Day: 06/26/2022

Radiofrequency ablation effective for most children with benign thyroid nodules

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Most children who undergo image-guided radiofrequency ablation for treatment of benign nonfunctional thyroid nodules have at least a 50% reduction in nodule volume 4 years after treatment, according to study data published in Thyroid.

“Radiofrequency ablation was effective in reducing the volume of benign nonfunctional thyroid nodules in children, providing significant symptomatic relief with a good safety profile during short- and long-term follow-up,” Xinguang Qiu, MD, of the department of thyroid surgery at The First Affiliated Hospital of Zhengzhou University in China, and colleagues wrote. “Radiofrequency ablation should be considered as a beneficial, minimally invasive treatment modality for selected pediatric patients.”

Radiofrequency ablation reduces mean volume of benign thyroid nodules by more than 50% in children
Children undergoing radiofrequency ablation for the treatment of benign thyroid nodules had a mean volume reduction ratio of 65% or more at 3 months, 6 months and 1 year of follow up. Data were derived from Li L, et al. Thyroid. 2022;doi:10.1089/thy.2021.0454.

Researchers reviewed data from 62 patients aged 18 years or younger with benign thyroid nodules treated with radiofrequency ablation at The First Affiliated Hospital of Zhengzhou University from July 2014 to August 2017 (75.8% girls; mean age, 14.4 years). Participants underwent an ultrasonography prior to the procedure to evaluate thyroid nodule composition and symptoms and had follow-up 3, 6 and 12 months after treatment. After 1 year, follow-up visits were performed annually. Ultrasonography and laboratory tests were repeated at each follow-up visit. Volume reduction ratio was calculated to assess the extent of nodule volume reduction.

Of the study cohort, 54 children had one thyroid nodule requiring treatment, and eight had two thyroid nodules. At 3 months, the mean volume reduction ratio was 65.1%, and increased to 74.7% at 6 months and to 77.5% at 1 year. The mean volume reduction ratio was 60.3% at 2 years, 68.5% at 3 years and 55.1% at 4 years. Thirty-six nodules had strong echogenicity or hyperechogenicity at 3 months, and six retained these characteristics at 6 months.

Sixteen of the 70 nodules began to regrow after initial treatment. Of the regrowing nodules, 56.3% had a volume reduction ratio below 50%, indicating a loss in treatment efficacy. Of those that lost treatment efficacy, 66.7% became larger than before treatment. Three nodules underwent a second radiofrequency ablation and surgery was performed on two other nodules.

Children requiring treatment of bilateral nodules had a lower volume reduction rate (13.6% vs. 74.1%; P < .001), lower technical efficacy (56.3% vs. 90.7%; P = .001) and higher regrowth rate (68.8% vs. 9.3%; P < .001) compared with unilateral nodules.

“We found that bilateral nodules requiring treatment had lower volume reduction rates, lower therapeutic efficacy and higher rates of regrowth, and the presence of bilateral nodules was an independent factor related to efficacy and regrowth,” the researchers wrote. “The specific reason for these associations is unclear. In addition, such results have not been reported in adult studies. Thus, radiofrequency ablation may not be appropriate for the treatment of bilateral thyroid nodules in children.”

Nodules with a higher cystic component had a higher volume reduction ratio than those with a lower cystic component (72.4% vs. 46.7%; P = .001). Nodules with higher vascularity had a lower regrowth rate than those with low vascularity (12.1% vs. 32.4%; P = .043). In all, 4.8% of patients had complications from the procedure.

The researchers wrote that radiofrequency ablation provides benefits for many patients, but those who undergo the procedure require long-term follow-up and the lack of a pathological exam means providers can not rule out malignancy.

“This treatment requires specialized treatment centers, specialized equipment, and highly skilled and experienced physicians, so access to radiofrequency ablation may also be a barrier to its use,” the researchers wrote. “Therefore, we believe that radiofrequency ablation is more likely to be a complementary treatment modality to surgical treatment.”

Artificial intelligence may be used to identify benign thyroid nodules

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An ultrasound-based artificial intelligence classifier of thyroid nodules identified benign nodules with sensitivity similar to fine-needle aspiration, according to data presented at ENDO 2022.

“Artificial analysis of thyroid ultrasound images can identify nodules that are very unlikely to be malignant,” Nikita Pozdeyev, MD, PhD, assistant professor at University of Colorado Anschutz Medical Campus, told Healio. “These are mostly spongiform nodules that have a less than 3% probability of malignancy.”

Nikita Pozdeyev, MD, PhD
Pozdeyev is an assistant professor at University of Colorado Anschutz Medical Campus.

Pozdeyev and colleagues trained a supervised deep learning classifier of thyroid nodules on 32,545 images of 621 thyroid nodules acquired from University of Washington. The classifier was then tested on an independent set of 145 nodules collected from the University of Colorado. The Big Transfer BiT-M ResNet-50×1 convolutional neural net architecture was modified to contain, 3, 4, 6 and 3 PreActBottleneck units per block 1 through 4. Weights pretrained on the ImageNet-21k dataset were loaded, and weights for blocks 3 and 4 fine-tuned for the binary classification task of distinguishing between benign and malignant thyroid nodules.

