McKelvey School of Engineering researchers have developed a noninvasive technology combining a holographic acoustic device with genetic engineering that allows them to precisely target affected neurons in the brain, creating the potential to precisely modulate selected cell types in multiple diseased brain regions. (Credit: Yaoheng Yang)
Brain diseases such as Parkinson’s disease involve damage in more than one region of the brain, requiring technology that could precisely and flexibly address all affected regions simultaneously. Researchers have developed a noninvasive technology combining a holographic acoustic device with genetic engineering that allows them to precisely target affected neurons in the brain. This has the potential to precisely modulate selected cell types in multiple diseased brain regions.
Hong Chen, associate professor of biomedical engineering and neurosurgery at Washington University in St. Louis and her team created AhSonogenetics, or Airy-beam holographic sonogenetics, a technique that uses a noninvasive wearable ultrasound device to alter genetically selected neurons in the brains of mice. Results of the proof-of-concept study were published in Proceedings of the National Academy of Sciences.
AhSonogenetics brings together several of Chen’s group’s recent advances into one technology. In 2021, she and her team launched Sonogenetics, a method that uses focused ultrasound to deliver a viral construct containing ultrasound-sensitive ion channels to genetically selected neurons in the brain. They use low-intensity focused ultrasound to deliver a small burst of warmth, which opens the ion channels and activates the neurons. Chen’s team was the first to show that sonogenetics could modulate the behaviour of freely moving mice.
In 2022, she and members of her lab designed and 3D-printed a flexible and versatile tool known as an Airy beam-enabled binary acoustic metasurface that allowed them to manipulate ultrasound beams. She also is developing Sonogenetics 2.0, which combines the advantage of ultrasound and genetic engineering to modulate defined neurons noninvasively and precisely in the brains of humans and animals. AhSonogenetics brings them together as a potential method to intervene in neurodegenerative diseases.
“By enabling precise and flexible cell-type-specific neuromodulation without invasive procedures, AhSonogenetics provides a powerful tool for investigating intact neural circuits and offers promising interventions for neurological disorders,” Chen said.
Sonogenetics gives researchers a way to precisely control the brains, while airy-beam technology allows researchers to bend or steer the sound waves to generate arbitrary beam patterns inside the brain with a high spatial resolution. Yaoheng (Mack) Yang, a postdoctoral research associate who earned a doctorate in biomedical engineering from McKelvey Engineering in 2022, said the technology gives the researchers three unique advantages.
“Airy beam is the technology that can give us precise targeting of a smaller region than conventional technology, the flexibility to steer to the targeted brain regions, and to target multiple brain regions simultaneously,” Yang said.
Chen and her team, including first authors Zhongtao Hu, a former postdoctoral research associate, and Yang, designed each Airy-beam metasurface individually as the foundation for wearable ultrasound devices that were tailored for different applications and for precise locations in the brain.
Chen’s team tested the technique on a mouse model of Parkinson’s disease. With AhSonogenetics, they were able to stimulate two brain regions simultaneously in a single mouse, eliminating the need for multiple implants or interventions. This stimulation alleviated Parkinson’s-related motor deficits in the mouse model, including slow movements, difficulty walking and freezing behaviours.
The team’s Airy-beam device overcomes some of the limits of sonogenetics, including tailoring the design of the device to target specific brain locations, as well as incorporating the flexibility to adjust target locations in a single brain.
Hu said the device, which costs roughly $50 to make, can be tailored in size to fit various brain sizes, expanding its potential applications.
“This technology can be used as a research platform to speed neuroscience research because of the capability to flexibly target different brain regions,” Hu said. “The affordability and ease of fabrication lower the barriers to the widespread adoption of our proposed devices by the research community for neuromodulation applications.”
Thinking about getting a new desk for your practice? That might be a good idea. Viruses, including SARS-CoV-2, can get passed from person to person via contaminated surfaces. But can some surfaces reduce the risk of this type of transmission without the help of household disinfectants? As reported in ACS Applied Materials & Interfaces, wood has natural antiviral properties that can reduce the time viruses persist on its surface – and some species of wood are more effective than others at reducing infectivity.
Enveloped viruses, like the coronavirus, can live up to five days on surfaces; nonenveloped viruses, including enteroviruses linked to the common cold, can live for weeks, in some cases even if the surfaces are disinfected. Previous studies have shown that wood has antibacterial and antifungal properties, making it an ideal material for cutting boards. But wood’s ability to inactivate viruses has yet to be explored, which is what Varpu Marjomäki and colleagues set out to study.
The researchers looked at how long enveloped and nonenveloped viruses remained infectious on the surface of six types of wood: Scots pine, silver birch, gray alder, eucalyptus, pedunculate oak and Norway spruce. To determine viral activity, they flushed a wood sample’s surface with a liquid solution at different time points and then placed that solution in a petri dish that contained cultured cells. After incubating the cells with the solution, they measured the number (if any) infected with the virus.
