A recent analysis of Swedish military conscripts found that increased body mass index (BMI) in adolescent men is strongly linked developing early atrial fibrillation (AF) as well as with subsequent worse clinical outcomes after being diagnosed with AF.
The study, published in the Journal of the American Heart Association, included 1 704 467 young men (average age of 18.3 years) enrolled in compulsory military service in Sweden from 1969 through 2005. During a median follow-up of 32 years, 36 693 cases of atrial fibrillation were recorded, at an average age of 52.4 years at diagnosis. Compared with men with a baseline BMI of 18.5–<20.0 kg/m2, men with a BMI of 20.0–<22.5 kg/m2 had a 1.06-times higher risk of developing atrial fibrillation and those with a BMI of 40.0–50.0 kg/ m2 had a 3.72-times higher risk.
In men diagnosed with atrial fibrillation who were followed for a median of approximately 6 years, investigators identified 3767 deaths, 3251 cases of heart failure, and 921 cases of ischaemic stroke. Compared with those with a baseline BMI of <20 kg/m2, those with a baseline BMI of >30 kg/m2 had 2.86-times, 3.42-times, and 2.34-times higher risks of these outcomes, respectively.
“Whether screening for atrial fibrillation in early adulthood among individuals with long-standing obesity and more robust follow-up and initiation of anticoagulants in people with long-standing obesity and atrial fibrillation may improve survival needs to be addressed in future randomised trials” said corresponding author Demir Djekic, MD, PhD, of Sahlgrenska University Hospital/Östra, in Sweden.
Researchers at Karolinska Institutet in Sweden have found that the perception of one’s own body is largely based on the brain making guesses that are based on probability theory, instead of direct sensory input. The researchers detailed their findings in a study recently published in the journal eLife.
The researchers posit that the way humans perceive their bodies is largely governed by probability assessments based on past experiences, combined with sensory information such as sight and touch, for example.
“The experience of one’s own body is a statistical estimate of reality based on sensory information, sensory uncertainty, and previous experiences that can be summarised in a mathematical model”, explains Henrik Ehrsson, professor at the Department of Neuroscience, Karolinska Institutet.
Why are these results important?
“The results clarify the computational functions that govern the perception of one’s own body. This perception thus arises, not only as a result of a “direct” interpretation of signals from sight, touch sense, and proprioception as the textbooks say, but rather is based on active “guesses” that the brain constantly makes based on probability theory and the information that can be extracted from the patterns of sensory signals”, says Henrik Ehrsson.
“When we varied the degree of time delay between the visual and tactile impressions in small steps, or blurred the image in the augmented reality glasses to increase uncertainty, the illusion changed in a way that can be described by equations and curves: increased delay gave a weaker feeling of the rubber hand as its own, while increased uncertainty (blurriness) made the illusion stronger”, says Marie Chancel, corresponding author of the study.
Based on the experiments, the researchers came up with a statistical explanatory model for the brain’s perceptual awareness of its own body.
Changes in body ownership
The next step is to try to understand how the statistical model that determines own-bodily awareness is implemented by neural networks in the brain. In a preliminary study, the researchers have shown that neural activity in posterior parietal cortex follows the Bayesian model well in experiments where they measure brain activity with functional magnetic resonance imaging. The researchers also want to investigate how their model can explain changes in bodily awareness in various psychiatric and neurological conditions, such as Schizophrenia and Anorexia.
A global study of over 28 000 people has provided the strongest evidence to date that lowering blood pressure in later life can cut the risk of dementia. The study, which included five randomised controlled trials, was published in the European Heart Journal, and constitutes the highest grade of evidence for this preventative association.
Dr Ruth Peters, Program Lead for Dementia in The George Institute’s Global Brain Health Initiative, said that with no significant dementia treatment breakthroughs being made, reducing the risk of developing the disease would be a welcome step forward.
“Given population ageing and the substantial costs of caring for people with dementia, even a small reduction could have considerable global impact,” she said.
“Our study suggests that using readily available treatments to lower blood pressure is currently one of our ‘best bets’ to tackle this insidious disease.”
Dementia is fast becoming a global epidemic, currently affecting an estimated 50 million people worldwide. This number is projected to triple by 2050 mainly from ageing populations.