“We used an approach used to train clinically relevant classifiers called transfer learning,” Pozdeyev said in a press conference. “We took a model trained on natural images like cars, dogs and humans, and then that model is trained on an image set with tens of millions of images. Then we modified that model to work on a specific task — in our case, to take ultrasound images of thyroid nodules and make a call: cancerous or benign.”

When scaled by nodule size and using six random cine clip images per nodule, the classifier achieved an area under receiver operating characteristic curve of 0.872 on five-fold cross-validation. In the training data set of thyroid nodules, the classifier achieved a sensitivity of 94%, a specificity of 52% and a negative predictive value of 96% when determining benign vs. malignant nodules.

In the independent test set of thyroid nodules, the classifier achieved a sensitivity of 97% and a specificity of 61%. The negative predictive value was 98.5% and the positive predictive value was 40%.

“Computer-assisted diagnosis systems will be increasingly used by physicians of all specialties, including endocrinology,” Pozdeyev told Healio. “Our proof-of-concept study showed that an artificial intelligence-based thyroid nodule classifier can objectively select thyroid nodules that are unlikely to be malignant, do not require fine-needle aspiration biopsy, and can be managed with active surveillance. The validation of such a computer-assisted diagnosis system in a prospective clinical trial will be necessary before introduction into clinical practice.”

Frequently asked questions about COVID-19 vaccines for infants, toddlers

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COVID-19 vaccines are now available for children as young as age 6 months in the United States.

The FDA has authorized and the CDC has recommended Moderna’s two-dose series at 25 g per dose for children aged 6 months through 5 years and Pfizer-BioNTech’s three-dose series at 3 g per dose for children aged 6 months to 4 years.

Below, Healio Pediatrics Editorial Board Member Leonard R. Krilov, MD, FAAP, FIDSA, FPIDS, chief of pediatric infectious diseases at NYU Langone Hospital – Long Island, answers some frequently asked questions about the vaccines.

Leonard R. Krilov

Healio: Is one vaccine preferred over the other?

Krilov: I think it’s a little too soon to answer that. I think there are pros and cons to each of the two.

Moderna has the advantage that it is only two doses and will be completed in a month. On the counter side, there did seem to be more adverse reactions in terms of fever and local pain, as well as fatigue and headache or irritability and sleep disturbances with this vaccine. Will that impact compliance with the second dose or how the vaccine will be perceived? Additionally, even though it is approved as a two-dose series with follow-up, there may well be an indication for a booster for this vaccine.

On the other side of the coin, the Pfizer vaccine at one-tenth of the adult dose seems to be associated with lower rates of local reactions and fever compared with placebo. However, the Pfizer vaccine requires three doses, and would take potentially up to almost 3 months to complete the series. The preliminary data suggested minimal, if any, protection after just the first two doses.

As in any clinical trial, you cannot put two experimental products head to head. The studies were conducted at different times with differing SARS-CoV-2 infection rates in the community and the data may not be totally comparable for the two vaccines. I think it is too soon to say where the favorability is going to be. Both vaccines are recommended equally. I’ll switch hats and put my parent hat on (although my children are grown) and suggest I would probably lean toward achieving protection sooner, but the most important thing is to get the children vaccinated.

Healio: As you mentioned, Pfizer’s vaccine is three doses. What are some ways a pediatrician can make sure a parent brings their child back for two follow-up vaccine appointments?

Krilov: Ensuring compliance with the vaccine series is important and needs to be emphasized to achieve the best level of protection. In a way, compliance is inversely proportional to number of doses or number of visits, so it is a concern that needs to be addressed.

I think we need to work with parents on demonstrating the significance of the infection, as well as the safety and benefits of the vaccine. The communication with the family should address the misconception that COVID-19 is a benign disease for young children and infants. Although we have not seen the mortality in young children from COVID-19 observed in the elderly and those with significant medical conditions, there have been more than 30,000 children aged younger than 5 years hospitalized with COVID-19 and more than 440 deaths in children aged younger than 4 years from this infection. More than one-half of these cases occurred in children with no pre-existing medical conditions.

The phrase I have used in these discussions is that although the infection is milder in children, it is not necessarily mild. It can still be a significant disease in terms of the acute illness and long COVID. Symptoms persisting for months have been described in children as well as in adults. Beyond this, discussing the safety and effectiveness of the vaccine in preventing severe disease should be included.

As we are trying to return to some degree of normalcy with no masks in school and increased in-person events, which is especially important for younger children’s speech development and socialization, I think vaccination is a critical part of our toolbox to help us get there safely. Telephone or text message reminders for second or third doses can be helpful in achieving compliance.

Healio: How can pediatricians counsel parents who may be hesitant about getting their young children vaccinated?

Krilov: I think there are two components to that discussion. One is certainly to emphasize that it is a safe and beneficial vaccine for their child. The other is that we need to spend some time addressing the misconception that this is a benign disease for the younger child, as described in the previous answer. In other words, we need to educate about what we’re vaccinating against. We have to be able to convincingly demonstrate that what we’re vaccinating against is worth preventing.

I think, in a way, for the other routine childhood vaccines, we are the victim of our own success. When people don’t see a lot of the vaccine-preventable diseases, they lose track of how significant they are, or were, and so therefore, can focus on potential concerns about reactions or the vaccines not being necessary. Maybe some of that’s true for COVID-19 as well, in the sense that the focus has been on older individuals and those with underlying medical issues. But I think it’s still significant for young children.

