New research published in the journal iSCIENCE has revealed new insights into early sensorimotor features and cognitive abilities of toddlers who are later diagnosed with Autism Spectrum Disorder (ASD). The research, led by Kristina Denisova, a professor of Psychology and Neuroscience at the CUNY Graduate Center and Queens College, takes an important step toward better understanding ASD so that more precise, individually tailored interventions can be developed.
ASD, typically diagnosed around the ages of 4 to 5 years, is a neurodevelopmental disorder with complex and varied presentations, including atypical communication and restrictive and repetitive patterns of behaviour. Moreover, cognitive abilities are often lower in individuals with ASD. Despite the established link between lower intelligence quotient (IQ) in infancy and a future diagnosis of ASD, not all children with ASD exhibit lower cognitive abilities during infancy. The study addresses the critical gap in knowledge regarding the early features that differentiate children with varying cognitive abilities who later develop ASD.
The research team investigated the relationship between movement and cognitive abilities in toddlers before their ASD diagnosis, both during sleep and wakefulness. The study posed two key questions: Do ASD children with lower IQ exhibit altered movement during sleep compared to children with higher IQ? Additionally, are lower motor skills during wakefulness characteristic of lower-IQ children with ASD compared to those of higher-IQ ASD toddlers?
The research was conducted in two stages. In the first sample, the team examined sensorimotor features obtained from sleep functional magnetic resonance imaging (fMRI) in 111 toddlers with ASD. In the second, independent sample, they analysed sensorimotor functioning during wakefulness in over 1000 toddlers with ASD, categorised by lower vs higher cognitive abilities.
The findings revealed that toddlers with ASD and lower IQs have significantly altered sensorimotor features compared to toddlers with ASD and higher IQs. Interestingly, the sensorimotor features of higher-IQ ASD toddlers were nearly indistinguishable from typically developing (TD) toddlers. This suggests that a higher IQ may confer resilience to atypical sensorimotor functioning, and conversely, that poor sensorimotor functioning may be a key marker for lower IQ in childhood autism.
Moreover, the study found that lower-IQ ASD toddlers consistently exhibited lower gross motor skills across various age milestones (6, 12, 18, 24, and 30 months). This disruption in early sensorimotor learning during critical developmental periods indicates a potential vulnerability in the brain’s motor control circuitry, associated with lower cognitive abilities in toddlers who later receive an ASD diagnosis.
“The implications of these findings are far-reaching,” said Denisova. “They underscore the need for more precise, tailored interventions for children with ASD, particularly those with lower cognitive abilities. Interventions for lower-IQ autistic children may need to focus on enhancing both sensorimotor and cognitive skills, while interventions for higher-IQ autistic children might prioritise leveraging their strengths to mitigate potential mental health consequences.”
Denisova emphasised the importance of future research in this area, particularly involving underserved families who face barriers in accessing early intervention services.
When the NKp46 receptor of the ILCs is blocked (right), the lupus nephritis recedes. Blue: cell nuclei. Credit: Charité | Frauke Schreiber
A Berlin-led research team has uncovered critical regulators of severe kidney damage in patients with the autoimmune disorder lupus. A small, specialised population of immune cells – called innate lymphoid cells (ILCs) – trigger an avalanche of effects that cause harmful kidney inflammation, also known as lupus nephritis.
The research, published this week in Nature, upends conventional wisdom that autoantibodies are primarily responsible for lupus nephritis.
“While autoantibodies are required for tissue damage, they are by themselves not sufficient. Our work reveals that ILCs are required to amplify the organ damage,” says Dr Masatoshi Kanda, a senior paper author who was a Humboldt Fellow at Max Delbrück Center and is now at the Department of Rheumatology and Clinical Immunology, Sapporo Medical University in Japan.
Lupus, or systemic lupus erythematosus, is most often diagnosed between the ages of 15 and 45. Symptoms can range from mild to severe. But what causes kidney damage in some patients – some to the point of requiring dialysis – has been unclear.
“The role of ILCs in lupus or lupus nephritis was entirely unknown,” says Professor Antigoni Triantafyllopoulou, a senior paper author at the German Rheumatology Research Center (DRFZ), an institute of the Leibniz Association, and at the Department of Rheumatology and Clinical Immunology at Charité – Universitätsmedizin Berlin. “We have now identified most of the circuit controlled by ILCs by looking at the whole kidney at single-cell resolution.”
