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It’s a good idea to have more vaccines: Dr Rakesh Mishra

In the coming months, we will understand more about the utility of different vaccines, says top scientist Dr Rakesh Mishra.

Shalini Bhardwaj

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Top scientist Dr Rakesh Mishra, who is a director of CSIR-CCMB labs, talked to The Sunday Guardian on mutant variants. Excerpts:

Q: What exactly is the double mutant variant and how is it going to affect us in future?

A: Double mutant variant as the name suggests has two changes in its genome one L is converted into R at 452 position and in one E is converted Q at 484 position. So when these two mutations are together, we call it double mutant and in cases that we have sequence genomes, these two mutation are going together, so that way, its giving its signature to a new variant. Particularly in Maharashtra, about 20% of the cases are due to this new variant as of now, although in other states it’s not very prominent. It’s 1 or 2% or even less.

Q: How it is going to affect and who is responsible for this mutant variant?

A. Responsible! Virus mutate in natural ways and if we allow the virus to spread, then it will have more chance to mutate and only people are allowing it spread so people are responsible in that way but while this is natural process we should keep that also in mind, as far as problems are considered since even in Maharashtra, where it is seen in highest proportion which is only 20 %, that means 80% of the cases of Maharashtra are not because of this variant and in other states we don’t see this variant so much. So this means this variant is not responsible for the recent rise in the cases; something else is responsible. Also, we have not seen increased symptoms or mortality; in fact more and more people are asymptomatic; not more than 85% and mortality has decreased, which means we understand the disease better and proper care has been given by doctors and that’s why mortality is less. This also means that this variant, like other circulating variants, is not more dangerous. So it not a fast spreader, it is not clinically more dangerous, but whether it will be a problem for the vaccine or not that is something we have to confirm because there are only reports that both of these mutations can have immune escape behavior.

If it was actually happening at least in our case, we would have seen by now some re-infection cases which we have not seen so far. May be, there is less data, so we can’t conclude very much but early indications are that immunity acquired by prior infection and therefore by vaccination is protecting against this virus as of now; so more data will be required. There are experimental ways of figuring that out which is to culture the virus in laboratory and see if the anti-bodies of vaccinated people or recovered people can neutralise this virus and that’s what we are doing and I am sure many laboratories are doing in the country. We have started culturing this virus and in the coming weeks, we’ll know if any protection of vaccine is compromised in this case, but that will take a little time. Early indications are that we need not to worry in that context here.

Q: Does the government require more vaccines to control such mutant variants?

A: It is always good to have. Vaccine is a weapon against infection. The more weapons you have, the better you are. These vaccines have come as a emergency approval and within a year the vaccine is available which most of us thought will not be possible. That it has happened is a remarkable achievement of the industry, the scientists and also of our regulatory bodies who have gone so carefully and given these approvals and they have proven to be right because the vaccine is safe. Now more than 5 crore people have taken vaccines and they are doing well. Vaccination in UK is reducing the infection significantly, that observation has already been made, so it is a very good tool. More is better so because these vaccines are emergency approval, we don’t understand fully, particularly the long-term effects of these vaccines or age group and other medical conditions; how long they will protect, which variant which one will protect; all those data will emerge only after vaccination follow up which is happening in many countries, including in our country.

In the coming months, we will understand more about the utility of different vaccines. Whether one vaccine is better for younger people, and another is better for older people, we don’t know today, but we might understand it in the coming months; so therefore, it is very good idea to have more vaccines. We should have 6, 10 vaccines, so that we can ensure that the pandemic is controlled and we don’t get into more problems in the future. In fact, we should try and vaccinate at a very high rate the largest number of people possible before the virus recovers and makes more variants. We can eliminate the virus by vaccinating large number of people. So that is a good strategy to follow and while we do all this, whether vaccination or no vaccination, Covid appropriate behaviour is the most important point today. So even if  we are vaccinated, it will take month, to month-and-a-half to get the full effect of the vaccine. The vaccine does not mean that you will not get infected, it means that we will not get very sick; that you make not require to go to the hospital and lives will be saved. But the virus may still hang around, so the most important thing is to wear masks and avoid crowing and do hand hygiene.