We want children to be able to do more and more and interact — that this is an important part of our toolbox help get there, maintain that. So, I think that is the track we need to take in order to be able to work with parents on showing the significance of the infection, as well as the safety and benefits of the vaccine.

Healio: Should parents start scheduling appointments now, or can the COVID-19 vaccine wait until they being their children in for a well visit or some other appointment?

Krilov: Because the vaccination is going to be administered over two or three visits, it might be hard to just totally dovetail into regular scheduled visits. And given, you know, the high levels of community spread in most areas of the country right now, I see no benefit to waiting. I understand it’s an extra visit, but I think the benefits are clear and the benefits should be achieved as soon as possible. It also should be noted that the COVID-19 vaccine can be given at the same time as other scheduled vaccines to avoid delays in getting vaccinated.

Healio : Do you think young children will eventually need a booster?

Krilov: Yes, I do think it is likely a booster for these children will be needed at some point, but it will require follow-up to determine if or when. Is this going to become like influenza, requiring periodic boosters for everyone? Are we going to settle into a more seasonal endemic pattern that will make timing of or need for boosters more predictable? Will there be additional waves this fall or winter, leading to recommendations for booster doses? Two and a half years ago we were talking about no hospital beds and having portable morgues in hospital parking lots, and now it’s a much more manageable disease. But again, there are still large numbers of cases.

I think the likelihood is this virus will continue to circulate, and with that, probably we will need periodic boosters. Is it going to be the same booster or, like influenza, is it going to be modified to match circulating variants? For example, omicron variant vaccines are in development now, so will the booster be with a different variant even to boost the immunity better? Will it turn out in a way down the road like influenza if we have multiple circulating variants to be a multivariant vaccine? It is still a bit premature to know the answer, but based on how immunity seems to wane for older children and adults, I do expect we will be looking at boosters for young children.

A New Statistical Method for Improved Brain Mapping

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Summary: Researchers propose a new, more robust statistical method for mapping the brain.

Source: Paris Brain Institute

Brain mapping consists in finding the brain regions associated with different traits, such as diseases, cognitive functions, or behaviours, and is a major field of research in neuroscience. This approach is based on statistical models and is subject to numerous biases.

To try to counter them, researchers from the ARAMIS team, a joint team between the Paris Brain institute and Inria, and their collaborators at the University of Queensland (Australia) and Westlake University (China), propose a new statistical model for brain mapping.

The results are published in the Journal of Medical Imaging.

Mapping the brain

Mapping the brain is a challenge that mobilizes many neuroscience researchers around the world. The goal of this approach is to identify the brain regions associated with different traits, such as diseases, cognitive scores, or behaviors.

This type of study is also known as “Brain-wide association study” and rely on an exhaustive screening of brain regions to identify those associated with the trait of interest.

“The difficulty is that we are looking for a needle in a haystack, except that we don’t know how many needles there are, or in our case, how many brain regions there are to find,” explains Baptiste Couvy-Duchesne (Inria), first author of the study.

Meeting the challenges of signal redundancy

A first challenge lies in the number of brain measurements available per individual, which can quickly reach one million or more.

In addition, brain regions are correlated with each other. Some regions are highly connected and associated with many others, like nodes in a network.

Others, however, are more isolated, either because they are independent of other brain regions or because they contribute to very specific cognitive trait or brain function. 

“If a brain region associated with our trait of interest is part of a highly connected network, the analysis will tend to detect the whole network, because the signal propagates within regions that are correlated with each other,” continues the researcher,

“This signal, which may seem very strong at first sight, is in fact redundant. How then can we find the region or regions that really contribute to the trait of interest within the network?”

To solve this problem, the researchers are proposing new statistical methods that are suited to the high dimensional image as well as for modelling the complex correlation structure within the brain.

Simulations to develop new statistical methods

In order to test the developed statistical methods, the researchers need very controlled data.

“We cannot compare methods directly on real traits or diseases, since we do not know what we are supposed to find,” explains Baptiste Couvy-Duchesne, “one method could find 10 regions associated with a trait, another 20, although we cannot tell which one is giving the correct answer.” 

The key to this solving problem is to use simulations. Researchers use real brain images, but study fake diseases or fake scores, which they have constructed to be associated with dozens or hundreds of predefined brain regions.

This way, they are able to check whether the statistical methods detect the expected regions, but also whether they detect others (‘false positives’). 

A more robust method and open questions

Once their method had been calibrated through these simulations (which revealed that the proposed approach was more accurate than the existing ones) the researchers used real traits as validation.

This shows a brain and a target
A first challenge lies in the number of brain measurements available per individual, which can quickly reach one million or more. Image is in the public domain

“Our new method finds fewer regions on average because it manages to remove some of the redundant associations. The next step is to apply it to study Alzheimer’s disease,” concludes the researcher.

A central result of the study it to demonstrate how pervasive are the redundant associations, using the current statistical methods. Thus, many associations identified to date may not be robust of directly pertinent for the trait studied.

In addition, several factors that are difficult to control can affect the quality of MRIs, such as head movements or the type of machines used, which can exacerbate the problem and lead to false associations.

