Olfactory dysfunction in COVID patients is common. Researchers recently searched the medical literature for studies reporting changes in olfactory structures detected through imaging tests of patients with COVID, and found that swelling in nasal passages is responsible for some temporary olfactory dysfunction. Their results in were published in The Laryngoscope.
A recent meta-analysis based on 83 studies provided high-quality evidence of a combined prevalence of olfactory dysfunction in 47.9% of COVID patients. Olfactory dysfunction is diagnosed more commonly among female patients and outpatients.
The researchers observed abnormality in olfactory clefts, which provide a crucial channel for airborne molecules to reach sensory olfactory neurons. The rate of abnormalities was nearly 16-fold higher in patients with COVID and olfactory dysfunction (63%) compared with controls (4%).
“Before this study, most scientists thought that the loss of smell in COVID was mainly due to inflammation and damage to the olfactory nerves. Now, we have compiled evidence from medical imaging that COVID loss of smell is also due to swelling and blockage of the passages in the nose that conduct smells,” said senior author Neville Wei Yang Teo, MRCS, MMed, of Singapore General Hospital.
“We think this is good news for patients who want to recover their sense of smell, since these blockages are expected to resolve with time, while nerve damage in comparison would likely be more difficult to recover from,” added lead author Claire Jing-Wen Tan, of the National University of Singapore. “These findings may not fully account for those who suffer from prolonged olfactory dysfunction, however, and further studies that evaluate patients in this group may provide more information.”
The data underpinning a controversial study of the use as vitamin C as a sepsis treatment may in fact be fraudulent, according to an analysis by an Australian physician and statistician, reports MedPage Today.
PhD student Kyle Sheldrick, MBBS, alleges that the pre- and post- comparison groups involved in the 94-patient study were too similar to be realistic.
In an interview with MedPage Today, Sheldrick said the case is “extreme”, stating that “This is probably the most obviously fake data I have seen. … These groups are more similar than would be probable.”
The paper, led by Paul Marik, MD – who led another COVID protocol study that has since been retracted – has been the subject of much debate in the intensive care community since it was published in 2017. The so-called HAT protocol was a simple regimen of hydrocortisone, ascorbic acid (vitamin C), and thiamine which could have saved many lives easily if it indeed worked. Obviously, there was much excitement worldwide about the significance of the findings – but not all were convinced.
“The effect size seemed just impossible,” said Nick Mark, MD, an ICU physician at Swedish Medical Center. “It seemed too good to be true.”
The trial was followed by larger studies, and so far none have shown shown a similar reduction in mortality, raising suspicions even further, Dr Mark said. With Sheldrick’s analysis, the penny dropped: “This was under our noses for 5 years,” Mark said. “This isn’t just a mistake. We know things can be done unethically, but to actually fake it? That it’s not just flawed, but perhaps actually fraudulent?”
Sheldrick told MedPage Today the key problem with the Marik paper is “probably the most common sign of fraud that we see, which is overly similar groups at baseline.” That is, people tend to fake data which do not vary enough from the average.
Sheldrick said he first looked at the study methods, which noted a pre- and post- comparison design, rather than a randomised or matched case-control design. With such a design, one would expect a more random distribution of baseline characteristics, but that wasn’t the case for the Marik paper, he said.
A further analysis with Fisher’s test showed that most P-values were 1, meaning they were distributed perfectly evenly across two time periods – and only one fell below 0.5. Instead, an even spread should be expected with an overall value of 0.5.
Sheldrick sent his findings to the journal CHEST and to Marik’s former employer Sentara Norfolk General Hospital, but had not heard back from either.
While Sentara Norfolk General Hospital did not respond to comment, and the journal CHEST could not confirm whether an investigation was underway but that it did take ethical concerns very seriously.
A spokesperson for Dr Marik emailed a statement to MedPage Today, claiming that the conclusions had been validated in several meta-analyses, and recommended the source examine “this and other research on the data before making false allegations on social media. Such claims are harmful and do not add to the public discourse.”