Current estimates put the cost at US$20–$40 000 per person with the condition each year.
Dr Peters explained that while many trials have looked at the health benefits of lowering blood pressure, few included dementia outcomes and even fewer were placebo-controlled.
“Most trials were stopped early because of the significant impact of blood pressure lowering on cardiovascular events, which tend to occur earlier than signs of dementia,” she said.
To examine the relationship between blood pressure and dementia more closely, researchers analysed five double-blind placebo-controlled randomised trials that used different blood pressure lowering treatments and followed patients until the development of dementia. A total of 28 008 individuals with an average age of 69 and a history of hypertension from 20 countries were included. Across these studies, the mid-range of follow up was just over four years.
“We found there was a significant effect of treatment in lowering the odds of dementia associated with a sustained reduction in blood pressure in this older population,” said Dr Peters.
“Our results imply a broadly linear relationship between blood pressure reduction and lower risk of dementia, regardless of which type of treatment was used.”
Researchers hope the results will help in designing public health measures to slow the advance of dementia as well as informing treatment, where there may be hesitancy in how far to lower blood pressure in older age.
“Our study provides the highest grade of available evidence to show that blood pressure lowering treatment over several years reduces the risk of dementia, and we did not see any evidence of harm,” said Dr Peters.
“But what we still don’t know is whether additional blood pressure lowering in people who already have it well-controlled or starting treatment earlier in life would reduce the long-term risk of dementia,” she added.
Haemophilia A, the most common severe form of haemophilia, affects almost exclusively males and can usually be with factor VII injections, but not for all sufferers, as the immune system may treat the factor as an intruder. New research has uncovered an important immune mechanism that targets B cells, which is crucial in making the the therapy effective. The study is published online in the Journal of Clinical Investigation.
Haemophilia A patients have a defect in factor VIII, a protein key for clotting. Most patients therefore receive an intravenous injection of the functional clotting factor every few days as treatment. But frequently, and especially at the start of treatment, the immune system recognises the injected agent as foreign to the body and attacks it. This is the most serious complication of haemophilia treatment because factor VIII can then no longer work.
In these cases, immune tolerance therapy, which was also developed at the University Hospital Bonn (UKB) more than 40 years ago, often helps. This involves regularly injecting the haemophilia sufferers with a high dose of factor VIII over several months, letting the immune system learn to tolerate it. The underlying immune mechanisms are unknown. “However, this doesn’t always work,” explains Prof Dr Johannes Oldenburg at the UKB. “In about 30 percent of patients, tolerance induction does not lead to success. So your body’s own defences continue to attack and destroy the factor VIII protein, which means that factor VIII cannot be used for treatment. We wanted to know the reason for this.”
To this end, the team looked at two cell types in the immune system, B cells and regulatory T cells. B cells recognise foreign molecules in the body and produce antibodies against them, which switch off the function of the molecule. For factor VIII, this means that it is no longer effective in haemophilia treatment.
Brake in the immune system
Regulatory T cells moderate the strength and duration of the immune response. The researchers have now found a new type of Treg cell that can act specifically against certain B cells rather than the overall immune response. “We were able to show that immunotolerance therapy results in the generation of regulatory T cells that exclusively induce B cells against factor VIII to commit suicide,” says Dr Janine Becker-Gotot of the Institute of Molecular Medicine and Experimental Immunology (IMMEI) at UKB. “These T cells have a sensor that allows them to recognise and attach to the corresponding B cells. In addition, they have the ability to push the self-destruct button on the surface of B cells.”
This button is a molecule called PD-1 which, on activation, leads to apoptosis. Every active B cell has this button. “Our experiments enabled us for the first time to detect regulatory T cells that can activate this self-destruct button only in very specific B cells, in order to specifically prevent unwanted immune responses,” explains IMMEI Director Prof Dr Christian Kurts.
The more PD-1 buttons the B cells against factor VIII carry on their surface, the easier it is for them to be driven to suicide by immune tolerance therapy. “The amount of PD-1 varies from person to person,” Becker-Gotot explains. “If it’s very low to begin with, there’s a good chance that many inhibitor-producing B cells will survive and continue to neutralise the injected factor VIII.”