Q: How does mutation takes place?

A: Mutation is a natural process of these viruses like is common flu we see every year. We get cough and cold; so is the same with the virus. Once it comes, our system fights it and within a week or 10 days, we get rid of it, but after a few months, it changes its coat and comes back and infects again. So it is the same thing happening with the coronavirus. The Covid-19 virus keeps changing, it is very natural. In fact, all of us are different because our ancestors had some mutants which we have inherited; that’s why we look different; all of us have genomic chances. They originated with mutation at some point or the other and mutation, if it is good for the species, it persists and if they are bad, we perish. Similarly, in virus, if the mutation is bad, that particular virus will die and if the mutation in advantageous for the virus, it will adopt better and spread more. So, it is a natural process for all living beings; that’s why we see variety in life.

Q: Do you think in future it can be deadly if people do not take care of themselves, and not follow the guidelines?

A: Absolutely. If lakhs and lakhs of people are infected and the virus is having a good time spreading all over, it will generate more variants and there is no doubt about that. Maybe we are lucky that the double mutant is not very dangerous at this moment, but in future, some other variant may emerge that may be more infectious and that may not respect vaccination. That may cause more mortality. All those things are possible; therefore, wearing masks and maintaining social distancing and hygiene is a must to defeat this virus.

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STUDY ASSERTS BLOOD ENZYME ACTIVITY LEVEL MAY INDICATE WHICH BREAST CANCERS ARE GROWING SLOW

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Patients with metastatic hormone receptor-positive breast cancer who have low activity levels of the enzyme sTK1 in their blood serum at the start of anti-estrogen treatment live longer and go longer without their disease progressing than patients with high levels, according to a recent study by SWOG (the Southwest Oncology Group) Cancer Research Network.

The findings of the study were published in the journal ‘Clinical Cancer Research’. The results suggest that patients with low sTK1 activity levels have a slow-growing disease that can be controlled initially with single-drug endocrine therapy for a prolonged period.

It remains to be determined whether these patients gain further benefit from adding a CDK4/6 inhibitor to their endocrine therapy. The findings come from an analysis of serum samples from 432 women with breast cancer who took part in the S0226 clinical trial, which was conducted by the SWOG Cancer Research Network, a cancer clinical trials group funded by the National Cancer Institute (NCI), part of the National Institutes of Health (NIH).

“SWOG researchers have demonstrated that a blood serum test can identify which of these patients have a slow-growing disease that might be controlled with a simple aromatase inhibitor pill alone,” said Dr Lajos Pusztai, MD, DPhil, professor of medicine (medical oncology) at Yale Cancer Center, who is a co-author on the paper.

Study S0226 found that most women with metastatic hormone-receptor-positive breast cancer who have not had previous treatment for their metastatic breast cancer live longer when they get a combination of the endocrine therapy drugs anastrozole and fulvestrant than when they get just anastrozole.

However, not all patients see extra benefit from the combination; some do just as well on a single drug. Having a way to identify which patients would not derive added benefit from the combination could save these patients the additional side effects and extra costs associated with taking two drugs instead of one.

The work was led by Costanza Paoletti, MD, who was then with the University of Michigan Rogel Cancer Center. She and her colleagues measured the level of serum thymidine kinase 1, or sTK1, considered a marker of cellular proliferation, in 1,726 samples taken from S0226 patients before the start of their treatment and at four-time points during treatment.

The samples were evaluated using a commercially available test known as the DiviTum assay, produced by Biovica International of Uppsala, Sweden, which measures levels of the enzymatic activity of sTK1. The researchers found what was considered high levels of the enzyme in samples from 171, or 40 per cent, of the patients.

Patients with high sTK1 levels, either before treatment or at any time during treatment, tended to have a significantly shorter period of time before their disease advanced (progression-free survival time, or PFS). Those with high levels at the start of treatment, or baseline, had a median PFS of only 11.2 months compared to 17.3 months for patients with low levels at baseline.

The high-sTK1 patients also died sooner, on average, than patients with low levels of the biomarker, with median overall survival times of just 30 months versus 58 months.

