Molnupiravir is being developed for the treatment of COVID, which has been submitted for review by the US Food and Drug Administration, but large-scale production to treat COVID is still a challenge. Now, researchers have engineered enzymes to help manufacture the pill, resulting in a much shorter synthesis with a higher yield than current methods. The details of their work are reported in ACS Central Science.
The oral antiviral molnupiravir was originally developed to treat influenza, and works by causing viruses to make errors when copying their own RNA, introducing mutations that inhibit replication. Recently, interim phase 3 clinical trial findings indicated that molnupiravir reduced the risk of hospitalisation and death from COVID for newly diagnosed, at-risk patients, and that it had equal effectiveness against different SARS-CoV-2 variants. Researchers set out to develop a shorter, higher-yielding and sustainable way to synthesise the molecule.
The team came up with a three-step synthesis of molnupiravir from ribose, a sugar molecule. They identified enzymes or chemical treatments to sequentially add the appropriate chemical groups to ribose to generate the molecule. For the second step of the synthesis, the team identified bacterial enzymes that weakly catalysed the desired reactions. Using in vitro evolution, they greatly enhanced these enzymes’ activities. The new synthetic route, which also included a phosphate recycling strategy, was 70% shorter and had a seven-fold higher overall yield than the original route.
A new study has revealed why arthritis has a tendency to flare up in the same location instead of around the body.
When joints flare up in people with rheumatoid arthritisand related diseases, the joints involved are often the same as those previously affected. For example, if arthritis started in the right knee, it is much more likely to flare there than in the left knee, even if the arthritis had been in remission for years. Because of this, each patient develops a highly individual disease pattern, though why this is so has remained unclear.
“Overwhelmingly, flares occur in a previously involved joint,” said Peter Nigrovic, MD, chief of the division of immunology at Boston Children’s Hospital. “Something in that joint seems to remember, ‘this is the joint that flared before.’”
A new study, co-led by Dr Nigrovic and published in Cell Reports, shows where that memory is housed: in a type of immune cell called a tissue-resident memory T cell. Specifically, these T cells reside in the synovium, the tissue that lines the inside of the capsule surrounding the joint. “We showed that these T cells anchor themselves in the joints and stick around indefinitely after the flare is over, waiting for another trigger,” said Dr Nigrovic. “If you delete these cells, arthritis flares stop.”
The team demonstrated this phenomenon in three separate mouse models of inflammatory arthritis. Two models used chemical triggers to cause joint inflammation, and the third had a protein knocked out that blocks the pro-inflammatory cytokine IL-1. Once activated, resident memory T cells in the joints rallied other immune cells, leading to an arthritis flares limited to specific joints. Elimination of these T cells prevented further flares from occurring.
“Right now, treatment of rheumatoid arthritis has to continue lifelong; although we can successfully suppress disease activity in many patients, there is no cure,” said Dr Nigrovic. “We think our findings may open up new therapeutic avenues.”
Dr Nigrovic also believes the findings apply to other types of autoimmune arthritis, including juvenile idiopathic arthritis.
Dermatology provided a cue for the researchers: tissue-resident memory T cells were originally found in skin, where a ‘memory’ pattern is well known to dermatologists. In psoriasis, for example, patients get recurrent plaques in the same places. The same often holds true in cutaneous hypersensitivity reactions, such as reactions to nickel in jewelry or wristwatches. “A person reacting to nickel through a belt buckle may also develop a rash on their wrist, where they wore a nickel-containing watch as a child,” observed Dr Nigrovic.
Over 28 million more years of life were lost than expected in 2020 in 31 upper-middle and high-income countries, according to a University of Oxford-led study published in the BMJ.
Save for a handful of exceptions, 37 countries examined including the US had more premature deaths than expected in 2020, with a higher rate in men than women.
Understanding the full impact of the COVID pandemic requires counting excess deaths, and analysing how premature those deaths are. Years of life lost (YLL) is a more detailed assessment of COVID’s impact on populations as it measures both the number of deaths and the age at which death occurs.
Researchers used this measure to estimate the changes in life expectancy and excess years of life lost from all causes in 2020. They compared the observed life expectancy and years of life lost in 2020 with historical trends in 2005-19 in 37 upper-middle and high-income countries.
Between 2005 and 2019, life expectancy at birth rose for both men and women in all the countries studied. In 2020, a drop in life expectancy was seen in both men and women in all countries save New Zealand, Taiwan, and Norway, where there was a life expectancy gain and Denmark, Iceland, and South Korea saw no change.
