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The circadian clock, which regulates numerous physiological processes such as the sleep-wake cycle, hormone synthesis, and metabolism, is a finely calibrated clock that is synced to the Earth’s 24-hour rotation cycle.

Felix Naef of EPFL recently identified the architecture of tissue-specific gene expression rhythms in humans, offering light on how sex and age affect our biological clocks. Molecular rhythms are often researched in model organisms using time-stamped measurements; however, such data are not commonly available in humans.

To overcome this, the researchers coupled known measurements from a large cohort of post-mortem donors with an unique computer technique developed to assign internal clock times to almost 1,000 donors.

“Interestingly, the data-science algorithm we developed turned out to resemble models from magnetic systems, which are well studied in statistical physics,” says Felix Naef. Using this innovative approach, the researchers obtained the first comprehensive and accurate whole-organism view of 24-hour gene expression rhythms in 46 human tissues.

The study found that the core clock machinery properties are conserved across the body and do not change significantly with sex and age. On the other hand, the analysis revealed extensive programs of gene expression rhythms across significant metabolism compartments, stress response pathways and immune function, and these programs peaked twice a day.

In fact, the emerging whole-body organization of circadian timing shows that rhythmic gene expression occurs as morning and evening waves, with the timing in the adrenal gland peaking first, while brain regions displayed much lower rhythmicity compared to metabolic tissues.

Dividing the donors by sex and age revealed a previously unknown richness of sex- and age-specific gene expression rhythms spread across biological functions. Strikingly, gene expression rhythms were sex-dimorphic (different in males and females) and more sustained in females, while rhythmic programs were generally reduced with age across the body.

Sex-dimorphic rhythms – referring to the differences between males and females – were particularly noticeable in the liver’s “xenobiotic detoxification”, the process by which the liver breaks down harmful substances. Additionally, the study found that as people grow older, the rhythm of gene expression decreases in the heart’s arteries, which may explain why older people are more susceptible to heart disease. This information could be useful in the field of “chronopharmacology,” which is the study of how a person’s internal clock affects the effectiveness and side effects of medication.

This study sheds fresh light on the complicated interplay of our body clock, sex, and age. Understanding these cycles may lead to novel methods of identifying and treating pathologies like sleep disorders and metabolic diseases.

Following a warning from the US Food and Drug Administration to “not to purchase or use EzriCare Artificial Tears due to potential contamination” the Central Drugs Standard Control Organization (CDSCO) under the Union Health ministry and the Tamil Nadu State Drug Controller have launched an investigation into the pharma firm producing this eyedrop, a report familiar with the situation said on Friday.

“Teams from CDSCO and TN State Drug Controller, comprising three officials, are on their way to the manufacturing plant located near Chennai. It’s a contract manufacturing plant supplying through others to the US market. This specific drug is not sold in India,” said the source. FDA has also restricted the imports of products manufactured by Global Pharma Private Healthcare Limited.

“The import alert prevents these products from entering the United States,” FDA said in a statement, adding “FDA is warning consumers and health care practitioners not to purchase and immediately stop using EzriCare Artificial Tears or Delsam Pharma’s Artificial Tears due to potential bacterial contamination. Using contaminated artificial tears increases the risk of eye infections that could result in blindness or death.”

The over-the-counter products, manufactured by Global Pharma Healthcare Private Limited, are intended to be ‘sterile’, the FDA noted.

Global Pharma has initiated a voluntary recall at the consumer level of all unexpired lots of EzriCare Artificial Tears and Delsam Pharma’s Artificial Tears, the source informed further.

The FDA also stated that the recall was recommended due to the company’s current good manufacturing practise (CGMP) violations, which included a lack of appropriate microbial testing, formulation issues (the company manufactures and distributes ophthalmic drugs in multi-use bottles without an adequate preservative), and a lack of proper controls regarding tamper-evident packaging.

According to a review of the most recent data published in The BMJ, some antidepressant drugs function for some pain disorders, but the majority are either useless or the evidence is insufficient.

