Tag Archives: #urine

Scientists Can Detect Brain Tumours Using A Simple Urine Or Blood Plasma Test (Medicine)

Researchers from the Cancer Research UK Cambridge Institute have developed two tests that can detect the presence of glioma, a type of brain tumour, in patient urine or blood plasma.

The team say that a test for detecting glioma using urine is the first of its kind in the world.

Although the research, published in EMBO Molecular Medicine, is in its early stages and only a small number of patients were analysed, the team say their results are promising.

The researchers suggest that in the future, these tests could be used by GPs to monitor patients at high risk of brain tumours, which may be more convenient than having an MRI every three months, which is the standard method.

When people have a brain tumour removed, the likelihood of it returning can be high, so they are monitored with an MRI scan every three months, which is followed by biopsy.

Blood tests for detecting different cancer types are a major focus of research for teams across the world, and there are some in use in the clinic. These tests are mainly based on finding mutated DNA, shed by tumour cells when they die, known as cell-free DNA (cfDNA).

However, detecting brain tumour cfDNA in the blood has historically been difficult because of the blood-brain-barrier, which separates blood from the cerebrospinal fluid (CSF) that surrounds the brain and spinal cord, preventing the passage of cells and other particles, such as cfDNA.

Researchers have previously looked at detecting cfDNA in CSF, but the spinal taps needed to obtain it can be dangerous for people with brain tumours so are not appropriate for patient monitoring.

Scientists have known that cfDNA with similar mutations to the original tumour can be found in blood and other bodily fluids such as urine in very low levels, but the challenge has been developing a test sensitive enough to detect these specific mutations.

The researchers, led by Dr Florent Mouliere who is based at the Rosenfeld Lab of the Cancer Research UK Cambridge Institute and at the Amsterdam UMC, and Dr Richard Mair, who is based at Cancer Research UK Cambridge Institute and the University of Cambridge developed two approaches in parallel to overcome the challenge of detecting brain tumour cfDNA.

The first approach works for patients who have previously had glioma removed and biopsied. The team designed a tumour-guided sequencing test that was able to look for the mutations found in the tumour tissue within the cfDNA in the patient’s urine, CSF, and blood plasma.

A total of eight patients who had suspected brain tumours based on MRIs were included in this part of the study. Samples were taken at their initial brain tumour biopsies, alongside CSF, blood and urine samples.

By knowing where in the DNA strand to look, the researchers found that it was possible to find mutations even in the tiny amounts of cfDNA found in the blood plasma and urine.

The test was able to detect cfDNA in 7 out of 8 CSF samples, 10 out of the 12 plasma blood samples and 10 out of the 16 urine samples.

For the second approach the researchers looked for other patterns in the cfDNA that could also indicate the presence of a tumour, without having to identify the mutations.

They analysed 35 samples from glioma patients, 27 people with non-malignant brain disorders, and 26 healthy people. They used whole genome sequencing, where all the cfDNA of the tumour is analysed, not just the mutations.

They found in the blood plasma and urine samples that fragments of cfDNA, which came from patients with brain tumours were different sizes than those from patients with no tumours in CSF. They then fed this data into a machine learning algorithm which was able to successfully differentiate between the urine samples of people with and without glioma.

The researchers say that while the machine learning test is cheaper and easier, and a tissue biopsy from the tumour is not needed, it is not as sensitive and is less specific than the first tumour-guided sequencing approach.

MRIs are not invasive or expensive, but they do require a trip to the hospital, and the three-month gap between checks can be a regular source of anxiety for patients.

The researchers suggest that their tests could be used between MRI scans, and could ultimately be able to detect a returning brain tumour earlier.

The next stage of this research will see the team comparing both tests against MRI scans in a trial with patients with brain tumours who are in remission to see if it can detect if their tumours are coming back at the same time or earlier than the MRI. If the tests prove that they can detect brain tumours earlier than an MRI, then the researchers will look at how they can adapt the tests so they could be offered in the clinic, which could be within the next ten years.

“We believe the tests we’ve developed could in the future be able to detect a returning glioma earlier and improve patient outcomes,” said Mair. “Talking to my patients, I know the three-month scan becomes a focal point for worry. If we could offer a regular blood or urine test, not only will you be picking up recurrence earlier, you can also be doing something positive for the patient’s mental health.”

