Around one in 500 men could be carrying an extra sex chromosome (X or Y), putting them at increased risk of diseases such as type 2 diabetes, atherosclerosis and thrombosis, according to a study published in Genetics in Medicine.
Researchers from the universities of Cambridge and Exeter analysed genetic data on 200 000 men aged 40 to 70 from UK Biobank. They found 356 men who carried either an extra X chromosome or an extra Y chromosome.
Some men have an extra X or Y chromosome – XXY or XYY, which is usually not obvious without a genetic test. Men with extra X chromosomes, a condition known as Klinefelter syndrome, are sometimes identified during investigations of delayed puberty and infertility; however, most are unaware that they have this condition. Men with an extra Y chromosome tend to be taller as boys and adults, but otherwise they have no distinctive physical features.
In today’s study, the researchers identified 213 men with an extra X chromosome and 143 men with an extra Y chromosome. As the participants in UK Biobank tend to be ‘healthier’ than the general population, this suggests that around one in 500 men may carry an extra X or Y chromosome.
Only a small minority of these men had a diagnosis of sex chromosome abnormality on their medical records or by self-report: fewer than one in four (23%) men with XXY and only one of the 143 XYY men (0.7%) had a known diagnosis.
By linking genetic data to routine health records, the team found that men with XXY have much higher chances of reproductive problems, including a three-fold higher risk of delayed puberty and a four-fold higher risk of being childless. These men also had significantly lower blood concentrations of testosterone. Men with XYY appeared to have a normal reproductive function.
Men with either XXY or XYY had higher risks of several other health conditions: a three-fold higher risk of developing type 2 diabetes, six-fold risk of venous thrombosis, three-fold risk of pulmonary embolism, and four-fold risk of chronic obstructive pulmonary disease (COPD).
It is unclear why an extra chromosome should increase the risk, said the researchers, or why the risks were so similar regardless of which sex chromosome was duplicated.
Yajie Zhao, a PhD student at the Medical Research Council (MRC) Epidemiology Unit at the University of Cambridge, the study’s first author, said: “Even though a significant number of men carry an extra sex chromosome, very few of them are likely to be aware of this. This extra chromosome means that they have substantially higher risks of a number of common metabolic, vascular, and respiratory diseases — diseases that may be preventable.”
Professor Ken Ong, also from the MRC Epidemiology Unit at Cambridge and joint senior author, added: “Genetic testing can detect chromosomal abnormalities fairly easily, so it might be helpful if XXY and XYY were more widely tested for in men who present to their doctor with a relevant health concern.
“We’d need more research to assess whether there is additional value in wider screening for unusual chromosomes in the general population, but this could potentially lead to early interventions to help them avoid the related diseases.”
Professor Anna Murray, at the University of Exeter, said: “Our study is important because it starts from the genetics and tells us about the potential health impacts of having an extra sex chromosome in an older population, without being biased by only testing men with certain features as has often been done in the past.”
Previous studies have found that around one in 1,000 females have an additional X chromosome, which can result in delayed language development and accelerated growth until puberty, as well as lower IQ levels compared to their peers.
A new research paper has signalled a crisis in medical research: “over 60% of trials are so methodologically flawed we cannot believe their results”. Researchers estimate that 88% of trial spending is wasted.
Dodgy research design and bad statistical methodology mean that most randomised trials are a waste of time, money and effort, and of no or dubious scientific value, say Stefania Pirosca, Frances Shiely, Mike Clarke and Shaun Treweek, in a new paper published in the journal Trials in early June.
Their paper examined 1659 randomised trials, involving 400,000 participants, that took place between May 2020 and April 2021 in 84 countries as well as 193 multinational trials.
The majority of trials (62%) showed a high risk of bias. More than half of trial participants were in these high risk of bias trials. Trials where the risk of bias was unclear accounted for 30% of those reviewed, while trials with a low risk of bias – those that can be trusted – accounted for just 8% of the total.