Results from their demonstrations with an enveloped coronavirus showed that pine, spruce, birch and alder need one hour to completely reduce the virus’ ability to infect cells, with eucalyptus and oak needing two hours. Pine had the fastest onset of antiviral activity, beginning after five minutes. Spruce came in second, showing a sharp drop in infectivity after 10 minutes.
For a nonenveloped enterovirus, the researchers found that incubation on oak and spruce surfaces resulted in a loss of infectivity within about an hour, with oak having an onset time of 7.5 minutes and spruce after 60 minutes. Pine, birch and eucalyptus reduced the virus’ infectivity after four hours, and alder showed no antiviral effect.
Based on their study data, the researchers concluded that the chemical composition of a wood’s surface is primarily responsible for its antiviral functionality. While determining the exact chemical mechanisms responsible for viral inactivation will require further study, they say these findings point to wood as a promising potential candidate for sustainable, natural antiviral materials.
The over-the-counter supplement nicotinamide riboside, a form of vitamin B3, increased the walking endurance of patients with peripheral artery disease, a chronic leg condition for which there are few effective treatments.
In a preliminary, randomised, double-blind clinical trial led by Northwestern University and University of Florida scientists, patients who took nicotinamide riboside daily for six months increased their timed walking distance by more than 17.3m, compared to a placebo group. As expected, walking speed declined in the placebo group, because peripheral artery disease causes progressive declines in walking performance.
“This is a signal that nicotinamide riboside could help these patients,” said Christiaan Leeuwenburgh, PhD, a UF professor of physiology and aging and senior author of the clinical trial report. “We are hoping to conduct a larger follow-up trial to verify our findings.”
Along with other researchers, Leeuwenburgh, whose research specialises in anti-aging treatments, collaborated with Mary M. McDermott, MD, a physician and professor of medicine at Northwestern University and an expert in peripheral artery disease.
The scientists recruited 90 people with an average age of 71 who had peripheral artery disease, or PAD, to test the effects of nicotinamide riboside. The supplement is increasingly popular as an anti-aging treatment (sales exceeded $60 million in 2022 in the US alone) but there has been scant evidence of any benefit in healthy people. Nicotinamide riboside is a precursor for the essential compound NAD, which plays roles in the body related to energy generation, improved blood flow and DNA repair.
Because PAD is associated with problems generating energy within muscle cells, McDermott and Leeuwenburgh thought that nicotinamide riboside, by improving energy generation, could help improve walking in people with the disease.
And indeed that’s what they found. Participants taking the supplement walked an average of 7m more in a six-minute walking test after six months, while those taking a placebo walked 10.3m less. Those who took at least 75% of the pills they were supposed to take performed even better, adding more than 30m to their walking distance, compared to people who took a placebo.
(The researchers also tested if resveratrol, a compound best known for being in red wine, could boost the effects of nicotinamide riboside; they found no additional benefits.)
PAD affects more than 8.5 million Americans over the age of 40. Caused by the buildup of fatty deposits in arteries, and associated with diabetes and smoking, the disease reduces blood flow to the limbs, especially the legs. Walking often becomes painful, and the disease typically causes declines in walking ability over time. Supervised walking exercise is first line therapy for PAD, but most people with the condition do not have access to supervised exercise.
In addition to a larger trial focused on patients suffering from PAD, Leeuwenburgh hopes to test the effects of nicotinamide riboside on walking performance in healthy older adults.
“We need to test it on a healthy older population before we recommend healthy people take it,” he said.
Coffee drinking is a heritable habit, and one that carries a certain amount of genetic baggage. Caffeinated coffee is a psychoactive substance, notes Sandra Sanchez-Roige, PhD, an associate professor at University of California San Diego. She is the corresponding author of a study published in the journal Neuropsychopharmacology that compared coffee-consumption characteristics from a 23andMe database in the United States with the UK Biobank.
Lead author Hayley H. A. Thorpe, PhD, at Western University in Ontario, explained that the team collected genetic data as well as self-reported coffee-consumption numbers to assemble a genome-wide association study (GWAS). The idea was to make connections between the genes that were known to be associated with coffee consumption and the traits or conditions related to health.
“We used this data to identify regions on the genome associated with whether somebody is more or less likely to consume coffee,” Thorpe explained. “And then identify the genes and biology that could underlie coffee intake.”
UC San Diego professor Abraham Palmer, PhD is also a lead researcher on the paper. He said that most people are surprised that there is a genetic influence on coffee consumption. “We had good reason to suspect from earlier papers that there were genes that influence how much coffee someone consumes,” he said. “And so, we weren’t surprised to find that in both of the cohorts we examined there was statistical evidence that this is a heritable trait. In other words, the particular gene variants that you inherit from your parents influence how much coffee you’re likely to consume.”
