, and this is a bit of a wild card,” said Aris Katzourakis, a specialist in viral evolution at the University of Oxford, UK.
The Omicron surge in South Africa suggests that the new variant has a fitness advantage over Delta, said Tom Wenseleers, an evolutionary biologist and biostatistician at the Catholic University of Leuven in Belgium. Omicron has some of the mutations associated with Delta’s high infectivity – but if increased infectivity alone explained its rapid growth, it would mean an R0 (reproduction number) in the 30s, said Wenseleers. “That’s very implausible.”
At present, Omicron appears to have an R0 of 1.36, after its initial surge, based on a continually updated estimate by Louis Rossouw, head of research and analytics at Gen Re. Weneseelers and other researchers instead suspect that Omicron’s rise may be due to its re-infection and vaccine evasion ability.
If Omicron is spreading, in part, because of its ability to evade immunity, it fits in with theoretical predictions about how SARS-CoV-2 is likely to evolve, says Sarah Cobey, an evolutionary biologist at the University of Chicago in Illinois.
As SARS-CoV-2’s infectivity gains start to slow, the virus will maintain its fitness by overcoming immune responses, said Cobey. If mutation halved a vaccine’s transmission blocking ability, this could open up a vast number of hosts. It’s hard to imagine any future infectivity gains providing the same boost.
The evolutionary path towards immune evasion and away from infectivity gains, is common among established respiratory viruses such as influenza, said Adam Kucharski, a mathematical epidemiologist at the London School of Hygiene and Tropical Medicine. “The easiest way for the virus to cause new epidemics is to evade immunity over time. That’s similar to what we see with the seasonal coronaviruses.”
Analysis has shown a wealth of Spike protein mutations that weaken the potency of neutralising antibodies resulting from infection and vaccination. Variants like Beta that have such mutations, have degraded – but not destroyed – vaccine effectiveness particularly against severe disease.
Compared with other variants, Omicron contains many more of these mutations, particularly in the region of spike that recognises host cells. Preliminary analysis from evolutionary biologist Jesse Bloom suggests that these mutations might render some portions of Spike unrecognisable to the antibodies raised by vaccines and previous infection with other strains. But lab experiments and epidemiological studies will be needed to fully appreciate the effects of these mutations.
Evolutionary costs and benefits Evolving to evade immune responses such as antibodies could also carry some evolutionary costs. A Spike mutation that dodges antibodies might reduce the virus’s ability to recognise and bind to host cells. The receptor-binding region of Spike, the main target for neutralising antibodies. is relatively small, explained Jason McLellan, a structural biologist at the University of Texas at Austin. Thus, the region might tolerate only small changes if it retains its main function of attaching itself to host cells’ ACE2 receptors.
Repeat exposures to different Spike versions, through infection with different virus strains, vaccine updates or both, eventually might build up a wall of immunity that SARS-CoV-2 will have difficulty overcoming. Mutations that overcome some individuals’ immunity might not work on the whole population, and T-cell-mediated immunity, another arm of the immune response, seems to be more resilient to changes in the viral genome.
SARS-CoV-2’s evasion of immunity might be slowed by these constraints, but they are unlikely to stop it, said Bloom. Evidence shows that some antibody-dodging mutations do not carry large evolutionary costs, said McLellan. “The virus will always be able to mutate parts of the Spike.”
A virus in transition How SARS-CoV-2 evolves in response to immunity has implications for its transition to an endemic virus. There wouldn’t be a steady baseline level of infections, says Kucharski. “A lot of people have a flat horizontal line in their head, which is not what endemic infections do.” Instead, the virus is likely to cause outbreaks and epidemics of varying size, like influenza and most other common respiratory infections do.
To predict what these outbreaks will look like, scientists are investigating how quickly a population becomes newly susceptible to infection, says Kucharski, and whether that happens mostly through viral evolution, waning immune responses, or the birth of new children without immunity to the virus. “My feeling is that small changes that open up a certain fraction of the previously exposed population to reinfection may be the most likely evolutionary trajectory,” said Rambaut.
The best outlook for SARS-CoV-2, but also the least likely, would be for it to follow measles. Lifetime protection results from infection or vaccination and the virus circulates largely on the basis of new births. “Even a virus like measles, which has essentially no ability to evolve to evade immunity, is still around,” said Bloom.
A more likely, but still relatively hopeful, parallel for SARS-CoV-2 is a pathogen called respiratory syncytial virus (RSV). Most people get infected in their first two years of life. RSV is a leading cause of hospitalisation of infants, but most childhood cases are mild. Waning immunity and viral evolution together allow new strains of RSV to sweep across the planet each year, infecting adults in large numbers, but with mild symptoms thanks to childhood exposure. If SARS-CoV-2 follows this path – aided by vaccines that provide strong protection against severe disease – “it becomes essentially a virus of kids,” Rambaut said.
Influenza offers two other scenarios. The influenza A virus, which drives global seasonal influenza epidemics each year, is characterised by the rapid evolution and spread of new variants able to escape the immunity elicited by past strains. The result is seasonal epidemics, propelled largely by spread in adults, who can still develop severe symptoms. Flu jabs reduce disease severity and slow transmission, but influenza A’s fast evolution means the vaccines aren’t always well matched to circulating strains.