The biggest life expectancy drop was in Russia (−2.33 years in men and −2.14 in women), the US (−2.27 and 1.61), Bulgaria (−1.96 and −1.37), Lithuania (−1.83 and −1.21), Chile (−1.64 in men), and Spain (−1.11 in women). Years of life lost declined in most countries in both men and women between 2005 and 2019, except Canada, Greece, Scotland, Taiwan, and the US.
In 2020, years of life lost were higher than expected in all countries except Taiwan and New Zealand, where there was a reduction in years of life lost, and Iceland, South Korea, Denmark, and Norway, where there was no evidence of a change in years of life lost. In the remaining 31 countries, more than 222 million years of life were lost in 2020, which is 28.1 million more than expected (17.3 million in men and 10.8 million in women).
The highest excess years of life lost (per 100 000) were in Russia (7020 in men and 4760 in women), Bulgaria (7260 and 3730), Lithuania (5,430 in men and 2,640 in women), and the US (4,350 in men and 2,430 in women).
Overall, excess years of life lost in 2020 were over five times greater (2510 per 100 000) than those associated with the seasonal influenza epidemic in 2015 (458 per 100 000).
The excess years of life lost were relatively low in people under 65 years, except in Russia, Bulgaria, Lithuania, and the US where the excess years of life lost was more than 2 000 per 100 000.
Most countries in Asia, Africa, and Latin America were excluded due to insufficient data, and researchers could not account for other factors, such as socioeconomic status, regional disparities, and race or ethnicity. However, the findings are largely in line with previous studies, and the use of authoritative national mortality data, together with a validated analytical approach, suggests that the results are robust.
“Our findings of a comparable or lower than expected YLL in Taiwan, New Zealand, Denmark, Iceland, Norway, and South Korea underscore the importance of successful viral suppression and elimination policies, including targeted and population based public health policy interventions,” the researchers wrote. “As many of the effects of the pandemic might take a longer time frame to have a measurable effect on human lives, continuous and timely monitoring of excess YLL would help identify the sources of excess mortality and excess YLL in population subgroups.”
Research studies suggest that unmet physical and psychological needs of patients with lung cancer have a significant impact on patients’ quality of life and affect their ability to continue with everyday activities.
Lung cancer is the leading cause of cancer death in the United States. No specific signs and symptoms exist for lung cancer, and most patients already have advanced disease at the time of presentation. In a study published in the European Journal of Cancer Care, researchers examined the impact of unmet needs on patients’ lives.
Analysing results from six studies involving 562 patients, researchers found that almost two thirds of the patients had been diagnosed with advanced cancer (stage III or IV), and most had been diagnosed for less than two years. There was a negative association between quality of life and unmet needs using two different measures. In two of the studies, the relationship was limited to physical and/or psychological needs.
In the physical domain, lack of energy and tiredness were common unmet needs, and uncertainty about the future, fears, and worry were among the most common in the psychological domain.
“This research underscores the high burden of unmet needs for individuals with lung cancer, often resulting from late diagnosis and associated lack of curative treatment,” said corresponding author Simon Dunne, PhD, of Dublin City University, in Ireland. “There is a need for early intervention and tailoring of pre-existing services to address unmet supportive care needs in this cancer group.”
A pioneering new study from Taiwan showed that focused ultrasound, which can be used to non-invasively target circuits in the brain, may benefit some patients with epilepsy who experience seizures which remain unresponsive to standard anti-seizure medications.
The results showed that of six patients with drug-resistant seizures, two patients had fewer seizures within three days of receiving focused ultrasound; however, one patient showed signs of more frequent subclinical seizures (which are not felt by the individual). The findings from the study were published in the journal Epilepsia.
Imaging tests performed after the treatment show that there were no negative effects on the brain. One patient reported a sensation of heat on the scalp during the treatment, and another patient experienced temporary memory impairment that resolved within three weeks.
“Neuromodulation is an alternative treatment for drug-resistant epilepsy. Compared with the present modalities used in neuromodulation for epilepsy, focused ultrasound can access deeper brain regions and focus on the main target of the epileptic network in a relatively less invasive approach,” explained senior author Hsiang-Yu Yu, MD, of Taipei Veterans General Hospital, in Taiwan. “It gives new hope and sheds new light for patients with drug-resistant epilepsy.”
Scientists have discovered that Toxoplasma gondii, a parasite known to cause illness in pregnant women and immunocompromised patients, could potentially enhance the treatment of various types of tumours.
