Researchers in the UK have evaluated a potential drug for the treatment of spinal cord injury (SCI), which could potentially regrow damaged nerves, and found it to be safe and tolerable. The results of their Phase 1 clinical trial were published in British Journal of Clinical Pharmacology and evaluated the KCL-286 drug, which activates retinoic acid receptor beta (RARb) in the spine to promote recovery.
There are no licensed drugs that can fix the adult central nervous system’s inability to regenerate. Implants have been able to restore some function, but for most, spinal cord injuries are life-changing.
Previous studies have shown that nerve growth can be stimulated by activating the RARb2 receptor, but no drug suitable for humans has been developed. KCL-286, an RARb2 agonist, was developed by Professor Corcoran and team and used in a first in man study to test its safety in humans.
The study by the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London, recruited 109 healthy males in a single ascending dose (SAD) adaptive design with a food interaction (FI) arm, and multiple ascending dose (MAD) arm. Participants in each arm were further divided into different dose treatments.
SAD studies are designed to establish the safe dosage range of a medicine by providing participants with small doses before gradually increasing the dose provided. Researchers look for any side effects, and measure how the medicine is processed within the body. MAD studies explore how the body interacts with repeated administration of the drug, and investigate the potential for a drug to accumulate within the body.
Researchers found that participants were able to safely take 100mg doses of KCL-286, with no severe adverse events.
Professor Jonathan Corcoran, Professor of Neuroscience and Director of the Neuroscience Drug Discovery Unit, at King’s IoPPN and the study’s senior author said, “This represents an important first step in demonstrating the viability of KCL-286 in treating spinal cord injuries. This first-in-human study has shown that a 100mg dose delivered via a pill can be safely taken by humans. Furthermore, we have also shown evidence that it engages with the correct receptor.
“Our focus can hopefully now turn to researching the effects of this intervention in people with spinal cord injuries.”
Dr Bia Goncalves, a senior scientist and project manager of the study, and the study’s first author from King’s IoPPN said, “Spinal Cord Injuries are a life changing condition that can have a huge impact on a person’s ability to carry out the most basic of tasks, and the knock-on effects on their physical and mental health are significant.
“The outcomes of this study demonstrate the potential for therapeutic interventions for SCI, and I am hopeful for what our future research will find.”
The researchers are now seeking funding for a Phase 2a trial studying the safety and tolerability of the drug in those with SCI.
Credit: Darryl Leja National Human Genome Research Institute National Institutes Of Health
While treatment for localised prostate cancer has a relatively high success rate, mortality is high in advanced metastatic cancer. The precise mechanism behind the spread of the tumour has not been fully explained. Researchers have now decoded the underlying cellular signal pathway and have demonstrated that the common diabetes drug metformin could provide a new treatment option. The study has just been published in the journal Molecular Cancer.
Using a complex mouse model, the research team under Lukas Kenner at the Medical University of Vienna examined prostate cancer cells and identified the key factors in the regulation of tumour cell growth and the way they interact with each other. The protein signal transducer and activator of transcription 3 (STAT3) plays the leading role – its activation by another protein called interleukin 6 (IL6) has been a focus for cancer researchers in connection with tumour progression for some time now.
“Interestingly, our study showed for the first time that permanent activation of STAT3 prevents the development of prostate cancer as well as the development and spread of metastases. Conversely, we discovered that the loss of the signal pathway between STAT3 and IL6 in the prostate can lead to massive tumour growth and metastasis, which significantly increases the aggressiveness of the cancer and the mortality rate,” explained Kenner.
Metformin as a potential medication
In the course of the study, the researchers also found that activation of STAT3 in the prostate leads to increased levels of cell components (LKB1/pAMPK) that are responsible for the regulation of glucose metabolism and are linked to type 2 diabetes mellitus. The proteins LKB1/pAMPK block certain cancer molecules (mTOR and CREB) and as a result also stop the tumour growing. “In light of this finding, we used a common diabetes drug in our research,” said Kenner. Kenner and his team discovered that the active ingredient metformin, which is used in the treatment of type 2 diabetes to regulate glucose levels, can significantly slow the progression of STAT3-positive prostate cancer, a condition with a metabolism that is very similar to type 2 diabetes. “As metformin is already available, our research findings could be useful in developing new treatment options for patients with STAT3-positive prostate cancer in the foreseeable future,” Kenner pointed out, looking ahead to further research into the newly discovered approach.