Bad trials – ones where we have little confidence in the results – are not just common, they represent the majority of trials in all countries and across most clinical areas. For instance, all trials looking at drugs and alcohol exhibited a high risk of bias. The most reliable field was anaesthesia, with 60% of trials exhibiting a low risk of bias.
The research team drew trial data from 96 reviews from 49 of the 53 clinical Cochrane Review Groups. Cochrane is an international organisation that helps to gather and propagate the results of medical research to better guide medical decision-making. This is done by experts compiling and evaluating research trials and results in “standardised, high-quality systematic reviews”.
Bad science was common everywhere. “No patient or member of the public should be in a bad trial and ethical committees, like funders, have a duty to stop this happening,” the paper’s authors write.
South Africa was bad, but Spain and Germany may be worse
In the seven trials reviewed that took place in South Africa, four had a high risk of bias, two had an unclear bias risk, and one trial was “good science”. This share of bad science is roughly similar to those found in the clinical trials done in the UK and USA. The most reliable health research science was done in multinational trials – with these, 23% of trials were a low risk of bias. (The authors didn’t identify the trials.)
The least reliable science, in countries that conducted 20 or more RCTs, was done in Spain and Germany, with 86% and 83% of the trials exhibiting a high risk of bias.
While results from just one year were interrogated, the paper’s authors found that their results map to similar studies, and that bad science can be expected to be the norm, over time.
This amounts to a massive waste of money and effort.
Statisticians and research method experts have been sounding the alarm on biased research for years, since Doug Altman’s 1994 paper in the British Medical Journal, “The scandal of poor medical research”.
Doctors want to know if they can rely on a particular treatment to produce a desired outcome, and need research that confers a degree of confidence. One way to do that – the most popular – is randomised control trials.
Randomised trials are great – but you need statisticians
Randomised control trials, also known as randomised trials, or RCTs, are for many (though not all), the gold standard for achieving scientific knowledge about a medical intervention – whether a drug or another type of therapy. The way that RCTs are conducted is crucial, as it is adherence to the method that gives people relying on the research confidence that the results produce scientific knowledge. See this explainer video for more: How do we know vaccines work?
But, if there is a high risk that the results were biased by errors in how they were conducted and how results were achieved, they should not be relied on. Pirosca and colleagues did not examine the type (or domain) of bias in the studies, arguing that having a high risk in one type of bias is sufficient to undermine the trial’s results.
In short, for Pirosca and colleagues, health research in randomised trials is bad when there is an identifiable risk of bias in the way that the results were obtained.
The large number of high risk of bias trials appears to be due to “a lack of input from methodologists and statisticians at the trial planning stage combined with insufficient knowledge of research methods among the trial teams”. You would not, they say by analogy, think it appropriate that a statistician conduct surgery, just because they are doing work in a surgical domain.
Bad science during COVID
Recent medical scandals in the headlines have highlighted the risks of bad science in medicine. The Covid pandemic has brought a boom in medical research, and popular attention to the results of medical research. This environment has produced some remarkable science, but it has also created scientific fiascos, like the one that surrounded ivermectin.
As GroundUp has previously reported, a review of studies investigating ivermectin as a possible therapy for Covid initially suggested that the deworming drug led to better outcomes in those that used it. On the face of it, the small studies that supported this conclusion seemed to provide promise for a low-cost, life-saving Covid intervention. But once the methodology and statistics were looked at closely, many of these papers were deemed unscientific – for instance, patients were excluded from analysis for no good reason. And once these trials were excluded from the review, the drug’s promise as a Covid treatment vanished.
Medical research watchdog Retraction Watch currently lists 12 papers purporting to investigate ivermectin that were subsequently withdrawn or for which concerns have been expressed. According to their records, 235 Covid papers have been withdrawn to date.
But the crisis is not insurmountable. Pirosca and colleagues say that relatively simple fixes would dramatically reduce the amount of untrustworthy health research – by ensuring that methodological principles that underlie RCTs are not compromised.