The parasite Toxoplasma gondii is a single-celled opportunistic protozoan capable of infecting a broad range of warm-blooded animals and has been reported in nearly one-third of the world’s human population. It has a number of health effects, including a strong link to schizophrenia and has even been associated with increased suicide attempts in mothers.
While many treatments have been able to treat tumours and prolong the lives of patients, there is a need to further enhance these. In the study, published in the Journal for ImmunoTherapy Cancer, scientists found that the commonly found parasite is able to sensitise ‘cold’ tumours, that is, tumours unlikely to trigger a strong immune response, to immune checkpoint blockade therapy.
The researchers believe that this finding could have broader therapeutic implications for many types of cancers.
T. gondii has to live inside the cells of its host and secretes numerous proteins to counter the host’s immune defences and to facilitate their own invasion and colonisation of the host cells. The researchers first built a T. gondii mutant strain with limited growth and disease-causing ability, but which is also able to manipulate the host immune system.
By directly injecting this mutant parasite into solid tumours, it induces inflammatory responses in those tumours and even in tumours located in a distant location in the mouse body. The researchers further demonstrated that this treatment approach has made tumours more responsive to treatment with immune checkpoint inhibitors.
This dual treatment significantly extended the survival of mice and reduced tumour growth in mouse models of melanoma, Lewis lung carcinoma, and colon adenocarcinoma.
Dr Hany Elsheikha, Associate Professor in the School of Veterinary Medicine and Science at the University of Nottingham, and one of the lead authors of the study, said: “The use of a mutant version of Toxoplasma gondii in the treatment of certain tumours in mice models has been previously reported. What makes this study different is the confirmation that intratumoural injection with mutant Toxoplasma gondii strain boosts antitumour immunity and the effectiveness of checkpoint inhibition therapy.
“These are significant findings and are relevant to future tumour therapy. The marked reduction in tumour size and the significant improvement in the survival of mice that received this novel combinational therapy is promising but should be interpreted with caution as further research is needed.”
There is an urgent need for vaccines against Group B streptococcus, a major cause of preterm births, disability and infant mortality worldwide, according to a UN-backed report published on Wednesday.
Group B streptococcus (GBS) is a gram-positive bacteria that colonises the gastrointestinal and genitourinary tract. It can be transmitted in utero, is linked to around 150 000 infant deaths each year, more than half a million preterm births and significant long-term disability.
The report by the World Health Organization (WHO) and the London School of Hygiene & Tropical Medicine (LSHTM) updates 2017 estimates, and reveals that the global burden of GBS is far higher than was previously recognised.
“This new research shows that Group B strep is a major and underappreciated threat to newborn survival and wellbeing, bringing devastating impacts for so many families globally,” said Dr Phillipp Lambach, Medical Officer from WHO’s Immunization, Vaccines and Biologicals department.
The report is the first to quantify the major contribution of GBS to preterm births, and to neurological impairments such as cerebral palsy, hearing and vision loss, that can occur following infection.
Around 15% of all pregnant women worldwide, nearly 20 million annually, carry the GBS bacterium in their vagina, which can then spread to a foetus, or to newborns during labour. At present, GBS disease prevention in newborns is by administering antibiotic prophylaxis to women during labour, if the bacterium is detected during pregnancy.
However, significant health risks remain, as this intervention is unlikely to prevent most GBS-associated stillbirths, preterm births, or GBS disease that occurs later after birth.
“It is difficult to describe the breadth or depth of the grief when your child dies, or the accompanying guilt, and how it changes you, your family, and your relationships forever,” said Debbie Forwood, whose daughter Ada was stillborn after she developed a GBS infection.
Vaccine development urged GBS burden is highest in low and middle-income countries, where screening and treatment are most challenging to implement, with regions such as sub-Saharan Africa having the highest rates of maternal GBS. Now is the time for action, said Joy Lawn, an LSHTM Professor who contributed to the report. While several candidate GBS vaccines are in development, none are yet available despite decades in the pipeline. The report calls for stepping up development of an effective GBS vaccine that could be administered to expectant mothers during routine pregnancy checkups.
The partners estimate more than 50 000 GBS-related deaths, and over 170 000 pre-term births, could be avoided if over 70 per cent of pregnant women were vaccinated.
Such protection could also be highly cost-effective, they added. Net benefits from a year of maternal vaccinations could reach as high as $17 billion, accruing over several years, provided doses are affordably priced. For Ms. Forwood, this would be a bittersweet development.
