Day: January 31, 2023

Categories : Medical Research & TechnologyTags :

New Mathematical Model for Potassium Homeostasis

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Blood samples
Photo by National Cancer Institute on Unsplash

Potassium is essential to normal cellular function, helping the cardiac muscle work correctly and aids in the transmission of electrical signals within cells. A new mathematical model published in PLOS Computational Biology sheds light on the often mysterious process of potassium homeostasis.

Using existing biological data, researchers at the University of Waterloo built a mathematical model that simulates how an average person’s body regulates potassium, both in times of potassium depletion and during potassium intake. Because so many foods contain abundant potassium, the body is continually storing, deploying, and disposing of potassium to keep it in a healthy range, ie the process of potassium homeostasis. Understanding potassium homeostasis is essential in helping diagnose the source of the problem when something goes wrong, for example, when kidney disease or medication leads to dysregulation.

“Too much potassium in the body, or hyperkalaemia, can be just as dangerous as hypokalaemia, or too little,” said study lead author Melissa M. Stadt, a PhD student in applied mathematics. “Dysregulation of potassium can lead to dangerous and potentially fatal consequences.”

The model could be used for a virtual patient trial, allowing researchers to generate dozens of patients and then predict which ones would have hyper- or hypokalaemia based on different controls.

“A lot of our models are pieces of a bigger picture,” said Anita Layton, professor of applied mathematics and Canada 150 Research Chair in mathematical biology and medicine. “This model is one new and exciting piece in helping us understand how our incredibly complex internal systems work.”

The model is especially exciting because it allows scientists to test the muscle-kidney cross-talk signal hypothesis. Scientists have hypothesised that skeletal muscles, which store most of the body’s potassium, can directly signal to the kidneys to dump potassium when there’s too much stores, and vice versa. When the mathematical researchers tested the hypothesis in their model, it more accurately reflected existing biological data regarding potassium homeostasis, suggesting that muscle-kidney cross talk might be an essential piece in the puzzle of potassium regulation.

Source: University of Waterloo

Categories : COVIDTags :

Updated Bivalent Boosters Offer Better Protection against Omicron

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Image by Ivan Diaz on Unsplash

A real-world effectiveness study of updated bivalent mRNA vaccines has shown that bivalent boosters are more effective than original monovalent boosters at preventing hospitalisation and death from the Omicron variant. The study was published today in The New England Journal of Medicine.

“While original COVID vaccines had been demonstrated to be safe and effective prior to the FDA’s authorisation, the Pfizer and Moderna bivalent vaccines that have been deployed in the United States since last fall were approved by the FDA for emergency use on the basis of non-clinical data for those two new vaccines,” explains Dr Danyu Lin, lead author on the study. “We were able to evaluate not only the effectiveness of the two bivalent boosters but also compare their effectiveness to that of monovalent boosters.”

Researchers at the at the University of North Carolina’s Gillings School of Global Public Health compared the incidence of severe Omicron infection resulting in hospitalisation or death for individuals aged 12 and up who received a monovalent or bivalent booster dose to those who did not. The study analysed vaccination and infection data of more than six million North Carolina residents from May to December of 2022, during which the Omicron variant’s BA.4.6/BA.5 and BQ.1/BQ.1.1 strains were predominant in the United States. Both the Pfizer and Moderna bivalent vaccines were included in the study, which also considered different age groups, previous infection status, and the number of booster doses already received.

The effectiveness of the booster was highest at roughly four weeks after administration and decreased afterward. Average effectiveness against severe infection resulting in hospitalisation or death over a three-month period was 25% for one monovalent booster dose and 62% for one bivalent booster dose.

“The increased effectiveness found in this study demonstrates why it’s important for people to protect themselves with the updated booster even if they had already gotten the original booster dose,” says Dr Zack Moore, State Epidemiologist with the North Carolina Department of Health and Human Services.

Source: University of North Carolina at Chapel Hill

Categories : Cardiovascular DiseaseTags :

Gum Infection may be a Risk Factor for Arrhythmia

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Dentist checking teeth
Image by Caroline LM on Unsplash

Periodontitis can lead to a litany of dental issues from bad breath to bleeding and tooth loss, and has long been suspected to be connected to other negative health outcomes in the body. Researchers at Hiroshima University have now found evidence that periodontitis could be connected to atrial fibrosis and arrythmias.

In a study published in JACC: Clinical Electrophysiology, the team found a significant correlation between periodontitis and fibrosis (which is 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.

“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. “We hypothesised 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 left atrial appendages were surgically removed from the patients, and the researchers analysed the tissue to establish the correlation between severity of the atrial fibrosis and severity of the gum disease. They found that the worse the periodontitis, the worse the fibrosis, suggesting that the inflammation of gums may intensify inflammation and disease 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, professor of cardiovascular medicine in Hiroshima University’s Graduate School of Biomedical and Health Sciences.

According to Nakano, in addition to improving other risk factors such as weight, activity levels, tobacco and alcohol use, periodontal care could aid in comprehensive atrial fibrillation management. However, she cautioned that this study did not establish a causal relationship, meaning that while gum disease and atrial fibrosis degrees of severity appear connected, researchers have not found that one definitively leads to 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. “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 easy 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.”

Next, the researchers said they hope to conduct future clinical trials to clarify if periodontal intervention reduces atrial fibrillation occurrence and improves patient outcomes.

Source: Hiroshima University

Categories : Cancer Cardiovascular Disease PaediatricsTags :

First Guideline for Heart Complications in Childhood Cancer Treatment

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Photo by National Cancer Institute on Unsplash

Experts led by researchers from the Murdoch Children’s Research Institute have created the world’s first international clinical guidelines to help prevent and treat heart complications in children undergoing cancer treatment.