More expenditure on statistical expertise will save money
A 2015 review examined 142 trials that exhibited a high risk of bias. The authors found that in half of the high risk trials, the methodological adjustments required to reduce the risk of bias would have been low or zero cost. Easy adjustments at the design stage would have made important improvements to 42% of trials that exhibited high risk of bias.
Pirosca and colleagues propose that no medical RCT should be funded or given ethical approval if it cannot prove that the team conducting the trial has a member that has methodological and statistical expertise. Every RCT should, in its design, use risk of bias tools to make sure that results are not compromised.
The expertise that could restore the worth to medical research is in short supply.
More methodologists and statisticians are needed, and money should be invested in training people with this expertise, and investing in applied methodology research and supporting infrastructure. The authors call for 10% of a funder’s budget.
This might seem like a lot of money, but, argue Pirosca and co, it would be a fraction of the cost of the wasted research in the year under review – estimated to be billions of rands.
The task is urgent: “Randomised trials have the potential to improve health and wellbeing, change lives for the better and support economies through healthier populations … Society will only see the potential benefits of randomised trials if these studies are good, and, at the moment, most are not.”
Scientists have successfully treated type 1 diabetes in mice using pancreatic beta-cell, target-specific, chimeric antigen-receptor (CAR) regulatory T cells (Tregs), showing the feasibility of replicating this in humans according to data presented at ENDO 2022, the Endocrine Society’s annual meeting.
The study was led by Professor Juan Carlos Jaume, MD, at the University of Toledo.
Adoptive cell transfer therapies with CAR cytotoxic T cells have proven effective for the treatment of haematologic malignancies. Prof Jaume and colleagues attempted to replicate an equally effective experimental treatment for type 1 diabetes using instead non-cytotoxic, anti-inflammatory Tregs.
“The purpose of this study was to determine if pancreatic beta-cell, target-specific, human CAR Tregs could also identify human pancreatic beta cells and home to human pancreatic islets in culture as they do in mice undergoing CAR Treg treatment for T1D,” Prof Jaume said.
The researchers drew blood one to two weeks prior to pancreas surgery, followed by a collection of a a 5cc wedge of the pancreas after the pancreas was removed for a clinically indicated reason, either cancer or pancreatitis.
The researchers isolated Tregs from the blood samples and expanded them in vitro. Those cells were genetically modified to express a beta-cell, target-specific CAR combined with a green fluorescence protein (GFP) marker.
The next step was to process the pancreas tissue for islet separation. Following this, they co-cultured the human pancreatic islets combined with the beta-cell, target-specific CAR Tregs.
Within 24 hours, confocal microscopy demonstrated the successful migration of the GFP positive, CAR Tregs onto the pancreatic islets. What’s more, the CAR Tregs significantly proliferated while in physical contact with the pancreatic islets in the subsequent 72 hours.
“Ours is the first successful, pancreatic beta-cell, target-specific CAR-Treg treatment of T1D in a humanized mouse model that closely resembles the human disease. Based on our mice and human in-vitro data, we believe treatment with pancreatic beta-cell, target-specific, CAR-Tregs will allow for recovery and reconstitution of beta cells in human T1D patients as well,” Prof Jaume said.
Amid an ongoing worldwide shortage of contrast agent for medical imaging, a new UC San Francisco research letter in JAMA described strategies that can be used to safely reduce contrast agent use in computed tomography (CT) by up to 83%.
The three conservation strategies are weight-based (rather than fixed) dosing, reducing contrast dose while reducing tube voltage on scanners, and replacing contrast-enhanced CT with nonenhanced CT when it will minimally affect diagnostic accuracy.
That third strategy – not using the contrast agent in certain CT scans where there is only a small improvement in accuracy – yielded the most dramatic reduction of contrast agent use: 78%.
“Contrast is essential in any situation where we need to assess the blood vessels – for example, for some trauma patients or those with a suspected acute gastrointestinal bleed – and it is also needed for evaluation of certain cancers, such as in the liver or pancreas,” said senior study author Rebecca Smith-Bindman, MD, professor at UCSF.