This wouldn’t be the first time concerns have been raised about data in a paper that Dr Marik co-authored. In November 2021, the Journal of Intensive Care Medicine (JICM) retracted an article by Marik and others on their MATH+ protocol for COVID. The retraction followed a communication that raised concerns about the accuracy of COVID mortality data from the hospital used in the article.
“It seems a bit improbable for someone to discover two miracle cures in three years,” Dr Mark commented to MedPage Today.
Dr Mark noted that the 2017 paper is widely cited, and even if the intervention was not directly harmful, the resources invested in subsequent large, high-quality trials of vitamin C and sepsis could have been better spent.
“While I’m really glad we did high-quality studies and had brilliant people working on this, it’s kind of a shame,” he said. “Instead of studying vitamin C based on a faulty premise, we could have spent our efforts elsewhere.”
An observational study with over 100 000 participants suggests that some artificial sweeteners are associated with increased cancer risk. The findings, published in PLOS Medicine, reflect other results from experimental studies.
The safety of artificial sweeteners has long been a subject of debate. To evaluate the potential carcinogenicity of artificial sweeteners, researchers analysed data from 102 865 French adults participating in the NutriNet-Santé study. The NutriNet-Santé study is an ongoing web-based cohort initiated in 2009 by the Nutritional Epidemiology Research Team (EREN). Participants enrolled voluntarily, and self-reported their medical history, sociodemographic, diet, lifestyle, and health data.
Researchers gathered data concerning artificial sweetener intake from 24-hour dietary records. After collecting cancer diagnosis information during follow-up, the researchers conducted statistical analyses to investigate the associations between artificial sweetener intakes and cancer risk. They also adjusted for a range of variables including age, sex, education, physical activity, medical history and dietary intake.
The researchers found that participants who consumed larger quantities of artificial sweeteners, particularly aspartame and acesulfame-K, had higher risk of overall cancer compared to non-consumers (hazard ratio 1.13). Higher risks were observed for breast cancer and obesity-related cancers.
In addition to being an observational study, there were a number of limitations; dietary intakes are self-reported. Selection bias may also have been a factor, as participants were more likely to be women, to have higher educational levels, and be more health-conscious. Additional research will be required to confirm the findings and clarify the underlying mechanisms.
According to the authors, “Our findings do not support the use of artificial sweeteners as safe alternatives for sugar in foods or beverages and provide important and novel information to address the controversies about their potential adverse health effects. While these results need to be replicated in other large-scale cohorts and underlying mechanisms clarified by experimental studies, they provide important and novel insights for the ongoing re-evaluation of food additive sweeteners by the European Food Safety Authority and other health agencies globally”.
First author Charlotte Debras added: “Results from the NutriNet-Santé cohort (n = 102 865) suggest that artificial sweeteners found in many food and beverage brands worldwide may be associated with increased cancer risk, in line with several experimental in vivo / in vitro studies. These findings provide novel information for the re-evaluation of these food additives by health agencies.”
Though light alcohol consumption may provide heart-related health benefits has been suggested observational research, a large study published in JAMA Network Open showed a link between all levels of alcohol intake and higher risks of cardiovascular disease. The researchers found that the supposed benefits of alcohol consumption may in fact be attributable to other healthy lifestyle factors common among light to moderate drinkers.
The study included 371 463 adult participants from the UK Biobank, average age 57 and consuming an average of 9.2 drinks per week. In line with previous findings, researchers found that the lowest heart disease risk was in light to moderate drinkers, followed by people who abstained from drinking. People who drank heavily had the highest risk. However, light to moderate drinkers also tended to have healthier lifestyles than abstainers, such as more physical activity and vegetable intake, and less smoking. One a few lifestyle factors were taken into account, any benefit associated with alcohol consumption was significantly reduced.