Beyond the development of more refined analysis methods, the issue of data quality and homogeneity remains crucial.

About this brain mapping research news

Abstract

A parsimonious model for mass-univariate vertex-wise analysis

Purpose: Covariance between gray-matter measurements can reflect structural or functional brain networks though it has also been shown to be influenced by confounding factors (e.g., age, head size, and scanner), which could lead to lower mapping precision (increased size of associated clusters) and create distal false positives associations in mass-univariate vertexwise analyses.

Approach: We evaluated this concern by performing state-of-the-art mass-univariate analyses (general linear model, GLM) on traits simulated from real vertex-wise gray matter data (including cortical and subcortical thickness and surface area). We contrasted the results with those from linear mixed models (LMMs), which have been shown to overcome similar issues in omics association studies.

Results: We showed that when performed on a large sample (N  =  8662, UK Biobank), GLMs yielded greatly inflated false positive rate (cluster false discovery rate >0.6). We showed that LMMs resulted in more parsimonious results: smaller clusters and reduced false positive rate but at a cost of increased computation. Next, we performed mass-univariate association analyses on five real UKB traits (age, sex, BMI, fluid intelligence, and smoking status) and LMM yielded fewer and more localized associations. We identified 19 significant clusters displaying small associations with age, sex, and BMI, which suggest a complex architecture of at least dozens of associated areas with those phenotypes.

Conclusions: The published literature could contain a large proportion of redundant (possibly confounded) associations that are largely prevented using LMMs. The parsimony of LMMs results from controlling for the joint effect of all vertices, which prevents local and distal redundant associations from reaching significance.

Artificial Neural Networks Model Facial Processing in Autism

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Summary: Artificial intelligence helps shed new light on why many with autism have a difficult time when it comes to processing emotions via facial expressions.

Source: MIT

Many of us easily recognize emotions expressed in others’ faces. A smile may mean happiness, while a frown may indicate anger. Autistic people often have a more difficult time with this task. It’s unclear why.

But new research, published June 15 in The Journal of Neuroscience, sheds light on the inner workings of the brain to suggest an answer. And it does so using a tool that opens new pathways to modeling the computation in our heads: artificial intelligence.

Researchers have primarily suggested two brain areas where the differences might lie. A region on the side of the primate (including human) brain called the inferior temporal (IT) cortex contributes to facial recognition.

Meanwhile, a deeper region called the amygdala receives input from the IT cortex and other sources and helps process emotions.

Kohitij Kar, a research scientist in the lab of MIT Professor James DiCarlo, hoped to zero in on the answer. (DiCarlo, the Peter de Florez Professor in the Department of Brain and Cognitive Sciences, is a member of the McGovern Institute for Brain Research and director of MIT’s Quest for Intelligence.)

Kar began by looking at data provided by two other researchers: Shuo Wang at Washington University in St. Louis and Ralph Adolphs at Caltech. In one experiment, they showed images of faces to autistic adults and to neurotypical controls.

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The images had been generated by software to vary on a spectrum from fearful to happy, and the participants judged, quickly, whether the faces depicted happiness. Compared with controls, autistic adults required higher levels of happiness in the faces to report them as happy.

Modeling the brain

Kar, who is also a member of the Center for Brains, Minds and Machines, trained an artificial neural network, a complex mathematical function inspired by the brain’s architecture, to perform the same task. The network contained layers of units that roughly resemble biological neurons that process visual information.

These layers process information as it passes from an input image to a final judgment indicating the probability that the face is happy. Kar found that the network’s behavior more closely matched the neurotypical controls than it did the autistic adults.

The network also served two more interesting functions. First, Kar could dissect it. He stripped off layers and retested its performance, measuring the difference between how well it matched controls and how well it matched autistic adults. This difference was greatest when the output was based on the last network layer.

Previous work has shown that this layer in some ways mimics the IT cortex, which sits near the end of the primate brain’s ventral visual processing pipeline. Kar’s results implicate the IT cortex in differentiating neurotypical controls from autistic adults.

The other function is that the network can be used to select images that might be more efficient in autism diagnoses. If the difference between how closely the network matches neurotypical controls versus autistic adults is greater when judging one set of images versus another set of images, the first set could be used in the clinic to detect autistic behavioral traits.

“These are promising results,” Kar says. Better models of the brain will come along, “but oftentimes in the clinic, we don’t need to wait for the absolute best product.”

Next, Kar evaluated the role of the amygdala. Again, he used data from Wang and colleagues. They had used electrodes to record the activity of neurons in the amygdala of people undergoing surgery for epilepsy as they performed the face task.

The team found that they could predict a person’s judgment based on these neurons’ activity. Kar reanalyzed the data, this time controlling for the ability of the IT-cortex-like network layer to predict whether a face truly was happy.

Now, the amygdala provided very little information of its own. Kar concludes that the IT cortex is the driving force behind the amygdala’s role in judging facial emotion.

Noisy networks

Finally, Kar trained separate neural networks to match the judgments of neurotypical controls and autistic adults. He looked at the strengths or “weights” of the connections between the final layers and the decision nodes. The weights in the network matching autistic adults, both the positive or “excitatory” and negative or “inhibitory” weights, were weaker than in the network matching neurotypical controls. This suggests that sensory neural connections in autistic adults might be noisy or inefficient.