Sanchez-Roige said the genetic influence on coffee consumption was the first of two questions the researchers wanted to address.
“The second is something that coffee lovers are really keen on learning,” Sanchez-Roige said. “Is drinking coffee good or bad? Is it associated with positive health outcomes or not?”
The answer is not definitive. The group’s genome-wide association study of 130 153 U.S.-based 23andMe research participants was compared with a similar UK Biobank database of 334 649 Britons, revealing consistent positive genetic associations between coffee and harmful health outcomes such as obesity and substance use. A positive genetic association is a connection between a specific gene variant (the genotype) and a specific condition (the phenotype). Conversely, a negative genetic association is an apparent protective quality discouraging the development of a condition. The findings get more complicated when it comes to psychiatric conditions.
“Look at the genetics of anxiety, for instance, or bipolar and depression: In the 23andMe data set, they tend to be positively genetically correlated with coffee intake genetics,” Thorpe said. “But then, in the UK Biobank, you see the opposite pattern, where they’re negatively genetically correlated. This is not what we expected.”
She said there were other instances in which the 23andMe set didn’t align with the UK Biobank, but the greatest disagreement was in psychiatric conditions.
“It’s common to combine similar datasets in this field to increase study power. This information paints a fairly clear picture that combining these two datasets was really not a wise idea. And we didn’t end up doing that,” Thorpe said. She explained that melding the databases might mask effects, leading researchers toward incorrect conclusions – or even cancelling each other out.
Sanchez-Roige says the researchers have some ideas about how the differences in results arose. To begin with, there was an apples-and-oranges aspect to the surveys. For instance, the 23andMe survey asked, “How many 5-ounce (cup-sized) servings of caffeinated coffee do you consume each day?” Compare it to the UK Biobank’s “How many cups of coffee do you drink each day? (Include decaffeinated coffee)”
Beyond serving size and the caffeinated/decaf divide, the surveys made no accommodation for the various ways coffee is served. “We know that in the U.K., they have generally higher preference for instant coffee, whereas ground coffee is more preferred in the U.S.,” Thorpe said.
“And then there’s the frappuccinos,” Sanchez-Roige added, citing the American trend of taking coffee loaded with sugary additives. Palmer mentioned other caffeinated drinks and especially in the context of the UK Biobank, tea, none of which were included in the GWAS, which addressed only coffee. Palmer added that the GWAS demonstrates the relationship between genotype and phenotype is more different than the relationship between coffee and tea.
“Genetics influences lots of things. For instance, it influences how tall you might be,” he said. “And those kinds of things probably would play out very similarly, whether you lived in the US or the UK But coffee is a decision that people make.”
Sanchez-Roige pointed out that coffee comes in a variety of forms, from instant to frappuccino, and is consumed amid cultural norms that differ from place to place. A person with a given genotype might end up having quite a different phenotype living in the UK versus the US.
“And that’s really what the data are telling us,” she said. “Because unlike height, where your behaviour doesn’t really have much to do with it, your behaviour and the choices you’re making in your environment play out in various ways. So the interaction between genotype and environment complicates the picture.”
The collaborators stressed the need for more investigation to unravel the relationships between genetics and the environment, focusing not only on coffee/caffeine intake but also other substance-use issues.
In low- and middle-income countries, anaemia reduction efforts are often touted as a way to improve educational outcomes and reduce poverty. A new study, published in Communications Medicine, evaluates the relationship between anaemia and school attendance in India, debunking earlier research that could have misguided policy interventions.
Kumar’s research explores the intersection of global health and poverty reduction. His latest work evaluates the relationship between anaemia and school attendance in India.
The study investigated whether there was a link between anaemia and school attendance in more than 250 000 adolescents ages 15 to 18. Earlier observational studies have shown a link between anaemia and attendance, even after accounting for variables such as gender and household wealth, according to Kumar. But the new study, which applied more rigorous econometric statistical analysis, did not find such a link, he said.
“Most previous research on this topic has used conventional study designs or focused on small geographical areas, which limits its policy relevance,” said study co-author Santosh Kumar, associate professor of development and global health economics at the University of Notre Dame, is co-author of the study. “Earlier estimates may have been distorted by unobserved household factors related to both anaemia and school attendance. So in this study, we focused on the relationship between anaemia and attendance among adolescents who were living in the same household.
“Ultimately,” Kumar said, “we found that the link between anaemia and schooling is more muted than previously suggested by studies that did not consider household-level factors.”
