Posted on Rheumatoid arthritis

Digital twin opens the way to effective treatment of Rheumatoid Arthritis

Illustration of digital twins


A vision of how digital twins can be used to tailor drugs: (A) Patients with different immune diseases. (B) Computers construct (C) digital twins of each patient’s disease mechanisms. These interact in molecular programmes, controlled by (D) switch proteins, which are measured in blood or tissue to (E) find the dominant protein(s) at which to target therapy. Illustration: The research group. CREDIT Karolinska Institutet

Inflammatory diseases like rheumatoid arthritis have complex disease mechanisms that can differ from patient to patient with the same diagnosis. This means that currently available drugs have little effect on many patients. Using so-called digital twins, researchers at Karolinska Institutet have now obtained a deeper understanding of the “off and on” proteins that control these diseases. The study, which is published in Cell Reports Medicine, can lead to more personalised drug therapies.

Many patients with inflammatory diseases such as rheumatoid arthritis, Crohn’s disease and ulcerative colitis, never feel fully healthy despite being on medication. It is a problem that causes significant suffering and expense. 

In an inflammatory disease, thousands of genes alter the way they interact in different organs and cell types. Moreover, the pathological process varies from one patient to another with the same diagnosis, and even within the same patient at different times.

It is exceedingly difficult to diagnose and treat such complex and varied changes. In a project that has been underway for five years, researchers from a constellation of institutions including Karolinska Institutet in Sweden have been trying to solve this problem and tailor drugs to individual patients by constructing and data-processing their digital twins, i.e. digital models of each patient’s unique disease mechanisms.

Now, the research group has found a possible solution: the changes can be organised in molecular programmes. These molecular programmes are regulated by a limited number of “off and on” switch proteins, of which some are known targets for drugs such as TNF inhibitors. But it is not a therapeutic option that helps everyone.

“Our analyses of patients who responded or didn’t respond to TNF therapy revealed different switch proteins in different individuals,” says the study’s corresponding author Mikael Benson, researcher at the Department of Clinical Science, Intervention and Technology, Karolinska Institutet. “Another important discovery was that the proteins did not switch off the diseases but were more like dimmer switches that raised or lowered the disease programmes.”

Every physiological process can be described with mathematical equations. This advanced digital modelling technique can be adjusted to a patient’s unique circumstances by analysing the activity of each and every gene in thousands of individual cells from blood and tissue. Such a digital twin can be used to calculate the physiological outcome if a condition changes, such as the dosage of a drugs.

Digital twins have revealed to the researchers new opportunities for the effective treatment of serious diseases.

“The methods can be developed to tailor the right combination of drugs for “on” proteins for individual patients,” Dr Benson continues. “The programmes we describe will be made available to the research community so that more clinical studies can be done of patients with different immune diseases.”

In the current study, the researchers combined analyses of a mouse model of rheumatoid arthritis and digital twins of human patients with various inflammatory diseases.

“Even though only the joints were inflamed in mice, we found that thousands of genes changed their activity in different cell types in ten organs, including the skin, spleen, liver and lungs,” says Dr Benson. “As far as I’m aware, this is the first time science has obtained such a broad picture of how many organs are affected in rheumatoid arthritis. This is partly due to the difficulty of physically sampling so many different organs.” 

Posted on Diabetes, Diet

Plant-based low-carbohydrate diet linked with lower risk of premature death for people with type 2 diabetes

Plant-based low-carbohydrate diet linked with lower risk of premature death for people with type 2 diabetes
Plant-based low-carbohydrate diet linked with lower risk of premature death for people with type 2 diabetes
  • Adhering to a plant-based low-carbohydrate diet was associated with a reduction in overall cardiovascular and cancer mortality among people with type 2 diabetes
  • Researchers observed the most substantial health benefits among people who not only adhered to this diet but also had other healthy habits, such as exercising, not smoking, and consuming alcohol in moderate amounts

Following a low-carbohydrate diet comprised primarily of plant-based foods was significantly associated with a lower risk of premature death among people with type 2 diabetes, according to a new study by researchers at Harvard T.H. Chan School of Public Health. It is the first prospective cohort study to examine the relationship between low-carbohydrate diet patterns and mortality among people with diagnosed type 2 diabetes.

“While avoiding refined and highly-processed carbohydrates has been widely recommended to lower the risk of developing type 2 diabetes, our study provides the first empirical evidence on how low-carb diets can help manage the progression of existing diabetes,” said lead author Yang Hu, research associate in the Department of Nutrition.

The researchers analyzed 34 years of health data from 7,224 women participating in the Nurses’ Health Study and 2,877 men participating in the Health Professionals Follow-up Study, all of whom developed type 2 diabetes after those studies began. The participants completed questionnaires on lifestyle and medical history every other year, allowing the researchers to assess the compositions of their diets and score them according to intake of animal proteins and fats, vegetable proteins and fats, high-quality carbohydrates, and low-quality carbohydrates.