Michelle Mitchell, Chief Executive of Cancer Research UK said, “While this is early research, it’s opened up the possibility that within the next decade we could be able to detect the presence of a brain tumour with a simple urine or blood test. Liquid biopsies are a huge area of research interest right now because of the opportunities they create for improved patient care and early diagnosis. It’s great to see Cancer Research UK researchers making strides in this important field.”

Sue Humphreys, from Wallsall, a brain tumour patient, said: “If these tests are found to be as accurate as the standard MRI for monitoring brain tumours, it could be life changing.

If patients can be given a regular and simple test by their GP, it may help not only detect a returning brain tumour in its earliest stages, it can also provide the quick reassurance that nothing is going on which is the main problem we all suffer from, the dreaded Scanxiety.

The problem with three-monthly scans is that these procedures can get disrupted by other things going on, such as what we have seen with the Covid pandemic. As a patient, this causes worry as there is a risk that things may be missed, or delayed, and early intervention is the key to any successful treatment.”


Reference:
Florent Mouliere et al. ‘Fragmentation patterns and personalized sequencing of cell-free DNA in urine and plasma of glioma patients.’ EMBO Molecular Medicine (2021). DOI: 10.15252/emmm.202012881


Provided by University of Cambridge

Oncotarget: Urine Protein Biomarkers Of Bladder Cancer (Medicine)

These Oncotarget findings suggest that urine IL-1α, IL-1ra and IL-8 are useful indicators of bladder cancer.

Oncotarget published “Urine protein biomarkers of bladder cancer arising from 16-plex antibody-based screens” which reported that the current study examines urine samples from 66 subjects, comprising of 31 Urology clinic controls and 35 bladder cancer patients, using a Luminex based screening platform.

ELISA validation was carried out for the top 4 prospective urine biomarkers using an independent cohort of 20 Urology clinic controls and 60 bladder cancer subjects.

Eight of these urine proteins were able to differentiate BC from control urine with ROC AUC values exceeding 0.70 at p < 0.0001, with specificity values exceeding 0.9. Upon ELISA validation, urine IL-1α, IL-1ra, and IL-8 were able to distinguish control urine from urine drawn from various bladder cancer stages, with IL-8 being the best discriminator.

These Oncotarget findings suggest that urine IL-1α, IL-1ra and IL-8 are useful indicators of bladder cancer.

These Oncotarget findings suggest that urine IL-1α, IL-1ra and IL-8 are useful indicators of bladder cancer.

Urine IL-8 not only distinguishes bladder cancer from controls, it also discriminates high grade from low grade disease, and the successive clinical stages of bladder cancer.

Dr. Chandra Mohan from The University of Houston said, “Bladder cancer (BC) is the sixth most common cancer diagnosis in the United States and is over four times more common in men than women.

Urine biomarkers could potentially provide preliminary confirmation of low-grade BC before invasive procedures are performed and facilitate surveillance of BC, as reviewed.

The present study implements a Luminex based screening platform with a cytokine/chemokine panel that simultaneously interrogates 16 urine biomarkers, followed by ELISA validation of 4 prospective urine biomarkers.

Of the 16 proteins screened by Luminex, 12 were within the detectable range and among these, 10 urine biomarkers showed significant elevation in BC compared to the controls.

ELISA validation for these 4 urine biomarkers was carried out using an independent cohort of 20 urology clinic controls and 60 BC subjects.

Of these 4 proteins, IL-8 displayed the highest significance in discriminating between controls and BC patients and discriminating highly advanced stages/grades of BC from less advanced stages/grades of BC.

The Mohan Research Team concluded in their Oncotarget Research Output that these studies indicate that urine IL-1α, IL-1ra, and IL-8 are potential biomarkers of BC, two of which re-affirm previous reports.

These studies shed additional light on the potential utility of these markers, since some of them also exhibit the ability to discriminate T1 and/or T2-T4 from Ta BC, as well as high grade from low grade BC.

Looking forward, systematic studies in larger patient cohorts are warranted to establish the specific clinical contexts in which these markers may be used, including the following: for initial diagnosis of BC, for surveillance of tumor recurrence, and/or for assessing treatment response following BCG therapy or other therapeutic modalities.