Importantly, patients with low sTK1 levels did just as well on the single drug anastrozole as on the combination. This means a measurement of pretreatment sTK1 level could potentially be used to determine whether a patient should start treatment with two-drug endocrine therapy (high sTK1) or single-drug endocrine therapy (low sTK1).

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STUDY FINDS PRIMARY CAUSE OF CURRENT OBESITY EPIDEMIC

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A new study has claimed that much of the blame for the current obesity epidemic lies on modern dietary patterns characterised by excessive consumption of foods with a high glycemic load: in particular, processed, rapidly digestible carbohydrates.

These foods cause hormonal responses that fundamentally change our metabolism, driving fat storage, weight gain, and obesity. The findings of the study were published in ‘The American Journal of Clinical Nutrition’.

Statistics from the Centers for Disease Control and Prevention (CDC) show that obesity affects more than 40 per cent of American adults, placing them at higher risk for heart disease, stroke, type 2 diabetes, and certain types of cancer.

The USDA’s Dietary Guidelines for Americans 2020 – 2025 further says that losing weight “requires adults to reduce the number of calories they get from foods and beverages and increase the amount expended through physical activity.”

This approach to weight management is based on the century-old energy balance model which states that weight gain is caused by consuming more energy than we expend. In today’s world, surrounded by highly palatable, heavily marketed, cheap processed foods, it’s easy for people to eat more calories than they need, an imbalance that is further exacerbated by today’s sedentary lifestyles.

Overeating, coupled with insufficient physical activity, is driving the obesity epidemic. On the other hand, despite decades of public health messaging exhorting people to eat less and exercise more, rates of obesity and obesity-related diseases have steadily risen.

The study points to fundamental flaws in the energy balance model, arguing that an alternate model, the carbohydrate-insulin model, better explains obesity and weight gain. Moreover, the carbohydrate-insulin model points the way to more effective, long-lasting weight management strategies.

According to lead author Dr David Ludwig, Endocrinologist at Boston Children’s Hospital and Professor at Harvard Medical School, the energy balance model doesn’t help us understand the biological causes of weight gain: “During a growth spurt, for instance, adolescents may increase food intake by 1,000 calories a day. But does their overeating cause the growth spurt or does the growth spurt cause the adolescent to get hungry and overeat?”

In contrast to the energy balance model, the carbohydrate-insulin model makes a bold claim: overeating isn’t the main cause of obesity.

Instead, the carbohydrate-insulin model lays much of the blame for the current obesity epidemic on modern dietary patterns characterised by excessive consumption of foods with a high glycemic load: in particular, processed, rapidly digestible carbohydrates.

When we eat highly processed carbohydrates, the body increases insulin secretion and suppresses glucagon secretion. This, in turn, signals fat cells to store more calories, leaving fewer calories available to fuel muscles and other metabolically active tissues.

The brain perceives that the body isn’t getting enough energy, which, in turn, leads to feelings of hunger. In addition, metabolism may slow down in the body’s attempt to conserve fuel. Thus, we tend to remain hungry, even as we continue to gain excess fat.

To understand the obesity epidemic, we need to consider not only how much we’re eating, but also how the foods we eat affect our hormones and metabolism. With its assertion that all calories are alike to the body, the energy balance model misses this critical piece of the puzzle.

While the carbohydrate-insulin model is not new–its origins date to the early 1900s–The American Journal of Clinical Nutrition perspective is the most comprehensive formulation of this model to date, authored by a team of 17 internationally recognised scientists, clinical researchers, and public health experts.

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New research uncovers link between inflammation and pancreatic cancer development

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A new discovery from researchers at The University of Texas MD Anderson Cancer Center has clarified the long-established connection between inflammation and pancreatic cancer development.

The findings of the study were published in the journal ‘Science’. According to the study, pancreatic cells display an adaptive response to repeated inflammatory episodes that initially protects against tissue damage but can promote tumour formation in the presence of mutant KRAS.

The authors demonstrated that mutant KRAS — which is found in roughly 95 per cent of all pancreatic cancers — supports this adaptive response, leading to selective pressure to maintain the cancer-causing mutation.

