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24/07/2024

Long COVID fatigue linked to malfunctioning mitochondria

At least 65 million people globally have long COVID.
The most common symptoms of long COVID include post-exertional malaise, cognitive impairment, brain fog, sleep problems, and fatigue, which can have a severe impact on a person’s life.
Researchers are still unsure why some people develop long COVID and its symptoms while others do not.
Researchers from the Amsterdam University Medical Center have discovered that the fatigue experienced by those with long COVID has a physical cause.
At least 65 million peopleTrusted Source around the world have long COVID, a condition where they continue to experience COVID-19 symptoms for months after their symptoms originally start.

The most common symptoms of long COVID are fatigue, dizziness, mobility issues, sleep problems, cognitive impairment, and brain fog or inability to concentrate.

These types of lingering symptoms can have a profound impact on a person’s life. A study published in June 2023 found more than half of people with long COVID reported their work, home, social, and private lives were severely impacted by the symptoms, with fatigue being the main problem.

Scientists are still unsureTrusted Source as to why some people develop long COVID and its symptoms while others do not.

Now researchers from the Amsterdam University Medical Center are helping to provide some answers with their new study — recently published in the journal Nature CommunicationsTrusted Source — that found the fatigue experienced by those with long COVID has a physical cause.

Impact of long COVID fatigue on life quality
Prof. Michèle van Vugt, professor of internal medicine at the Amsterdam University Medical Center and co-lead author of this study, told Medical News Today she and her colleagues decided to look for a physical cause of the tiredness experienced by people with long COVID because of the impact it has on their lives.

“Those long COVID patients used to be like you and me totally integrated [into] society with a job, social life, and private life,” Prof. van Vugt explained. “After their COVID infection, for some of them, nothing was left because of their extreme fatigue. And this happened not only in one patient but many more — too many for only [a] psychological cause.”

Past studies report that fatigue is the most common symptomTrusted Source reported by people who have long COVID.

A study published in December 2023Trusted Source found that people with long COVID self-report persistently continuously low levels of health-related quality of life, as well as a high level of disability and declined levels of physical and mental health.

And research published in April 2023 Trusted Sourcereported that fatigue caused by long COVID may cause structural changes to the brain.

Lowered mitochondrial function
For this study, Prof. van Vugt and her team recruited 25 people with long COVID and 21 healthy control participants. They were all asked to take a cycling test for approximately 15 minutes, that was designed to push them to maximum exertion.

According to researchers, the cycling test caused a worsening of symptoms in the participants with long COVID, known as post-exertional malaiseTrusted Source (PEM), resulting in worsening of fatigue for up to 7 days after.

Scientists examined blood and muscle tissue samples from all participants both one week before the cycling test and one day after.

They found various abnormalities in the muscle tissue of the participants with long COVID, including lowered functioning of the mitochondriaTrusted Source of the muscle. Known as the “powerhouse of the cell,” mitochondria are responsible for making the energy needed to power the body’s cells.

“So, the cause of the fatigue is really biological,” Prof. van Vugt explained. “The brain needs energy to think. Muscles need energy to move. This discovery means we can now start to research an appropriate treatment for those with long COVID.”

Tailored exercises: Good or bad for long COVID?
Prof. van Vugt said the the research team was surprised by their study’s findings related to muscle tissue abnormalities.

“However, we [could then] understand much better the symptoms of fatigue in the patients,” she added.

When asked about the next steps planned for this research, Prof. van Vugt said they plan to examine whether the same muscle alterations can be found in other post-infectious patients to hopefully uncover the cause of these changes in the muscle, leading to proof of concept studies for treatment.

“Doctors should acknowledge the complaints of long COVID patients and we should advise very carefully about performing tailored exercisesTrusted Source. And as researchers, we should support our medical colleagues with our gained knowledge to support patients with their symptoms and in the meantime [try] to discover a biomarker as a diagnostic tool plus finally a treatment.”