Finally, these newer urine biomarkers need to be compared against the performance of current yardsticks such as the Bladderchek and UroVysion FISH assay.

DOI – https://doi.org/10.18632/oncotarget.27941

Full text – https://www.oncotarget.com/article/27941/text/

Featured image: ROC-AUC curves for urine IL-8 in distinguishing different stages of bladder cancer. ROC-AUC curves were generated for urine IL-8 to determine its discriminatory capability among different BC groups. AUC values and p-values are listed on each curve. The closer the AUC value is to 1, the higher the discriminatory potential of the protein to distinguish between the two sample groups, with maximized sensitivity and specificity. All comparisons exhibited AUC values of 0.77 or higher, with p-values < 0.0001, except for the comparison between low grade versus urology clinic controls. © Correspondence to – Chandra Mohan – cmohan@central.uh.edu


Reference: Vanarsa K., Enan S., Patel P., Strachan B., Sam Titus A. Sam Crosslee Louis, Dennis A., Lotan Y., Mohan C. Urine protein biomarkers of bladder cancer arising from 16-plex antibody-based screens. Oncotarget. 2021; 12: 783-790. Retrieved from https://www.oncotarget.com/article/27941/text/


Provided by Impact Journals LLC

Urine of COVID-19 Patients Could Predict Who Will Develop Severe Disease (Medicine)

Inflammatory markers were higher in people with high blood pressure and diabetes

Urine analysis of COVID-19 patients revealed elevated levels of specific biomarkers of the immune system compared to those who were not infected with the coronavirus. In addition, levels of these inflammatory markers were higher in patients with comorbidities such as high blood pressure and diabetes, according to researchers from Wayne State University in Detroit. The findings will be presented virtually at the American Physiological Society’s (APS) annual meeting at Experimental Biology 2021.

Researchers said they undertook this study in hopes of determining whether biomarkers of COVID-19 could predict which individuals will develop “overly exuberant immune responses,” also called a cytokine storm. They chose to screen the urine of COVID-19 patients because of its non-invasive nature that doesn’t require the use of needles or blood samples.

Scientists said they hope the results of this study will translate to a regular screening process for COVID-19 patients to predict who is more likely to develop severe disease and to aid in a successful treatment strategy.

NOTE TO JOURNALISTS: To schedule an interview with a member of the research team, and/or request the abstract, “Urine cytokines as biomarkers in COVID-19 patients,” please contact the APS Communications Office or call 301.634.7314. Find more research highlights in the APS Newsroom.

Featured image: Dragana Komnenov, PhD, Wayne State University, Detroit © Dragana Komnenov


Provided by American Physiological Society


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TGen-led Study Confirms Cell-free DNA in Urine As Potential Method for Cancer Detection (Medicine)

If successful, non-invasive method could transform detection and treatment outcomes

Urinalysis has long been a staple of physical exams to detect and manage a number of diseases and disorders, but not cancer. What if it were that easy, though, and cancer was detected in its very earliest stages when the disease responds more favorably to treatment and improved outcomes are more likely?

That was the question posed by scientists at the Translational Genomics Research Institute (TGen), an affiliate of City of Hope, who have found a way of zeroing in on early-stage cancer by analyzing short strands of cell-free DNA in urine. Their study’s findings were published today in the scientific journal Science Translational Medicine.

Previous thought once held that DNA fragments in urine were degraded at random and were too short to provide any meaningful information about a disease as complex as cancer. TGen and City of Hope researchers and their colleagues from Baylor University and Phoenix Children’s Hospital found that these DNA fragments are not random at all, and can clearly indicate a difference between healthy individuals and those with cancer. 

“There are many steps between where we are now and where we want to go — detecting cancer from a urine sample — but without doubt this is an encouraging first step,” said Muhammed Murtaza, M.B.B.S., Ph.D., an Associate Professor and Co-Director of TGen’s Center for Noninvasive Diagnostics, and the study’s senior author.

Dr. Murtaza previously led a team of TGen scientists who pioneered the use of circulating tumor DNA in blood, using genetic fragments to detect cancer with a simple blood draw. This “liquid biopsy” method sidesteps the need for many surgical biopsies of suspected tumors, and means that physicians can monitor cancer in their patients more frequently given the less invasive nature of the procedure.