“We discovered that a single transient inflammatory event induced long-term transcriptomic and epigenetic reprogramming of epithelial cells that cooperated with oncogenic KRAS to promote pancreatic tumours long after the inflammation was resolved,” said corresponding author Andrea Viale, MD, assistant professor of Genomic Medicine.

“In the setting of repeated pancreatitis, KRAS mutations can be acquired early on to limit tissue damage, suggesting the existence of a strong evolutionary pressure to select mutated cells and providing a possible explanation for the nearly universal presence of mutant KRAS in pancreatic cancers,” Viale added.

Inflammation has long been linked to tumour development in several cancer types, but the specific reasons behind this connection were previously unclear.

The research team, led by co-first authors Edoardo Del Poggetto, PhD, postdoctoral fellow, and I-Lin Ho, a graduate student in the Viale Laboratory, sought to study the effect of pancreatitis — a condition of inflammation in the pancreas linked with a higher risk of pancreatic cancer — on pancreatic epithelial cells.

The researchers stimulated transient inflammation in a model system of inducible KRAS-driven pancreatic cancer. Inflammation caused immediate pathological changes in pancreatic cells, but they resolved within one week.

However, activation of KRAS even months following the resolution of inflammation resulted in accelerated tumour formation compared with controls, suggesting that inflammation drives long-term changes in epithelial cells that cooperate with mutant KRAS to promote cancer development.

Deep molecular analysis of epithelial cells following a single inflammatory event demonstrated substantial reprogramming of gene expression and epigenetic regulation that persisted long after recovery of the tissue damage, a process the researchers termed “epithelial memory.”

This cellular reprogramming activated pathways related to cell survival, proliferation and embryonic development, which are similar to pathways active during cancer development. The cellular reprogramming caused by inflammation also facilitated the acquisition of acinar-to-ductal metaplasia (ADM), a reversible process in which pancreatic acinar cells acquire features of ductal cells.

Acinar cells are responsible for producing and secreting digestive enzymes, while ductal cells are responsible for delivering those enzymes to the small intestine. ADM, a process that normally occurs in response to pancreatic damage, is thought to be a pancreatic cancer precursor.

In the context of epithelial memory, repeated inflammatory episodes resulted in the rapid and extensive appearance of ADM with minimal signs of cellular damage, suggesting that cellular reprogramming protects the pancreas against an accumulation of tissue damage. These findings also clarify that ADM is not a cancer precursor state, but rather an adaptive response to inflammation. Previous research has shown that KRAS mutations can induce and stabilise ADM.

Here, the authors demonstrated that induction of mutant KRAS during repeated inflammations resulted in more pronounced ADM and virtually no tissue damage. Thus, the authors predict that cells undergoing inflammation would have a strong positive selection for KRAS mutations or other alterations that stimulate ADM and limit damage accumulations.

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MOTHERS ARE NOW HESITANT TO HAVE ANOTHER BABY DUE TO COVID-19 PANDEMIC

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New study reveals nearly half of New York City mothers who had been trying to have another baby before the coronavirus pandemic began stopped in the first few months of the outbreak.

The findings of the study were published in the journal ‘JAMA Network Open’. Led by researchers at NYU Grossman School of Medicine, the survey of 1,179 mothers in New York City also found that one-third of women who had been thinking about becoming pregnant before the pandemic but had not yet begun trying said they were no longer considering it.

“Our findings show that the initial COVID-19 outbreak appears to have made women think twice about expanding their families and, in some cases, reduce the number of children they ultimately intend to have,” said study lead author and epidemiologist Linda Kahn, PhD, MPH.

“This is yet another example of the potential long-lasting consequences of the pandemic beyond the more obvious health and economic effects,” added Kahn.

Pregnancy becomes riskier and more difficult to achieve as women age, so the delays prompted by the pandemic may lead to increased health risks for both mother and child, as well as the need for costly fertility treatments, she added.

Kahn, an assistant professor in the Departments of Pediatrics and Population Health at NYU Langone Health, noted that all of the women in the study already had at least one child age 3 or younger.