This shows a woman's face
Researchers have primarily suggested two brain areas where the differences might lie. Credit: MIT

To further test the noise hypothesis, which is popular in the field, Kar added various levels of fluctuation to the activity of the final layer in the network modeling autistic adults. Within a certain range, added noise greatly increased the similarity between its performance and that of the autistic adults.

Adding noise to the control network did much less to improve its similarity to the control participants. This further suggest that sensory perception in autistic people may be the result of a so-called “noisy” brain.

Computational power

Looking forward, Kar sees several uses for computational models of visual processing. They can be further prodded, providing hypotheses that researchers might test in animal models.

“I think facial emotion recognition is just the tip of the iceberg,” Kar says.

They can also be used to select or even generate diagnostic content. Artificial intelligence could be used to generate content like movies and educational materials that optimally engages autistic children and adults. One might even tweak facial and other relevant pixels in what autistic people see in augmented reality goggles, work that Kar plans to pursue in the future.

Ultimately, Kar says, the work helps to validate the usefulness of computational models, especially image-processing neural networks. They formalize hypotheses and make them testable. Does one model or another better match behavioral data?

Impostor Syndrome: When Self-Doubt Gets the Upper Hand

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Summary: Impostor syndrome, or a fear that a person’s abilities will be exposed as a “deception”, can appear regardless of age, gender, or level of intelligence.

Source: Martin Luther University

People who systematically underestimate themselves and their own performance suffer from so-called impostor phenomenon. They think that any success is due to external circumstances or just luck and chance. Those people live in constant fear that their “deception” will be exposed.

In a new study in Personality and Individual Differences psychologists from Martin Luther University Halle-Wittenberg (MLU) show for the first time that even under real-life conditions the phenomenon appears regardless of age, gender, and intelligence.

Up until now it had only been investigated on the basis of surveys or individual cases.

It is common for people to question their abilities now and again.

“A healthy amount of reflection and self-doubt can protect a person from acting rash,” explains Kay Brauer from the Institute of Psychology at MLU. However, there are people who are permanently plagued by a massive amount of self-doubt despite delivering a good performance, such as getting good grades or getting positive feedback at work.

“They think that all of their successes are not a product of their skill or hard work, instead they attribute their own successes to external circumstances, for example to luck and chance, or believe that their performance is massively overestimated by others. Failures, on the other hand, are always internalized, as the result of their own shortcomings,” Brauer adds.

These people suffer from so-called impostor phenomenon.

This personality trait has so far only been investigated in so-called vignette studies.

“These studies determine how strongly the participants agree with various theoretical statements, such as that they find it difficult to accept praise or that they are afraid of not being able to repeat what they have achieved,” Brauer explains.

The psychologists from Halle examined the topic for the first time under real-life conditions.

Seventy-six participants completed a range of intelligence tests and received positive feedback on them, regardless of their actual performance. They were then asked why they think they did so well.

The study showed two things: First, the self-reported degree of impostor phenomenon is not related to actual measured intelligence or performance. Secondly, the test supported the assumption that people with a tendency to the impostor phenomenon devalue their objectively measured performance and attribute positive results to external causes such as luck and chance, but not to their own abilities.

“These results are also completely unrelated to age and gender,” says Kay Brauer.

This shows a broken mask
This personality trait has so far only been investigated in so-called vignette studies. Image is in the public domain

A permanent underestimation of one’s own abilities is often accompanied by the fear that this supposed intellectual deception will be exposed sooner or later and that people will pay the price for this.

The impostor phenomenon was first described in 1978 by US psychologists Pauline Clance and Suzanne Imes. They observed that there is a particularly high number of successful women who do not think they are very intelligent.

“The impostor phenomenon is not defined as a mental illness. However, people who suffer from it show a higher susceptibility to depression,” says Brauer, who hopes that the new study will pave the way for possible interventions.

Alzheimer’s Disease Affects Most Known Biological Pathways in the Brain

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Summary: Out of 341 known biological pathways, 91% are linked to Alzheimer’s disease.

Source: Beth Israel Deaconess Medical Center

Nearly 6 million older adults have Alzheimer’s disease in the United States, a number expected to double by 2050.

Already the sixth leading cause of death, Alzheimer’s disease is a complex neurodegenerative disease that causes memory loss, confusion, poor judgment, depression, delusions and agitation that robs people of their ability to live independently.

Currently, the biological mechanisms underlying Alzheimer’s disease are poorly understood; as a result, there are few effective treatments and no cure for the disease.

In a recent study, a research team led by scientists at Beth Israel Deaconess Medical Center (BIDMC) conducted a systematic assessment of more than 200,000 scientific publications to understand the breadth and diversity of biological pathways—key molecular chain reactions that drive changes in cells—that contribute to Alzheimer’s disease by research over the last 30 years.

The team found that, while nearly all known pathways have been linked to the disease, the most frequently associated biological mechanisms—including those related to the immune system, metabolism and long-term depression—have not significantly changed in 30 years, despite major technological advances.

The scientists’ work, published in Frontiers in Aging Neuroscience, will advance research into the mechanisms of neurodegeneration.