But if SARS-CoV-2 evolves to evade immunity more sluggishly, it might come to resemble influenza B. That virus’s slower rate of change, compared with influenza A, means that its transmission is driven largely by infections in children, who have less immunity than adults.
How quickly SARS-CoV-2 evolves in response to immunity will also determine the need for vaccine updates. The current offerings will probably need to be updated at some point, says Bedford. In a preprint5 published in September, his team found signs that SARS-CoV-2 was evolving much faster than seasonal coronaviruses and even outpacing influenza A, whose major circulating form is called H3N2. Bedford expects SARS-CoV-2 to eventually slow down to a steadier state of change. “Whether it’s H3N2-like, where you need to update the vaccine every year or two, or where you need to update the vaccine every five years, or if it’s something worse, I don’t quite know,” he says.
Although other respiratory viruses, including seasonal coronaviruses such as 229E, offer several potential futures for SARS-CoV-2, the virus may go in a different direction entirely, say Rambaut and others. The sky-high circulation of the Delta variant and the rise of Omicron, aided by inequitable vaccine roll-outs to lower-income countries and minimal control measures in certain large developed countries such as the US, offer fertile ground for SARS-CoV-2 to take additional surprising evolutionary leaps.
For instance, a document prepared by a UK government science advisory group in July raised the possibility that SARS-CoV-2 could become more severe or evade current vaccines by recombining with other coronaviruses. Continued circulation in animal reservoirs, such as mink or white-tailed deer, brings more potential for surprising changes, such as immune escape or heightened severity.
It may be that the future of SARS-CoV-2 is still in human hands. Vaccinating as many people as possible, while the jabs are still highly effective, could stop the virus from unlocking changes that drive a new wave. “There may be multiple directions that the virus can go in,” said Rambaut, “and the virus hasn’t committed.”
A study following the effects of delayed umbilical cord clamping in preterm babies has found significant reduction in subsequent mortality and disability. The findings were published in The Lancet Child and Adolescent Health.
The study was a two-year follow up of the Australian Placental Transfusion Study, the award-winning and largest-ever clinical trial of delayed cord clamping of babies born before 30 weeks. Infants born preterm (before 37 weeks’ gestation) have poorer outcomes than infants at term, especially if born before 32 weeks.
The new study compared outcomes for over 1500 babies from the initial study, 767 with caregivers aiming for 60 second delay in clamping and 764 with caregivers aiming for cord clamping before 10 seconds after delivery.
Researchers found that delaying clamping reduces a child’s relative risk of death or major disability in early childhood by 17%. This included a 30% reduction in mortality before age two. In addition, 15% fewer infants in the delayed-clamping group needed blood transfusions after birth.
The leader of the study, Professor William Tarnow-Mordi, said the simple process of aiming to wait a minute before clamping will have significant global impact.
“It’s very rare to find an intervention with this sort of impact that is free and requires nothing more sophisticated than a clock. This could significantly contribute to the UN’s Sustainable Development goal to end preventable deaths in newborns and children under five – a goal which has really suffered during the pandemic,” he said.
“Applied consistently worldwide, aiming to wait a minute before cord clamping in very preterm babies who do not require immediate resuscitation could ensure that an extra 50 000 survive without major disability in the next decade,” said biostatistician Dr Kristy Robledo from the University of Sydney who led the two-year follow-up analysis.
“In other words, for every 20 very preterm babies who get delayed instead of immediate clamping, one more will survive without major disability.”
Delayed umbilical cord clamping is routine in full term babies to allow the newborn time to adapt to life outside the womb, however, until recently, clinicians generally cut the cord of preterm babies immediately so urgent medical care could be given.
“Ten years ago, umbilical cords were routinely clamped quickly after a very preterm birth and the baby was passed to a paediatrician in case the child needed urgent help with breathing,” said Professor Tarnow-Mordi.
“But we now know that almost all very preterm babies will start breathing by themselves in the first minute, if they are given that time.”
“We think that, after delaying cord clamping, babies get extra red and white blood cells and stem cells from the placenta, helping to achieve healthy oxygen levels, control infection and repair injured tissue.”
The childhood follow-up to the Australian Placental Transfusion Study is the largest world-wide two-year follow up of preterm cord clamping providing the best evidence so far on positive outcomes at two years of age.
In 2017, a systematic review of randomised trials in nearly 3000 preterm babies provided the first evidence indicating that delayed umbilical cord clamping might have benefits for preterm infants and their mothers. While the World Health Organization recommends that newborns, including preterm babies who do not require positive pressure ventilation should not have their cord clamped earlier than one minute after birth this has not always been consistently applied.
“Moving forward it’s vital that perinatal professionals record the time of first breath and cord clamping to the second during births to allow for robust, large-scale data to further our work in this area,” said co-author Professor Jonathan Morris.
“Intensive staff training in the new protocols will also be vital as it can be daunting to delay treatment in very early and sick babies, but the evidence suggests this results in the best outcomes for these children.”