As a result, it is possible that the challenges of caring for a young child during the peak of New York City’s outbreak and subsequent lockdown may have played a role in their hesitancy to have another baby.

Early evidence has already identified a birthrate decline in the United States during the coronavirus pandemic. Recent data showed that the country saw roughly 300,000 fewer births in 2020 than experts had expected based on annual fertility trends, with a particular drop in the last two months of the year, which corresponds with fewer conceptions at the beginning of the outbreak in March.

However, until now, few investigations have explored the root causes behind individual parents’ decisions to delay pregnancy. The new study is the first to examine pregnancy plans among mothers during the first wave of COVID-19 in New York City. For the investigation, the researchers analysed data from an ongoing pregnancy and child health study. In the survey, which collected data beginning in mid-April 2020, the mothers were asked to recall their pregnancy plans before the pandemic as well as whether they were still going forward with their plans at the time of the survey.

Among the findings, the study revealed that fewer than half of mothers who had stopped trying to become pregnant were certain they would resume trying to become pregnant once the pandemic ended, suggesting that they may abandon rather than just delay their plans to expand their families, Kahn said.

In addition, those with higher stress levels and greater financial insecurity were especially likely to postpone or end their plans for an additional child.

According to the study authors, this finding highlights the importance of financial health in parents’ decisions around pregnancy and suggests that additional financial support for families may be needed to address the nation’s ongoing fertility decline, which began in 2008.

“These results emphasise the toll the coronavirus has taken not only on individual parents but perhaps on fertility rates overall,” said study senior author epidemiologist Melanie Jacobson, PhD, MPH.

Jacobson, a research scientist in the Division of Environmental Pediatrics at NYU Langone, cautions that the investigation only included women who were planning to have children and did not account for unplanned pregnancies.

She said the study authors next plan to repeat the survey with the same group of mothers and explore the potential impact of vaccination, an option not available at the time of the survey.

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Research finds breastfeeding is being overtly discouraged by infant formula websites

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Despite public health efforts to support breastfeeding and informed choice, during a news study, an analysis of websites for baby formula manufacturers found that their messages and images discourage breastfeeding while touting the benefits of the formula.

The study, led by researchers at the NYU School of Global Public Health and published in the journal Public Health Nutrition, is the first to compare information and portrayals of breastfeeding with infant formula feeding on manufacturer websites directed at U.S. consumers. “Many factors influence parents’ decision to breastfeed or use formula, including breastfeeding support and work schedules. But we also know that marketing and advertising play a critical role,” said Jennifer Pomeranz, assistant professor of public health policy and management at NYU School of Global Public Health and the study’s lead author. “It is important to understand the messages caregivers are receiving directly from formula companies, whose websites are targeting pregnant women and new parents with marketing claims disguised as feeding advice and support.”

Breastfeeding has many well-documented benefits for infants and mothers. Because breast milk is a complete source of nutrition for babies and can protect them from infections and certain diseases later in life, the U.S. and global health authorities recommend breast milk as the sole source of nutrition during a child’s first six months and encourage continued breastfeeding.

Previous research shows that marketing from formula companies can influence norms and attitudes around infant feeding and may use unsubstantiated health claims to promote formula and diminish confidence in breast milk. To prevent this, the World Health Organization urges countries to ban the marketing of formula to consumers; while the U.S. still allows it, the Surgeon General recommended that infant formula be marketed in a way that does not discourage breastfeeding.

Pomeranz and her colleagues analyzed the websites of three major formula brands that make up 98 per cent of the U.S. market, as well as two organic brands, to compare messages and images about breastfeeding and breast milk with those about infant formula feeding.

The researchers found that substantial messaging on the five formula manufacturers’ websites focused on discouraging breastfeeding. The websites actually contained more messages about breastfeeding or breast milk than formula, but much of the breastfeeding content (40 per cent) focused on challenges, such as having a low supply of breast milk or difficulty latching.

The websites were significantly more likely to mention the benefits of formula (44 per cent)–for instance, statements that formula provides brain and gastrointestinal benefits–than benefits of breastfeeding or breast milk (26 per cent).