When prescribing antidepressants for pain, researchers advocated for a more sophisticated approach. From 2000 to 2015, the usage of antidepressants in OECD countries more than doubled, and their off-label (unapproved) use to treat common pain illnesses such as fibromyalgia, persistent headaches, and osteoarthritis is thought to be a contributing factor.

To explore this further, a team of researchers led by Giovanni Ferreira at the University of Sydney carried out an overview of the effectiveness, safety, and tolerability of antidepressants for pain according to condition.

They searched databases for systematic reviews comparing any antidepressant with placebo for any pain condition in adults and found 26 eligible evidence reviews published between 2012 and 2022 involving 156 separate trials and over 25,000 participants.

These reviews reported on the effectiveness of eight classes of antidepressant covering 22 pain conditions (42 distinct antidepressant versus placebo comparisons). Almost half (45%) of the trials in these reviews had ties to industry.
Using data from each review, the researchers estimated relative risks of pain or average differences in pain between groups on a 0-100 point scale, taking account of dose, treatment duration, and number of trials and participants.

They also assessed safety and tolerability (withdrawals due to adverse events), certainty of evidence, and risk of bias. Findings were then classified from each comparison as effective, not effective, or inconclusive.
No review provided high certainty evidence on the effectiveness of antidepressants for pain for any condition.
Nine reviews provided evidence that some antidepressants were effective compared with placebo for nine conditions in 11 distinct comparisons.

For example, moderate certainty evidence suggested that serotonin-norepinephrine reuptake inhibitors (SNRIs) were effective for back pain (average 5.3 points lower on the pain scale than placebo), postoperative pain, fibromyalgia, and neuropathic pain.

Low certainty evidence suggested that SNRIs were effective for pain linked to breast cancer treatment, depression, knee osteoarthritis, and pain related to other underlying conditions. Low certainty evidence also suggested that selective serotonin reuptake inhibitors (SSRIs) were effective for people with depression and pain related to other conditions; and that tricyclic antidepressants (TCAs) were effective for irritable bowel syndrome, neuropathic pain, and chronic tension-type headache.

For the other 31 comparisons, antidepressants were either not effective (five comparisons) or the evidence was inconclusive (26 comparisons). Most safety and tolerability data were imprecise, indicating that the safety of antidepressants for several conditions is still uncertain.

This was a well designed review based on a thorough literature search and the researchers took steps to minimise the impact of issues such as differences in study design and quality, imprecision, and publication bias.
But they acknowledge that most comparisons had a limited number of trials, and results may not apply to antidepressants prescribed for symptoms linked to pain conditions, such as fatigue or sleep disturbance. Caution is also needed in interpreting these findings because 45% of the trials forming the evidence for this review had ties to industry, they add.

In conclusion, they said: “Some antidepressants were efficacious for some pain conditions; however, efficacy appears to depend on the condition and class of antidepressant. The findings suggest that a more nuanced approach is needed when prescribing antidepressants for pain.”

These findings suggest that for most adults living with chronic pain, antidepressant treatment will be disappointing, say researchers in a linked editorial. They acknowledge that clinicians continue to prescribe medicines for which the evidence is poor because they see that some people respond to them, albeit modestly, but say other less potentially harmful options, such as exercise and support with mobility and social isolation, can help people to live well with pain.

For people with pain, compassionate and consistent relationships with clinicians remain the foundations of successful care, they write. Studies must also involve people living with pain to ensure, among many other things, that pain research is meaningful to those living with pain and helps them and their clinicians make better shared decisions about treatments, they conclude.

Women who have any of the five major pregnancy problems, such as preterm birth or pre-eclampsia, have an elevated risk of ischemic heart disease for up to 46 years after giving birth.

The Swedish study’s findings were published in The BMJ. All major unfavourable pregnancy outcomes, according to the researchers, should be recognised as lifelong risk factors for ischemic heart disease, and women should be offered adequate therapy to assist avoid its development.

Heart disease is the largest cause of death among women globally, and it occurs when the blood arteries supplying the heart become restricted or obstructed.

Adverse pregnancy outcomes have been related to an increased risk of heart disease in the future.

Despite the fact that approximately one-third of women have a poor pregnancy result during their reproductive years, few studies have looked at several outcomes in the same group of women, making it difficult to make clear conclusions.