Photo by Miguel Á. Padriñán: https://www.pexels.com/photo/syringe-and-pills-on-blue-background-3936368/
The South African Pharmacy Council (SAPC) has been given judicial go-ahead to introduce its Pharmacy-Initiated Management of Antiretroviral Treatment (PIMART) initiative, which will allow specially trained pharmacists to manage and prescribe medicine to patients with HIV and tuberculosis.
Pretoria High Court Judge Elmarie van der Schyff has dismissed an application brought by a doctors’ organisation – the IPA Foundation – for the setting aside of the programme.
She said the pilot project had emphasised the value of the initiative, which was in line with the World Health Organisation’s vision to promote widely accessible primary health care.
“The untapped value of pharmacists in fighting HIV was also emphasised by the efficient role pharmacies played in meeting health care needs and providing health care services during the Covid-19 pandemic,” she said.
“The need to widen access to first line ART and TPT therapy on a community level is not a figment of SAPC’s imagination but a dire need that is also evinced in other countries.”
The IPA Foundation approached the court, under the Promotion of Administrative Justice Act (PAJA), seeking to review and set aside the SAPC’s decision to implement PIMART.
IPA claimed that the SAPC had failed to give interested parties an adequate opportunity to comment before the initiative was implemented. It further contended that PIMART unjustifiably encroached on the domain of medical practitioners and was in conflict with legislation.
IPA also accused SAPC of misleading the Director-General of Health, claiming there had been extensive consultation with stakeholders, which led to the approval and issuing of permits for the initiative.
The SAPC said the application should be dismissed. It said pharmacy-provided primary healthcare was a well known and functional concept in South Africa and PIMART was simply a “widening of this”.
Referring to the background and context, Judge van der Schyff said, in line with WHO recommendations that all people living with HIV must be provided with ART, the department of health had requested the SAPC to consider and implement interventions that would ensure that patients had increased access to medicines.
This led to the SAPC requesting the Director-General in August 2018 to consider issuing permits to pharmacists who had completed supplementary training, to manage patients and to dispense medication under PIMART.
In March 2021, the SAPC published a notice for public comment regarding the adoption of PIMART. The first permits were issued in August that year.
However, IPA submitted objections outside of the timeline for comments. It said this was because its members were struggling with another wave of the Covid-19 pandemic.
“Pharmacists and doctors operate in distinct and separate professional domains, the boundaries of which are closely guarded and some tension exists … IPA’s objection to PIMART seems to be rooted, partially at least, in this professional tension.
“This is evidenced by its fear that the decision to implement PIMART might ‘open the floodgates’ and ‘pave the way for pharmacists to ultimately treat and prescribe other schedule 4 drugs in respect of acute illnesses’,” the Judge said.
She noted, however, that the National Drugs Policy, in line with WHO guidelines, promoted “task shifting” to advance access to medicine and that at primary level, prescribing should be competency based, not occupation based.
Any alleged adverse effect that PIMART held for a medical practitioner had to be considered against the need to expand primary health care services aimed at preventing and treating HIV and providing first-line ART therapy.
Judge van der Schyff said the initiative gave members of the public a choice as to whether they wanted to approach a pharmacist, who had been issued with a permit, or a general practitioner.
In considering procedural fairness, the judge said there was nothing sinister in the timing of the notice calling for comment, that the project was not something hidden in secrecy and “I find it improbable, as alleged, that none of IPA’s members had timeous knowledge of the board notice”.
The decision to implement PIMART also fell within the ambit of the SAPC’s powers.
Evidence also showed that the PIMART training course was developed to ensure that pharmacists who successfully completed the training would be suitably qualified to safely and effectively assist in providing ART.
Judge van der Schyff dismissed the review application and ordered IPA to pay the costs.
Professor Francois Venter, former President of the Southern African HIV Clinicians Society and Director of Ezintsha, an HIV research organisation at Wits University, commented, “I hope this is the end of it. The pharmacies are an essential part of the health system, and pharmacists internationally play a big role in expanding HIV services.”
