In a new study, researchers found that a new drug under development, zerlasiran, depleted levels of lipoprotein(a) by more than 80% in participants with increased cardiovascular risk. The drug was well tolerated and the findings, published in JAMA Network, suggest that this could be the first viable treatment for elevated levels of lipoprotein(a).
Elevated levels of lipoprotein(a) (LPa) – a type of cholesterol – is a genetic risk factor for cardiovascular disease. Present in 20% of the population, it increases the risk of atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis. Currently, there are no interventions which can bring down high LPa levels: it is unresponsive to diet, exercise, and other lifestyle changes and there is no available drug.
Zerlasiran, a small-interfering RNA that targets synthesis of LPa serum concentration, was developed to fill this gap. It is effectively a gene silencer that shuts down LPA, a gene which produces a protein found only in LPa. This in turn is expected to reduce cardiovascular risk.
A phase I clinical trial had shown that zerlasiran was safe and effective.
For the study, researchers enrolled 178 patients (average age 63.7 years, 46 female) with ASCVD and LPa concentrations greater than or equal to 125nmol/L. They were randomised to subcutaneously receive zerlasiran 300mg or 450mg, or a placebo, every 16 or every 24 weeks. The least-squares mean placebo-adjusted time-averaged percent change in LPa serum concentrations was −85.6%, −82.8%, and −81.3% for the 450mg every 24 weeks, 300mg every 16 weeks, and 300 mg every 24 weeks groups, respectively. The most common adverse events were injection site reactions, with mild pain occurring in 2.3% to 7.1% of participants in the first day following drug administration. There were 20 serious adverse events in 17 patients, none considered related to the study drug. For the group receiving a 300mcg dose every 16 weeks, it was found that even at the 60 week follow-up, 28 weeks after the last administration, that lipoprotein(a) serum concentrations were still 60% lower than baseline.
New research published in Nature has shown that the recombinant shingles vaccine, as with the live version, might have a protective effect against dementia.
While evidence is emerging that the live herpes zoster (shingles) vaccine might protect against dementia, it has now been replaced by recombinant vaccines in many countries. But a lack of data meant that whether the recombinant vaccines conferred the same benefit was unknown. Fortunately, since there was a rapid switch from live to recombinant vaccines, there was an opportunity for a natural experiment to compare the risk of dementia between vaccine types.
The study demonstrated that the recombinant vaccine is associated with a significantly lower risk of dementia in the 6 years post-vaccination. Specifically, receiving the recombinant vaccine is associated with a 17% increase in diagnosis-free time, translating into 164 additional days lived without a diagnosis of dementia in those subsequently affected.
The recombinant shingles vaccine was also associated with lower risks of dementia than were two other vaccines commonly used in older people: influenza and tetanus–diphtheria–pertussis vaccines. The effect was robust across multiple secondary analyses, and was present in both men and women but was greater in women. These findings should stimulate studies investigating the mechanisms underpinning the protection and could facilitate the design of a large-scale randomised control trial to confirm the possible additional benefit of the recombinant shingles vaccine.
An exhaustive four year-long study has shown that metformin reduces the effect of ageing. Using a wide array of ageing indicators, the researchers found that metformin resulted in about six year regression in brain ageing. They reported their findings in Cell.
Prior research and anectodal evidence suggested that metformin had an anti-ageing effect. Given to flies, worms and rodents, the drug showed evidence of rejuvenation. People taking metformin also reported feeling younger the longer they took it for.
In a rigorous 40-month study, the researchers gave metformin to 12 elderly male cynomolgus macaques and 18 other cynomolgus monkeys the drug daily. They were aged 13–16 years, equivalent to 40–50 in human years. A control group was used, as well as middle-aged and younger controls to account for ageing effects.
The study encompassed a comprehensive suite of physiological, imaging, histological, and molecular evaluations, substantiating metformin’s influence on delaying age-related phenotypes at the organismal level.
Tissue samples were taken at regular intervals, we leveraged pan-tissue transcriptomics, DNA methylomics, plasma proteomics, and metabolomics to develop innovative monkey aging clocks and applied these to gauge metformin’s effects on ageing.