Collecting a urine sample reduces the physical invasiveness to zero, Dr. Murtaza explained, and may eliminate a lab visit, given that the sample could be collected at home and mailed in for analysis.

By studying tissue samples from children with various cancers, whose malignancies often move extraordinarily fast, and adults with pancreatic cancer, whose early detection is critical to their disease outcomes, researchers mapped the DNA fragmentation profiles in their urine.

“We found that certain regions of the genome are protected from fragmentation in urine from healthy individuals, but the same regions are more fragmented in patients with cancer,” Dr. Murtaza said.

The fragmentation profiles were remarkably similar across multiple individuals; the length of the DNA fragments were similar, the regions of the genome where the fragmentation occurred were consistent, and informed researchers what type of cells contributed the fragments.

Ajay Goel, Ph.D., chair of the Department of Molecular Diagnostics and Experimental Therapeutics and Associate Director for Basic Science at City of Hope, a world-renowned independent research and treatment center for cancer and diabetes, is one of the study’s authors. He is a leading expert in developing early-detection blood tests for colon, pancreatic and ovarian cancers.

“If the study results come to fruition, our urinalysis technology would be a remarkable breakthrough in the detection of many cancers, especially in pancreatic cancer,” Dr. Goel said. “If cancer is detected early, it could substantially lower the mortality rate for what is currently the third leading cause of cancer death in the U.S.”

While early results are promising, the researchers indicate the need to test their findings in much larger populations of cancer patients and identify differences between men and women, young and old, and those with co-morbidities, such as diabetes and other chronic diseases.

“This is a fundamental new finding and provides a potentially dynamic path forward for the early diagnosis of cancer, given that urine is one of the easiest samples to collect,” said Daniel D. Von Hoff, M.D., TGen Distinguished Professor and one of the paper’s authors. “If follow-on studies yield positive results, I could one day see this test becoming an integral part of one’s annual physical.”

Support for this study — Analysis of recurrently protected genomic regions in cell-free DNA found in urine — was provided by the Ben and Catherine Ivy Foundation, the National Cancer Institute, Science Foundation Arizona, Arizona Women’s Board, and the Baylor Scott and White Research Institute.

NOTE: See a short video that helps explain the technology behind TGen’s urine cancer test at: 


Provided by Tgen


About TGen, an affiliate of City of Hope

Translational Genomics Research Institute (TGen) is a Phoenix, Arizona-based nonprofit organization dedicated to conducting groundbreaking research with life-changing results. TGen is affiliated with City of Hope, a world-renowned independent research and treatment center for cancer, diabetes and other life-threatening diseases: CityofHope.org.  This precision medicine affiliation enables both institutes to complement each other in research and patient care, with City of Hope providing a significant clinical setting to advance scientific discoveries made by TGen. TGen is focused on helping patients with neurological disorders, cancer, diabetes and infectious diseases through cutting-edge translational research (the process of rapidly moving research toward patient benefit). TGen physicians and scientists work to unravel the genetic components of both common and complex rare diseases in adults and children. Working with collaborators in the scientific and medical communities worldwide, TGen makes a substantial contribution to help our patients through efficiency and effectiveness of the translational process. For more information, visit: tgen.org. Follow TGen on FacebookLinkedIn and Twitter @TGen.

Specific Genes Increase the Risk of Bedwetting (Biology)

In a large-scale study of Danish children and young people, researchers from Aarhus University have for the first time found genetic variants that increase the risk of nocturnal enuresis – commonly known as bedwetting or nighttime incontinence. The findings provide completely new insights into the processes in the body causing this widespread phenomenon.

Researchers have long known that nighttime incontinence is a highly heritable condition. Children who wet the bed at night often have siblings or parents who either suffer from or have suffered from the same condition. But until now, science has been unable to pinpoint the genes concerned.

In collaboration with the Danish research project iPSYCH and a team of international colleagues, researchers from Aarhus University have for the first time identified genetic variants that increase the risk of bedwetting. The results have just been published in the scientific journal The Lancet Child & Adolescent Health.