Doing ‘the right thing’ for one’s health, be it eating well, exercising, or going for an annual HIV test or blood pressure check, is easier said than done. One way to nudge people to make these ‘right’ decisions is to offer rewards or incentives. Discovery Health Medical Scheme’s Vitality programme is probably the best local example of such an incentive programme.
While incentive programmes have made a splash in private healthcare, they’ve hardly caused a ripple in South Africa’s public sector. In fact, the only public sector incentive of any notable scale of which we are aware was the vouchers that were offered to people who got vaccinated against SARS-CoV-2. There have been several scientific studies of cash transfers and other incentives, but the data is relatively limited and the differences between studies were substantial, as indicated in this review of cash transfers for HIV prevention, among others.
Evidence from other countries has shown that a targeted public sector incentive programme could yield significant positive results. The Indian Government launched a programme called Janani Suraksha Yojana (JSY) in 2005, “with the goal of reducing the numbers of maternal and neonatal deaths” using a conditional cash transfer scheme to encourage giving birth in a health facility. In those who benefited from the scheme, there was a reduction of 4.1 perinatal deaths per 1000 pregnancies and a reduction of 2.4 neonatal deaths per 1000 live births.
As Spotlight has recently reported, South Africa is doing relatively poorly against its diabetes and hypertension targets and substantially better against its HIV targets. Yet, we can find no evidence that the Department of Health has given serious thought to incentive programmes in these various areas.
Some might argue that the impact of such programmes is unproven and that they are too expensive. No doubt, a carbon copy public sector version of Vitality is wishful thinking. But are there any elements of it worth copying or adapting for the public sector?
“It has always amazed me that incentives are always so OK for rich people like me, on Discovery, but somehow unacceptable for poor people ‘who should do it for their own good’ in the public system,” says Professor Francois Venter, who heads up Ezintsha at the University of the Witwatersrand. He describes it as patronising.
Venter says that while hugely complex issues like controlling non-communicable diseases (NCDs) and obesity can’t be solved with incentives, they could certainly be added to the very limited toolbox of the existing arsenal being used to prevent disease or death through early detection, testing, and screening. He says incentives “definitely should not be dismissed right off the bat when it comes to the 84% of people who rely on the public system”.
The power of ‘points’
An estimated 60% of diseases across the board are caused by unhealthy lifestyles, according to a 2022 study published in the International Journal of Environmental Research and Public Health. In line with such evidence, Discovery’s Vitality programme is primarily focused on encouraging its members to make healthier lifestyle choices.
“Vitality aims to leverage behaviour change techniques, most notably using incentives, to motivate or nudge members to adopt healthy behaviours,” says Dr Mosima Mabunda, who is the Head of Wellness at Vitality. She says that four core factors are implicated in most NCDs, namely an unhealthy diet, a lack of physical activity, smoking, and alcohol misuse.
The Vitality programme is complex and uses a wide range of incentives and rewards to motivate members, including giving members monetary rebates for healthy food purchases, subsidised gym membership, and a comprehensive points-based system that rewards a range of healthy lifestyle choices. These points can be converted to cash or used at a range of local retailers. There is an incredible variety of Vitality rewards that range from discounts on flights to discounts at movie theatres.
According to a Discovery report, the “overall impact of Vitality on mortality rates is significant”. By “making people healthier” they say they have achieved an average reduction in mortality of 13%.
Several experts interviewed by Spotlight point out that most of this data has not been published in reputable, peer-reviewed journals. Even so, it is certainly plausible that Vitality’s annual incentivised health check helps with earlier diagnosis of hypertension, diabetes, and even HIV. Similarly plausible is the idea that points may successfully incentivise some people to exercise more. Scepticism of the health benefits of other elements of the Vitality programme may well be warranted – it is hard to know without independent analysis.
Importance of early detection
The underlying logic of such incentive systems is typically that the savings due to behaviour change or early detection outweighs the cost of the incentives. Put another way, the private sector isn’t just doing this to help people stay healthy, they are also doing it to save money. The costs and benefits for state-run incentive programmes will obviously look very different, but there may well be cases where the benefits of incentives outweigh their costs.