The findings have important implications for policymakers seeking to improve education in low- and middle-income countries like India, Kumar said. India has widespread school attendance issues and struggles with health conditions such as anaemia caused by iron deficiency, particularly in children and adolescents. The country has pushed to improve educational outcomes, in keeping with the United Nations’ Sustainable Development Goals, Kumar said. But to achieve that, he said, more research is needed to pinpoint an evidence-based intervention.
The latest study builds on an earlier one in which Kumar and fellow researchers helped evaluate the results of an iron fortification school lunch program for students ages 7 and 8 in India. That study showed that fortification reduced anaemia but did not affect students’ performance in school. A forthcoming study, set to launch in summer 2024, will look at iron fortification for children ages 3 to 5. The research hypothesis is that an early-age nutritional intervention among preschoolers would make a significant impact on physical and cognitive development.
“Our findings have implications for policymakers who want to improve educational outcomes and reduce poverty,” Kumar said. “Effective policies are based on evidence. We need more rigorous statistical analysis to examine the causal relationship between anaemia and education.
“This work ties into my larger research agenda, which explores the intersection of global health and poverty reduction. I want to use my academic research to support human dignity by helping to identify evidence-based health policies that will make a tangible difference in people’s lives.”
In Parkinson’s disease, a reduction in the gut bacteria of genes responsible for synthesising the essential B vitamins B2 and B7 was found. Credit: Reiko Matsushita
A study led by Nagoya University in Japan has revealed a link between gut microbiota and Parkinson’s disease (PD). The researchers found that the gut bacteria genes responsible for synthesising vitamins B2 and B7 were reduced. This gene reduction was also linked to low levels of agents that help maintain the integrity of the intestinal barrier, which when weakened causes the inflammation seen in PD. Their findings, published in npj Parkinson’s Disease, suggest that treatment with B vitamins to address these deficiencies can be used to treat PD.
PD is characterized by a variety of physical symptoms that hinder daily activities and mobility, such as shaking, slow movement, stiffness, and balance problems. While the frequency of PD may vary between different populations, it is estimated to affect approximately 1-2% of individuals aged 55 years or older.
Various physiological processes are heavily influenced by the microorganisms found in the gut, which are collectively known as gut microbiota. In ideal conditions, gut microbiota produce SCFAs and polyamines, which maintain the intestinal barrier that prevents toxins entering the bloodstream. Toxins in the blood can be carried to the brain where they cause inflammation and affect neurotransmission processes that are critical for maintaining mental health.
To better understand the relationship between the microbial characteristics of the gut in PD, Hiroshi Nishiwaki and Jun Ueyama from the Nagoya University Graduate School of Medicine conducted a metanalysis of stool samples from patients with PD from Japan, the United States, Germany, China, and Taiwan. They used shotgun sequencing, a technique that sequences all genetic material in a sample. This is an invaluable tool because it offers researchers a better understanding of the microbial community and genetic makeup of the sample.
They observed a decrease in the bacterial genes responsible for the synthesising of riboflavin (vitamin B2) and biotin (vitamin B7) in patients diagnosed with PD. Riboflavin and biotin, derived from both food and gut microbiota, have anti-inflammatory properties, which may counteract the neuroinflammation seen in diseases like PD.
B vitamins play crucial roles in the metabolic processes that influence the production and functions of short-chain fatty acids (SCFAs) and polyamines, two agents that help maintain the integrity of the intestinal barrier, preventing toxins entering the bloodstream. An examination of fecal metabolites revealed decreases of both in patients with PD.
The findings indicate a potential explanation for the progression of PD. “Deficiencies in polyamines and SCFAs could lead to thinning of the intestinal mucus layer, increasing intestinal permeability, both of which have been observed in PD,” Nishiwaki explained. “This higher permeability exposes nerves to toxins, contributing to abnormal aggregation of alpha-synuclein, activating the immune cells in the brain, and leading to long-term inflammation.”
He added, “Supplementation therapy targeting riboflavin and biotin holds promise as a potential therapeutic avenue for alleviating PD symptoms and slowing disease progression.”
The results of the study highlight the importance of understanding the complex relationship among gut microbiota, metabolic pathways, and neurodegeneration. In the coming years, customised therapy could potentially be based on patients’ unique microbiome profiles. By altering bacterial levels in the microbiome, doctors can potentially delay the onset of symptoms associated with diseases like PD.
“We could perform gut microbiota analysis on patients or conduct faecal metabolite analysis,” Nishiwaki said. “Using these findings, we could identify individuals with specific deficiencies and administer oral riboflavin and biotin supplements to those with decreased levels, potentially creating an effective treatment.”
The study, “Meta-analysis of shotgun sequencing of gut microbiota in Parkinson’s disease,” was published in npj Parkinson’s Disease on May 21, 2024, at DOI:10.1038/s41531-024-00724-z.
