The exercise stress test, which involves treadmill exercise test with electrocardiogram (ECG), is one of the most familiar tests in medicine. While exercise testing typically is focused on diagnosing coronary artery disease, a recent study from Mayo Clinic finds that exercise test abnormalities, such as low functional aerobic capacity, predicted non-cardiovascular causes of death such as cancer in addition to cardiovascular-related deaths. These new findings are published in Mayo Clinic Proceedings.
The exercise stress test is noninvasive, easily available and provides important diagnostic information. In addition to the ECG itself, the test produces data on functional aerobic capacity, heart rate recovery and chronotropic index, the standardised measure of heart rate during exercise that reflects age, resting heart rate and fitness.
“In our exercise testing cohort, non-cardiovascular deaths were more frequently observed than cardiovascular deaths,” says Thomas Allison, PhD, MPH, director of Mayo Clinic’s Integrated Stress Testing Center and the study’s senior author. “Though this was a cardiac stress test, we found that cancer was the leading cause of death, at 38%, whereas only 19% of deaths were cardiovascular. Exercise test results including low exercise capacity, low peak heart rate, and a slow recovery of the heart rate after exercise test were associated with increased mortality.”
The study looked at 13 382 patients who had no baseline cardiovascular issues or other serious diseases and who had completed exercise tests at Mayo Clinic between 1993 and 2010, then were followed closely for a median period of 12.7 years.
The findings suggest that clinicians should focus not only on ECG results but on data in the exercise test results such as low functional aerobic capacity, low chronotropic index and abnormal heart rate recovery. Patients should be encouraged to increase their physical activity if these results are atypical, even if the ECG results show no significant cardiovascular-related risk, Dr Allison says.
A study of twins who fought in World War II showed that concussion early in life is tied to having lower scores on tests of thinking and memory skills decades later as well as having more rapid decline in those scores than twins who did not have a concussion, or traumatic brain injury (TBI). The study is published in Neurology®, the medical journal of the American Academy of Neurology.
“These findings indicate that even people with traumatic brain injuries in earlier life who appear to have fully recovered from them may still be at increased risk of cognitive problems and dementia later in life,” said study author Marianne Chanti-Ketterl, PhD, MSPH, of Duke University in Durham, North Carolina. “Among identical twins, who share the same genes and many of the same exposures early in life, we found that the twin who had a concussion had lower test scores and faster decline than their twin who had never had a concussion.”
The study involved 8662 men who were World War II veterans. The participants took a test of thinking skills at the start of the study when they were an average age of 67 and then again up to three more times over 12 years. Scores for the test can range from zero to 50. The average score for all participants at the beginning of the study was 32.5 points.
A total of 25% of the participants had experienced a concussion in their life.
Twins who had experienced a concussion were more likely to have lower test scores at age 70, especially if they had a concussion where they lost consciousness or were older than 24 when they had their concussion. Those twins with traumatic brain injury with loss of consciousness, more than one traumatic brain injury and who had their injuries after age 24 were more likely to have faster cognitive decline than those with no history of traumatic brain injury.
For example, a twin who experienced a traumatic brain injury after age 24 scored 0.59 points lower at age 70 than his twin with no traumatic brain injury, and his thinking skills declined faster, by 0.05 points per year.
These results took into account other factors that could affect thinking skills, such as high blood pressure, alcohol use, smoking status and education.
“Although these effect sizes are modest, the contribution of TBI on late life cognition, in addition to numerous other factors with a detrimental effect on cognition, may be enough to trigger an evaluation for cognitive impairment,” Chanti-Ketterl said. “With the trend we are seeing with increased emergency room visits due to sports or recreation activity injuries, combined with the estimated half million members of the military who suffered a TBI between 2000 and 2020, the potential long-term impact of TBI cannot be overlooked. These results may help us identify people who may benefit from early interventions that may slow cognitive decline or potentially delay or prevent dementia.”
A limitation of the study was that traumatic brain injuries were reported by the participants, so not all injuries may have been remembered or reported accurately.
Females’ kidneys are known to be more resilient to disease and injury, so what about them can be applied to treat males’ kidneys? A new USC Stem Cell-led study published in Developmental Cell describes not only how sex hormones drive differences in male and female mouse kidneys, but also how lowering testosterone can “feminise” this organ and improve its resilience.
“By exploring how differences emerge in male and female kidneys during development, we can better understand how to address sex-related health disparities for patients with kidney diseases,” said Professor Andy McMahon, the study’s corresponding author, and the director of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at the Keck School of Medicine of USC.