The results highlighted a significant slowing of aging indicators. A number of organs that seemed to benefit included the kidneys, lungs and the skin. The greatest effect was seen in the brain, however. Metformin exerts a substantial neuroprotective effect, preserving brain structure and enhancing cognitive ability. In this case, treated monkeys had brain activity comparable to those six years younger.
The geroprotective effects on primate neurons were partially mediated by the activation of Nrf2, a transcription factor with anti-oxidative capabilities. The researchers say that this work pioneers the systemic reduction of multi-dimensional biological age in primates through metformin, paving the way for advancing pharmaceutical strategies against human aging.
The researchers have also started a much larger phase 2 human trial, with 120 participants.
The world’s first partial face and whole eye transplant has yielded important insights towards the development of functional eye transplants.
Over one year ago, a surgical team at NYU Langone Health transplanted part of a donor face onto a 46-year old power line worker who had suffered extensive facial injuries and the loss of his left eye. They also transplanted a complete eye into the patient, connecting it up to blood vessels and nerves, to see whether it was possible for an eye to survive. Now, findings on the health of the transplanted eye published in JAMA reveal that the eye is healthy but no light has been seen from it.
For the roughly 40 million people around the world without sight in either eye, stem cell research has been the most recent hope for regaining vision in many cases of trauma and disease.
In the eye transplant, the optic nerve was attached and immunosuppression used. Fluorescein angiography showed that perfusion of the globe and retinal were maintained throughout the immediate postoperative period. Optical coherence tomography revealed atrophy of inner retinal layers and attenuation and disruption of the ellipsoid zone.
Crucially, the retina of the transplanted eye responded to light as confirmed by serial electroretinography. MRI scans demonstrated the integrity of the transplanted visual pathways and potential occipital cortical response to light stimulation of the transplanted eye. However, after one year, no light in the eye was observed by the patient.
As discussed in an accompanying editorial published in JAMA Network, whole eye transplantation (WET) has been regarded as one of the most difficult yet important transplant procedures to attempt developing. In 1978, a report from the National Eye Institute advisory stated that “[a]t present, any effort to transplant a mammalian eye is doomed to failure by the ganglion cell axon’s inability to withstand cutting, by the difficulty of insuring adequate circulation of blood to the transplanted eye during or shortly after operation, and lastly by immune rejection of foreign tissue.”
With this transplant case, the issues of adequate circulation and immune rejection have now been shown to be surmountable, the authors point out. Other issues to address concern connecting the cranial nerves to enable opening of the eyelid.
View of the spinal cord. Credit: Scientific Animations CC4.0
In a recent study published in Nature, researchers prevented T cells from causing the normal autoimmune damage that comes with spinal cord injury, sparing neurons and successfully aiding recovery in mouse models.
In spinal cord injury, the wound site attracts a whole host of peripheral immune cells, including T cells, which result in both beneficial and deleterious effects. Notably, antigen-presenting cells activate CD4+ T cells to release cytokines, ultimately leading to neuroinflammation and tissue destruction. This neuroinflammation is notably most pronounced during the acute phase of spinal cord injury. The problem is that these same T cells have a neuroprotective effect initially, only later developing autoimmunity and attacking the injury site.
Using single cell RNA sequencing, the researchers found that CD4+ T cell clones in mice showed antigen specificity towards self-peptides of myelin and neuronal proteins. Self-peptides have been implicated in a wide range of autoimmune conditions.
Using mRNA techniques, the researchers edited the T cell receptor, so that they shut off after a few days. In mouse models of spinal cord injury, they showed notable neuroprotective efficacy, partly as a result of modulating myeloid cells via interferon-γ.
Their findings provided insights into the mechanisms behind the neuroprotective function of injury-responsive T cells. This will help pave the way for the future development of T cell therapies for central nervous system injuries, and perhaps treatments for neurodegenerative diseases such as Alzheimer’s.
Pressure from ageing populations, stagnant growth and growing medical costs will mean that medical aid schemes will make above-inflation rate hikes, reveals Momentum Health marketing officer Damian McHugh. He made the comments at Momentum Health Solutions’ virtual Healthcare Insights Summit on Tuesday (30 July), where he also noted that the same demands on medical funds are serving to put NHI even further out of reach, estimating a budget of some R1.3 trillion.