The study also used new techniques in Mendelian randomisation, which uses genetic variants to determine whether an observed link between an exposure and an outcome is consistent with a causal effect. “Newer and more advanced techniques in ‘non-linear Mendelian randomisation’ now permit the use of human genetic data to evaluate the direction and magnitude of disease risk associated with different levels of an exposure,” said senior author Krishna G. Aragam, MD, MS, a cardiologist at MGH and an associate scientist at the Broad Institute. “We therefore leveraged these new techniques and expansive genetic and phenotypic data from biobank populations to better understand the association between habitual alcohol intake and cardiovascular disease.”
When such genetic analyses were performed on samples taken from participants, they found that individuals with genetic variants that predicted higher alcohol consumption were indeed more likely to consume greater amounts of alcohol, and more likely to have hypertension and coronary artery disease. The analyses also revealed significant differences in cardiovascular risk across the spectrum of alcohol consumption for both males and females, with minimal risk increase when going from zero to seven drinks per week, much higher risk increases when progressing from seven to 14 drinks per week, and greatly increased risk for 21 or more drinks per week. Notably, the findings suggest a rise in cardiovascular risk even at “low risk” levels (ie below two drinks per day for men and one per day for women).
This discovery of an exponential rather than liner relationship between alcohol intake and cardiovascular risk is was supported by an additional analysis of data on 30 716 participants in the Mass General Brigham Biobank. Therefore, cutting back on large consumption of alcohol may have even more clinical benefits than cutting back on moderate amounts.
“The findings affirm that alcohol intake should not be recommended to improve cardiovascular health; rather, that reducing alcohol intake will likely reduce cardiovascular risk in all individuals, albeit to different extents based on one’s current level of consumption,” said Dr Aragam.
The amygdala, which is enlarged in two-year-old children with autism spectrum disorder (ASD), begins its accelerated growth between 6 and 12 months of age, suggests a study appearing in the American Journal of Psychiatry. The findings indicate that therapies to reduce the symptoms of ASD might have the greatest chance of success if they begin in the first year of life, before the amygdala begins its accelerated growth.
The amygdala, which is involved in processing emotions, such as interpreting facial expression in typically developing children increases substantially in volume from 7.5 to 18.5 years of age. The amygdala in children with autism is initially larger, but does not undergo the age-related increase observed in typically developing children.
The study included 408 infants, 270 of whom with an increased ASD risk from having an older sibling with ASD, 109 typically developing infants, and 29 infants with Fragile X syndrome. The researchers conducted MRI scans of the children at 6, 12 and 24 months of age. They found that the 58 infants who went on to develop ASD had a normal-sized amygdala at 6 months, but an enlarged amygdala at 12 months and 24 months. Moreover, the faster the rate of amygdala overgrowth, the greater the severity of ASD symptoms at 24 months. The infants with Fragile X syndrome had no differences in amygdala growth but enlargement of the caudate, which was linked to increased repetitive behaviours.
The researchers suggested that difficulty in processing sensory information during infancy may stress the amygdala, leading to its overgrowth.
In an interview with 702, CSIR senior researcher Dr Ridhwaan Suliman warned that 20% of South Africans still do not have any immunity to COVID, either from vaccination or prior infection. Since the start of the pandemic in South Africa, he has been tweeting his graphs of infections and explaining the science to the public.
Explaining the figure, he said: “It’s an extrapolation of recent research studies that show sero-prevalence levels across the country, up to about 80% currently. That means levels of immunity of people having previous infections, so natural immunity, plus acquired immunity through vaccination. So based on the 80% sero-prevalence levels, it means there’s still 20% that are susceptible… and 20% of South Africa’s population leaves 12 million people who don’t have levels of immunity or sero-prevalence currently.”
This number is however greatly increased from a previous survey conducted in January 2021, which reported a 19.1% rate.
He pointed out that this leave South Africa with a large number of people who are immune-naïve to COVID, who are therefore at risk of more severe consequences such as hospitalisation and death. However, the high levels of immunity means that, as seen in the Omicron wave, outcomes are reduced in severity.
Interviewer Bruce Whitfield asked Dr Suliman his opinion of prospective waves, as evidenced by increasing infections in countries like the US and China, and indeed, his own observations of queues starting to build up outside mobile COVID testing stations.