It is also possible that in some instances incentives are actually needed more urgently by users of the public sector than the private. As Professor Harsha Thirumurthy, who is an expert on behavioural economics and health incentives based at the University of Pennsylvania points out, “the majority of Vitality members don’t face barriers like transport costs” or even being located many kilometres away from the nearest state facility.
Late diagnosis or poor disease control has high human and economic costs in both the public sector and private. According to a 2013 study published in the Global Health Action journal, uncontrolled diabetes caused 8000 new cases of blindness and 2000 new amputations in South Africa in 2009 alone. More recent statistics reveal the situation is getting worse. In 2018, then KwaZulu-Natal MEC for Health Dr Sibongiseni Dhlomo revealed that six amputations occur every single day – which equates to over 2100 a year – in that province.
And the financial implications are staggering. For example, a 2022 literature review that looked at the costs of treating common NCDs in South Africa, estimated the cost of treating one person for one year with medication for type 2 diabetes to be roughly between R1000 and R3500 in the public sector. In comparison, the study also looked at the costs of treating common complications of uncontrolled diabetes. For example, diabetes-related renal disease was estimated to cost roughly R67 000 per person per year.
Screening for diabetic retinopathy, an eye condition that causes vision loss, costs between R110 and R370 per person. In comparison, the cost of treating ophthalmic disease in people with diabetes is estimated to be R59 000 per person per year.
These are only the health system costs and don’t include the costs of serious complications and lifelong disability to individuals, families, and communities.
Barriers to healthy lifestyle choices
Most experts we spoke to agree that the Vitality programme in its entirety is too complex and expensive to be replicated at scale in the public sector. Additionally, helping the majority of the population make healthy lifestyle choices, particularly those around healthy diets and physical activity, is a mammoth task and exceeds the ambit and powers of the National Department of Health.
“It’s really important to appreciate that there are so many environmental, social, [and] structural factors that make it difficult for people to quote-unquote ‘do the right thing’ when it comes to health-related behaviours,” says Thirumurthy. “For example, people are constantly subjected to advertising of unhealthy food products. Many are living in environments that make it hard to eat a healthy diet even if they wanted to.
“To really make a difference, we have to take a step back and identify the overall system-level or structural changes that could be made to influence people’s diets and other health behaviours. We need to think about what types of government regulation and policy levers can be utilised to achieve better health outcomes,” says Thirumurthy, who is also the co-founder of South Africa’s first ‘nudge unit’, based at Wits University called Indlela: Behavioural Insights for Better Health, which is focused on identifying low-cost behavioural solutions to public health challenges.
As Spotlight previously reported, many of these issues are flagged in South Africa’s recently published Strategy for the Prevention and Management of Obesity in South Africa 2023 – 2028. But while most experts we interviewed felt the strategy flagged the right issues, there was also agreement that the strategy didn’t set out a realistic plan for dealing with those issues. And not finding ways to deal with these issues is costing a lot of money.
In 2018, the public sector cost of treating patients diagnosed with diabetes alone totalled R2.7 bn “and would be R21.8 bn if both diagnosed and undiagnosed patients are considered”, according to a 2020 report about the health promotion of NCDs published by the South African Medical Research Council (SAMRC). Moreover, in real terms, it is estimated that by 2030 the cost of all type 2 diabetes cases will soar to R35.1 bn.
According to Thirumurthy, incentive-based interventions represent one creative solution with the potential to help improve health outcomes and reduce the financial burden on the health system in the long term. “I’m not saying incentives or rewards-based programmes are going to save the day, so to speak. However, they do represent a small but important part of an overall policy package that is necessary to address NCDs. Global experience suggests this policy package should prioritise regulatory interventions, including taxes on sugary sweetened beverages and other unhealthy foods, but incentive-based interventions can certainly be a useful addition to a broader strategy or policy package,” he says.
A public sector annual health check?
Early detection is one area where the public sector could potentially benefit from copying a private sector incentive scheme.
Vitality’s annual health check is a free screening and testing consultation that includes HIV testing, mental health screening, body mass index evaluation, blood pressure check and a blood glucose test, among other things. Members are rewarded handsomely with points, simply for showing up. Critically, these checks are offered at many pharmacies and are thus relatively easy to access.
