Tag: 22/3/22

Categories : COVIDTags :

SARS-CoV-2 Shows no Signs of Resistance to Paxlovid – For Now

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SARS-CoV-2 infecting a human cell
Infected cell covered with SARS-CoV-2 viruses. Source: NIAID

Researchers monitoring SARS-CoV-2 for signs of resistance have found that Pfizer’s COVID drug Paxlovid is still effective against the coronavirus. Published in the journal Cell Research, [PDF] the study is one of the first to explore the full extent of mutations, but also provides evidence that mutations are moving in the direction of developing resistance to the drug.

Researchers concluded that Paxlovid’s mechanism of suppressing SARS-CoV-2 is still effective. The antiviral drug works by jamming the cell machinery of a key protein, known as the ‘main protease’ or Mpro, involved in replicating the virus. A number of antiviral drugs target viral proteases, such as those for HIV and hepatitis C.

With the global spread of Omicron, resulting in recent severe outbreaks in Asian countries which have previously pursued “zero COVID” strategies, the virus has been observed for signs of evolving treatment resistance. With only a few drugs that are available to treat COVID, physicians are counting on treatments like Paxlovid to stem the spread.

However, while the virus is currently not resistant, genetic analysis showed that the virus is starting to evolve in the direction of strains that could evade current treatments.

“There is hope, at least for now,” said study author Jun Wang, an associate professor at Rutgers University. “At this point, Omicron is still new enough so that treatments are still working. But as more people take Paxlovid, we will expect drug resistance to emerge.”

The scientists accessed a public database known as GISAID, studying the Mpro sequences of all strains of COVID detected so far. The protein is central to the reproduction of the virus and the target of the antiviral Paxlovid.

Comparing more recent strains with earlier strains around the world, the scientists searched for mutations in genetic sequences of Mpro that occur when a virus replicates. Mutations can lead to possible new structures of Mpro, which are generally correlated with drug resistance.

“We wanted to pick out if there is a mutation in the protease that’s a ‘red flag,’” A/Prof Wang said. “We did that because, generally speaking, as we have seen in the past, this would be the first sign of the development of resistance.”

The researchers found the top 25 most common new mutations in the main protease of many Omicron strains, a discovery A/Prof Wang characterised as “concerning,” with the most common one called P132H. When they tested Paxlovid against the Mpro with the P132H mutation, the antiviral was still effective. X-ray crystallography confirmed this by showing that the P132H did not change the Mpro structure significantly.

“Although this mutation does not cause drug resistance to Paxlovid, this implies that the virus can still evolve to create additional mutations that might cause drug resistance,” A/Prof Wang stated. “When a drug gets widespread use, it is just a matter of time before resistance appears.”

A/Prof’s Wang’s lab is working to develop new antivirals against COVID by targeting the Mpro and another key protein known as the papain-like protease. The best approach, he said, is to create a “cocktail” containing multiple antivirals to thwart resistance, as with HIV/AIDS and HCV.

Source: Rutgers University

Categories : Neurodegenerative DiseasesTags :

Lithium May Prevent Dementia in Elderly Patients

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Old man
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A University of Cambridge study appears to show that older adults who received lithium were less likely to develop dementia. The findings, which appear in the journal PLOS Medicine, are in agreement with other recent studies and could pave the way for larger investigations.

Dementia, the most common form of which is Alzheimer’s, currently represents the leading cause of death in elderly Western populations, but there are no preventative treatments available.

“The number of people with dementia continues to grow, which puts huge pressure on healthcare systems,” said Dr Shanquan Chen from Cambridge’s Department of Psychiatry, the paper’s first author. “It’s been estimated that delaying the onset of dementia by just five years could reduce its prevalence and economic impact by as much as 40 percent.”

In previous studies have proposed, lithium was proposed as a possible treatment for those with a dementia diagnosis or early cognitive impairment, but it is unclear whether it can delay or even prevent the development of dementia altogether, as these studies were limited in size.

Lithium is a mood stabiliser usually prescribed for conditions such as bipolar affective disorder and depression. “Bipolar disorder and depression are considered to put people at increased risk of dementia, so we had to make sure to account for this in our analysis,” said Dr Chen.

The researchers analysed data from 29 618 NHS patients who accessed mental health services between 2005 and 2019. Patients were all over 50 years of age, with a mean age just under 74, had received at least a one-year follow-up appointment, and had not been previously diagnosed with either mild cognitive impairment or dementia.