The findings showed a 24% reduction in all-cause mortality among those adhering to a low-carbohydrate dietary pattern. The health benefits were stronger for low-carbohydrate diets emphasising plant-based foods and high-quality carbohydrates, such as fruits, vegetables, and whole grains. Those diets were also associated with lower cardiovascular disease and cancer mortality. Low-carbohydrate diets emphasising animal products and low-quality carbohydrates, such as potatoes, added sugars, and refined grains, were not significantly associated with lower mortality.

The researchers observed the strongest health benefits among people adhering to other healthy habits, such as not smoking, regularly exercising, and drinking alcohol in moderation, alongside a plant-based low-carbohydrate diet.

“This study, once again, underscores the importance of diet quality when choosing among various diets for diabetes control and management,” said Qi Sun, senior author and associate professor in the Departments of Nutrition and Epidemiology.

Posted on Diabetes, Pain Management

Spinal cord stimulation may help diabetic neuropathy.

Spinal cord stimulation may help diabetic neuropathy
Spinal cord stimulation may help diabetic neuropathy


People with painful diabetic neuropathy may be able to get relief from high-frequency spinal cord stimulation, according to a preliminary study released today, February 28, 2023, that will be presented at the American Academy of Neurology’s 75th Annual Meeting being held in person in Boston and live online from April 22-27, 2023.

Diabetic neuropathy is nerve damage due to diabetes and can lead to pain and numbness, most often in the hands and feet. About 25% of the 37 million Americans with diabetes have painful diabetic neuropathy.

“Diabetic neuropathy often results in poor quality of life, depression, anxiety and impaired sleep, and the available medications can be ineffective for many people or have side effects that people can’t tolerate,” said study author Erika Petersen, MD, of the University of Arkansas in Little Rock. “These results are exciting because there is an urgent need for more effective therapies.”

The study involved 216 people who had painful diabetic neuropathy symptoms for at least one year that were not responding to medications. Half of the people received spinal cord stimulation plus regular medical treatment for six months. Half received only regular medical treatment. After six months, people had the option to switch to the other treatment. People were followed for a total of two years.

Spinal cord stimulation involves a device that is implanted under the skin. The device delivers electrical stimulation to the spinal cord to cut off pain signals to the brain.

After six months, the people who received stimulation reported 76% decrease in their average pain amount, while the people who did not receive stimulation had a 2% increase in their average amount of pain. In tests of their motor function, sensation and reflexes, improvements were seen in 62% of those receiving stimulation compared to 3% of those receiving medication only.

A total of 93% of those receiving medication only and eligible to cross over chose to receive the stimulation after six months, while none of those receiving the stimulation wanted to receive medication only.

After two years, people reported 80% improvement in their average pain amount, and 66% continued to have improvement in motor function, sensation and reflexes.

None of the participants had their devices removed because they were not effective. Eight people had infections related to the device. Three of those cleared up and five people, or 3%, had their devices removed due to infection, which Petersen said is within the range reported for people receiving spinal cord stimulation for other conditions.

Petersen also noted that the high-frequency stimulation appears to provide greater pain relief than low-frequency stimulation. High-frequency stimulation also does not create the “pins and needles” sensation that comes with low-frequency stimulation.

“This study demonstrates that high-frequency stimulation provides long-term pain relief with acceptable safety,” Petersen said. “The improvements in motor function, sensation and reflexes suggest that this therapy could have disease-modifying potential.”

Petersen said, “Confirmation of results through studies in larger groups of people could further strengthen our understanding of this spinal cord stimulation therapy for the treatment of painful diabetic neuropathy.”

Posted on Autism

Social deficits and seizures in autism type tied to overexcited brain circuits – please do read the headline is a bit too clickbaity, but the article is interesting

Genetic subtype of autism and schizophrenia has duplicated gene that triggers overactive brain
Genetic subtype of autism and schizophrenia has duplicated gene that triggers overactive brain


Northwestern Medicine scientists have identified the cause of a genetic subtype of autism and schizophrenia that results in social deficits and seizures and humans.

Scientists have discovered a key feature of this subtype is a duplicated gene that results in overactive or overexcited brain circuits. The subtype is called 16p11.2 duplication syndrome. 

“We found that genetic changes found in humans are more likely to have seizures and social deficits,” said lead author Marc Forrest, research assistant professor of neuroscience at Northwestern University Feinberg School of Medicine.

Peter Penzes, senior author of the study, and his team also showed when they reduced the levels of a gene — PRRT2 — in the duplicated region, brain activity in mice returned to normal, normal social behaviour was restored, and seizures decreased.

“Our data, therefore, demonstrates that brain over-activation could be causing both seizures and social deficits in this syndrome and that too much PRRT2 is responsible for this,” Forrest said.

The study was recently published in Nature Communications and was conducted in the laboratory of Penzes, director of the Center for Autism and Neurodevelopment and the Ruth and Evelyn Dunbar Professor of psychiatry and behavioural sciences at Northwestern.

Because the gene PRRT2 regulates how neurons talk to each other, inhibiting synapses or connection points between neurons could help treat both seizures and autism symptoms in this syndrome, Forrest said. This approach could also be used more broadly in other neurodevelopmental disorders with brain over-activation, which has been shown in other subtypes.