Test to show in whom immunotolerance therapy is useful
Interestingly, B cells also produce more PD-1 once they come into contact with regulatory T cells. “We can now test how strong this reaction is,” the researcher says. “If PD-1 levels go up shortly after starting immune tolerance therapy and then stay up, that’s a clear sign that the treatment is going to be successful.” The team is currently developing a blood test that can be used to detect whether or not immune tolerance therapy is working in patients during the prolonged treatment.
“Our findings have great basic scientific value,” explains Prof Kurts. “And not just for haemophilia, but also for other congenital disorders where missing proteins are replaced therapeutically. In the long term, they could also be used to develop new treatments.”
New research in the Annals of Internal Medicine provides strong evidence that vitamin D deficiency is associated with premature death, prompting calls for people to follow healthy vitamin D level guidelines.
The study by the University of South Australia found that premature mortality increased in line with the severity of Vitamin D deficiency.
First author and UniSA PhD candidate, Josh Sutherland, says that while vitamin D has been connected with mortality, it has been challenging to establish causal effects.
“While severe vitamin D deficiency is rarer in Australia than elsewhere in the world, it can still affect those who have health vulnerabilities, the elderly, and those who do not acquire enough vitamin D from healthy sun exposure and dietary sources,” Sutherland says.
“Our study provides strong evidence for the connection between low levels of vitamin D and mortality, and this is the first study of its kind to also include respiratory disease related mortality as an outcome.
“We used a new genetic method to explore and affirm the non-linear relationships that we’ve seen in observational settings, and through this we’ve been able give strong evidence for the connection between low vitamin D status and premature death.
“Vitamin D deficiency has been connected with mortality, but as clinical trials have often failed to recruit people with low vitamin D levels – or have been prohibited from including vitamin deficient participants – it’s been challenging to establish causal relationships.”
The Mendelian randomisation study (an alternative to the gold standard of a randomised controlled trial) evaluated 307 601 records from the UK Biobank. Low levels of vitamin D were noted as less than <25 nmol/L with the average concentration found to be 45.2 nmol/L. Over a 14-year follow up period, researchers found that the risk for death significantly decreased with increased vitamin D concentrations, with the strongest effects seen among those with severe deficiencies.
Senior investigator Professor Elina Hyppönen says more research is now needed to establish effective public health strategies that can help achieve national guidelines and reduce the risk of premature death associated with low vitamin D levels.
“The take-home message here is simple – the key is in the prevention. It is not good enough to think about vitamin D deficiency when already facing life-challenging situations, when early action could make all the difference,” Prof Hyppönen says.
“It is very important to continue public health efforts to ensure the vulnerable and elderly maintain sufficient vitamin D levels throughout the year.”
An international study published in JAMA comparing new and older treatments against complicated urinary tract infections has found that a new drug combination of cefepime and enmetazobactam to be more effective, especially against drug-resistant strains.
Researchers in the ALLIUM Phase 3 clinical trial showed that a combination of the drugs cefepime and enmetazobactam was more effective in treating both complicated urinary tract infections (UTIs) and acute pyelonephritis (AP), a bacterial infection causing kidney inflammation, than the standard combination of piperacillin and tazobactam. UTIs are considered complicated when they are associated with risk factors such as fevers, sepsis, urinary obstruction or catheters, that increase the danger of failing antibiotic therapy.
“This new antibiotic was superior to the standard-of-care therapy,” said Professor Keith Kaye at Rutgers Robert Wood Johnson Medical School, the study’s lead author. “It represents an exciting option for treatment.”
Prof Kaye added this drug combination also fights an often-dangerous category of bacterial illnesses caused by pathogens known as extended spectrum beta-lactamase (ESBL) infections, named for an enzyme the bacteria produce. ESBL-producing bacteria can’t be killed effectively by many of the antibiotics conventionally used to treat infections, such as penicillins and cephalosporins.
“We are looking for antibiotics that are active against resistant bacteria, such as ESBLs, and we found this new combination to be highly effective,” Prof Kaye said.
The trial was conducted at 90 sites in Europe, North and Central America, South America and South Africa from September 2018 to November 2019. More than 1000 patients participated in the study. Some 79% of the patients receiving the new combination of cefepime and enmetazobactam were successfully treated for their illness, as opposed to 58.9% of those receiving the conventional treatment of piperacillin and tazobactam.