“As many as sixteen per cent of all seven-year-olds suffer from nocturnal enuresis and although many of them grow out of it, one to two per cent of all young adults still have this problem. It is a serious condition, which can negatively affect children’s self-esteem and well-being. For example, the children may be afraid of being bullied, and often opt out of events that involve overnight stays,” says Jane Hvarregaard Christensen, who is one of the researchers behind the study.

Regulates urine production

In the study, the researchers studied the genes of 3,900 Danish children and young people, who had either been diagnosed with nocturnal enuresis or had taken medication for it. This group was subsequently compared to 31,000 children and young people who did not suffer from the problem.

“We identified two locations in the genome where specific genetic variants increase the risk of bedwetting. The potential causal genes which we point to play roles in relation to ensuring that our brain develops the ability to keep urine production down at night, that the bladder’s activity is regulated and registered, and that we sleep in an appropriate way, among other things,” explains first author of the study, Cecilie Siggaard Jørgensen.

The study also shows that commonly occurring genetic variants can explain up to one-third of the genetic risk of bedwetting. This means that genetic variants which all of us have may lead to involuntary nocturnal enuresis, when they occur in a certain combination.

“But you can still also have all the variants without wetting the bed at night, because there are other risk factors in play that we haven’t mapped yet – both genetic and environmental. So it’s clear that this is very complex and that it’s not possible to talk about a single gene that causes nocturnal enuresis,” says Jane Hvarregaard Christensen.

Particularly vulnerable

The study also shows that children with many genetic variants that increase the risk of ADHD are particularly vulnerable to developing bedwetting.

“Our findings don’t mean that ADHD causes bedwetting in a child, or vice versa, but just that the two conditions have common genetic causes. More research in this area will be able to clarify the details in the biological differences and similarities between the two disorders,” she emphasises.

As the study is a first-time study, the researchers also examined more than 5,500 people from Iceland, where they found that the same genetic variants also appear to increase the risk of nocturnal enuresis.

“This means that we can be more certain that our findings are not coincidental. In the future, we wish to find out whether the same genetic variants increase the risk of bedwetting in children in other parts of the world. Bedwetting is not just an issue in northern European but affects millions of children all over the world,” she says.

The researchers hope to be able to further clarify the causes of nocturnal enuresis. It is very likely that it will be possible to identify even more genes and thereby gain a deeper understanding of what is required for a child to become dry at night.

“At present we still can’t use a child’s genetic profile to predict, for example, whether the child will grow out of its condition or whether a particular treatment works. Perhaps this will be possible in the future when more detailed studies have been conducted,” says Jane Hvarregaard Christensen.

Behind the results

The study is a so-called genome-wide association study (GWAS). By examining thousands of genetic variants spread out in the entire genome, a GWAS makes it possible to point to statistically significant correlations between specific genetic variants and nighttime incontinence in the persons who are examined.

The study is a collaboration between researchers at the Department of Biomedicine, Aarhus University and the Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital. Researchers from the Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, and deCODE genetics have also contributed.

The study is financed by the Lundbeck Foundation and the Stanley Foundation.

Reference: Cecilie S Jørgensen, Veera M Rajagopal, Jakob Grove et al., “Identification of genetic loci associated with nocturnal enuresis: a genome-wide association study”, The Lancet, 2021. https://doi.org/10.1016/S2352-4642(20)30350-3 https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(20)30350-3/fulltext

Provided by Aarhus University

Lipid Biomarkers in Urine Can Determine the Type of Asthma (Medicine)

In a new study, researchers at Karolinska Institutet in Sweden have used a urine test to identify and verify a patient’s type of asthma. The study, which has been published in the American Journal of Respiratory and Critical Care Medicine, lays the foundation for a more personalized diagnosis and may result in improved treatment of severe asthma in the future.

Sven-Erik Dahlén, professor at the Institute of Environmental Medicine, Karolinska Institutet. © Mattias Ahlm

About 10 percent of the Swedish population suffers from asthma, a disease that has become increasingly widespread over the past 50 years, with annual global mortality of around 400,000 according to the World Health Organization. Asthma is characterized by chronic inflammation in the airways, which can result in symptoms including coughing, mucous formation and shortness of breath.

There are many types of asthma, and symptoms can vary between individuals, from mild to severe. Currently, in order to make an asthma diagnosis, a wide-ranging investigation is conducted that can consist of multiple elements including patient interviews, lung function tests, blood tests, allergy investigations and x-rays.