If one take’s McHugh’s figures and projects into the coming years, these above-inflation hikes make the target an ever increasing-one, steadily sending the current estimates even further from the realms of affordability. This is a situation which national health schemes of far wealthier countries are now encountering.
This comes as the Council for Medical Schemes advised the 1st of August of inflation plus “reasonable utilisation estimates” resulting in a recommendation to keep under 8.5%. But it given the pressures on medical aid schemes, this is unlikely to be adhered to, as last year already saw increases in excess of this.
Medical aid cost pressures
The CMS acknowledged that above-inflation medical cost increases are inevitable due to “unique industry factors such as technological advancement, the ageing population, and the increasing prevalence of chronic diseases.”
Last year, Discovery Health Medical Scheme (DHMS) announced a weighted average increase of 7.5%, for 2024 – but its comprehensive “premium” segment rose by 13%. Both Momentum and BestMed announced weighted increases of 9.6% for 2024, while Bonitas managed to contain its increases to 6.9% (though its comprehensive cover rose to 9.6%). MediHelp surged to 15.96%, though it justified this increase as its options were the lowest-priced on the market.
Medical aid scheme growth is slow, at best around 0.5% per annum, while there is considerable pressure on subscriber income. Low income brackets only spend around 4% on healthcare, while middle and high income brackets spent 6% and 7%, respectively.
But with claims on the increase, many medical aids are having to tap into reserves and reducing solvency. Many medical aids are running close to 100% claims ratio – obviously a very bad situation for them to find themselves in.
These cost pressures result in a reduction in benefits, with the burden being shifted by reducing day-to-day benefits and members moving to Efficiency Discount Options (EDOs) – in turn, reducing the risk contribution income received by the schemes.
Rate hikes inevitable
In its recommended guidelines for 2025 released in Circular 35 of 2024, the CMS advised that medical aid schemes limit their contribution increases in line with CPIThis was based on the Reserve Bank’s latest inflation forecast which expects headline inflation to average 4.4% and 4.5% in 2025 and 2026, respectively. With last year’s estimated of an additional 3.2% to 3.8%, that works out to about 8.5%. But the CMS noted that medical aid schemes have historically had increases in excess of CPI+4%.
The COVID pandemic bucked the trend, resulting in – though many medical aid schemes saw record profits as procedures were deferred. Price increases were deferred, with increases kept below inflation for 2021 and 2022, with an uptick in 2023.
McHugh pointed out that growth in medical aid schemes has remained largely flat, and the ageing of the insured lives was linked to increasing claims costs as health problems became more complex. He revealed that claims costs per life had risen from about R15 000 in 2017 to R21 000 in 2022. This, spread across the population of South Africa, would require an NHI budget of R1.3 trillion.
Source: CMS Circular 35 of 2024
Breaking down the expenditures, McHugh said that medical schemes spent 37% on hospitals and 28% on specialists, while medicine accounted for 16% and GPs a mere 5%. The CMS also noted that hospitals and specialists had seen greater relative increases than other areas. For the essential coverage of hospitals, medicines, GPs, and dentists, that would amount to R363 billion.
Looking ahead with a little maths
One can take simple compound interest to McHugh’s figures, and even applying the CMS’ best-case “reasonable utilisation estimate” of 3.2%, for say 20 years from will mean that costs rise by 87% in today’s rands. That means the NHI’s ‘basic’ coverage would rise to R682 billion and the full coverage amounting to an incredible R2.4 trillion.
But this nothing special to South Africa. The UK’s NHS costs have similarly grown, at 3.6% per annum in real terms. And that growth has to come out of the GDP: from 3.6% of the GDP in 1949-50 to 8.2% in 2022-23, with a surge to 10.5% in the COVID pandemic.
The UK has now put measures in place to constrain cost growth to 1%, but it remains to be seen whether this will be effective without compromising service delivery. How South Africa can even contemplate an NHI where, 20 years from now, private scheme medical costs run to R39 000 per person in the best case scenario.
While McHugh did not mention the recent High Court blow to the NHI Act that found a key part of it unconstitutional, he described the legal challenge process that would see that part sent back to the National Assembly and the president.
McHugh however struck a note of optimism, noting that the public-private partnerships of the COVID pandemic showed a way forward for NHI and universal healthcare in South Africa. The 2024 elections bring the possibility of the same historic benefits for the population as the 1994 ones.