In order to address this, researchers from the United States and Sweden set out to investigate the links between five key poor pregnancy outcomes and long-term risks of ischemic heart disease in mothers.

They identified 2,195,266 women in Sweden with no history of heart disease who gave birth to a single live infant at the average age of 27 between 1973 and 2015.

Using nationwide medical records, they then tracked cases of ischemic heart disease from delivery date to December 2018 (average follow-up time 25 years, up to a maximum of 46 years).

The five major adverse pregnancy outcomes of interest were preterm delivery (less than 37 weeks gestation), small for gestational age at birth, pre-eclampsia, other blood pressure disorders of pregnancy, and gestational diabetes.

Other important factors were taken into account, such as mother’s age, number of children, education level, income, body mass index, smoking, and history of high blood pressure, diabetes, or high cholesterol.

Overall, ischemic heart disease was diagnosed in 83,881 (3.8%) women at an average age of 58 years. The results show that women who experienced any of five major adverse pregnancy outcomes showed an increased risk of subsequent ischemic heart disease.

For example, in the 10 years after delivery, relative rates of ischemic heart disease were increased twofold in women with other hypertensive disorders of pregnancy (46 extra cases per 100,000 person years), 1.7-fold in those with preterm delivery (19 extra cases per 100,000), 1.5-fold in those with pre-eclampsia (12 extra cases per 100,000), 1.3-fold in those with gestational diabetes, and 1.1-fold in those who delivered a small for gestational age infant, after adjusting for all other factors.

Women who experienced several adverse pregnancy outcomes showed further increases in risk. In the 10 years after delivery, rates of ischemic heart disease with 1, 2, or 3 or more adverse pregnancy outcomes were 1.3-fold, 1.8-fold, and 2.3-fold (20, 34, and 58 cases per 100,000 person years), respectively.

Most relative rates decreased over time but remained significantly increased (1.1-fold to 1.5-fold) even 30-46 years after delivery, and were only partially explained by shared genetic or environmental factors within families.

This is an observational study so can’t establish cause and the researchers can’t rule out the possibility that ischemic heart disease was underreported or that unreported maternal smoking, obesity, or other risk factors during pregnancy may have affected their results.

However, the large sample size based on highly complete nationwide birth and medical registry data and long-term follow up prompt the researchers to say that all major adverse pregnancy outcomes should be recognised as lifelong risk factors for ischemic heart disease.

“Women with adverse pregnancy outcomes should be considered for early preventive evaluation and long term risk reduction to help prevent the development of ischemic heart disease,” they conclude.

The prospect of treating Alzheimer’s disease and other neurodegenerative diseases by infusing healthy, new immune cells into the brain has expanded dramatically. Researchers from the Universities of California, Irvine, and Pennsylvania have successfully overcome the brain’s resistance to them, so overcoming a significant barrier.

Their discovery of microglia, a type of brain cell, opens up a new universe of therapeutic and preventive alternatives for neurodegenerative illnesses.

In the Journal of Experimental Medicine, the team’s paper is published. When microglia are healthy, they serve as the central nervous system’s resident front-line disease warriors. “However, there is overwhelming evidence that they can become dysfunctional in many neurological conditions,” said Mathew Blurton-Jones, UCI professor of neurobiology & behaviour and study co-lead author, adding, “Until recently, scientists have mainly been looking at the mechanisms that drive microglial dysfunction and trying to find drugs to change their activity. But with this study, we’ve found a way to harness microglia themselves to treat those diseases potentially.”

Frederick ‘Chris’ Bennett, assistant professor of psychiatry at Penn and co-lead author, added: “There is an obstacle because once our own microglia develop in the location where they are supposed to be in our brains, they don’t give up that space. They block the ability to deliver new cells that would take their place. If you want to insert donor microglia, you have to deplete the host microglia to open up the room.”

Bennett and his laboratory partnered with Blurton-Jones and his lab on the project.

Microglia depend on signalling by a protein on their surface called CSF1R for their survival. The FDA-approved cancer drug pexidartinib has been found to block that signalling, killing them. This process would seem to offer a way to clear space in the brain to insert healthy donor microglia. However, there is a dilemma – unless the pexidartinib is stopped before the donor microglia are added, it will eliminate them, too. But once the drug is terminated, the host microglia regenerate too fast to effectively put in the donor cells.