Published in JACC:Advances, the guidelines cover cardiovascular disease assessment, screening and follow-up, for paediatric patients receiving cancer treatment with new molecular therapies, immunotherapy, chemotherapy and radiotherapy.

The expert consensus has defined the high-risk group of cancer patients who should undergo a heart check-up, standardised an approach to screening and surveillance during treatment and provided recommendations to protect vulnerable young hearts.

Murdoch Children’s Associate Professor Rachel Conyers said while international guidelines to monitor poor heart side effects during therapy exist for adult patients, none were specific to children.

Associate Professor Conyers said the success of new cancer drugs had increased the chances of cardiac side effects that occur early on during therapy, sometimes within days, which warranted closer heart health surveillance and earlier monitoring.

“Recent advances in treating childhood cancer have resulted in survival rates of more than 80 percent. However, improving serious health outcomes in survivors remains an important and essential focus and prevention is key,” she said.

“Heart complications are a leading cause of death for childhood cancer survivors, second only to cancer relapse. Modern treatments including precision medicine have broadened the agents that can cause heart problems.”

Childhood cancer survivors are 15 times more likely to have heart failure and eight times more likely to have heart disease than the general population.

Associate Professor Conyers said the guidelines would be an indispensable tool for clinicians to significantly reduce the harmful impact of cancer drugs on children’s hearts.

“The guidelines are a major advance for the cardio-oncology field as before this there was no defined approach for surveillance or follow up of pediatric patients during treatment despite new therapeutics having early heart complications such as high blood pressure, abnormal heart beats and heart failure,” she said.

The Australian and New Zealand expert group consisted of pediatric and adult cardiologists and pediatric oncologists who undertook a Delphi consensus approach across 11 areas of cardio-oncology care. The Australian New Zealand Children’s Oncology Group endorsed the study with the guidelines useful for any tertiary institutes treating pediatric oncology patients or initiating cardio-oncology clinics.

Source: Murdoch Children’s Research Institute

Categories : Antibiotics Diseases, Syndromes and ConditionsTags :

Antibiotic Regimen may be Ineffective in TB Meningitis

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Tuberculosis bacteria
Tuberculosis bacteria. Credit: CDC

Research in animal models published in Nature Communications shows that an approved antibiotic regimen for multidrug-resistant (MDR) tuberculosis (TB) may not work for TB meningitis. Limited human studies also provide evidence that a new combination of drugs is needed to develop effective treatments for TB meningitis due to MDR strains.

In the study from Johns Hopkins Children’s Center, the investigators showed that the Food and Drug Administration (FDA)-approved regimen of three antibiotics – bedaquiline, pretomanid and linezolid (BPaL) – used for treating TB of the lungs due to MDR strains, is not effective in treating TB meningitis because bedaquiline and linezolid struggle to cross the blood-brain barrier.

Tuberculosis, caused by the bacteria Mycobacterium tuberculosis, is a global public health threat. About 1%–2% of TB cases progress into TB meningitis, the worst form of TB, which leads to an infection in the brain that causes increased fluid and inflammation.

“Most treatments for TB meningitis are based on studies of treatments for pulmonary TB, so we don’t have good treatment options for TB meningitis,” explains Sanjay Jain, M.D., senior author of the study and director of the Johns Hopkins Medicine Center for Infection and Inflammation Imaging Research.

In 2019, the FDA approved the BPaL regimen to treat MDR strains of TB, specifically those that lead to pulmonary TB. However, there are limited data on how well these antibiotics cross the blood-brain barrier.

In an effort to learn more, the research team synthesised a chemically identical and imageable version of the antibiotic pretomanid. They conducted experiments in mouse and rabbit models of TB meningitis using positron emission tomography (PET) imaging to noninvasively measure pretomanid penetration into the central nervous system as well as using direct drug measurements in mouse brains. In both models, researchers say PET imaging demonstrated excellent penetration of pretomanid into the brain or the central nervous system. However, the pretomanid levels in the cerebrospinal fluid (CSF) that bathes the brain were many times lower than in the brains of mice.

“When we have measured drug concentrations in the spinal fluid, we have found that many times they have no relation to what’s happening in the brain,” says Elizabeth Tucker, MD, a study first author and an assistant professor of anaesthesiology and critical care medicine. “This finding will change how we interpret data from clinical trials and, ultimately, treat infections in the brain.”

Next, researchers measured the efficacy of the BPaL regimen compared with the standard TB treatment for drug-susceptible strains, a combination of the antibiotics rifampin, isoniazid and pyrazinamide. Results showed that the antibacterial effect in the brain using the BPaL regimen in the mouse model was about 50 times lower than the standard TB regimen after six weeks of treatment, likely due to restricted penetration of bedaquiline and linezolid into the brain. The bottom line, says Jain, is that the “regimen that we think works really well for MDR-TB in the lung does not work in the brain.”

In another experiment involving healthy participants, three male and three female aged 20–53 years, first-in-human PET imaging was used to show pretomanid distribution to major organs, according to researchers.

Similar to the work with mice, this study revealed high penetration of pretomanid into the brain or central nervous system with CSF levels lower than those seen in the brain. “Our findings suggest pretomanid-based regimens, in combination with other antibiotics active against MDR strains with high brain penetration, should be tested for treating MDR-TB meningitis,” says study author Xueyi Chen, MD, a paediatric infectious diseases fellow, who is now studying combinations of such therapies.

Limitations included the small quantities of the imageable version of pretomanid per subject (micrograms) used. However, current evidence suggests that studies with small quantities of a drug are a reliable predictor of the drug biodistribution.

Source: Johns Hopkins Medicine