Unusual immune cells
ILCs are a small group of immune cells that – unlike most other immune cells that circulate throughout the body – live in a specific tissue or organ.
“They are in the tissue all the time, from the time of embryonic development, which makes them very different from other immune cells,” says Professor Andreas Diefenbach, a senior paper author and director of the Institute of Microbiology, Infectious Diseases and Immunology at Charité – Universitätsmedizin Berlin.
Diefenbach’s lab was among those that discovered ILCs in the mid-2000s. Most of his research is focused on ILCs in the gut and how they modify tissue function. In this study, Triantafyllopoulou and Kanda teamed up with his group and Dr Mir-Farzin Mashreghi at the DRFZ to find out whether ILCs were present in the kidney and what role they might play in lupus nephritis.
The whole single-cell picture
To unravel this mystery, the team turned to single-cell RNA sequencing, which identifies genes that are active, or “switched on,” in individual cells and helps researchers understand the cell’s identity and function.
Kanda, a rheumatologist who was studying bioinformatics in Professor Norbert Hübner’s lab at the Max Delbrück Center at the time, developed a specialized protocol for single-cell RNA sequencing of mouse and human kidneys. “Masatoshi’s protocol was very good at pulling out and preserving multiple types of kidney cells, which gave us a much more complete overview of how lupus affects the whole kidney,” explains Triantafyllopoulou. The team sequenced nearly 100 000 individual kidney and immune cells of various types and functions.
The key receptor
Through experiments in mice, the team learned that a subgroup of ILCs with a receptor called NKp46 must be present and activated to cause lupus nephritis. When NKp46 is activated, this subgroup of cells ramped up production of a protein called GM-CSF, which stimulates invading macrophages to multiply. In the kidney, a flood of incoming macrophages caused severe tissue damage and fibrosis.
“These ILCs are really amplifiers in this system,” Diefenbach says. “They are small in population, but they seem to fertilise the whole process.”
When the team blocked NKp46 with antibodies or the receptor was genetically removed, kidney tissue damage was minimal. They also blocked GM-CSF with similar anti-inflammatory effects.
“Critically, autoantibody levels did not change when NKp46 was inhibited, but kidney tissue damage was reduced, which shows autoantibodies are not directly responsible for kidney inflammation,” Triantafyllopoulou explains.
The team also compared the results to sequencing data from tissue taken from human patients with lupus and found ILCs present, though more work is required to fully understand how to target ILCs in human kidneys. Nevertheless, the insights gained through these detailed studies point to new antibody therapies for patients with severe forms of lupus. The hope is to prevent the need for kidney dialysis in these patients.
Cheri Nel launched a court case against Vertex to force them to allow their generic cystic fibrosis drug to be imported into South Africa. Credit: Spotlight
By Catherine Tomlinson
Last year a South African woman took a multibillion-dollar United States pharmaceutical company to court with the aim of securing access to life-changing cystic fibrosis medicines. That case has now been dropped following a reduction in the price charged for the medicines in South Africa.
Cheri Nel, a Johannesburg-based investment banker, has dropped a potentially landmark court case against Vertex Pharmaceuticals. Nel was asking the Gauteng Division of the High Court in Pretoria to grant a compulsory licence to allow generic versions of a cystic fibrosis medicine called Trikafta to be imported into South Africa. No such compulsory licences on medicines have ever been granted in South Africa.
Trikafta, which was registered in the United States in 2019, has been hailed as a “miracle” treatment for cystic fibrosis, which causes severe damage to the lungs, digestive system and other organs in the body. The medicine is effective in treating around 90 percent of people living with the condition. It significantly improves the quality of life of people living with cystic fibrosis, eliminating many of its debilitating symptoms, while also slowing the disease’s progression and extending survival.
In February 2023, when Nel launched her lawsuit against the Boston-headquartered pharmaceutical company, the only way people in South Africa could access Trikafta was by travelling to Argentina to buy it from an Argentinian company selling a generic version of the medicine.
This is because Vertex, the company that holds the patents on Trikafta in South Africa, refused to register the medicine with the South African Health Products Regulatory Authority (SAHPRA) or identify a local distributor that could import unregistered Trikafta via Section 21 authorisations – a mechanism allowing importation of unregistered medicines.