– Prof. Michèle van Vugt
A condition that is challenging to treat
MNT also spoke with Dr. David Cutler, a board-certified family medicine physician at Providence Saint John’s Health Center in Santa Monica, CA, about this study. Dr. Cutler was not involved in the research.

Dr. Cutler commented that the topic of long COVID sparks controversy and strong emotions because it remains poorly defined, difficult to diagnose, and challenging to treat.

“Despite scientific consensus about its existence, the lack of a definitive diagnostic test and its variable presentation continues to make many skeptical of its existence,” he explained. “As a clinician, [I find that] this [research] is helpful in reassuring long COVID sufferers that what they are experiencing is physically real, and not merely psychological.”

“Lacking a specific cure for this condition, the most important treatment physicians can provide is reassurance,” Dr. Cutler continued.

“Patients must be allowed [an] opportunity to present their symptoms to a receptive physician, they must be thoroughly evaluated to exclude other conditions, the diagnosis of long COVID should then be specifically endorsed, patients need to be informed of the generally favorable long-term prognosis, and adequate follow-up provided. This is the basis for optimal reassurance.”

– Dr. David Cutler
Regarding fatigue, Dr. Cutler said a program of graded exerciseTrusted Source to avoid worsening symptoms seems to be best.

“However, at this point, the findings of this one study of just 25 patients does not significantly enhance our ability to treat these patients’ complaints of fatigue,” he added. “But it does help to explain their symptoms which aids in reassurance and lessens anxiety. Future research could be aimed at attempts to lessen fatigue with various regimens of exercise, nutritional support, and emotional therapy to ease the suffering of those with long COVID.”

January 13, 2024 — Facts checked

24/07/2024

Migraine linked to increased risk of IBD in new study

More than 1 billion people around the world have at least one migraine attack each year.
Previous research shows that migraine can potentially increase a person’s risk for several health issues, including gastrointestinal conditions.
New research from Seoul National University College of Medicine in South Korea says there may also be a link between migraine and an increased risk for inflammatory bowel disease (IBD).
More than 1 billion peopleTrusted Source globally have at least one migraine attack each year.

Previous studies show that migraine can potentially increase a person’s risk for other conditions, including strokeTrusted Source, heart diseaseTrusted Source, epilepsyTrusted Source, sleeping issuesTrusted Source, and anxiety and depressionTrusted Source.

Migraine has also been linked to some gastrointestinal conditionsTrusted Source, including irritable bowel syndrome (IBS)Trusted Source.

Now, researchers from Seoul National University College of Medicine in South Korea say there may also be a link between migraine and an increased risk for irritable bowel disease (IBD), which is an umbrella term that includes Crohn’s disease and ulcerative colitis.

The study was recently published in the journal Scientific ReportsTrusted Source.

Migraine and IBD: An unsurprising connection
According to Dr. Brooks D. Cash, professor and chief of the division of Gastroenterology, Hepatology, and Nutrition at UTHealth Houston in Texas, who was not involved in this study, the field of gastroenterology has recognized for many years that migraine has been associated with many chronic gastrointestinal syndromes and diseases.

“The data in this report supports previous reports of an association between migraine headaches and IBD,” Dr. Cash told Medical News Today.

Dr. Rudolph Bedford, a board-certified gastroenterologist at Providence Saint John’s Health Center in Santa Monica, CA, who was also not involved in this study, told MNT that the research results were not surprising.

“[With] inflammatory bowel disease we do see some extra-intestinal manifestations including things involving the eye or ocular findings, which may be neurogenic in nature, so it wasn’t surprising,” Dr. Bedford added.

This is not the first study to look at a connection between migraine and IBD.

A study published in March 2021 of people in the United States found a higher prevalenceTrusted Source of migraine or severe headaches among adults with IBD than in those without.

Research published in March 2023 reported an increased prevalence of IBD in people with migraine with and without aura.

Could migraine increase risk of inflammatory bowel disease?
For the current study, researchers analyzed data from more than 10 million people through the nationwide healthcare system for South Korean citizens. About 3% of the study population had IBD.