Cancer patients who participate in clinical trials hoping for better outcomes fare no better than those who do not, when setting aside the new treatment’s effect, according to the results of a study published in the Journal of the American Medical Association. The analysis found that while overall, trials had a positive benefit, this effect diminished after accounting for various factors common to trial participants such as being younger. Evidence of publication bias was also uncovered.
Participation in a clinical trial may confer a survival benefit to cancer patients is known as a trial effect, and results from access to effective new therapies (the treatment effect), but it is also thought that a trial’s closer monitoring provides a distinct benefit as well (the participation effect). The treatment effect only applies if the treatment proves to be effective, while the participation effect should apply regardless of treatment effect. But the evidence for the participation effect has been conflicting. A pair of reviews, one conducted in 2001 and the other in 2004, found no evidence of a participation effect.
The researchers therefore sought to account for biases and confounding in differences between routine care patients and trial patients. A search was performed for studies comparing survival outcomes for the two groups between January 1 2000 and August 31 2022, which turned up 12 791 records. After screening for eligibility and duplicates, this yielded 39 studies (85 comparisons) for analysis. These comparisons involved haematologic (21%), breast (16%), lung (14%), central nervous system (7%), prostate (7%), and pancreatic cancers (5%), as well as melanoma (6%). The remaining 24% consisted of bladder, cervical, colorectal, oesophageal, gastric, head and neck, kidney, ovarian, and solid mix tumours. One-third of the comparisons involved advanced or metastatic cancer.
Initially, the meta-analysis revealed a statistically significant overall survival benefit for trial participants (HR [hazard ratio], 0.76) when all studies were pooled without regard to their design or quality. But in study subsets matching trial participants and routine care patients for eligibility criteria, the survival benefits diminished (HR, 0.85). Finally, the survival benefit disappeared when only high-quality studies were pooled (HR, 0.91). They also disappeared when estimates were adjusted for potential publication bias (HR, 0.94).
Further analysis (using funnel plots and Egger’s regression test) indicated there was a publication bias against studies which lacked a participation effect.
In an accompanying editorial, Wilson et al. note that the participation effect explains that, “Patients in trials are generally younger, fitter, have fewer comorbidities, and come from higher socioeconomic groups; this enrollment bias largely explains the participation effect. The implications of this finding are important for understanding how trials are often viewed in clinical practice. The participation effect is often used to promote the view that “a clinical trial is the best treatment option, ‘but this may be a false narrative.”
Corresponding author Jonathan Kimmelman, PhD concluded: “Our findings provide reassurance that inability to enroll in a cancer trial doesn’t disadvantage a patient, at least in terms of survival. Our findings can help patients (and physicians) focus their consent discussions on the most relevant and evidence-based benefits of trial participation: the prospects of advancing the care of future patients.”
Approximately one in seven patients who discontinued their use of antidepressants experienced discontinuation symptoms, according to a wide-ranging analysis published in The Lancet Psychiatry. In arriving at this figure, the researchers accounted for a high frequency of anticipated discontinuation symptoms.
The emergence of adverse symptoms after antidepressant cessation has been described as far back as 1959, but was mostly neglected until the late 1990s. Today, the existence of antidepressant discontinuation symptoms is widely accepted, with transnational guidelines suggesting safe tapering. They can be highly variable and non-specific, with the most frequently reported symptoms being dizziness, headache, nausea, insomnia, and irritability. It has been reported that symptoms typically occur within a few days and are usually transient, but can last up to several weeks or months.
The incidence and severity of symptoms remained controversial however, with estimates ranging up to a majority (56%) of patients experiencing them, half of them severe. Previous reviews have been criticised for bias, and medical opinions are polarised on the subject.
The researchers reviewed 79 studies involving more than 21 000 participants, and found that about one-third of patients experienced symptoms such as headaches, nausea, insomnia, and irritability after accounting for patient expectations. Even in patients taking placebo, 17% experienced symptoms – suggesting that this is attributable to patient expectations about the adverse effects of stopping the drug.
After taking this into account, roughly one in seven individuals had antidepressant discontinuation symptoms. Neither tapering nor abrupt cessation of the drugs made no difference in the proportion of people who experienced discontinuation symptoms.