“Only a GBS vaccine could have saved Ada. When a vaccine can be widely rolled out, I will weep and scream with the unfairness that it came too late for her, and for all the other babies who are needlessly suffering and dying every year that it is delayed,” she said.
“But I will also weep with joy that in the future, many more will live, and their families will be saved from the living hell that is the death of a child.”
University of Utah scientists have discovered a new type of neuron in the retina, which will help fill in our understanding of how sensory information is relayed.
In the central nervous system a complex network of neurons communicate with each other to relay sensory and motor information. In this chain of communication, a type of neuron called interneurons serve as intermediaries . A research team led by Ning Tian, PhD, identified a previously unknown type of interneuron in the mammalian retina. Their findings were published in the journal PNAS.
This discovery is a major step forward for the field as scientists strive to build a better understanding of the central nervous system by identifying all classes of neurons and their connections.
“Based on its morphology, physiology, and genetic properties, this cell doesn’t fit into the five classes of retinal neurons first identified more than 100 years ago,” said Dr Tian. “We propose they might belong to a new retinal neuron class by themselves.”
The research team called their discovery the Campana cell after its shape, which resembles a hand bell. Campana cells relay visual signals from both types of light-sensing rod and cone photoreceptors in the retina, however their exact purpose is the subject of ongoing research. Experiments revealed that Campana cells remain activated for an unusually long time – as long as 30 seconds – in response to a 10 millisecond light flash stimulation.
“In the brain, persistent firing cells are believed to be involved in memory and learning,” said Dr Tian. “Since Campana cells have a similar behaviour, we theorise they could play a role in prompting a temporal ‘memory’ of a recent stimulation.”
New research from the US has found that older adults who experienced social isolation had higher blood levels of interleukin-6 and C-reactive protein, two markers of inflammation that can have long-term negative impacts for the health of individuals as they age.
Social isolation is a risk factor for morbidity and mortality comparable to well-established risk factors including smoking, hypertension, and a sedentary lifestyle. The specific biological mechanisms that connect social isolation to morbidity and mortality remain unclear.
The study, published in the Journal of the American Geriatrics Society, used data from the National Health and Aging Trends Study (NHATS), which included a nationally representative sample of 4648 Medicare beneficiaries aged 65 years and older. The researchers defined social isolation with a multi-domained typology that considers living arrangement, core discussion network, religious attendance, and social participation The authors noted that clinical and social interventions that address social isolation among older adults may influence biological processes such as inflammation, as well as their potentially negative effects.
Credit: JAGS
“Our findings demonstrate an important association between social isolation and biological processes. This work is a step in the journey to disentangle the mechanisms by which social isolation leads to higher levels of morbidity and mortality,” said lead author Thomas K.M. Cudjoe, MD, MPH, of Johns Hopkins School of Medicine. “My hope is that investigators incorporate objective measures of social isolation and biological markers in future longitudinal studies so that we might continue to advance our understanding of these complex biopsychosocial interactions.”
In Scotland, about one in 20 people diagnosed with type 2 diabetes achieve remission from the disease, according to research appearing in PLOS Medicine. This suggests people are achieving remission outside of research trials and without bariatric surgery. Recognition of individuals in remission, following their progress, and understanding better the factors linked to remission could result in improved initiatives to help others.
In 2019 there were an estimated 463 million people with diabetes in the world, 90–95% of whom have type 2 diabetes. Ageing populations, growing obesity and sedentary lifestyles are increasing these numbers. The likelihood of achieving remission after 15% weight loss has been shown to be mainly determined by the duration of diabetes, with responders having better beta‐cell function at baseline.
Some people with type 2 diabetes have achieved remission after bariatric surgery, or after taking part in a research trial of a very low-calorie diet, but it is unknown how many people in the general population are in remission. Mireille Captieux at the University of Edinburgh and colleagues used a Scottish national register of people with type 2 diabetes to estimate the number of people in remission in 2019 and described the characteristics of those in remission and not in remission.
Of 162 316 patients aged > 30 who were eligible for the analysis, 7710 (5%) were in remission in 2019. Individuals in remission tend to have not previously taken glucose lowering medication; have lost weight since their diagnosis; be older; have lower blood sugar levels at diagnosis; or have had bariatric surgery. This finding helps to establish a baseline for future studies, and could also help clinicians identify patients with whom to discuss remission and weight loss.
Captieux added, “We have been able to show, for the first time, that 1 in 20 people in Scotland with type 2 diabetes achieve remission. This is higher than expected and indicates a need for updated guidelines to support clinicians in recognising and supporting these individuals.”