Through the data, scientists found the incidence of IBD was significantly higher in people who had migraine compared to those who did not.

Scientists also reviewed the data through subgroups of Crohn’s disease and ulcerative colitis incidences. People with migraine in both subgroups had a higher risk of developing either condition when compared to people without migraine.

After a migraine diagnosis, researchers found people were at a higher risk of developing Crohn’s disease, with a significant rise after a 5-year follow-up.

Additionally, within the subgroups, scientists reported that the impact of migraine on the risk of developing ulcerative colitis was more prominent in men than women.

Study results not definitive
Based on these findings, the research team suggests that people with migraine be monitored carefully for the development of IBD.

However, Dr. Cash stated that the data presented do not convincingly support that approach or recommendation.

“The odds ratios that were reported in this study, which can be thought of as the increased odds of an outcome (e.g., developing IBD) with a given exposure (e.g., migraine headaches), were consistently between one to two, which is not far from definitive and can be easily misinterpreted or misrepresented,” he explained.

“The results are, at best, suggestive of an association between migraines and IBD, which we were already aware of based on previous research and deserve to be further evaluated. However, the minimal increase in the odds of developing IBD reported in this study is not sufficient to recommend increased monitoring of patients with migraines for the development of Crohn’s disease or ulcerative colitis.”

– Dr. Brooks D. Cash
Importance of identifying potential IBD triggers
Dr. Bedford said it is important to identify potential health issues that may trigger IBD, as a doctor may be able to mitigate the symptoms of IBD if they know what may be associated with it.

“Migraines can be very debilitating and you may want to identify those people with migraines,” he continued. “We don’t normally question patients with inflammatory bowel disease whether or not they have migraine headaches, so it probably rates as something that should be done more frequently.”

“These results add to an already relatively robust body of research suggesting that chronic pain syndromes are statistically more common in patients with chronic GI syndromes or diseases,” Dr. Cash said.

“We do not have enough information or proof yet to establish a causal relationship either way. But this data can be used to explain some therapeutic approaches that may benefit both GI and neurologic symptoms in patients with migraines,” he added.

Research next steps
Regarding the next steps for this research, Dr. Cash said that mechanistic data evaluating the possible reasons for these consistent observations of association is needed.

“Right now, all we have are hypotheses,” he continued. “Are there changes in the gut-brain communication pathways or sensory perceptions in the enteric and central nervous systems? Is the gut microbiome involved? Are there psychological and stress-mediated factors at play?”

“Once clinical relationships such as these have been identified, we need to move toward trying to explain why those relationships may exist,” Dr. Cash added. “That, in turn, may lead us to develop more targeted and effective therapies that can address multiple symptoms/syndromes.”

Dr. Bedford suggested researchers look for an association between IBD flares and migraine occurring at the same time. As migraine is associated with serotonin release, he encouraged researchers to examine how the serotonin transporters within the GI tract, small bowel, and colon might play a role.

“I think just questioning our patients in terms of quality of life issues — is there any way that we can mitigate their migraine headaches, potentially preventing their inflammatory bowel disease flare, or vice versa, is certainly something to look into,” Dr. Bedford said.

January 13, 2024 — Facts checked.

24/07/2024

An awakening in next-generation molecular diagnostics
CRISPR and next-generation sequencing are transforming molecular diagnostics, from infectious disease to early cancer detection. Where might the science lead?
Automated, high-throughput sequencing systems (above) have made an indelible impact on life sciences research. They are now poised to transform molecular diagnostics.Credit: Martin Krzywinski/SPL/Getty Images

CRISPR gene editing and next-generation sequencing (NGS) have transformed clinical and life sciences research. CRISPR permits the selective targeting and editing of specific nucleotide sequences, with a degree of accuracy and ease unachievable just a few years ago. NGS allows for high-throughput, precise and affordable DNA or RNA sequencing.