First authors Lingyun “Ivy” Xiong and Jing Liu from the McMahon Lab and their collaborators identified more than 1000 genes with different levels of activity in male and female mouse kidneys, in a study supported by the National Institutes of Health. The differences were most evident in the section of the kidney’s filtering unit known as the proximal tubule, responsible for reabsorbing most of the nutrients such as glucose and amino acids back into the blood stream. Most of these sex differences in gene activity emerged as the mice entered puberty and became even more pronounced as they reached sexual maturity.
Because female kidneys tend to fare better in the face of disease or injury, the researchers were interested how the gene activity of kidneys becomes “feminised” or “masculinised” – and testosterone appeared to be the biggest culprit.
To feminize the kidneys of male mice, two strategies worked equally well: castrating males before puberty and thus lowering their natural testosterone levels, or removing the cellular sensors known as androgen receptors that respond to male sex hormones.
Intriguingly, three months of calorie restriction – which is an indirect way to lower testosterone – produced a similar effect. Accordingly, calorie restriction has already been shown to mitigate certain types of kidney injuries in mice.
To re-masculinize the kidneys of the castrated males, the researchers only needed to inject testosterone. Similarly, testosterone injection masculinised the kidneys of females who had their ovaries removed before puberty.
The scientists performed some similar experiments with mouse livers. Although this organ also displays sex-related differences, the hormones and underlying factors driving these differences are very different than those at play in the kidney. This suggests that these sex-related organ differences emerged independently during evolution.
To test whether the same genes are involved in sex-related kidney differences in humans, the scientists analysed a limited number of male and female donor kidneys and biopsies. When it came to genes that differed in their activity between the sexes, there was a modest overlap of the human genes with the mouse genes.
“There is much more work to be done in studying sex-related differences in normal human kidneys,” said McMahon. “Given the divergent outcomes for male and female patients with kidney disease and injury, this line of inquiry is important for making progress toward eventually closing the gap on these sex-related health disparities.”
In the ensuing court battle between Discovery Health and the Road Accident Fund (RAF) over reimbursements to be paid on motor vehicle claims, medical schemes members had always sought clarity or a position from the Council for Medical Schemes regarding this. In normative terms, the CMS is not obliged to release commentary on matters remote to its mandate, however, as a responsible regulator, it became a necessary act to clear any anomality.
Medical scheme members usually do not always have the full understating of the arrangements between RAF and medical schemes. At best, members sometimes have difficulty engaging with their scheme’s rules or RAF due to language barrier or be it of a technical nature of the matter.
In terms of the Medical Schemes Act 131 of 1998 (the “MSA”), Medical Schemes undertake liability in return for a contribution by among others granting assistance in defraying expenditure incurred in connection with the rendering of any relevant health services.
MSA further obliges medical schemes to pay for Prescribed Minimum Benefits (PMB), which include any emergency medical condition, under which motor vehicle claims could fall, in full. Unless a claim is specifically excluded in terms of the schemes’ rules and/or does not meet the criteria in terms of the definition of relevant healthcare, the medical scheme must still pay.
Most medical schemes provide for the handling of motor vehicle claims in their rules, wherein members of medical aid can claim compensation from the Road Accident Fund (the “RAF”) for such claims and any future healthcare services which may arise due to such motor vehicle accident.
It is also common cause that where RAF is responsible for claims, which a medical scheme has paid in terms of its rules and the MSA, that the RAF should refund to such medical scheme the amounts paid. Members of medical schemes who would have claimed directly from the RAF and received compensation for such claims, must also pay such amounts back to the medical scheme. This is commonly known as subrogation.
Should a member not receive any compensation from the RAF even after claiming, the scheme remains liable for the costs of the treatment subject to the registered scheme rules and must not be required to repay/refund such funds to the scheme.
The scheme may, however, attempt to recover such amounts paid from the RAF for the benefit of its members.
Subrogation allows medical schemes to minimise losses as a result of these claims and keep members’ contributions reasonable, by holding responsible parties accountable. It also prevents members from being “overcompensated” or unjustifiably enriched for the loss since they should not receive double compensation from both the medical scheme claim payout and the recovery from the RAF.
It must be emphasized that the financial risk associated with health interventions for which the need is uncertain is equitably shared within the covered population through a risk pool managed by medical schemes under the Medical Schemes Act. Therefore, CMS cannot condone a situation where members of medical schemes are forced to be out of pocket due to the non-payment of medical costs by RAF where these have since been paid out by medical schemes.
In line with our mandate under Section 7 of the Medical Schemes Act, it is not in the members interest if medical schemes are required to claw back payment made on behalf of members due to non-payment of these costs by RAF.