Dr Suliman replied that although the infections have been driven by the highly transmissible Omicron B.A.2 variant which is also dominant in South Africa, it “hasn’t resulted in a further uptick or resurgence following our fourth wave of the original Omicron strain, and so we’re currently in an ‘inter-wave’ period with low levels of transmission.”
He says that the situation is encouraging, with hospitalisations at their lowest levels seen since before the first wave in May 2020, but that this is still an inter-wave period.
Regarding when the fifth wave would be, Dr Suliman pointed out that each of the previous four waves “have been very cyclical or regular, with three months in between each wave.” Based on this, he said that he expects another wave is likely around the end of April or beginning of May.
However, he said that this should not be looked on with fear “because even with a surge in high levels of infection we do have high levels of population immunity which we hope will continue, and we will have less severe outcomes of hospitalisation and death even with those high levels.”
Writing for MedPage Today, two experts examine the possibility of chemical weapon use in Ukraine. Gavin Harris, MD assistant professor of infectious diseases and critical care, and Joel Zivot, MD, an associate professor of anaesthesiology/critical care, both of Emory University School of Medicine, explained the consequences of such an attack, noting that Russia has used such weapons in the past.
Though it’s uncertain whether Russia would launch a chemical attack, A/Profs Harris and Zivot wrote: “one thing is clear: in a large-scale chemical attack within the current Russian-Ukrainian conflict, the prospect of any meaningful healthcare response is bleak.”
Chemical agents fall under a number of classifications, which include blistering/vesicants such as mustard gas, blood agents such as hydrogen cyanide, choking/pulmonary agents such as chlorine gas, incapacitating agents such as opioids, and nerve agents such as sarin or the Russian-made Novichok. Development of modern chemical weapon traces back to the 1930s with the development of various nerve agents: organophosphorus cholinesterase inhibitors, each with particular potency.
Russia has recently complained to the UN Security Council that Ukraine and the US were cooperating to produce chemical and biological weapons for use in the war. The US government has responded that Russia is laying this claim to prepare for its own use of such weapons in Ukraine.
The preparation of chemical and biological agents can be done in secret, and easily introduced into the air, water, or food supply.
Invisible and odourless, nerve agents include sarin, soman, tabun, and the American-produced VX. The V agents were at one time considered to be the most toxic agents ever produced and are ten times more toxic than sarin. VX, tonnes of which was produced by the US government, can kill a person rapidly after they have been exposed to an infinitesimal amount.
Exposure to such nerve agents can cause a “constellation of symptoms,” according to the authors. “Nerve agents block the action of acetylcholinesterase, and this leads to accumulation of the neurotransmitter acetylcholine,” they wrote. “High levels of acetylcholine in the synaptic cleft causes overstimulation of cholinergic receptors. Symptoms related to excess accumulation of acetylcholine are divided into three groups: muscarinic, nicotinic, and central. Overstimulation of muscarinic cholinergic receptors causes pupil constriction, glandular hypersecretion, urination, defecation, sweating, and vomiting. Nicotinic symptoms are weakness and ultimately paralysis. Central nervous system poisoning will manifest as irritability, delirium, fatigue, lethargy, seizures, coma, and death by respiratory depression.”
Chemical weapons would have a devastating impact on already strained healthcare systems, A/Profs Harris and Zivot concluded. “Such weapons can create a complex mass casualty event where the treating personnel and the healthcare facilities may themselves be within the zone of conflict,” they wrote. “Chemical and biologic attacks require intense and complex treatment, and in both types of attacks, treating personnel may themselves be at risk of becoming exposed and therefore decontamination may be required before the initiation of any supportive treatments. Emergency and medical providers would also need to have access to proper respiratory protection and hazardous material/chemically resistant suits, and in a widespread attack, in an ever-deteriorating war zone like Ukraine, such treatment capacity would be highly limited.”
The authors note that such an attack would not be the first for Russia, which has shown a willingness to use chemical agents on more than one occasion.