Of these patients, 548 had been treated with lithium and 29 070 had not. For the group that had received lithium, 53, or 9.7%, were diagnosed with dementia. For the group that had not received lithium, 3,244, or 11.2%, were diagnosed with dementia.

After controlling for factors such as smoking, other medications, and other physical and mental illnesses, lithium use was associated with a lower risk of dementia, both for short and long-term users. However, since the overall number of patients receiving lithium was small and this was an observational study, larger clinical trials would be needed to establish lithium as a potential treatment for dementia.

Another limitation of the study was the number of patients who had been diagnosed with bipolar disorder, which is normally associated with an increased risk of dementia. “We expected to find that patients with bipolar disorder were more likely to develop dementia, since that is the most common reason to be prescribed lithium, but our analysis suggested the opposite,” said Dr Chen. “It’s far too early to say for sure, but it’s possible that lithium might reduce the risk of dementia in people with bipolar disorder.”

Additional research is now needed to see if lithium really does have a benefit in these conditions.

Source: University of Cambridge

Categories : PaediatricsTags :

Wits University Tests Nirsevimab to Protect Against RSV in Infants

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Wits University has reported that a drug to prevent respiratory syncytial virus (RSV) in infants is safe and effective, enabling ways to protect vulnerable groups such as preterm babies from the virus.

RSV is a major cause of lower respiratory tract infection (LRTI) and hospitalisation in infants. Globally, approximately one-third of all hospitalisations for lower respiratory tract illness are caused by RSV. Hence, there is a serious unmet medical need for RSV protection in healthy infants born at term.

The Wits Vaccines and Infectious Diseases Analytics (Wits VIDA) research unit was the lead South African collaborator in a phase 2/3 study to investigate the efficacy and safety of Nirsevimab, in healthy late-preterm and term infants.

Nirsevimab is a monoclonal antibody against RSV with an extended half-life. Monoclonal antibodies are antibodies that have a high degree of specificity (mono-specificity) for an antigen or epitope, and are generally well tolerated. Monoclonal antibodies are typically derived from a clonal expansion of antibody-producing malignant human plasma cells. Because they are large proteins (typically 150-200 000 daltons in size) they require parenteral, often intravenous, administration.

Nirsevimab has an extended half-life of three to four months, and is able to provide protection for the entire RSV season, which usually lasts for three to four months.

Compared to term infants, late preterm infants (born at 32 to 37 weeks) have a higher hospitalisation and mortality risk from RSV, due to their relative physiologic and metabolic immaturity. Late preterm infants are at increased risk of a host of morbidities and mortality, including respiratory distress and failure, feeding difficulties, poor growth, hypoglycaemia, hyperbilirubinemia, and hypothermia.

The study, published in the New England Journal of Medicine, found that the drug Nirsevimab significantly protected infants against RSV disease in the Phase 3 MELODY trial, and protected high risk children in a separate study known as MEDLEY.

“This intervention provides the opportunity to protect young infants against the most common cause of hospitalisation from lower respiratory tract infections – RSV – which kills between 60 000 to 190 000 babies each year, mainly in low- and middle-income countries,” says Wits Professor of Vaccinology Shabir Madhi, Director of Wits VIDA, and a co-author of the study.

The findings showed 74.5% efficacy against medically attended lower respiratory tract infections caused by RSV in healthy infants.

Furthermore, Nirsevimab is the first potential immunisation for all infants to demonstrate sustained protection across the entire RSV season with a single dose.

“The new drug provides the opportunity of protecting infants, including high-risk groups – such as those born prematurely or with chronic lung or congenital heart disease – against the leading cause of hospitalisation for lower respiratory tract infections among infants globally,” says Madhi.

Source: Wits University

Categories : Environmental EffectsTags :

New Evidence-based Recommendations for Light Exposure

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For the first time, a set of recommendations have been drawn up to provide guidance for human exposure to light throughout the day and at nighttime, based on the amount of blue light in the environment. The recommendations are detailed in PLOS Biology.

Modern lifestyles, with 24-hour access to electric light and reduced exposure to natural daylight, can disrupt sleep and negatively impact health, well-being, and productivity. A new report in PLOS Biology addresses the issue of exactly how bright lighting should be during the day and in the evening to support healthy body rhythms, restful sleep, and daytime alertness.