Moreover, manufacturers compared formula feeding to breastfeeding, rather than comparing their brands positively to other brands.

Images on the websites also illustrated the benefits of formula–including the ease of feeding, with babies holding their own bottles–while making breastfeeding look difficult and labour intensive.

“Infant formula manufacturers’ repeated communication about breastfeeding problems such as reduced breast milk supply or sore nipples, coupled with images of women holding their breasts to breastfeed, implies that breastfeeding is hard, painful work. These recurring messages may ultimately discourage breastfeeding,” said Pomeranz.

“Even if websites frame their ‘advice’ as providing solutions to the problems identified, it is completely inappropriate for a formula company to disseminate information–let alone negative information–about breastfeeding to new parents and mothers in particular,” added Pomeranz.

The researchers identified other marketing tactics on formula websites, including the use of discounts or coupons, contact information for sales representatives, and claims of health and nutritional benefits of infant formula over breast milk.

“These marketing practices directed towards U.S. consumers would be legally suspect in other countries, many of which follow W.H.O. recommendations and prohibit direct-to-consumer marketing of infant formula,” added Pomeranz.

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NEW INSIGHTS INTO FUNDAMENTAL WORKINGS OF IMMUNE SYSTEM IN RESPONSE TO SKIN CANCER THERAPY

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New research led by the University of Birmingham suggests that skin cancer patients could have a better prognosis if their T cells send messages from five specific genes in their immune response to drugs given to treat the disease.

The research, carried out in mice, cells in the laboratory, and using publicly available data from patients with advanced melanoma before and after treatment with Nivolumab therapy, was published in the journal Immunity. T cells are white blood cells that protect the body from harm from viruses, bacteria, and cancer cells and explore their environments by using their T cell receptor (TCR) to recognise fragments – called antigens – of microbes or damaged cancer cells.

The TCR controls the behaviour of the T cell and can send messages to the T cells’ command centre to kick-start an immune response. This process is important for vaccine research and treatment of autoimmune conditions but is particularly of interest for cancer treatments to improve the anti-tumour function of T cells.

The researchers carried out the study to better understand how the amount of antigen controls how the TCR sends messages to the T cells’ command centre, and how this affects the type of immune response. They wanted to explore how antigen amounts control the expression of so-called ‘immune checkpoints’ that act as brakes on immune responses. It is these immune brakes, such as one called PD1, that are the target of drugs that seek to increase the immune response in cancer immunotherapy.

Lead author Dr David Bending, of the University of Birmingham’s Institute of Immunology and Immunotherapy, explained: “Through our research, we discovered that the amount of antigen determined how many immune checkpoints or immune brakes a T cell had on its cell surface.

“When we exposed T cells to the highest amounts of antigen, they stopped sending signals to their command centre, and this was because they had increased the number of immune brakes, which shut down the messengers. This made these T cells unable to respond to antigens for a period.”

By blocking one of the immune brakes, called PD1, the researchers were able to re-awaken some of these ‘unresponsive’ T cells. They found that these re-awakened T cells not only started sending messages to their command centres, but the messages they sent were louder and clearer.

“The response from the command centre was that the T cells started to increase the number of messages from five specific genes,” added Dr Bending. “By looking for the messages from these five genes, we were able to show that these stronger and louder messages were increased in melanoma patients who survived for longer on drugs that block the immune brake PD1. We think that this means that those cancer patients whose immune cells can send messages from these five genes in response to drugs that target PD1, a good outcome is far more likely.”

The researchers said their finding shows that the immune system likely requires an optimal level of stimulation to mount the most effective immune response in skin cancer patients. Dr Bending added: “Our research gives us an interesting insight into fundamental workings of the immune system. It suggests that both the amount of antigen around a T cell and also the number of immune brakes the T cells have at their surface are very important in controlling immune responses. Furthermore, we have shown that we can alter the balance of the immune response through stopping some of these immune brakes, which results in a stronger T cell response.”

The study has generated a new potential readout to monitor patients on drugs targeting PD1 in cancer. It also may be useful for exploring the potential of combinations of drugs that target multiple immune checkpoints to try to further re-awaken T cells in cancer patients.

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