This quandary has challenged efforts to treat people with certain rare and severe neurologic conditions. One is Krabbe disease, in which the body’s cells can’t digest certain fats that are highly abundant in the brain. Currently, clinicians use bone marrow transplantation and chemotherapy to try to introduce new immune cells similar to microglia into the brain. But this approach can be toxic and must be carried out before Krabbe symptoms manifest.

“Our team believed that if we could overcome the brain’s resistance to accepting new microglia, we could successfully transplant them into patients using a safer, more effective process in order to target a great number of diseases,” said co-first author Sonia Lombroso, a Penn PhD student and member of the Bennett Lab, adding, “We decided to investigate whether we could make the donor microglia resistant to the drug that eliminates their host counterparts.”

The researchers used CRISPR gene-editing technology to create one amino acid mutation, known as G795A, which they introduced into donor microglia produced from human stem cells or a mouse microglial cell line. Then they injected the donor microglia into humanized rodent models while administering pexidartinib, with exciting results.

“We discovered that this one small mutation caused the donor microglia to resist the drug and thrive, while the host microglia continued to die off,” said co-first author Jean-Paul Chadarevian, a UCI PhD student who is a member of the Blurton-Jones Lab, adding, “This finding could lead to many options for developing new microglial-based treatments. Pexidartinib is already approved for clinical use and appears to be relatively well tolerated by patients.”

Approaches could range from fighting disease by replacing dysfunctional microglia with healthy ones to designing microglia that can recognize imminent threats and strike against them with therapeutic proteins before they cause harm.
The UCI-Penn team believes treatments based on this kind of microglial method could be developed within a decade. Their subsequent investigations include studying in rodent models how to use the approach to attack the brain plaques associated with Alzheimer’s and to counter Krabbe and other similar diseases.

Researchers discovered that young adults who experience sorrow or depression are more likely to acquire cardiovascular disease (CVD) and have poor heart health, according to a recent study that reviewed data from over 500,000 participants between the ages of 18 and 49. The findings add to a growing body of studies associating CVD to depression in young and middle-aged people, implying that the association may begin in adolescence.

The study, published in the Journal of the American Heart Asssociation, also found that young adults who self-reported feeling depressed or having poor mental health days had higher rates of heart attacks, strokes and risk factors for heart disease compared with their peers without mental health issues. “When you’re stressed, anxious or depressed, you may feel overwhelmed, and your heart rate and blood pressure rises. It’s also common that feeling down could lead to making poor lifestyle choices like smoking, drinking alcohol, sleeping less and not being physically active — all adverse conditions that negativity impact your heart,” says Garima Sharma, M.B.B.S., associate professor of medicine at Johns Hopkins Medicine and senior author of the study.

Sharma and her colleagues looked at data from 593,616 adults who participated in the Behavioral Risk Factor Surveillance System, a self-reported, nationally representative survey conducted between 2017 and 2020. The survey included questions about whether they have ever been told they have a depressive disorder, how many days they experienced poor mental health in the past month (0 days, 1-13 days or 14-30 days), whether they had experienced a heart attack, stroke or chest pain, and if they had cardiovascular disease risk factors.

Risk factors include high blood pressure, high cholesterol, being overweight/obese, smoking, diabetes, and poor physical activity and diet. People who had two or more of these risk factors were considered to have suboptimal cardiovascular health.

One in five adults self-reported having depression or frequently feeling low, with the study noting that there could have been higher rates during the last year of the study, which was the first year of the COVID-19 pandemic. According to the U.S. Centers for Disease Control and Prevention, the percentage of U.S. adults who experienced depression or anxiety jumped from 36.4% to 41.5% during the first year of the pandemic, with the highest spike among people ages 18 to 29.

The study revealed that, overall, those who self-reported several days of feeling down had a stronger link to cardiovascular disease and poor heart health. Compared with people who reported no poor mental health days in the past 30 days, participants who reported up to 13 poor mental health days had 1.5 times higher odds of CVD, while those with 14 or more days of poor mental health had double the odds. Associations between poor mental health and CVD did not differ significantly by gender or urban/rural status.