An international body of leading scientific experts was brought together to draw up the first evidence-based, consensus recommendations for healthy daytime, evening, and nighttime light exposure. These recommendations provide much needed guidance to the lighting and electronics industries to aid the design of healthier environments and to improve how we light our workplaces, public buildings, and homes.

The new report took on a key question – how to properly measure the extent to which different types of lighting might influence circadian rhythms and sleep patterns. Light affects these patterns via a specialised type of cell in the eye that uses a light sensitive protein, melanopsin, that is distinct from the opsin in the rods and cones that support vision (and upon which traditional ways of measuring “brightness” are based). Since melanopsin is most sensitive to blue-cyan light, the new recommendations used a newly-developed light measurement standard tailored to this unique property: melanopic equivalent daylight illuminance. Analysis of data from a variety of studies proved that this new measurement approach could provide a reliable way of predicting the effects of light on human physiology and body rhythms, and so could form the basis of widely applicable and meaningful recommendations.

A crucial next step will be to integrate the recommendations into formal lighting guidelines, which currently focus on visual requirements rather than effects on health and well-being. Additionally, advances in LED lighting technology and the availability of low-cost light sensors are expected to increase the ease with which individuals can optimise their personal light exposure to best support their own circadian rhythms in line with the new recommendations.

Professor Timothy Brown, who brought the international exports together for the report added: “These recommendations provide the first scientific consensus, quantitative, guidance for appropriate daily patterns of light exposure to support healthy body rhythms, nighttime sleep and daytime alertness. This now provides a clear framework to inform how we light any interior space ranging from workplaces, educational establishments and healthcare facilities to our own homes.”

Source: Science Daily

Categories : Diseases, Syndromes and Conditions GenderTags :

Sex Differences in Nonalcoholic Fatty Liver Disease Explained

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Toilet sign male and female
Photo by Tim Mossholder on Unsplash

Investigators may have discovered the reason why fewer women than men develop nonalcoholic fatty liver disease (NAFLD). They published their findings in Nature Communications.

One of the most common disorders globally, NAFLD is a leading cause of death worldwide. Its progressive form, ‘nonalcoholic steatohepatitis’ (NASH), affects about 30% of all NAFLD patients, and can lead to cirrhosis and liver cancer. Despite intensive research, the underlying mechanisms of NAFLD/NASH are still poorly understood and effective treatment is lacking as a result.

However, it is known that NAFLD/NASH is more common among men than women, especially premenopausal women. The reasons for this are still unclear, but evidence so far suggests that oestrogen plays a protective role. On the other hand, the protein formyl peptide receptor 2 (FPR2) is known to play an important role in mediating inflammatory responses in multiple organs. However, no study so far has determined its role in the liver. Could FPR2 be involved in the sex-related differences regarding NAFLD prevalence and severity?

Addressing this question, a research team led by Professor Youngmi Jung of Pusan National University, Korea, recently conducted a study using mice model, shedding light on the role of FPR2 in NAFLD/NASH and its relationship to the observed sex-based differences. This work is among the very few studies on NAFLD that relies on sex-balanced animal experiments rather than the more common male-only designs.

The researchers first found that Fpr2 was highly expressed in healthy livers of female mice. Furthermore, it was expressed differently in the livers of male and female mice that were fed a special NAFLD-inducing diet. Silencing the Fpr2 gene made the male and female mice equally vulnerable to NAFLD, suggesting that FPR2 has a protective effect on the liver.

Interestingly, the researchers also found that FPR2 production in the liver is mediated by oestrogen. Males supplemented with external oestrogen produced more Fpr2 and were more resistant to NAFLD, whereas females that had their ovaries removed exhibited reduced liver Fpr2 levels. “Taken together, our findings suggest that FPR2 is a potential therapeutic target for developing pharmacological agents to treat NAFLD/NASH,” says Prof Jung. “In addition, our results could help in the development of gender-based therapies for NASH.”

This unprecedented discovery of the female-specific production of FPR2 in the liver and its role in providing resistance against NAFLD/NASH will hopefully pave the way not only for novel treatments but also a more comprehensive and sex-aware approach when doing science. Prof Jung remarked on this: “Our research highlights the pressing need for designing and developing better sex-balanced animal experiments, considering that the sex-specific expression of FPR2 in the liver had been completely overlooked in previous studies.”

Source: Pusan National University