A breakthrough study published in The American Journal of Pathology describes a new machine-learning model that may improve accuracy in early diagnosis of hepatocellular carcinoma and monitoring the impact of treatment.
Early diagnosis of hepatocellular carcinoma (HCC) – one of the most fatal malignancies – is crucial to improve patient survival. In this breakthrough study, investigators report on the development of a serum fusion-gene machine-learning model. This important screening tool may increase the five-year survival rate of patients with HCC from 20% to 90% because of its improved accuracy in early diagnosis of HCC and monitoring the impact of treatment.
HCC is the most common form of liver cancer and accounts for around 90% of cases. Currently, the most common screening test for the HCC biomarker, serum alpha-foetal protein, is not always accurate, and up to 60% of liver cancers are only diagnosed in advanced stages, resulting in a survival rate of only around 20%.
Lead investigator Jian-Hua Luo, MD, PhD, Department of Pathology, High Throughput Genome Center, and Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, explained: “Early diagnosis of liver cancer helps save lives. However, most liver cancers occur insidiously and without many symptoms. This makes early diagnosis challenging. What we need is a cost-effective, accurate, and convenient test to screen early-stage liver cancer in human populations. We wanted to explore if a machine-learning approach could be used to increase the accuracy of screening for HCC based on the status of the fusion genes.”
In the search for a more effective and efficient diagnostic tool to predict non-HCC and HCC cases, investigators analysed a panel of nine fusion transcripts in serum samples from 61 patients with HCC and 75 patients with non-HCC conditions using real-time quantitative reverse transcription PCR (RT-PCR). Seven of the nine fusions were frequently detected in HCC patients. The researchers generated machine-learning models based on serum fusion-gene levels to predict HCC in the training cohort, using the leave-one-out cross-validation approach.
A four fusion gene logistic regression model produced an accuracy of 83% to 91% in predicting the occurrence of HCC. When combined with serum alpha-foetal protein, the two-fusion gene plus alpha-foetal protein logistic regression model produced 95% accuracy for all the cohorts. Furthermore, quantification of fusion gene transcripts in the serum samples accurately assessed the impact of the treatment and was able to monitor for the recurrence of the cancer.
Dr. Luo commented, “The fusion gene machine-learning model significantly improves the early detection rate of HCC over the serum alpha-fetal protein alone. It may serve as an important tool in screening for HCC and in monitoring the impact of HCC treatment. This test will find patients who are likely to have HCC.”
Dr. Luo concluded, “Early treatment of liver cancer has a 90% five-year survival rate, while late treatment has only 20%. The alternative to this test is to subject every individual with some risk of liver cancer to imaging analysis every six months, which is very costly and ineffective. In addition, when imaging results are ambiguous, this test will help to differentiate malignant versus benign lesions.”
One of the biggest stories in HIV in the last year was that a class of medicines called statins could help reduce cardiovascular disease in people living with the virus. In response, treatment guidelines in the United States were quickly updated, but the picture is more complicated in South Africa. Spotlight’s Elri Voigt explores why the case for widespread use of statins by people living with HIV is less compelling in South Africa than in some other countries.
People living with HIV, provided they are stable on antiretroviral therapy, are affected by the same diseases as those who don’t have HIV, including cardiovascular disease, says Professor Mpiko Ntsekhe, head of Cardiology at Groote Schuur Hospital in Cape Town.
The key difference, he says, is that although both groups of people get the same spectrum of diseases, people living with HIV get those diseases more frequently and earlier. One way to think about this, he explains, is to imagine twins who are identical in every way except one is living with HIV. The twin living with HIV is more likely to get cardiovascular disease than the other twin.
And these differences can be substantial. Current evidence shows that people living with HIV have a twofold increased risk of developing cardiovascular disease compared to people not living with HIV, says Professor Hans Strijdom. He is the Head of the Division of Medical Physiology and Deputy Director of the Centre for Cardio-Metabolic Research in Africa (CARMA) at Stellenbosch University. The cardiovascular risk attributable to HIV, Strijdom adds, is now believed to be equivalent to that posed by traditional risk factors such as smoking. This prompted an editorial in 2018 in one of the top cardiovascular journals, Circulation, advocating for HIV to be recognised as a major cardiovascular risk factor.
He explains that people living with HIV who are stable on treatment are living longer, making them susceptible to the normal risk posed by older age. They also have “modifiable risk factors, in other words lifestyle risk factors”, like a higher smoking and alcohol use incidence, as well as increasing rates of being overweight and obesity. Strijdom says that living with HIV, even when someone is stable on treatment, causes low-grade inflammation, which over time increases a person’s risk for cardiovascular disease. “That all in combination are the current theories [of] why we think that they have a bigger risk of cardiovascular disease,” he says.