In addition, about 1 in 35 people experienced severe discontinuation symptoms. Desvenlafaxine, venlafaxine, imipramine, and escitalopram were associated with higher frequencies of discontinuation symptoms, and imipramine, paroxetine, and either desvenlafaxine or venlafaxine were associated with higher symptom severity. The authors cautioned that there was substantial heterogeneity of results.
While irritable bowel syndrome (IBS) is commonly associated with symptoms outside the intestine, it was not known whether these symptoms differed according to the subtypes of the condition. A new study published in Neurogastroenterology and Motility investigated the prevalence, and found that the IBS-M (mixed bowel habits) subtype had the highest prevalence of most extra-intestinal symptoms symptoms.
The researchers carried out a descriptive cross-sectional study patients with IBS according to Rome IV criteria. They were classified according to subtypes: IBS-D (diarrhoea-predominant), IBS-C (constipation-predominant), and IBS-M (mixed bowel habits). Of the 4862 patients included; there were 608 IBS-D (12.5%), 1978 IBS-C (40.7%), and 2276 IBS-M (46.8%).
Participants completed a patient health questionnaire-9 (PHQ-9) score for depressive symptoms, with IBS-M the highest at 12.7 compared to 11.1 for IBS-D and 10.5 for IBS-C. They also completed an IBS-severity scoring system (IBS-SSS) questionnaire.
Overall, the study found the following results:
IBS-M:
Overweight
High IBS-SSS of 320
Depressive symptoms (80.0%)
Multiple extra-intestinal symptoms
Arthralgia (62.4%)
Chronic cervicalgia (81.0%)
Extremity numbness (64.5%)
Atopic dermatitis (28.2%)
IBS-C:
Lower body mass index
Low BS-SSS of 290
IBS-D:
Overweight (30.9%)
Higher food intolerance perception (9.5%)
History of cholecystectomy (17.8%)
Faecal incontinence (36.2%)
The authors concluded that, “The prevalence of most extra-intestinal symptoms is higher among patients with IBS-M. Further research is needed to better characterize IBS subtypes, which could potentially help refining tailored therapeutic strategies.”
In adults with sepsis or septic shock, β-lactams are recommended by Surviving Sepsis Campaign guidelines, in a prolonged (after an initial bolus) rather than intermittent infusions – but owing to only moderate quality of evidence this is currently a weak recommendation. Now, a new systematic review and meta-analysis comparing the two approaches across multiple clinical trials has found a survival benefit for prolonged infusion The findings appear in JAMA.
To address whether prolonged infusions of β-lactams improve clinically important outcomes in critically ill adults with sepsis or septic shock, the study investigators searched medical databases for relevant randomised controlled trials comparing β-lactam infusion types in critically ill adults with sepsis or septic shock. The primary outcome was 90-day mortality, with secondary outcomes including intensive care unit (ICU) mortality and clinical cure.
In all, they found 18 eligible trials that included 9108 critically ill adults with sepsis or septic shock (median age, 54 years; 5961 men [65%]), 17 trials (9014 participants) contributed data to the primary outcome.
The pooled estimated risk ratio for all-cause 90-day mortality for prolonged infusions of β-lactam antibiotics compared with intermittent infusions was 0.86, with high certainty and a 99.1% posterior probability that prolonged infusions were associated with lower 90-day mortality. There was high certainty that prolonged infusion of β-lactam antibiotics was associated with a reduced risk of ICU mortality (risk ratio, 0.84) and moderate certainty of an increase in clinical cure (risk ratio, 1.16).
The findings were tempered with the authors’ understanding that, “Potential challenges associated with prolonged infusion administration, including drug instability and incompatibility with other intravenous medications, the need for a dedicated intravenous portal, and the potential effect on clinical workload, require some considerations before broad implementation. Future studies should determine the optimal duration of infusion when β-lactam antibiotics are administered as prolonged infusions.”
The authors concluded that, “Among adults in the intensive care unit who had sepsis or septic shock, the use of prolonged β-lactam antibiotic infusions was associated with a reduced risk of 90-day mortality compared with intermittent infusions. The current evidence presents a high degree of certainty for clinicians to consider prolonged infusions as a standard of care in the management of sepsis and septic shock.”