Together, the technologies have fostered numerous advances in basic molecular and cell biology and disease research; the discovery of CRISPR even earned the researchers behind it a Nobel Prize in 2020. They are also aiding in the development of new gene and cancer therapies, such as CAR-T cells.

While those achievements are widely recognized, the impacts of CRISPR and NGS on molecular diagnostics could be just as profound. A few diagnostics based on CRISPR and NGS have already reached the clinic, but the number of applications in development is far greater. Those diagnostics could enable early disease detection, accurate disease monitoring and more agile administration of precision therapies across numerous fields.

As in the early days of immunosorbent assays or fluorescence in situ hybridization, CRISPR and NGS present significant opportunities for those developing molecular diagnostics. Where does the science stand, and where might it lead?

CRISPR as a diagnostic tool
In 2016, the Zika outbreak in the Americas set the stage for the first approved CRISPR diagnostic1. Since then, CRISPR diagnostics have been used to detect the Lassa and Ebola viruses, along with SARS-CoV-22,3. Infectious disease outbreaks have driven development thus far. But any setting that requires high selectivity of a known genetic target, such as the analysis of tumour samples, identification of inherited genetic variants or non-invasive prenatal testing (NIPT), is a possible candidate for CRISPR diagnostics4.

CRISPR is best known as a gene editing system in which a Cas9 protein is paired with a guide RNA engineered to complement a target DNA. When the target DNA is identified, Cas9 cleaves the sequence at a defined site, permitting gene excision or insertion.

The mechanism behind CRISPR-based diagnostics is similar to gene editing, in that it uses an engineered guide RNA. But it typically employs different Cas proteins, namely Cas 12, Cas 13 and Cas 14. Those proteins can be modified to generate fluorescent signals in the presence of a target nucleotide sequence, whether DNA or RNA, making the system suitable for assays or imaging.

While most researchers develop their own CRISPR diagnostics, two commercial platforms have recently arisen to speed the process. SHERLOCK was developed by Feng Zhang’s group at the Broad Institute, and DETECTR was created by Jennifer Doudna, who received a Nobel Prize for the discovery of CRISPR-Cas9, along with her team at the University of California, Berkeley5,6. Both platforms use CRISPR to offer rapid in vitro identification of target sequences at attomolar sensitivity.

As with any molecular diagnostic, CRISPR tests need sufficient target DNA for detection. For that reason, they often rely on an amplification step before detection. That is most frequently accomplished through polymerase chain reaction (PCR), a tried-and-true method that requires thermocyclers to amplify nucleotide sequences. Unlike true PCR-based diagnostics, such as reverse transcriptase PCR (RT-PCR), CRISPR diagnostics can use other amplification methods, too, which presents an advantage.

“When you start thinking about doing this in a clinician’s office, or in the field, they don’t have thermocyclers,” says Matthew Poling, Product Manager for Genome Editing products at Thermo Fisher Scientific. “For these diagnostics to move into patient-centric point-of-care work, LAMP is becoming more promising.”

LAMP, or loop-mediated isothermal amplification, is an emerging technique that permits the amplification of nucleotide sequences at a constant temperature. Rather that separating double stranded DNA with heat, as in PCR, LAMP requires a DNA polymerase, such as EquiPhi29 or Bsm DNA polymerase, to actively ‘unzip’ and amplify double stranded DNA. The technique can also be adapted to detect RNA sequences.

Along with CRISPR reagents, Thermo Fisher Scientific offers various LAMP polymerases as lyophilization-compatible enzymes. These lyo-ready enzymes are glycerol-free and remain stable when shipped and stored, making them better suited for use in the field or at the point-of-care.

Using CRISPR for cancer diagnostics
Among the clinical fields that might benefit from CRISPR diagnostics, oncology is perhaps the largest. While it’s not yet possible to walk into a doctor’s office and ask for a CRISPR test, researchers are working on it. In a proof-of-principle experimental setting, scientists used the SHERLOCK platform to detect known cancer mutations5. Others are taking different approaches.