Important study findings
Arguably, the biggest news from last year’s International AIDS Society (IAS) Conference in Australia was findings from a study on heart disease in people living with HIV. The trial, called REPRIEVE, showed that a class of cholesterol-busting drugs called statins can prevent a lot of cardiovascular disease events in people living with HIV whose cardiovascular disease (CVD) risk score meets a certain threshold. Spotlight previously reported on these findings, which showed that compared to placebo, daily treatment with 4mg oral pitavastatin – a specific statin – led to a 35% reduction in major adverse cardiovascular events (MACE) in people living with HIV classified to be at risk of cardiovascular disease.
When the findings were presented at the IAS conference, the study’s principal investigator, Dr Steven Grinspoon, said that while the researchers still have to assess more of the data collected to get a clearer picture of things, like the mechanisms driving cardiovascular disease across regions and conduct additional sub-group analyses, the study has already shown that using pitavastatin can save lives.
These sub-group analyses were discussed in greater detail at the Conference on Retroviruses and Opportunistic Infections (CROI) held in Denver in March this year. For the most part, the use of pitavastatin in the manner prescribed by REPRIEVE was considered a huge success, and the United States has since changed its guidelines to include the use of statins in the primary prevention of atherosclerotic cardiovascular disease.
Why it is different in South Africa
However, for low-and-middle-income countries like South Africa, the case for pitavastatin might not be as clear-cut. In fact, a panel discussion at CROI was dedicated to exploring the implications of the REPRIEVE findings for such countries.
Ntsekhe, who was a speaker on the CROI panel, tells Spotlight that data from REPRIEVE’s sub-group analyses reveal there was a striking difference in event rates – which in the case of the study are MACE in those who were getting the placebo – by country income status. He explains that as predicted in high-income countries, the event rates were high, while in low-and-middle income countries – particularly in Sub-Saharan Africa – event rates were very low.
He says one of the reasons for the difference in event rates was that the screening tool used in REPRIEVE worked well to identify those people living with HIV who might benefit from pitavastatin in high-income countries like the United States, but it did not work well in Sub-Saharan Africa.
This means using pitavastatin as part of a primary prevention strategy is a much more effective intervention in high-income countries than in low-and-middle income countries like in Sub-Saharan Africa because the cardiovascular disease profile is so different.
Ntsekhe explains the term cardiovascular disease itself is broad and all-encompassing and there are many forms, including valve disease, heart muscle disease, and vascular disease. The dominant form of cardiovascular disease in the high-income countries (which he refers to as the Global North) is known as atherosclerotic cardiovascular disease, which is characterised by a build-up of fatty deposits and plaque in the arteries.
In Sub-Saharan Africa though, Ntsekhe says “atherosclerotic cardiovascular disease is but one of many forms of cardiovascular disease”, taking the fourth or fifth place in the ranking of types of major heart disease.
Research conducted in high-income countries don’t always take differences in disease burden into account, according to Ntsekhe. This means that interventions researched in high-income countries and shown to be effective in that context won’t necessarily work as well in low-and-middle income countries like South Africa.
Strijdom concurs that while results from REPRIEVE in the global context were a game-changer, the findings are not easily transferable to South Africa’s context because pitavastatin is mainly aimed at reducing “bad cholesterol” and coronary artery disease (also called atherosclerosis).
‘Taking money away’
During the panel discussion at CROI, Ntsekhe asked whether Sub-Saharan Africa could justify taking money away from other health programmes that work in order to invest in pitavastatin.
“I said basically what should be a priority for us is a) finding tools that can better identify those at risk and b) continuing to focus on what our local data suggests are the priority areas,” Ntsekhe says.
“If your entire prevention strategy is aimed at atherosclerotic cardiovascular disease, but it isn’t the dominant cause of disease [in your country], you’re going to be treating a whole host of people to try and tackle this thing that affects very few in a sense,” he says.
“It was not anything about REPRIEVE, it was a wonderful study, the hypothesis was tested, and it was shown to be correct, the intervention we know works,” Ntsekhe says. “It really then comes down to regional areas to think very carefully about how best they’re going to get their biggest bang for their buck,” he says. “We have to carefully consider the local context, local burden, we have set local health priorities, and weigh benefit and cost before we adopt new interventions or recommendations.”
SA’s cardiovascular disease burden
While Strijdom says we don’t have great data, he points to a large systematic review and meta-analysis published in 2018 in Circulation, which estimates that around 15% of the total cardiovascular disease burden in South Africa is attributable to HIV. “It’s probably higher than that. I would say that probably about one in five people with heart disease have heart disease because of HIV in South Africa,” he says, adding “that figure is probably only going to increase”.
Because of this, he says, there is a need for proper and clear primary healthcare guidelines specifically aimed at managing cardiovascular disease in people living with HIV, which we don’t currently have.