Of the 20% of patients from the overall group belonging to the subset of those with ESBL infections, 73% receiving cefepime and enmetazobactam achieved a clinical cure, as opposed to 51% on the standard therapy.
The antibiotic cefepime is a fourth-generation cephalosporin that was approved for use in the 1990s and is available generically. Enmetazobactam, an experimental drug made by the French biopharmaceutical company Allecra Therapeutics, is a beta-lactamase inhibitor, meaning it attacks the beta-lactamases, including the types of enzymes produced by ESBL-producing bacteria. The drug combination has been fast-tracked for approval by the U.S. Food and Drug Administration (FDA).
The Life Oncology unit at Life Vincent Pallotti Hospital today launched the Ethos™ radiotherapy system, a revolutionary new technology, the first in Sub-Saharan Africa, which uses artificial intelligence (AI) and adaptive treatment to adjust cancer treatments in response to patients’ unique, changing needs.
The Ethos™ radiotherapy system allows radiotherapy specialists to treat cancer patients with the most accurate, precision techniques. “Adaptive therapy provides the ability to adapt the treatment plan based on tumour and anatomical changes. The goal is to better target the tumour, reduce radiation dose of healthy tissue, and potentially improve overall outcomes”, says Dr Louis Kathan, Life Healthcare’s Chief Medical Officer in South Africa.
Dr Kathan, who is also a radiation oncologist with close to 15 years of patient treatment experience, explains that the streamlined workflow of Ethos™ radiotherapy is enabled by its AI-driven planning and contouring capabilities. “The system allows us to use AI to adapt to a patient’s anatomy. This allows us to make decisions more efficiently on a daily basis based on each patient’s individual needs. The ability of the machine to deliver on-couch adaptive treatment puts the patient at the centre of care”, he added.
“Clinicians globally have waited for the day when they have the ability to adapt radiotherapy treatments to changes in patient anatomy. Typically changes to a patient’s treatment plan due to changes in anatomy require time-consuming re-scanning and re-planning between treatment sessions, which could take up to two days. The Ethos™ radiotherapy adaptive technology allows the treatment plan to be adjusted daily, in real-time and the treatment to be planned and administered, all within 20 to 30 minutes”, says Kulthum Ismail, unit manager: radiation therapy at the Life Oncology unit based at Life Vincent Pallotti Hospital.
The planning and treatment all happen in one session, making it a faster process compared to existing radiotherapy technology, although Kulthum added that there is still a big role to play for current systems being used.
Kulthum Ismail, unit manager: radiation therapy at the Life Oncology unit based at Life Vincent Pallotti Hospital
The Life Oncology unit at Life Vincent Pallotti Hospital is committed to delivering the very best oncology care with substantial investments made in recent years to technologies to place the hospital at the forefront of advanced treatments in surgical-, medical-, gynaecological- and radiation oncology. These include:
The Novalis Tx delivery system
Image guided radiosurgery for tumour motion monitoring
Minimally invasive frameless radiosurgery for patient comfort
Radiofrequency ablation
Elements Multiple Brain Mets Stereotactic Radiosurgery System which delivers powerful treatment that targets multiple brain metastases (more than one cancer lesion in the brain) simultaneously, faster and more precisely
The Ethos™ radiotherapy system at Life Vincent Pallotti Hospital is already being used to treat patients with cervical, rectum, lung and prostate cancer. In time, other cancers are hoped to be included in the treatment programme.
“The Ethos™ radiotherapy system offers a faster and more personalised, targeted approach to radiotherapy treatment which means we really are placing the patient at the centre of care,” said Adam Pyle, Life Healthcare’s CEO for South Africa. “It’s our way of navigating our patients into the future of oncology care as we continue to live our purpose of making life better.”
Pete Wharton-Hood, Group Chief Executive for Life Healthcare added that the Group’s aspiration to be a leading cancer care provider has taken a substantial step forward with the expansion at the Life Oncology unit at Life Vincent Pallotti Hospital in Cape Town. “As a people and patient-centric organisation, we continuously seek ways to build on our existing technological offerings and services to consistently improve patient outcomes, enhance our patient experience and drive accessible and affordable healthcare. This means we get to better support our specialists who we partner with, so that together we continue delivering improved patient quality, patient experience, efficiency, and clinical excellence.”