“However, most CT scans are done for less specific indications such as abdominal pain in a patient with suspected appendicitis,” Prof Smith-Bindman added. “These can and should be done without contrast during the shortage, because the loss of information in these patients will be acceptable for most patients.”
The global shortage of contrast agent started in April with a COVID-related supply chain disruption of GE Healthcare in Shanghai and is expected to last at least several more weeks. More than 54 million diagnostic imaging exams using contrast agents are done every year in the US, a majority being CT scans, and these conservation methods could continue past the current shortage to reduce the use of contrast agent in general, the authors noted.
Referring clinicians are key to conservation Researchers modelled the three strategies individually and in combination using a sample of 1.04 million CT exams in the UCSF International CT Dose Registry from January 2015 to March 2021.
On its own, weight-based dosing for abdomen, chest, cardiac, spine and extremity imaging reduced contrast agent use by 10%; reducing the tube voltage in appropriate patients allowed a contrast agent reduction of 25%. These two measures combined with using non-contrast CT when possible led to a total reduction of 83%.
Following all three strategies at once may not be possible for some facilities, but each can help conserve supply, Prof Smith-Bindman said. And it is not just radiologists who need to know about them.
“Given the acute shortage, it’s important that clinicians who order imaging exams coordinate with radiology to cancel scans that aren’t absolutely necessary, postpone exams that can be safely delayed, replace CT with MRI and ultrasound where possible, and order an unenhanced scan where possible. Further, clinicians should communicate with their patients about why this is necessary. It is crucial that contrast be conserved for clinical situations where its use is essential for accurate diagnosis,” said Prof Smith-Bindman.
After the shortage ends, medical facilities should consider continuing some of these practices that conserve contrast agent, she added. For example, reducing the tube voltage not only reduces the contrast agent used but also lowers the radiation dose. Tailoring doses weight allows lower dosing volumes for many patients.
In addition, Prof Smith-Bindman noted that this analysis highlights the large amount of contrast agent that is wasted when single-dose vials are used Hospitals and imaging centres that routinely use single-dose contrast agent vials should consider using larger multi-dose vials, which allows for exact dosing and obviates the need to discard unused portions, she said.
“By carrying some of these practices forward, we can mitigate future supply-chain risk and reduce overall waste,” said Smith-Bindman.
Using bacteriophages, viruses which prey on bacteria, is an emerging alternative to antibiotic use but with limited evidence. Now, with a new paper published in Clinical Infectious Diseases, collaborators report 20 new case studies on the use of the experimental treatment in Mycobacterium infections, with successes in more than half of the patients.
This is the largest ever set of published case studies for bacteriophage (or ‘phage’) therapy, giving unprecedented detail on their use to treat dire infections while laying the groundwork for a future clinical trial.
“Some of those are spectacular outcomes, and others are complicated,” said Professor Graham Hatfull at the University of Pittsburgh. “But when we do 20 cases, it becomes much more compelling that the phages are contributing to favourable outcomes – and in patients who have no other alternatives.”
The patients in the study had an infection from one or more strains of Mycobacterium, a group of bacteria that can cause deadly, treatment-resistant infections in those with compromised immune systems or cystic fibrosis. In 2019, Prof Hatfull led a team showing the first successful use of phages to treat one of these infections.
“For clinicians, these are really a nightmare: They’re not as common as some other types of infections, but they’re amongst some of the most difficult to treat with antibiotics,” said Prof Hatfull. “And especially when you take these antibiotics over extended periods of time, they’re toxic or not very well-tolerated.”
Since 2019, Prof Hatfull and his lab have fielded requests from more than 200 clinicians looking for treatments for their patients, working with them to find phages that could be effective against the particular strain of bacteria infecting each patient.
This newest paper, with collaborators from 20 institutions, dramatically expands the body of published evidence on the effectiveness of the therapy.
“These are incredibly brave physicians, jumping off the ledge to do an experimental therapy to try to help patients who have no other options,” said Prof Hatfull. “And each of these collaborations represents a marker that can move the field forward.”