Harveer Dev, a clinical lecturer and group leader in the Early Detection Programme at the Cancer Research UK Cambridge Centre, is currently working to analyse and identify prevalent biomarkers in prostate cancer. He is developing a CRISPR-based platform called ProCASP that can map genetic variants in individual tumours to help predict their susceptibility to certain drugs.

“The aim of it,” Dev says, “is to map the functional contribution of specific genes within an individual patient’s tumours.” Dev says that he hopes his work will eventually translate into a diagnostic that informs a patient’s treatment plan.

“If there were another layer of information that we could add to that,” he says, “we think that’s going to be quite important in shaping the specific treatment that individual patients receive.”

In cancer and elsewhere, CRISPR diagnostics still face challenges. For example, current CRISPR diagnostics cannot yet be leveraged in a high-throughput setting. Also, all CRISPR-based diagnostic platforms require a single known target sequence, which can be particularly challenging in certain cancers and other multifactorial inherited disorders. Until CRISPR tools have advanced to be applied to multiple genes at once, diagnoses that require this type of multiplexing may be more suited to next-generation sequencing tools.

Next generation sequencing in diagnostics
Like CRISPR, next-generation sequencing (NGS) technologies have quickly advanced from a standard research application to a complex diagnostic tool.

“When NGS became affordable, it enabled hypothesis-free experiments, where you don’t need to know what you’re looking for,” says Žana Kapustina, R&D manager at Thermo Fisher Scientific in Vilnius, Lithuania.

Today, rapid parallel sequencing enables researchers to seek out unknown genetic variants, as in rare diseases, or screen for a panel of possible genetic variants all at once. The method has become foundational to oncology, namely in the development of liquid biopsies or companion diagnostics for precision therapies, and it is being investigated for applications in the diagnosis of hereditary hearing and vision loss, genetic cardiomyopathies and autosomal dominant polycystic kidney disease, among others. NGS also permits single cell sequencing, which allows the discovery of biomarkers at the level of an individual cell.

NGS techniques are, at this point, well codified, but a few persistent challenges remain for researchers. One is library preparation. In any NGS screen, researchers start by fragmenting sample DNA into small segments and labelling them for easy identification. The fragments are then sequenced and the results are analysed. That can be a time-consuming process.

“Unfortunately,” Kapustina says, “we cannot skip library prep, but we’re trying to make those workflows as compact and convenient as possible.” Thermo Fisher offers a range of standardized reagents that support library preparation for both Ion Torrent and Illumina sequencers, along with expert-led services for those developing specific diagnostics.

Another challenge for researchers is sample stability. “It’s very important for people using liquid handlers or robotic systems, as they [add their samples and] leave it for a period of time—up to a few days,” says Sigita Činčiūtė, product manager at Thermo Fisher in Vilnius. Thermo Fisher actively consults with researchers to help them build workflows and diagnostics that will take such considerations into account.

Expanding the diagnostic toolkit
The arrival of technologies suitable for molecular diagnostics is not very common. The molecular diagnostics market is still dominated by decades-old PCR and ELISA tests. The development of CRISPR and NGS diagnostics presents a rare chance to expand that portfolio.

Both techniques have proven easy to adapt and scale, allowing for the rapid development and testing of diagnostic candidates, and they are both relatively low cost, making them more palatable for insurers and health systems. They also complement each other. NGS allows for the identification of unknown variants or the screening for several known biomarkers at once. Single-sequence CRISPR diagnostics are well-suited for use in the field or point-of-care.

It’s unlikely that CRISPR and NGS diagnostics will supplant more established methods. Rather they will almost certainly expand access to different kinds of diagnostic information presently out of reach. Dev, for his part, is already using multiple tools to diagnose prostate cancer.

“Whatever diagnostic tool we end up relying upon, it’s going to be multimodal,” he says. “None of these tools are likely to exist in isolation”

That is good news for those pursuing molecular diagnostics, or for the development of CRISPR and NGS applications even further afield in agriculture or biofuels. But most importantly, it is good news for patients.

January 13, 2024 — Facts checked

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24/07/2024

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