A study published in the Journal of Pediatric Hematology/Oncologyfound that blood transfusion is associated with adverse outcomes, including infection and higher rates of tumour recurrence — in paediatric solid tumour oncology patients following surgical removal of the tumour.
“Blood transfusion is obviously hugely important when used in the appropriate clinical scenario, but there are some downsides,” said study author Shannon Acker, MD, an assistant professor of paediatric surgery in the University of Colorado School of Medicine. “It’s pro-inflammatory and suppresses the immune system because your body reacts to foreign tissue. It can be a vital intervention, but I think we’re starting to be a little more thoughtful about giving patients blood products.”
Understanding paediatric blood transfusion
Dr Acker and colleagues pursued this research, in part, because while the effects of packed red blood cell (PRBC) transfusion in adult populations have been widely studied, data are sparser for paediatric patients.
“It’s fairly well-documented that in adult patients, perioperative blood transfusion for solid tumour resection is associated with certain adverse outcomes,” Dr Acker explained. “But paediatric cancers are more rare, so they’re more challenging to study. We need more data to understand whether what we know to be true in adult cancers is also true in paediatric cancers.”
Using retrospective data on more than 260 paediatric patients over 11 years, the researchers included malignant solid tumours removed by surgeons across all surgical disciplines. Dr Acker acknowledges that grouping different types of cancer into one study lessens the validity of the research because different cancers have different outcomes, “but we needed a place to start so we can begin working toward more collaborative, multi-centre paediatric oncology research,” she said.
Higher rates of complications
Of the 360 paediatric patients who underwent tumour resection, 194 received a blood transfusion within 30 days of surgery.
Analysing the data, they saw that children who received a blood transfusion had higher rates of post-surgery infectious complications, a shorter disease-free interval, and higher rates of tumour recurrence. They also adjusted for receiving pre-operative chemotherapy and still found that blood transfusion was associated with higher rates of post-operative infectious complications and a shorter disease-free interval.
No relationship was seen between tumour type and rate of infectious complications or disease-free interval.
Providing the best patient care
An aim of the research and its findings is to continue supporting and facilitating conversations and practices about patient care. “Packed red blood cells carry oxygen to the body and help tissues get the oxygen that they need,” Acker says. “They’re essential. It used to be common practice that if a surgeon was taking out a tumour and the patient was losing blood, they would immediately get two units.”
She added that blood transfusion now is recognised as “not a totally benign intervention, so instead of immediately giving a patient two units, we start with one and see if that leads to an appropriate response. Our research shows that each additional unit increases risk of adverse outcomes, so we want to continue being thoughtful in using this intervention.”
Acker adds that a further goal of the research is to work with members of paediatric oncology surgical consortiums to draw data from national and international centres. “The data we have are good, but I don’t think they’re enough to convince people to change institutional protocols. If we can get more validated, multi-centre data, we can begin to look at a more granular level at timing of transfusions and types of cancers so we can continue providing the best patient care.”
A new way of understanding sex-biased diseases has been developed by scientists at UC San Francisco (UCSF). Their evolutionary biology-based theory, published in in Science, is that males and females took opposing paths in a trade-off between immunity and metabolism that happens in the liver. This helped males fight bacterial infections from wounds received in dominance fights, while helping females store subcutaneous fat to survive when food is scarce.
Working with mice, the scientists described the activity of a signalling pathway that regulates lipids, storing fat in the liver in males and releasing it into the bloodstream in females. This pathway also responds to growth hormone.
This phenomenon may have shaped male biology in ways that increase risk from modern, high-calorie diets. The findings are particularly important for fatty liver, which affects a quarter of the US population. It is seen predominantly in men until women reach menopause.
“Scientists have only recently started to understand there are these profound differences between males and females,” said Holly Ingraham, PhD, UCSF professor and co-senior author of the study. “Understanding these differences is going to be the key to unlocking therapeutics for sex-biased diseases. Fatty liver is one example.”
The experiments found that male mice were three times more likely than females to survive infection with E. coli. The females developed hyperlipidaemia, a condition that is also seen in humans with severe sepsis. Lowering their lipid levels helped them to survive.