“The burden of Alzheimer’s disease is steadily increasing, driving us towards a neurological epidemic,” said Winston A. Hide, Ph.D., director of the Precision RNA medicine Core Facility at BIDMC and an associate professor of medicine at Harvard Medical School.

“Our findings suggest that not only is this disorder incredibly complex, but that its pathology includes most known biological pathways. This means that the disease’s effects are far broader in the body than we realized.”

The team performed an exhaustive text search of 206,324 pathway-specific dementia publication abstracts published since 1990. Next, they looked at 341 known biological pathways and determined how many publications linked a given pathway to the disease.

The researchers found that 91 percent of pathways—all but seven—were linked to Alzheimer’s disease. Nearly half of the pathways were linked to Alzheimer’s disease in more than 100 scientific papers.

This shows a brain
The team found that, while nearly all known pathways have been linked to the disease, the most frequently associated biological mechanisms—including those related to the immune system, metabolism and long-term depression—have not significantly changed in 30 years, despite major technological advances. Image is in the public domain

They also found that the top-ranked 30 pathways most frequently referred to in literature remained relatively consistent over the last 30 years suggesting that most studies of the disease have focused on a small subset of all the known disease-associated pathways.

“Clinical trials aiming to either delay the onset or slow the progression of Alzheimer’s disease have largely failed,” said study first author Sarah Morgan, a postdoctoral researcher at BIDMC during the extent of this research and now a lecturer at Queen Mary University of London.

“Given that an unexpected diversity of pathways is associated with Alzheimer’s disease, a wide range of disease processes are not being successfully targeted in clinical trials. We hypothesize that comprehensively targeting more of the associated underlying mechanisms in Alzheimer’s disease will increase the chances of success in future drug trials.”

Facts about diabetes and COVID-19 vaccination

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Susan Weiner

Stephen W. Ponder

Susan Weiner, MS, RDN, CDCES, FADCES, talks with Stephen W. Ponder, MD, FAAP, CDCES, about the effects of COVID-19 infection and vaccination for people with diabetes.

Weiner: We know people with diabetes are at higher risk for severe illness with COVID-19. Can they lower their diabetes-related risk?

COVID-19 prevention for people with diabetes
Health care professionals can lead by example and share their experience for people with diabetes who are reluctant to get a COVID-19 vaccine.

Ponder: The same steps used by others to reduce the risk of COVID infection applies to persons with diabetes — even more so. The basics: Masking, social distancing, avoiding large crowds and frequent hand-washing are vital to lowering risk for infection. A medical mask or N95 quality mask is more useful than a cloth mask if someone must go into risky areas. But keep in mind that friends and family members can also transmit the infection. Around our inner circle, there is always a greater tendency to let our guard down.

Isolation and hygiene measures, while essential, are not enough. Immunization with either the Moderna or the Pfizer vaccine, plus a later booster, provides the best proven method to lower risks for serious illness or death from COVID-19. Getting boosted with the non-original vaccine brand is a clever idea.

Working to get the best achievable blood glucose profile is associated with greater resiliency against any infection, COVID included. That means lowering HbA1c toward the goal set by the person with diabetes and the diabetes provider or team. If someone is overweight or obese, their risk is higher for serious effects from a COVID infection. If someone smokes or vapes, their risk is also higher. This is a good reason to resolve to make lifestyle changes that would help in all those areas.

Persons with diabetes are at elevated risk for death and serious illness from COVID-19. The need to take protective measures listed above is still important. Although spared from the worst outcomes, someone taking precautions can still get infected and spread the infection — even unknowingly — to others.

Persons with diabetes share many of the same risk factors as persons without diabetes: overweight or obesity, other chronic illnesses, poor health habits, etc. While many of these behaviors cannot be changed overnight, they will add to the risk one carries with a COVID infection, vaccinated or not.

Weiner: Do COVID vaccines affect blood glucose levels?

Ponder: The metabolic response a person has to any vaccine is an individual one. This is the same with COVID vaccines. Aside from a sore arm, the signs and symptoms are the same as with other vaccines and can range from nothing at all to fatigue, malaise, headache, gastrointestinal upset, low-grade fever and body aches. As with any other vaccine, the impact on blood glucose levels may be none to minimal to large. In most instances, it is more likely to be minimal.

In my case, there were no measurable effects on my blood glucose profiles after any of the COVID vaccines I received. I have also received influenza, shingles, pneumonia, hepatitis and tetanus vaccines as an adult and experienced no issues with my blood sugar after any of them either. Nevertheless, it is possible the immune response to any vaccine could influence one’s blood glucose. Therefore, I recommend careful attention to blood glucose levels after any vaccine, COVID or otherwise. Someone who experiences unexpected blood glucose changes should remember to employ their basic diabetes skills — correction doses of carbs or insulin — to manage them effectively.

Weiner: How do you discuss COVID vaccines with someone who may be reluctant to get one?

Ponder: Leading by example is one way to passively encourage others. If asked, I am happy to share that I was early to get my vaccine series, plus my later booster. As mentioned above: I experienced no serious adverse effects at all. I also have many patients and their parents who share their experiences with me that they did not have adverse reactions. For those who did have reactions, they were mild and quickly passed.