According to Belinda Kahler, Wellness Specialist for Vitality, there is data that suggests that the inclusion of a screening questionnaire for depression in their annual health check yields significant benefits for both the scheme and its members. She says that members who complete the screening and are flagged as high-risk are over three times more likely to seek professional help which “fosters early detection and management which reduces complications and ultimately reduces healthcare costs”.
One way a public sector version of this could work would be for the state to contract with nurses at private sector pharmacies and GPs to provide the checkups in addition to public sector clinics. This would make it much easier for people to access these checkups, and may well boost early diagnosis of diabetes, hypertension, and other diseases, especially if an incentive is included. For this to work, the public sector data systems to facilitate the capturing of measurements and test results will have to be in place, but presumably, work along these lines is already underway for the NHI data system that is being developed. Many public-sector clients already collect their medicines from private-sector pharmacies and some were vaccinated against SARS-CoV-2 at private-sector pharmacies – so it won’t be breaking entirely new ground to add checkups to the mix.
According to Thirumurthy, programmes that are ongoing, requiring daily or weekly action, are not feasible or sustainable for the public health system at this stage as they are too resource-intensive, requiring constant monitoring, and reward allocation. “But incentivising a once-off or annual behaviour, such as going for a vaccination or health check, is not only more likely to succeed compared to daily behaviours like going to the gym or taking a certain number of steps, it is also much more cost-effective and much easier for a government to implement,” he says.
He says addressing healthy lifestyles is incredibly difficult and preventive care interventions represent a more attainable goal for the National Department of Health. Screening, preventive care, and early detection save money and lives, but it is notoriously difficult to get patients to engage in the health system before they get really sick or experience noticeable symptoms. More often than not, patients seek care too late to prevent costly complications.
“Depending on the particular behaviour, test or screening combination that is incentivised, a programme like this could really move the needle on the intended health outcome and equate to money well spent in future averted healthcare costs,” says Thirumurthy.
Dr Brendan Maughan-Brown, who is the Chief Research Officer at the Southern Africa Labour and Development Research Unit, points out that “we really are going to have a collision of comorbidities in the next seven to eight years” fuelled by an ageing HIV population. “All these NCDs are going to become even more burdensome to the health system – already in some areas, over 25% of people over 50 are living with HIV. This is going to be a major challenge for the health system, insurers, and the NHI, so thinking about solutions now, including a proposed annual health check or screening, is a good place to start.”
What should incentives look like?
Once-off or annual programmes do not need to be expensive, according to Dr Sophie Pascoe, who is the Indlela Co-Director. “They would require a level of coordination, but there are many companies who I’m sure would be willing to come on board as sponsors. The big supermarket chains could subsidise grocery vouchers or incentives could be in the form of airtime backed by one of the big mobile networks, for example,” she says. These partnerships would “benefit everybody” by encouraging those targeted behaviours, while sponsors would profit from the exposure and an increase in their customer base.
“I think part of the problem is, when we mention the word ‘incentives’, everyone imagines a lot of money and big rewards. But the rewards don’t need to be big or costly,” she says.
Maughan-Brown, who is also an expert in behavioural economics and the behavioural determinants of HIV risk, says that for an incentivised preventive programme to be successful, there needs to be a comprehensive understanding of the various “hassle factors” faced by those who rely on the public health sector. What would be valuable to people? Transport, airtime, grocery vouchers, child care, paid leave from work or something else? He says a lot of work would need to be done to understand what rewards will work and there needs to be a level of flexibility because different people will need or value different incentives.
Pascoe, in turn, suggests that a lottery incentive could be added and would be inexpensive to augment an immediate but smaller reward that would be received directly after the health check or screening intervention, for example.
She adds that another difficulty when it comes to advocating for this kind of programme is that tangible benefits or outcomes will only be seen in the long term, while government is more receptive to programmes or policies with clear and quick results.
Venter has similar concerns. He says there is a perception that these programmes are expensive to implement and run. “But that is only part of the issue,” he says, “I find it bizarre that I get incentivised left, right, and centre by Discovery, yet every time we raise it for poor people, I get told ‘they should be doing it, anyway’. It makes no sense.” As it stands, Venter says that problematic and pervasive perceptions need to be addressed before any incentive-based programme will even likely be considered by policy-makers and government officials, and even international funders, civil society, and the media for that matter.