The investigators then examined how males and females respond to the contemporary environmental challenge of overeating by feeding the mice high-fat chow. males developed fatty liver and glucose intolerance, but females did not. This was true even when males and females gained a similar amount of weight.
Searching the literature for something that could explain this, the team identified a transcription factor called BCL6, which prevents the breakdown of fat in the liver and is much more present in male mice.
Deleting the gene for this protein eliminated liver fat in the males, and also their ability to survive the infection.
“The host defence programs in the liver are the predisposing factors that drive fatty liver in males,” said Joni Nikkanen, PhD, a postdoctoral fellow and one of the study researchers.
“We have an evolutionary perspective on why such programs have developed — because they protect males against bacterial infections,” he said. “But in another context, these same programs are not good for you anymore, and you will develop more severe fatty liver.”
The team also examined how the presence of BCL6 affected gene expression in the liver. This process begins at puberty when males produce more testosterone, and their pituitary glands start to secrete growth hormone in sharp peaks and valleys.
These intermittent bursts, likely testosterone-regulated, are important. When researchers infused male mice continuously with growth hormone the way it is secreted in females, BCL6 disappeared from their livers, and they lost the ability to fight E. coli infection.
The results point to growth hormone as a potential therapy for adults with fatty liver disease, an idea that is currently being tested. Its effects are already well established in children whose pituitaries don’t produce enough growth hormone. Male children especially tend to develop fatty liver, but it goes away when they are given growth hormone to treat their short stature.
The work also expands the scientific view of how the body fights infection to include organs like the liver.
“The fight is still between the infection and the immune system,” said Omer Gokcumen, PhD, an evolutionary anthropologist at the University at Buffalo and a co-author of the study. “But the liver is determining the battlefield.”
Researchers have found that exposure to e-cigarette aerosols can cause heart arrhythmias in animal models – both in the form of premature and skipped heart beats. The study findings, published in Nature Communications, suggest that exposure to certain chemicals in e-cigarette liquids (e-liquids) promote arrhythmias and cardiac electrical dysfunction.
“Our findings demonstrate that short-term exposure to e-cigarettes can destabilise heart rhythm through specific chemicals within e-liquids,” said Alex Carll, assistant professor in the UofL Department of Physiology who led the study. “These findings suggest that e-cigarette use involving certain flavors or solvent vehicles may disrupt the heart’s electrical conduction and provoke arrhythmias. These effects could increase the risk for atrial or ventricular fibrillation and sudden cardiac arrest.”
The researchers tested the cardiac impacts of inhaled e-cigarette aerosols solely from the main two ingredients in e-liquids (nicotine-free propylene glycol and vegetable glycerin) or from flavoured retail e-liquids containing nicotine. They found that for all e-cigarette aerosols, the animals’ heart rate slowed during puff exposures and sped up afterwards as heart rate variability declined, indicating fight-or-flight stress responses. In addition, e-cigarette puffs from a menthol-flavoured e-liquid or from propylene glycol alone caused ventricular arrhythmias and other conduction irregularities in the heart.
This work adds to a growing body of research on the potential toxicity and health impacts of e-cigarettes reported by the American Heart Association Tobacco Regulation and Addiction Center, for which UofL serves as the flagship institute.
“The findings of this study are important because they provide fresh evidence that the use of e-cigarettes could interfere with normal heart rhythms – something we did not know before,” said collaborating researcher Professor Aruni Bhatnagar. “This is highly concerning given the rapid growth of e-cigarette use, particularly among young people.”
As e-cigarette use has grown nationwide, the potential advantages and harms of vaping have been debated. Since vaping does not involve combustion, it exposes users and bystanders to little if any carbon monoxide, tar or cancer-causing nitrosamines compared with conventional cigarettes. However, e-cigarettes can deliver aldehydes, particles and nicotine at levels comparable to combustible cigarettes. Vaping might help smokers quit combustible cigarettes, but the appeal and addictiveness of e-cigarettes may encourage youth to vape amidst unknown long-term risks or take up smoking. More than 25% of high schoolers and 10% of middle schoolers in the U.S. reported using e-cigarettes before the pandemic.
“Our team’s findings that specific ingredients in e-cigarette liquids promote arrhythmias indicates there is an urgent need for more research into the cardiac effects of these components in both animals and humans,” A.Prof Carll said.