Going on patient health and presence of Mycobacterium in samples, the team found that the therapy was successful in 11 out of 20 cases. No patients showed any adverse reactions to the treatment.
In another five patients the results of the therapy were inconclusive, and four patients showed no improvement. According to Prof Hatfull, even these apparent failures are key to making the therapy available to more patients. “In some ways, those are the most interesting cases,” he said. “Understanding why they didn’t work is going to be important.”
Several unexpected patterns emerged from the case studies. In 11 cases, researchers were unable to find more than one kind of phage that could kill the patient’s infection, even though standard practice would be to inject a cocktail of different viruses so the bacteria would be less likely to evolve resistance.
“If you’d asked me whether that was a good idea three years ago, I would have had a fit,” Prof Hatfull said. “But we just didn’t observe resistance, and we didn’t see a failure of treatment from resistance even when using only a single phage.”
Additionally, the team saw that some patients’ immune systems attacked the viruses, but only in a few cases did that render the virus ineffective. And in some instances, the treatment was still successful despite such an immune reaction. The study paints an encouraging picture for the therapy, said Prof Hatfull, opening up the possibility for new phage regimens that clinicians could use to maximise the treatment’s chance of success.
Along with the study’s significance to patients facing Mycobacterium infections, it also represents a substantial advance for the wider field of phage therapy. One concern is that researchers may be only publishing case studies of successful phage therapy.
“A series of consecutive case studies, where we’re not cherry-picking, is a much more transparent way of looking to see what works and what doesn’t,” said Prof Hatfull. “This adds considerable weight to the sense that the therapy is safe.”
This is still a very early stage in the development of phage therapy, and phages have not even begun to be tailored for treatment, Prof Hatfull said.
Music session interventions were found to reduce anxiety among patients admitted to the intensive care unit (ICU), according to a systematic review and meta-analysis in the Journal of Clinical Nursing.
Reviewing 25 studies, music was found to significantly reduce anxiety scores overall, regardless of the system of measurement, reported Öznur Erbay Dalli, RN, MSc, PhD, of Bursa Uludag University in Turkey, and colleagues.
Music also significantly reduced anxiety scores versus standard care, including prescribed drugs or care protocol as part of usual treatment. This was comparable to noise-reducing methods. In the ICU, noise is an important driver of stress, the authors explained.
Throughout history, music has been used as one of the “proven non-pharmacological tools” to reduce anxiety, depression, and pain and to increase patient comfort, they added.
Dr Dalli told MedPage Todaythat ICU nurses and other healthcare workers may complement their daily routine care with music to reduce the anxiety of ICU patients and to avoid the side effects of medications, which are commonly used for treating anxiety.
No effect on diastolic blood pressure, respiration rate, or heart rate due to the music was seen. Subgroup analysis showed that multiple sessions produced better outcomes.
The researchers searched for studies published up to January 2022. All of the 25 included studies were randomised controlled trials or controlled clinical trials in 9 different countries with 1751 participants in total. Average age was 59 and 57% were male.
Of the anxiety assessment tools, the State-Trait Anxiety Inventory was the most commonly used tool (9 studies), followed by the Fear, Anxiety, and Stress Scale (4 studies) and the Visual Analogue Scale for Anxiety (2 studies).
Music interventions were mostly recorded music, although one study included a harp being played live. Music was used during rest times in most studies, though in four studies, music was used during specific procedures, like catheterisation or endotracheal suctioning.
No side effects were reported in the studies examined, but some patients objected to the choice of music, something which could be addressed by consultation with family members.
Limitations to the study included the fact that it was “difficult or impossible” to blind participants and other healthcare personnel involved in the study due to the nature of the intervention, which could lead to a “high risk of performance bias,” the authors noted. Additionally, the range of protocols and evaluation techniques used among the studies resulted in high heterogeneity.
Publication bias was possible due certain studies having small sample sizes, and a lack of available data.