“Our work now shows that we can focus our efforts on targeting the PRRT2 pathway for novel therapies, and these could potentially cure core symptoms of 16p11.2 duplication syndrome,” Forrest said. “If we learn how the 16p11.2 duplication causes illness, maybe we can also learn more about what causes autism and schizophrenia, in general, and create better treatments.”

Neurodevelopmental disorders affect 10 million in U.S.

Neurodevelopmental disorders such as intellectual disability, autism and schizophrenia are common and affect approximately 3%, or about 10 million people in the U.S., but no effective treatments are available. The 16p11.2 duplication syndrome affects about 0.3% of these individuals or about 30,000 people in U.S.

“We lack a clear understanding of what causes neurodevelopmental disorders. Therefore, it is difficult to design good treatments,” Forrest said.

Different changes in DNA sequence can cause neurodevelopmental disorders

Genetic studies in the past decade have taught scientists that many different changes in the DNA sequence can cause neurodevelopmental disorders. One example is copy number variants (CNVs).

CNVs are deletions or duplications of chromosomal DNA. Unlike Trisomy 21 (Down syndrome), where an entire chromosome is copied, in CNVs just a small amount of genetic material is affected. In the CNV, Penzes and his team studied (the 16p11.2 duplication), about 30 genes on chromosome 16 are duplicated. 

The scientists are the first to look at protein changes that occur in a mouse model’s presence of the 16p11.2 duplication.

“This is important because proteins are the actual building blocks of the brain and neuronal circuits and offer unique insights compared to mRNA expression, which researchers have looked at previously,” Forrest said.

Posted on Diabetes

The first study to show childhood obesity is linked to increased risk of four of the five newly proposed subtypes of adult-onset diabetes.


First study to show childhood obesity is linked to increased risk of four of the five newly proposed subtypes of adult-onset diabetes


New research published in Diabetologia (the journal of the European Association for the Study of Diabetes [EASD]) is the first to show that childhood obesity is associated with an increased risk of four of the five recently proposed subtypes of adult-onset diabetes. The study is by Yuxia Wei, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden, and colleagues.

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In 2018, a ground-breaking study identified five novel subtypes of adult-onset diabetes: severe autoimmune diabetes (SAID, including type 1 diabetes and latent autoimmune diabetes in adults [LADA]) and four subtypes of type 2 diabetes (severe insulin-deficient diabetes [SIDD], severe insulin-resistant diabetes [SIRD], mild obesity-related diabetes [MOD] and mild age-related diabetes [MARD]).  SIDD, SIRD, MOD and MARD are collectively classified as type 2 diabetes. These subtypes of diabetes differ in their clinical characteristics, complications and genetic backgrounds. It is unclear if they also differ in modifiable risk factors.

The prevalence of childhood obesity is rising worldwide. Childhood adiposity has been linked to several chronic diseases, including type 1 diabetes in children and type 2 diabetes; however, it has never been investigated in relation to the recently proposed subtypes of adult-onset diabetes. In this study, the authors aimed to compare the effects of childhood body size on the risk of different diabetes subtypes occurring in adults. They used a statistical technique known as Mendelian randomisation (MR), where genetic information is used to study the link between an environmental risk factor and a disease while accounting for the influence of other risk factors.

The authors used data from the UK Biobank for their study.  They extracted summary statistics for childhood body size from a genome-wide association study of 453,169 European participants who self-reported body size (thinner, about average, and plumper/bigger) at the age of 10 years in the UK Biobank study. The study incorporated more than 200 genetic mutations as indicators of childhood body size and linked them to LADA (267) and the other types of diabetes(275).

The results showed higher levels of childhood adiposity (children who perceive themselves as being plumper/bigger than other children compared to children who perceive themselves as being of average body size) were linked to a 62% increased risk of LADA, a doubling of the risk of SIDD, a near-trebling of the risk of SIRD, and a 7-times increased risk of MOD. The only diabetes subtype showing no association with childhood obesity was MARD.

Previous studies of this kind (using MR) have found that childhood body size is linked to a doubling of risk for both type 1 diabetes (mean age of diagnosis 16 years) and type 2 diabetes. The authors say: “We extend these findings by demonstrating that childhood adiposity is a risk factor for four out of the five recently proposed diabetes subtypes.”

The authors say their study reveals potentially different mechanisms linking childhood adiposity to different diabetes subtypes. The link between childhood body size and SIRD or MOD is expected, given the adverse effects of adiposity on insulin sensitivity. Interestingly, children with higher levels of adiposity also had higher risks of LADA and SIDD, both of which are characterised by insulin deficiency. This phenomenon may be explained by the fact that impaired insulin secretion is affected jointly by excess fat around the pancreas and insulin resistance.

The authors conclude: “Our analyses indicate that childhood obesity is a risk factor for four of the five proposed novel subtypes of adult-onset diabetes, regardless of whether they are classified as being primarily characterised by autoimmunity, insulin deficiency, insulin resistance or obesity. Childhood obesity appears to be a risk factor for essentially all types of diabetes in adults, except for mild age-related diabetes. This stresses the importance of preventing obesity in children.”