Unfortunately, leading by example does not directly address the widespread misinformation regarding COVID vaccines. The internet is the best place to find answers to questions that best suit our biases. Combined with some fancy talk and big technical words, health disinformation sites are ideally suited to confuse and sow doubt in the minds of good people. Such sites also aim to drive a wedge of distrust and suspicion regarding advice from reputable sources. COVID has highlighted this dark side of social media and the internet regarding its impact on our unity as a people.

In these cases, I realize there is little more I can do than provide support should it be necessary later. People must choose for themselves. Parents must also choose for their children. Frankly, there are no patients in my practice who follow every piece of preventive advice or recommendation given by me — or any other health care professional for that matter. Recommendations about COVID vaccines are no different in that regard, and I must live with that. It saddens me when I hear of serious illness or even death befalling someone who chose not to receive vaccines they were eligible for.

Weiner: What other advice do you give people with diabetes regarding COVID-19 infection or vaccination?

Ponder: The greatest medical advancements of the 20th century were the creation of antibiotics and vaccines. This saved countless lives globally for more than a century and continues to do so each day. Sadly, this is taken for granted in many areas of the world, especially in the U.S. Infectious diseases, regardless of their origins, are part of our collective past, present and future.

Most people with diabetes are dominating or living productive lives with a disease that was uniformly fatal before the 20th century. Success over diabetes is possible due to science and good sense to leverage every available tool with prudent and proactive decisions made each day. If you fall ill to COVID, the science behind its management improves daily. Vaccines unequivocally blunt COVID’s impact on us. Oral FDA-approved medications are now available to keep early COVID from overwhelming the body. As a person with diabetes, take these facts into account as you make your own choices regarding COVID-19 prevention and management.

Hypothyroidism more prevalent during late perimenopause, postmenopause

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The prevalence of hypothyroidism — overt and subclinical — is higher among women during the late menopause transition and postmenopause compared with premenopause, according to study findings.

Mira Kang

Seungho Ryu

“Accumulated data on menopausal transition suggest that the late menopausal transition stage, among other stages, seems to be the most critical period during which various menopausal symptoms and measurable physiologic changes are likely to manifest,” Mira Kang, MD, PhD, associate professor and vice chief information officer of the data management committee at Samsung Medical Center in Seoul, South Korea, and Seungho Ryu, MD, PhD, professor at the Center for Cohort Studies, Total Healthcare Center at Kangbuk Samsung Hospital, told Healio. “Our findings add to the existing line of evidence, reflecting an increasing trend in the occurrence of abnormal thyroid function in the late menopausal stage. It would be of interest to find out what mechanisms or factors play into the increased prevalence of the hypothyroid state during the late transition period in future investigations.”

Overt hypothyroidism prevalence increases in late perimenopause and postmenopause
The prevalence of over hypothyroidism is significantly higher in women during late perimenopause and postmenopause compared with premenopause. Data were derived from Kim Y, et al. Thyroid. 2022;doi:10.1089/thy.2021.0544.

Kang, Ryu and colleagues collected data from 53,230 women aged 40 years or older (mean age, 47.1 years) who participated in the Kangbuk Samsung Health Study at the Kangbuk Samsung Hospital Total Healthcare Center in Seoul and Suwon, South Korea, and had a health examination performed between 2014 and 2018. The Stages of Reproductive Aging Workshop + 10 criteria were used to determine menopausal stages. Electroluminescence immunoassays were conducted to measure serum thyroid-stimulating hormone, free thyroxine and free triiodothyronine levels.

The findings were published in Thyroid.

Free T3 and TSH levels were highest in the study cohort during postmenopause. Free T4 levels were similar between premenopause and postmenopause.

In multivariable-adjusted analysis, the prevalence of overt hypothyroidism was higher in late perimenopause (adjusted prevalence ratio [aPR] = 1.61; 95% CI, 1.12-2.3) and postmenopause (aPR = 1.66; 95% CI, 1.16-2.37) compared with premenopause (P = .002). Similarly, the prevalence of subclinical hypothyroidism was higher during late perimenopause (aPR = 1.22; 95% CI, 1.06-1.4) and postmenopause (aPR = 1.24; 95% CI, 1.07-1.44) compared with premenopause (P = .001). No increased prevalence in overt and subclinical hyperthyroidism was observed during the different menopausal stages.

“There is substantial resemblance between symptoms of menopause and those of thyroid abnormalities, such as weight gain, fatigue, cold intolerance, mood swings and anxiety,” Kang and Ryu said. “Thus, existing thyroid problems may easily go overlooked, thereby delaying treatment. Thyroid dysfunction, if left untreated, may be associated with significant morbidity and impaired quality of life, and, in women approaching menopause, thyroid dysfunction may exacerbate certain menopausal symptoms. Therefore, it is critical that the prevalence and risk distributions of thyroid abnormalities across different stages of menopausal transition be clearly defined to facilitate timely intervention.”

More women had a serum TSH level of greater than 5 IU/mL during late menopause transition (aPR = 1.26; 95% CI, 1.11-1.43) and postmenopause (aPR = 1.29; 95% CI, 1.13-1.48) compared with premenopause (P < .001). A higher prevalence of low free T4 levels was observed during late perimenopause (aPR = 1.76; 95% CI, 1.24-2.51) and postmenopause (aPR = 1.9; 95% CI, 1.34-2.68) compared with premenopause (P < .001). Women were more likely to have low free T3 levels of less than 2 pg/mL during late perimenopause compared with premenopause (aPR = 2.4; 95% CI, 1.36-4.23; P =.014).