“The relationship between depression and heart disease is a two-way street. Depression increases your risk of heart issues, and those with heart disease experience depression,” says Yaa Adoma Kwapong, M.D., M.P.H., a postdoctoral research fellow at Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease and lead author of the study. “Our study suggests that we need to prioritize mental health among young adults and perhaps increase screening and monitoring for heart disease in people with mental health conditions and vice versa to improve overall heart health.”

Dr Shashivadhanan

The Fourth industrial revolution has brought about convergence of physical, digital and biological world. Newer technologies are disrupting all fields of health care in a distinct way. Recently we have Chat GPT which promises to change the Health Care Landscape. Chat Generative Pre-Trained Transformer (GPT) is a type of artificial intelligence based natural language processing software.

It was developed by open AI and launched in Nov 2022. Since then, its spreading faster than the covid pandemic. It has the remarkable ability to choose the most appropriate answer to any posed question with human like conversational ability. The data you feed, is the data which it uses to answer your queries. One must be cautioned, as the answers can be wrong, biased and prejudiced, as it is running on data fed to it by humans. In spite of its short comings in its current form, it promises exciting options to doctors and patients.

For Doctors it can present patient data in a summarized form. It can help physician to choose the right treatment option. With explosion in medical knowledge, it is humanly impossible to keep abreast with the latest in any field. Chat GPT can be a perfect solution to this problem by keeping doctors in synch with the latest in their field of interest. It has immense potential in enhancing doctor patient communication.

Translating clinical notes to patient friendly version / language can create a stronger bond between the two. Communication through patient portals outside the ambit of scheduled appointment will have a lot more relevance. These factors will give doctors time to concentrate more on their core specialty.

For the patients Chat GPT promises to be a harbinger of personalized medicine. Like a virtual assistant, it can warn patient regarding drug sensitivity, drug interaction and predict about their probable response to a prescribed treatment. The dos and don’ts can be tailor made to each patient in a personalized format. The more important question is, “will these disruptive technologies make medical professionals jobless or extinct”? As of now, the answer is,” No”.

These newer technologies when applied to treating humans, needs a fine balance between knowledge, wisdom, creativity, and empathy. Researchers have also found that physician’s sentiment about patients is a dimension to decision making that machines cannot gauge. Arriving at a diagnosis and treating a patient is a nonlinear process. It requires creativity in problem-solving skills and intuition that chat bots, algorithms and robots can never have.

AI can analyze huge complex data. It can come up with treatment options. However, its final interpretation will always be within the realm of humans. Newer technologies are here to help, assist, and empower the care giver and not, to compete in deliverance of health care. AI, Big Data Analysis, Machine Learning, Robots, 3D printing, Quantum computing Nanotechnology and now Chat GPT are technologies which are double edged swords. If harnessed ethically it can transform humans to superhumans. If not, the entire human race may face extinction. In which direction it goes, only time will tell.

Periodontitis, often known as gum disease, can cause a variety of dental issues, ranging from bad breath to bleeding and tooth loss. Researchers at Hiroshima University determined that it may be linked to considerably more significant diseases elsewhere in the body, specifically the heart.

The team discovered a significant correlation between periodontitis and fibrosis (scarring to an appendage of the heart’s left atrium that can lead to an irregular heartbeat called atrial fibrillation) in a sample of 76 patients with cardiac disease in a study published in JACC: Clinical Electrophysiology.

“Periodontitis is associated with a long-standing inflammation, and inflammation plays a key role in atrial fibrosis progression and atrial fibrillation pathogenesis,” said first author Shunsuke Miyauchi, assistant professor with the Hiroshima University’s Health Service Center.

He is also affiliated with the university’s Graduate School of Biomedical and Health Sciences, adding, “We hypothesized that periodontitis exacerbates atrial fibrosis. This histological study of left atrial appendages aimed to clarify the relationship between clinical periodontitis status and degree of atrial fibrosis.”