The United States list price for Trikafta is currently over $300 000 (around R5.5 million at the current rand/dollar exchange rate) per person per year, which South Africans feared they would also have to pay if or when Vertex finally started supplying its medicine in the country. Researchers in the United Kingdom have estimated that Trikafta can be produced for under $6000 (around R110 000 at the current rand/dollar exchange rate) per person per year.
When Nel filed the case, generic Trikafta from Argentina – called Trixacar – was much cheaper than Vertex’s product (but still prohibitively expensive for many) at around $60 000, or almost R1 million per person per year. But the Argentinian company selling generic Trixacar faced potential patent infringement challenges if it shipped Trixacar to South Africa. Thus, the only way to get the medicine into South Africa at the time was to travel to Argentina to collect it. People living with cystic fibrosis in South Africa learnt how to do this through an informal network or Buyers Club of people around the world that were reliant on the Argentinian product.
Launching a legal case
Nel argued that Vertex was abusing its patents in South Africa by refusing to make Trikafta available in the country on reasonable terms, while also blocking other manufacturers from supplying the medicine in the country. If successful, Nel’s case would have allowed generic Trikafta to be shipped directly to South Africa, removing the need for travel to Argentina to access the medicine.
According to Nel, Vertex argued in the company’s answering documents to her legal filing that, as she was the only named applicant in the case, a compulsory licence for importation could only be considered for her.
Nel then worked with the South African Cystic Fibrosis Association (SACFA) to get other people living with cystic fibrosis admitted as co-applicants in the case. This process of seeking more people to join her case, she said, was time-consuming, difficult, and expensive, but more than 100 people were working towards being admitted as co-applicants before the case was dropped.
Under pressure, Vertex starts providing Trikafta in South Africa
As the case gained momentum and made headlines around the world, Vertex finally opened the door to allow some people living in South Africa to access their product.
In May 2024, Vertex identified Equity Pharmaceuticals as the local company through which Trikafta could be imported into South Africa via Section 21 authorisations. These authorisations are granted by SAHPRA to enable importation of an unregistered medicine and are meant to be used in exceptional circumstances to remedy the need for an unregistered medicine, such as when there is a shortage of the registered product.
While Vertex has not confirmed to Spotlight or stated publicly the price of Trikafta for people living in South Africa, Nel and Doctors Without Borders’ Candice Sehoma told us that the company is charging around R400 000 ($22 000) for a year’s supply of the medicine.
While still unaffordable for many and much higher than the estimated cost of manufacturing, the R400 000 price is drastically lower than the R5.5 million price charged in the United States and originally feared for South Africa.
It seems improbable that Vertex would have offered the much reduced price to people living in South Africa had Nel not launched the court case
Some medical schemes now paying for Trikafta
As emerged in April this year, Vertex reached an agreement with some medical schemes in South Africa to provide the medicine for people on top-end plans.
“Four private healthcare providers are currently funding Trikafta for eligible patients and we are open for conversations with more insurance companies,” Vertex’s spokesperson Daria Munsel confirmed to Spotlight.
The exact nature of the conversations and/or agreements between Vertex and medical schemes in South Africa however remains somewhat unclear.
Discovery Health‘s CEO, Dr Ron Whelan, told Spotlight it has engaged Vertex about the “benefits available” and “affordable access” of the class of medications that Trikafta falls in but there is “no specific commercial agreement in place” in South Africa.
He noted that Discovery Health Medical Scheme members on the comprehensive and executive plans have a suite of benefits available for the treatment of cystic fibrosis with medicines like Trikafta “of up to R400 000 per annum” for eligible people.
According to Vertex, uptake of its product has been swift and is already starting to make a difference in the lives of people living with cystic fibrosis in South Africa. “Over 100 South Africans with CF [cystic fibrosis] have been prescribed our triple combination treatment in just the first two months of the medicine being available,” said Munsel.
The cystic fibrosis registry, an initiative which seeks to identify and collect data on the outcomes of people living with cystic fibrosis in South Africa, identified 525 people living with cystic fibrosis in the country as of December 2020. Experts believe there are many more undiagnosed cases.
Why did Nel drop the case?
Not only is Vertex’s price for people in South Africa now lower than the 2023 price of Argentinian generics, but the cost of a year’s supply of generic Trikafta from Argentina have increased from around $60 000 to around $100 000 due to hyperinflation in that country.