Kang and Ryu said longitudinal studies are needed to assess temporal associations between menopausal stages and thyroid function.

“In addition, the clinical and prognostic significance of thyroid dysfunction in women during the menopausal transition should also be explored.” Kang and Ryu said. “Lastly, since our population consisted of Korean women, our findings need to be extended to populations of other ethnicities.”

PERSPECTIVE

Arti Bhan, MD, FACE)

Arti Bhan, MD, FACE

Thyroid dysfunction is common in women and frequently manifests at the time of puberty, pregnancy and menopause. Symptoms related to menopause and thyroid disorders can overlap, leading to delayed diagnosis and treatment of underlying thyroid disease. There are data suggesting that adequate treatment of thyroid disorders can improve climacteric symptoms, thereby improving quality of life and possibly reducing the need for estrogen supplementation.

The authors conducted a cross-sectional study of 53,230 Korean women aged 40 years or older and stratified them by menopausal stages. Thyroid hormone levels were measured, and an increased prevalence of overt and subclinical hypothyroidism was observed in the late transition and postmenopausal stages. Subclinical and overt hyperthyroidism were not associated with menopause.

Current guidelines do not recommend routine screening for thyroid dysfunction in asymptomatic individuals. However, case-finding is recommended in women at increased risk for hypothyroidism or with symptoms. Diagnosis of thyroid disorders during menopause is important as thyroid hormone concentration can affect the intensity and frequency of menopausal symptoms. In addition, undiagnosed thyroid disease can affect cardiovascular health and increase long-term morbidity. This study suggests that screening women for thyroid dysfunction during the menopausal transition is prudent.

Arti Bhan, MD, FACE

Endocrine Today Editorial Board Member

Division Head, Endocrinology

Henry Ford Health System

Poor sleep quality linked to higher type 1 diabetes distress in young adults

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Young adults with type 1 diabetes have more diabetes distress symptoms with shorter sleep time, lower sleep efficiency and higher sleep variability, according to a study published in The Science of Diabetes Self-Management and Care.

“When an individual has inadequate sleep quantity or quality, a functional deficit occurs between the amygdala and ventral anterior cingulate cortex, resulting in decreased mood, a heightened response to negative stimuli and altered inhibitory function,” Stephanie Griggs, PhD, RN, assistant professor at the Frances Payne Bolton School of Nursing and faculty associate at the Schubert Center for Child Studies at Case Western Reserve University, told Healio. “Sleep extension has restorative benefits, normalizes inhibitory function and suppresses amygdala hyperactivity, thereby resulting in fewer or no emotional or physical symptoms.”

Stephanie Griggs, PhD, RN
Griggs is an assistant professor at the Frances Payne Bolton School of Nursing and faculty associate at the Schubert Center for Child Studies at Case Western Reserve University.

Griggs and colleagues conducted a cross-sectional study enrolling 46 young adults aged 18 to 30 years with type 1 diabetes for at least 6 months and no other major health problems (mean age, 22.3 years; 67.4% women; 84.8% non-Hispanic white). Participants with obstructive sleep apnea or working night shift were excluded. Adults wore the Spectrum Plus device on their wrist to measure sleep-wake data. Sleep quality was assessed through the 19-item Pittsburgh Sleep Quality Index. The 17-item Diabetes Distress Scale measured diabetes emotional stress, and diabetes symptoms were measured with the 34-item Diabetes Symptom Checklist – Revised. The 8-item PROMIS version 1.0 questionnaire measured general emotional distress. Each participant wore a Dexcom G4 continuous glucose monitor or shared data from their own device during the study. Clinical and demographic data were collected through electronic medical records.

Of the study cohort, 54.3% slept fewer than 7 hours per night. The cohort had a mean sleep quality score of 5.91, with a score of greater than 5 signifying poor sleep quality.

Moderate emotional distress was reported by 30.4% of the cohort, and 41.3% met the criteria for moderate diabetes distress. Females reported having more hypoglycemia symptoms (P = .001) and fatigue symptoms (P =.008) compared with males.

Having a shorter total sleep time (r = –.32; P = .032), longer sleep onset latency (r = .36; P = .014) and worse sleep efficiency (r = –.35; P = .018) were associated with greater diabetes emotional distress. The associations remained significant after adjusting for sex and BMI. High sleep variability was associated with more neurologic pain symptoms (r = .32; P = .028). Longer sleep onset latency was associated with more psychological cognitive symptoms (r = .37; P = .012), more hyperglycemia symptoms (r = .33; P = .024) and a higher total symptom burden (r = .3 P = .042).

“Promoting sleep through extension and decreasing variability may help mitigate diabetes symptoms,” Griggs said. “Diabetes and primary care providers should routinely assess sleep health and address diabetes management issues that may be interfering with nocturnal sleep, such as nocturnal hyperglycemia or hypoglycemia.”

Griggs said future researchers should clarify the directionality of the associations between sleep duration and the timing of symptoms, and whether promoting sleep mitigates diabetes symptoms over time.