Strijdom says what we have at the moment since the rollout of the 2019 National ART Clinical Guidelines is very basic guidelines. This involves screening someone who has just been diagnosed with HIV by taking their blood pressure, and testing urine for glucose and proteins, and an assessment of their general cardiovascular disease risk by taking their medical and family history. These guidelines, according to Strijdom, only make provision for routine screening at baseline, but screening guidelines at follow-up visits are insufficient.
“I am, however, aware of the fact that there is progress especially from the integrated chronic disease management model which is currently being piloted in South Africa – and hopefully with that will come much more definitive and universal guidelines,” he says. “The bottom line is that South Africa, in its public health [sector] especially, really very quickly needs to come up with very clear and more comprehensive guidelines to actively manage cardiovascular disease risk in people with HIV.”
Need for annual screening
Strijdom suggest that to improve screening for cardiovascular disease risk in people living with HIV, there needs to be annual screening of people’s weight, their measure of body fat based on height and weight, waist circumference, blood pressure, cholesterol and triglyceride levels as well as testing urine samples for kidney function. There also needs to be a thorough family and medical history conducted for each patient.
“It’s not really a very expensive or very exhaustive list of stuff that you have to do. Unless of course they have specific symptoms and signs that leads you in a specific direction that you then have to perhaps do an ECG [a test used to evaluate the functioning of the heart] or cardiac imaging but that is usually determined by what you get from their history and clinical examination,” he says.
Ntsekhe says public health strategies to combat the growing burden of non-communicable diseases (NCDs), including cardiovascular disease, in South Africa must be strengthened. These include screening and prevention tools like checking a patient’s blood pressure and blood glucose, advising against smoking and alcohol as well as promoting health lifestyle choices like exercise and weight loss. These interventions should be offered to everyone, regardless of whether they are living with HIV or not, he says.
“The thing about NCDs and cardiovascular disease, for the most part, they are diseases of lifestyle and behaviour. So, when you talk prevention, it’s not always about drug prevention,” he says. “It’s more about intensification of those [interventions] that are already in the public domain, are very effective, and cost very little. Many of the public health and primary healthcare guidelines do advise local ministries, local health authorities on what should be happening.”
In terms of public education, Stritjdom says people need to be aware that there is something like high blood pressure. “If people are aware they will come to the clinic and will say please measure my blood pressure,” he says.
“Our health system is understandably focused on infectious diseases, but if we are not careful, we will then be totally unprepared to tackle the epidemic that will have replaced it. Namely, cancer, heart disease, stroke, obesity, diabetes, and it will totally overwhelm our public healthcare system,” he says.
Neurons in the brain of an Alzheimer’s patient, with plaques caused by tau proteins. Credit: NIH
A new study by investigators from Mass General Brigham suggests that whether a person inherits risk of Alzheimer’s disease from their mother or father influences risk of biological changes in the brain that lead to disease. By evaluating 4400 cognitively unimpaired adults ages 65–85, the team found those with a history of Alzheimer’s disease (AD) on either their mother’s side or both parents’ sides had increased amyloid in their brains. Their results are published in JAMA Neurology.
“Our study found if participants had a family history on their mother’s side, a higher amyloid level was observed,” said senior corresponding author Hyun-Sik Yang, MD, a neurologist at Mass General Brigham.
Yang said that previous smaller studies have investigated the role family history plays in Alzheimer’s disease. Some of those studies suggested maternal history represented a higher risk of developing Alzheimer’s, but the group wanted to revisit the question with cognitively normal participants and access to a larger clinical trial data set.
The team examined the family history of older adults from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study, a randomized clinical trial aimed at AD prevention. Participants were asked about memory loss symptom onset of their parents. Researchers also asked if their parents were ever formally diagnosed or if there was autopsy confirmation of Alzheimer’s disease.
“Some people decide not to pursue a formal diagnosis and attribute memory loss to age, so we focused on a memory loss and dementia phenotype,” Yang said.
Researchers then compared those answers and measured amyloid in participants. They found maternal history of memory impairment at all ages and paternal history of early-onset memory impairment was associated with higher amyloid levels in the asymptomatic study participants. Researchers observed that having only a paternal history of late-onset memory impairment was not associated with higher amyloid levels.
“If your father had early onset symptoms, that is associated with elevated levels in the offspring,” said Mabel Seto, PhD, first author and a postdoctoral research fellow in the Department of Neurology at the Brigham. “However, it doesn’t matter when your mother started developing symptoms – if she did at all, it’s associated with elevated amyloid.”
Seto works on other projects related to sex differences in neurology. She said the results of the study are fascinating because Alzheimer’s tends to be more prevalent in women. “It’s really interesting from a genetic perspective to see one sex contributing something the other sex isn’t,” Seto said. She also noted the findings were not affected by whether study participants were biologically male or female.