‘Already incentivised’
National Department of Health Spokesperson, Foster Mohale, told Spotlight that his department “is not against incentivisation but each preventive programme has its own issues and each community of health system user has different incentives for staying well”. He agrees that the “public health benefits of health checks and health screening” have the potential to “result in early detection and reduced costs to the health system”.
However, he says that these services are already incentivised and that considering interventions inspired by Vitality is “inappropriate”. Asked about the nature of the current public sector incentives, he said, “[It] depends on what one sees as an incentive! For me, a gym membership, Fitbit, express check-in queue or cheap flights are of no value and I regard them as an insult. For others, they rush to ‘benefit’. For the majority of South Africans, a visit from the [community health worker] is the incentive!”
Mohale argues that, by definition, incentive “means inducement, motivation, motive, reason, encouragement” and that, “in the true spirit of incentives”, “testing and screening services are incentivised through health promotion in ALL public health clinics, and in school health programmes”.
He says that “the massive programme for HIV testing [is] incentivised through free testing [and] specific clinics”. He adds that the department offers another incentivised programme in the form of adherence clubs, where groups of about 30 people who are on chronic medication meet regularly, share their experiences with each other and receive some screening and counselling from healthcare workers.
NOTE:Professor Francois Venter is quoted in this article. Venter is a member of Spotlight’s Editorial Advisory Panel. The panel provides the Spotlight editors with advice and feedback on the quality and relevance of Spotlight’s public interest health journalism. The Spotlight editors, however, remain editorially independent and solely responsible for all editorial decisions. Read more on the role and purpose of the panel here.
Researchers have identified brain injuries that may underlie hidden consciousness, a puzzling phenomenon in which brain-injured patients are unable to respond to simple commands, making them appear unconscious despite having some level of awareness.
“Our study suggests that patients with hidden consciousness can hear and comprehend verbal commands, but they cannot carry out those commands because of injuries in brain circuits that relay instructions from the brain to the muscles,” says study leader Jan Claassen, MD, associate professor of neurology at Columbia University.
The findings, published in the journal Brain, could help physicians more quickly identify brain-injured patients who might have hidden consciousness and better predict which patients are likely to recover with rehabilitation.
Brain circuits disrupted in patients with hidden consciousness
Hidden consciousness, also known as cognitive motor dissociation (CMD), occurs in 15–25% of patients with brain injuries stemming from head trauma, brain haemorrhage, or cardiac arrest.
In previous research, Claassen and colleagues found that subtle brainwaves detectable with EEG are the strongest predictor of hidden consciousness and eventual recovery for unresponsive brain-injured patients.
But the precise pathways in the brain that become disrupted in this condition were unknown.
In the new study, the researchers used EEG to examine 107 brain injury patients. The technique can determine when patients are trying, though unable, to respond to a command such as “keep opening and closing your right hand.”
The analysis detected CMD in 21 of the patients. The researchers then analysed structural MRI scans from all of the patients.
“Using a technique we developed called bi-clustering analysis, we were able to identify patterns of brain injury that are shared among patients with CMD and contrast to those without CMD,” says co-lead author Qi Shen, PhD, associate research scientist in the Claassen lab.
The researchers found that all of the CMD patients had intact brain structures related to arousal and command comprehension, supporting the notion that these patients were hearing and understanding the commands but were unable to carry them out.
“We saw that all of the CMD patients had deficits in brain regions responsible for integrating comprehended motor commands with motor output, preventing CMD patients from acting on verbal commands,” says Claassen.
The findings may allow researchers to better understand which brain injury patients have CMD, which will be useful for clinical trials that support recovery of consciousness.
More research is required before these approaches can be applied to clinical practice. “However, our study shows that it may be possible to screen for hidden consciousness using widely available structural brain imaging, moving the detection of CMD one step closer to general clinical use,” Claassen says.
“Not every critical care unit may have resources and staff that is trained in using EEG to detect hidden consciousness, so MRI may offer a simple way to identify patients who require further screening and diagnosis.”