Moreover, the non-recovery of these costs by medical schemes negatively and unfairly withdraws from the entire risk pool that is aimed at benefitting the whole membership.
The World Health Organization (WHO) defines pooling as “…accumulation and management of revenues in such a way as to ensure that the risk of having to pay for healthcare is borne by all members within the pool, not by each contributor individually…” (WHO, 2000).
By implication, the refusal to refund medical schemes by RAF leads to the unfair deterioration of the entire risk pool funds.
Within this background, CMS believes that the refusal to refund medical schemes by RAF is not in line with the provisions of the Medical Schemes Act and it is not in the interest of beneficiaries of medical schemes.
DISCLAIMER: COUNCIL FOR MEDICAL SCHEMES. 2023
This document has been prepared by the author(s) from the Council for Medical Schemes Legal Services Unit and Benefits Management Unit. The views and information expressed in this article are for information purposes only. CMS cannot be held liable for any incorrectness of statements and statistical errors. Recommendations and conclusions are based on the author(s) research outcomes/findings and does not necessarily espouse or state as a CMS policy stance. The information is subject to change without notice. Companies and individuals wishing to use the information must reference the CMS in company reports, news reports, interviews, panel discussions etc.
A human neutrophil interacting with Klebsiella pneumoniae (pink), a multidrug–resistant bacterium that causes severe hospital infections.
Credit: National Institute of Allergy and Infectious Diseases, National Institutes of Health
New “hypervirulent” strains of the bacterium Klebsiella pneumoniae have emerged in healthy people in community settings, prompting researchers to investigate how the human immune system defends against infection by it. After exposing the strains to components of the human immune system in vitro, they found that some strains were more likely to survive in blood and serum than others, and that neutrophils are more likely to ingest and kill some strains than others. The study, published in mBio, was led by researchers at NIH’s National Institute of Allergy and Infectious Diseases (NIAID).
“This important study is among the first to investigate interaction of these emergent Klebsiella pneumoniae strains with components of human host defence,” Acting NIAID Director Hugh Auchincloss, MD, said. “The work reflects the strength of NIAID’s Intramural Research Program. Having stable research teams with established collaborations allows investigators to draw on prior work and quickly inform peers about new, highly relevant public health topics.”
K. pneumoniae was identified over a hundred years ago as a cause of serious, often fatal, human infections, mostly in already ill or immunocompromised patients and especially if hospitalised. Over decades, some strains developed resistance to multiple antibiotics. Often called classical Klebsiella pneumoniae (cKp), this bacterium ranks as the third most common pathogen isolated from hospital bloodstream infections. Certain other Klebsiella pneumoniae strains cause severe infections in healthy people in community settings (outside of hospitals) even though they are not multidrug-resistant. They are known as hypervirulent Klebsiella pneumoniae, or hvKp. More recently, strains with both multidrug resistance and hypervirulence characteristics, so-called MDR hvKp, have emerged in both settings.
NIAID scientists have studied this general phenomenon before. In the early 2000s they observed and investigated virulent strains of methicillin-resistant Staphylococcus aureus (MRSA) bacteria that had emerged in US community settings and caused widespread infections in otherwise healthy people.
Now, the same NIAID research group at Rocky Mountain Laboratories in Hamilton, Montana, is investigating similar questions about the new Klebsiella strains, such as whether the microbes can evade human immune system defenses. Their findings were unexpected: the hvKp strains were more likely to survive in blood and serum than MDR hvKp strains. And neutrophils had ingested less than 5% of the hvKp strains, but more than 67% of the MDR hvKp strains – most of which were killed.
The researchers also developed an antibody serum specifically designed to help neutrophils ingest and kill two selected hvKp and two selected MDR hvKp strains. The antiserum worked, though not uniformly in the hvKp strains. These findings suggest that a vaccine approach for prevention/treatment of infections is feasible.
Based on the findings, the researchers suggest that the potential severity of infection caused by MDR hvKp likely falls in between the classical and hypervirulent forms. The work also suggests that the widely used classification of K. pneumoniae into cKp or hvKp should be reconsidered.
The researchers also are exploring why MDR hvKp are more susceptible to human immune defences than hvKp: Is this due to a change in surface structure caused by genetic mutation? Or perhaps because combining components of hypervirulence and antibiotic resistance reduces the bacterium’s ability to replicate and survive in a competitive environment.
As a next step, the research team will use mouse models to determine the factors involved in MDR hvKp susceptibility to immune defences. Ultimately, this knowledge could inform treatment strategies to prevent or decrease disease severity.