With Vertex now offering a price lower than the cost of Argentinian generics, Nel decided that her legal case was no longer the best avenue to enhance access to the medicine. The aim of the case “was to get access to the medication… to put pills in patients’ mouths”, she told Spotlight.
Nel said it is now probably better to redirect efforts to getting government at national or provincial levels to buy the medicine for patients in the public sector.
“There is a lot of work still to be done… my efforts are still there, it’s just being redirected,” she said.
“The fact that Trikafta will now be available in South Africa at a much lower price compared to generic versions globally, certainly undercuts the legal case for a compulsory license,” said Tendai Mafuma of SECTION27, a public interest law centre. The Treatment Action Campaign and Doctors Without Borders, represented by SECTION27, were admitted as friends of the court in the case.
Why won’t Vertex register its product in SA?
While much has changed because of Nel’s legal action, Vertex has held fast on its refusal to register Trikafta with SAHPRA.
When asked about Vertex’s plans to register Trikafta in South Africa, Munsel said: “We strongly believe that this [Section 21 Authorisation] is the fastest and most efficient route to sustainable access in South Africa, which does not require a regulatory filing.”
While registering medicines can be onerous and time consuming, it is a routine practice required for pharmaceutical companies to operate around the world. Full registration also typically requires that safety, effectiveness and quality is more closely scrutinised than is the case with Section 21 authorisations.
Nel believes that Vertex has chosen not to register Trikafta in South Africa because of the price transparency requirements embedded in South African law. If other countries know what price South Africa is paying then they may also demand a lower price, she said.
The law requires that there is a transparent pricing system for medicines sold in the private sector, but these requirements do not extend to unregistered medicines imported through Section 21 authorisations, explained Mafuma.
Note: SECTION27 was involved in the court case that is the subject of this article. Spotlight is published by SECTION27, but is editorially independent – and independence that the editors guard jealously. Spotlight is a member of the South African Press Council.
The lines on this diagram of the brain represent connections between various areas of the cerebral cortex involved in language processing. When we read, the neurons in these areas fire in precise synchronicity, a phenomenon known as “co-rippling.” Photo credit: UC San Diego Health Sciences
Researchers at University of California San Diego School of Medicine have brought us closer to solving how the brain processes information from specialised areas into a whole. By delving into the brain with intracranial electroencephalography, they observed how neurons synchronise across the human brain while reading. The findings are published in Nature Human Behaviour and are also the basis of a thesis by UC San Diego School of Medicine doctoral candidate Jacob Garrett.
“How the activity of the brain relates to the subjective experience of consciousness is one of the fundamental unanswered questions in modern neuroscience,” said study senior author Eric Halgren, Ph.D., professor in the Departments of Neurosciences and Radiology at UC San Diego School of Medicine. “If you think about what happens when you read text, something in the brain has to turn that series of lines into a word and then associate it with an idea or an object. Our findings support the theory that this is accomplished by many different areas of the brain activating in sync.”
This synchronisation of different brain areas, called “co-rippling” is thought to be essential for binding different pieces of information together to form a coherent whole. In rodents, co-rippling has been observed in the hippocampus, the part of the brain that encodes memories. In humans, Halgren and his colleagues previously observed that co-rippling also occurs across the entire cerebral cortex.
To examine co-rippling at the mechanistic level, Ilya Verzhbinsky, an MD/PhD candidate completing his research in Halgren’s lab, led a study published in PNAS that looked at what happens to single neurons firing in different cortical areas during ripples. The present study looks at the phenomenon with a wider lens, asking how the many billions of neurons in the cortex are able to coordinate this firing to process information.
“There are 16 billion neurons in the cortex – double the number of people on Earth,” said Halgren. “In the same way a large chorus needs to be organised to sound as a single entity, our brain neurons need to be coordinated to produce a single thought or action. Co-rippling is like neurons singing on pitch and in rhythm, allowing us to integrate information and make sense of the world. Unless they’re co-rippling, these neurons have virtually no effect on the other, but once ripples are present about two thirds of neuron pairs in the cortex become synchronised. We were surprised by how powerful the effect was.”
Co-rippling in the cortex has been difficult to observe in humans due to limitations of noninvasive brain scanning. To work around this problem, the researchers used an approach called intracranial electroencephalography (EEG) scanning, which measures the electrical activity of the brain from inside the skull. The team studied a group of 13 patients with drug-resistant epilepsy who were already undergoing EEG monitoring as part of their care.