During a hostage crisis in 2002, where Chechen rebels took over a Moscow theatre and took 700 hostages, Russian authorities used a gas to incapacitate the rebels – as well as the hostages. The gas may have been a mixture of remifentanil/halothane or an aerosolised form of carfentanil, a synthetic opioid that is approximately 10 000 times more potent than morphine. Overdoses from carfentanil from substance abuse have been seen in recent years. In many cases of opioid overdose, death from respiratory failure is a consequence. After the raid, at least 33 Chechens and 129 hostages died, mostly from gas exposure and inadequate medical care. Russian authorities refused to release information on the gas used, hindering emergency response.
Russia has also apparently used Novichok, which may be up to eight times as potent as VX, in recent high-profile attempts to kill opponents of the Russian government. The most recent use of Novichok was an attempted assassination of Alexei Navalny, a prominent Russian dissident. Though whether Novichok was the agent, Navalny’s treatment was for nerve agent exposure, featuring large doses of atropine. Though he survived, his treatment was an intensive, organised effort. A large attack using Novichok or other chemical agent in Ukraine promises to be almost entirely lethal to civilians, military and first responders.
COVID vaccination during pregnancy is not associated with a higher risk of pregnancy complications, according to a large scale Swedish and Norwegian study published in the journal JAMA.
The study, which comprised almost 160 000 pregnancies, found there to be no increase in the risk of preterm birth, growth retardation, low Apgar scores at birth or the need for neonatal care after vaccination against COVID during pregnancy.
“The results are reassuring and can hopefully make pregnant individuals more willing to get vaccinated,” said co-first author Anne Örtqvist Rosin, researcher at the Department of Medicine, Karolinska Institutet.
Studies have shown that, compared to non-pregnant peers, pregnant women are at risk of serious COVID requiring intensive care with a higher risk of death. Preterm births are also more likely in pregnant women with severe COVID. COVID vaccines have been available in Sweden and Norway since January 2021, and in May 2021 Sweden recommended all pregnant individuals to have a COVID jab, followed in August by Norway.
“We’re still seeing that vaccination rates are lower than in the rest of the population, so it’s likely that there’s some concern about how the vaccines affect the pregnant individual and the foetus,” explained Dr Örtqvist Rosin. “When the vaccines were produced, pregnant women were not included in the large clinical studies, and until now there have been no population-based data about any risk there might be to them.”
The researchers linked Sweden’s Pregnancy Register and Norway’s Medical Birth Register to each country’s vaccination register to obtain data on if and when pregnant individuals were vaccinated and with which vaccine. The study included a total of 157 521 individuals who gave birth between January 2021 and January 2022, of whom 18% had been vaccinated. It was found that vaccinated individuals were at no higher risk than unvaccinated of developing one of the studied complications.
The majority of the pregnant individuals included in the study were vaccinated after week 12 in accordance with current recommendations, and 95% received an mRNA vaccine. This should be factored in when interpreting the results, which were similar for the different mRNA vaccines regardless of whether one or two doses were given. Vaccination during the third trimester and vaccination with the Moderna vaccine was associated with a slightly lower risk of needing neonatal care.
A possible benefit of vaccination during pregnancy is that the antibodies generated pass through the placenta, conferring a certain degree of protection against COVID to the newborn baby.
“We’re now planning to study how long this protection lasts, and if SARS-CoV-2 infection or vaccination during pregnancy has any other lasting effects on the child’s health,” said joint last author Professor Olof Stephansson at the Karolinska Institutet .
In a study published in Hypertension, Osaka University researchers have demonstrated an association between the use of mineralocorticoid receptor antagonists (MRAs) and an improved renal prognosis in individuals with chronic kidney disease CKD in real-world settings.
As CKD progresses, the initiation of renal replacement therapy (RRT), which includes dialysis and kidney transplantation, may be necessary for life support in kidney failure. MRAs, which include spironolactone, eplerenone and potassium canrenoate, are commonly used to reduce swelling, blood pressure, and urine protein levels in people with CKD. However, the study was motivated by a lack of information on the link between MRA treatment and the initiation of RRT in a real-world population.