Yang noted one limitation of the study is some participants’ parents died young, before they could potentially develop symptoms of cognitive impairment. He said social factors like access to resources and education may have also played a role in when someone acknowledged cognitive impairment and if they were ever formally diagnosed.
“It’s also important to note a majority of these participants are non-Hispanic white,” Seto added. “We might not see the same effect in other races and ethnicities.”
Seto said the next steps are to expand the study to look at other groups and examine how parental history affects cognitive decline and amyloid accumulation over time and why DNA from the mother plays a role.
Reisa Sperling, MD, a co-author on the paper, principal investigator of the A4 Study and a neurologist at Mass General Brigham, said the findings could be used soon in clinical translation.
“This work indicates that maternal inheritance of Alzheimer’s disease may be an important factor in identifying asymptomatic individuals for ongoing and future prevention trials,” Sperling said.
When a magnet is heated up, it reaches a critical point where it becomes demagnetisated. Called “criticality,” this point of high complexity is reached when a physical object is transitioning smoothly from one phase into the next.
Now, a new Northwestern University study has discovered that the brain’s structural features reside in the vicinity of a similar critical point – either at or close to a structural phase transition. Surprisingly, these results are consistent across brains from humans, mice and fruit flies, which suggests the finding might be universal. Although the researchers don’t know what phases the brain’s structure is transitioning between, they say this new information could enable new designs for computational models of the brain’s complexity and emergent phenomena.
“The human brain is one of the most complex systems known, and many properties of the details governing its structure are not yet understood,” said Northwestern’s István Kovács, the study’s senior author. “Several other researchers have studied brain criticality in terms of neuron dynamics. But we are looking at criticality at the structural level in order to ultimately understand how this underpins the complexity of brain dynamics. That has been a missing piece for how we think about the brain’s complexity. Unlike in a computer where any software can run on the same hardware, in the brain the dynamics and the hardware are strongly related.”
“The structure of the brain at the cellular level appears to be near a phase transition,” said Northwestern’s Helen Ansell, the paper’s first author. “An everyday example of this is when ice melts into water. It’s still water molecules, but they are undergoing a transition from solid to liquid. We certainly are not saying that the brain is near melting. In fact, we don’t have a way of knowing what two phases the brain could be transitioning between. Because if it were on either side of the critical point, it wouldn’t be a brain.”
While researchers have long studied brain dynamics using functional magnetic resonance imaging (fMRI) and electroencephalograms (EEG), advances in neuroscience have only recently provided massive datasets for the brain’s cellular structure. These data opened possibilities for Kovács and his team to apply statistical physics techniques to measure the physical structure of neurons.
For the new study, Kovács and Ansell analysed publicly available data from 3D brain reconstructions from humans, fruit flies and mice. By examining the brain at nanoscale resolution, the researchers found the samples showcased hallmarks of physical properties associated with criticality.
One such property is the well-known, fractal-like structure of neurons. This nontrivial fractal-dimension is an example of a set of observables, called “critical exponents,” that emerge when a system is close to a phase transition.
Brain cells are arranged in a fractal-like statistical pattern at different scales. When zoomed in, the fractal shapes are “self-similar,” meaning that smaller parts of the sample resemble the whole sample. The sizes of various neuron segments observed also are diverse, which provides another clue. According to Kovács, self-similarity, long-range correlations and broad size distributions are all signatures of a critical state, where features are neither too organised nor too random. These observations lead to a set of critical exponents that characterise these structural features.
“These are things we see in all critical systems in physics,” Kovács said. “It seems the brain is in a delicate balance between two phases.”
Kovács and Ansell were amazed to find that all brain samples studied – from humans, mice and fruit flies – have consistent critical exponents across organisms, meaning they share the same quantitative features of criticality. The underlying, compatible structures among organisms hint that a universal governing principle might be at play. Their new findings potentially could help explain why brains from different creatures share some of the same fundamental principles.
“Initially, these structures look quite different – a whole fly brain is roughly the size of a small human neuron,” Ansell said. “But then we found emerging properties that are surprisingly similar.”
“Among the many characteristics that are very different across organisms, we relied on the suggestions of statistical physics to check which measures are potentially universal, such as critical exponents. Indeed, those are consistent across organisms,” Kovács said. “As an even deeper sign of criticality, the obtained critical exponents are not independent – from any three, we can calculate the rest, as dictated by statistical physics. This finding opens the way to formulating simple physical models to capture statistical patterns of the brain structure. Such models are useful inputs for dynamical brain models and can be inspirational for artificial neural network architectures.”
Next, the researchers plan to apply their techniques to emerging new datasets, including larger sections of the brain and more organisms. They aim to find if the universality will still apply.