The patients’ left atrial appendages were surgically removed, and the tissue was studied to determine the relationship between the severity of the atrial fibrosis and the severity of the gum disease. They discovered that the worse the periodontitis, the worse the fibrosis, implying that gum inflammation may exacerbate inflammation and illness in the heart.

“This study provides basic evidence that periodontitis can aggravate atrial fibrosis and can be a novel modifiable risk factor for atrial fibrillation,” said corresponding author Yukiko Nakano, a cardiovascular medicine professor at Hiroshima University’s Graduate School of Biomedical and Health Sciences.

Periodontal care, in addition to decreasing other risk factors such as weight, activity levels, and cigarette and alcohol use, according to Nakano, could benefit in the overall therapy of atrial fibrillation. However, she emphasised that this study did not show a causal association, which means that while gum disease and the severity of atrial fibrosis appear to be linked, researchers have not found that one causes the other.

“Further evidence is required for establishing that periodontitis contributes to the atrial fibrosis in a causal manner and that periodontal care can alter fibrosis,” Nakano said, adding, “One of our goals is to confirm that periodontitis is a modifiable risk factor for atrial fibrillation and to promote dental specialists’ participation in comprehensive atrial fibrillation management. Periodontitis is an easily modifiable target with lower cost among known atrial fibrillation risk factors. Thus, the achievement of this study series may bring benefits for many people worldwide.”

Following that, the researchers stated that they intend to undertake additional clinical trials to see whether periodontal intervention reduces the occurrence of atrial fibrillation and improves patient outcomes.

According to new research, adults who sustained any form of brain injury during a 30-year study period had double the rate of mortality as those who did not, and mortality rates among those with moderate or severe head injuries were nearly three times higher.

The study’s findings were reported in JAMA Neurology. Over 23 million persons aged 40 and over in the United States report a history of head injury with loss of consciousness. Head injuries can be caused by a variety of factors, including car accidents, inadvertent falls, and sports injuries. Furthermore, brain damage has been related to a variety of long-term health issues such as disability, late-onset epilepsy, dementia, and stroke.

Studies have previously shown increased short-term mortality associated with head injuries primarily among hospitalized patients. This longitudinal study evaluated 30 years of data from over 13,000 community-dwelling participants (those not hospitalized or living in nursing home facilities) to determine if a head injury has an impact on mortality rates in adults over the long term. Investigators found that 18.4 per cent of the participants reported one or more head injuries during the study period, and of those who suffered a head injury, 12.4 per cent were recorded as moderate or severe. The median period of time between a head injury and death was 4.7 years.

Death from all causes was recorded in 64.6 per cent of those individuals who suffered a head injury, and in 54.6 per cent of those without any head injury. Accounting for participant characteristics, investigators found that the mortality rate from all causes among participants with a head injury was 2.21 times the mortality rate among those with no head injury. Further, the mortality rate among those with more severe head injuries was 2.87 times the mortality rate among those with no head injury.

“Our data reveals that head injury is associated with increased mortality rates even long-term. This is particularly the case for individuals with multiple or severe head injuries,” explained the study’s lead author, Holly Elser, MD, PhD, MPH a Neurology resident at Penn. “This highlights the importance of safety measures, like wearing helmets and seatbelts, to prevent head injuries.”

Investigators also evaluated the data for specific causes of death among all participants. Overall, the most common causes of death were cancers, cardiovascular disease, and neurologic disorders (which include dementia, epilepsy, and stroke). Among individuals with head injuries, deaths caused by neurologic disorders and unintentional injury or trauma (like falls) occurred more frequently.

When investigators evaluated specific neurologic causes of death among participants with head injury, they found that nearly two-thirds of neurologic causes of death were attributed to neurodegenerative diseases, like Alzheimer’s and Parkinson’s disease. These diseases composed a greater proportion of overall deaths among individuals with head injury (14.2 per cent) versus those without (6.6 per cent).

“Study data doesn’t explain why the cause of death in individuals with head injuries is more likely to be from neurodegenerative diseases, which underscores the need for further research into the relationship between these disorders, head injury, and death,” said Andrea L.C. Schneider, MD, PhD, an assistant professor of Neurology at Penn.