“We conducted a retrospective analysis of clinical data from over 3100 individuals with CKD,” explained lead author Tatsufumi Oka. “We evaluated MRA treatment in various populations of people with CKD, including those with diabetes, heart disease, and severely impaired renal function.”
The research team made use of a marginal structural model to analyse the association between MRA use and the initiation of RRT across multiple patient subgroups.
“Our analysis showed that MRA use was associated with a 28% lower rate of RRT initiation and a 24% lower rate of the combined outcomes of RRT initiation and death,” says senior author Jun-Ya Kaimori.
The researchers found a reduced risk for RRT initiation across various subgroups of people with CKD, including those with and without diabetes and those with severely impaired renal function. These findings highlight the association of MRA use and improved renal outcomes in a real-world population of CKD patients with varying health backgrounds. Overall, the study findings support the use of MRAs in treatment plans for various groups of people with CKD who are not undergoing dialysis.
University of Utah researchers have discovered a novel mechanism that infectious bacteria use to rapidly adapt to environmental stress, which could help explain why certain types of common infections such as sepsis can be so persistent.
The mechanism, described in the journal Nucleic Acids Research, alters the precision with which the bacteria make the proteins that carry out most of the work in cells. These changes may improve the bacteria’s chance for survival.
“Understanding how pathogens survive stressful situations can reveal new targets for development of anti-microbial drugs and vaccines,” said the study’s senior author, Professor Matthew Mulvey.
Adapt or die Bacteria infecting a host are exposed to stresses such as acidity or antibiotics. If even one of the bacteria’s key pathways for survival is crippled, the entire population could die off.
However, bacteria can adapt, an ability that relies on a slight twist to basic principles of biology.
Traditionally, each gene is thought to carry instructions for making a single kind of protein. A molecule called transfer RNA (tRNA) then uses these instructions to oversee protein production in the cell. In times of stress, though, random changes to the tNRA-mediated process can be an especially quick way to alter a cell’s array of proteins. This can generate useful new proteins that help the organism to thrive.
“There is a growing appreciation that a little bit of noise in the system can be good,” Prof Mulvey said.
Shifting expectations A graduate student in the lab happened to stumbled onto a bacterial enzyme, MiaA, which turned out to be both sensitive to environmental stress and key to regulating protein expression. In one experiment, he created a version of an especially pathogenic bacteria that lacked the gene that encodes MiaA.
“Every kind of stress we exposed the MiaA-deficient strain to seemed to cause problems,” said the study’s co-first author Matthew Blango, PhD, who is now a junior research group leader at the Leibniz Institute for Natural Product Research and Infection Biology in Jena, Germany. “So, we really thought that this protein might be playing an important role in gene regulation.”
Bacteria lacking MiaA did not thrive and did not cause urinary tract infections or sepsis in mice. This same effect also occurred with bacteria manipulated into expressing too much MiaA. “There appears to be a Goldilocks zone, where just the right amount of MiaA allows the optimal stress response,” Dr Blango said.
Seeing how badly things went when MiaA levels were out of balance, Brittany Fleming, PhD, the study’s co-first author, investigated further. She discovered that knocking out MiaA caused random ‘frameshifting’ – an error where tRNA delivers three-letter genetic codes to be translated into proteins that are off by one letter. For example, a genetic code of “CAT CAT GTA” might read as “ATC ATG TA…” when frameshifted. In the bacteria, the result of such a shift was impaired production of important proteins and production of unexpected proteins.
Another co-first author, graduate student Alexis Rousek, showed that changing levels of MiaA could alter the availability of key metabolites that feed into other important stress response pathways within the bacteria. These findings implicate MiaA as a key player within a web of pathways that can impact pathogen stress resistance
Prof Mulvey says his lab’s next step is learning how environmental stress alters MiaA levels within bacteria.
The implications for this research may extend beyond infection control. Humans express a version of MiaA that is linked to certain cancers and metabolic diseases. “What we learned about how MiaA works is likely to be relevant to research on cancer and other non-infectious human diseases,” Mulvey said.