Participants were shown a series of animal names interspersed with strings of random consonants or nonsense fonts and then asked to press a button to indicate the animal whose name they saw. The researchers observed three stages of cognition during these tests: an initial hierarchical phase in visual areas of the cortex in which the participant could see the word without conscious understanding of it; a second stage in which this information was “seeded” with co-ripples into other areas of the cortex involved in more complex cognitive functions; and a final phase, again with co-ripples, where the information across the cortex is integrated into conscious knowledge and a behavioural response – pressing the button.
The researchers found that throughout the exercise, co-rippling (~100ms-long ~90Hz oscillations) occurred between the various parts of the brain engaged in these cognitive stages, but the rippling was stronger when the participants were reading real words.
The study’s findings have potential long-term implications for the treatment of neurological and psychiatric disorders, such as schizophrenia, which are characterised by disruptions in these information integration processes.
“It will be easier to find ways to reintegrate the mind in people with these disorders if we can better understand how minds are integrated in typical, healthy cases,” added Halgren.
More broadly, the study’s findings have significant implications for our understanding of the link between brain function and human experience.
“This is a fundamental question of human existence and gets at the heart of the relationship between mind and brain,” said Halgren. “By understanding how our brain’s neurons work together, we can gain new insights into the nature of consciousness itself.”
Further action needed, according to a University of Bonn study on child and adolescent nutrition
Photo by Patrick Fore on Unsplash
University of Bonn researchers have analysed data on sugar intake among children and adolescents in a long-term study, finding that intake has been declining steadily since 2010 – but is still above the level recommended by the World Health Organization (WHO). The results, to be published in the European Journal of Nutrition, are already available online.
“Our study concerns the intake of free sugars,” explains Dr Ines Perrar, who is a research associate at the University of Bonn Institute of Nutritional and Food Science (IEL) and lead author of the study. “There is debate on whether sugar, like salt and fats, is linked to the development of chronic diseases.” The WHO defines “free” sugar as any form of sugar, including honey, syrup and fruit juice concentrates, added by a manufacturer or when preparing food and beverages at home. Free sugar also includes sugar naturally occurring in juices.
For their project, IEL researchers analysed data from the “Dortmund Nutritional and Anthropometric Longitudinally Designed” cohort study (DONALD). The DONALD study has been ongoing since 1985, gathering detailed data on nutrition, metabolism, growth and health of children and adolescents. “Study participants weigh and document everything they eat and drink on three consecutive days every year,” relates Dr Ute Nöthlings, Professor of Nutritional Epidemiology at the IEL. “Referring to our Institute’s in-house nutrient database, we are able to estimate intake of certain nutrients, including free sugars.”
Sugar intake too high among adolescents in particular
The authors evaluated 4218 sets of three-day weighing dietary records by 751 children and adolescents between ages three and 18 in the years 2010–2023. “Our finding is that free sugar intake continues to decline,” Dr Perrar notes, “but average daily intake still exceeds the level recommended by the WHO and the German Nutrition Society (Deutsche Gesellschaft für Ernährung, DGE) of a maximum 10% of total daily energy intake.”
An analysis of DONALD back in 2019 already indicated that free sugar intake has been declining since 2005, then in 2016 a median value of approximately 16% of daily energy intake was determined. That value has subsequently declined further to 11.7%. The researchers surmise this trend may be explained by increased awareness of the health consequences of excessive consumption of sugar-sweetened beverages and certain other sugary foods.
While the decline definitely represents good progress, there are noteworthy age group differences, as Professor Nöthlings points out, who is director of the DONALD study, spokesperson for the Transdisciplinary Research Area (TRA) Sustainable Futures and a member of the Life and Health TRA at the University of Bonn: “During the observation period, we saw a relatively high intake of free sugars around 15 percent of the daily energy intake in some cases, particularly among adolescents aged six to 14. The intake then declines significantly with increasing age.”
Actual sugar intake likely higher
The researchers point out that the actual sugar intake is likely higher than the study data suggests, due in part to potential under-reporting by the study participants self-reporting on what they eat. In addition, the study is not broadly representative of society, as the design of this large study favours participation by families of a rather higher socioeconomic status who are generally more aware regarding nutrition and health issues.