“There are no simple methods to determine what type of asthma an individual has, knowledge that is particularly important in order to better treat patients suffering from the more severe types of the disease,” says Craig Wheelock, associate professor at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, and the last author of the study.

In this new study, research groups at Karolinska Institutet have made an important discovery, which can offer a simple but clear contribution to a correct diagnosis.

Using a mass spectrometry-based methodology developed in the Wheelock laboratory, they were able to measure urinary metabolite levels of certain prostaglandins and leukotrienes –eicosanoid signalling molecules that are known mediators of asthmatic airway inflammation.

“We discovered particularly high levels of the metabolites of the mast cell mediator prostaglandin D2 and the eosinophil product leukotriene C4 in asthma patients with what is referred to as Type 2 inflammation,” says Johan Kolmert, postdoctoral researcher at the Institute of Environmental Medicine, Karolinska Institutet, and first author of the study. “Using our methodology, we were able to measure these metabolites with high accuracy and link their levels to the severity and type of asthma.”

Johan Kolmert, postdoctoral researcher at the Institute of Environmental Medicine, Karolinska Institutet. © Private photo

The study is based on data from the U-BIOPRED study (Unbiased BIOmarkers in PREDiction of respiratory disease outcomes), which was designed to investigate severe asthma. The study included 400 participants with severe asthma, which often requires treatment with corticosteroid tablets, nearly 100 individuals with milder forms of asthma and 100 healthy control participants.

In addition to the increased eicosanoid metabolite levels associated with asthma type and severity, the study shows that measurement using a urine test provides improved accuracy relative to other measurement methods, for example certain kinds of blood tests.

“Another discovery was that levels of these metabolites were still high in patients who were seriously ill, despite the fact that they were being treated with corticosteroid tablets. This highlights the need for alternative treatments for this group of patients,” explains Johan Kolmert.

The researchers were also able to replicate the discovery in urine samples from a study of schoolchildren with asthma, that was conducted by the paediatricians Gunilla Hedlin, Jon Konradsen and Björn Nordlund at Karolinska Institutet.

Craig Wheelock, associate professor at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet. © Antonio Checa

“We could see that those children who had asthma with Type 2 inflammation were displaying the same profiles of metabolites in the urine as adults,” says Sven-Erik Dahlén, professor at the Institute of Environmental Medicine, Karolinska Institutet, who led the work together with Craig Wheelock.

According to the researchers, this study of severe asthma may be the largest evaluation of eicosanoid urinary metabolites conducted worldwide, and may be an important step towards future biomarker-guided precision medicine.

Treatment with steroid inhalers is often sufficient for patients with mild asthma, but for those with severe asthma it may be necessary to supplement with corticosteroid tablets. Corticosteroids are associated with several side-effects, such as high blood pressure, diabetes and harm to the eyes and bones.

“To replace corticosteroid tablets, in recent times several biological medicines have been introduced to treat patients with Type 2 inflammation characterised by increased activation of mast cells and eosinophils,” Sven-Erik Dahlén says. “However, these treatments are very expensive, so it is an important discovery that urine samples may be used to identify precisely those patients who will benefit from the Type 2 biologics.”

The study has been funded by the EU and the IMI, the Swedish Heart-Lung Foundation, the Swedish Research Council and ALF Medicine.

Reference: Kolmert J, Gómez C, Balgoma D, Sjödin M, Bood J, Konradsen JR, Ericsson M, Thörngren JO, James A, Mikus M, Sousa AR, Riley JH, Bates S, Bakke PS, Pandis I, Caruso M, Chanez P, Fowler SJ, Geiser T, Howarth P, Horváth I, Krug N, Montuschi P, Sanak M, Behndig A, Shaw DE, Knowles RG, Holweg CTJ, Wheelock ÅM, Dahlén B, Nordlund B, Alving K, Hedlin G, Chung KF, Adcock IM, Sterk PJ, Djukanovic R, Dahlén SE, Wheelock CE; U-BIOPRED Study Group, on behalf of the U-BIOPRED Study Group. Urinary Leukotriene E4 and Prostaglandin D2 Metabolites Increase in Adult and Childhood Severe Asthma Characterized by Type 2 Inflammation. A Clinical Observational Study. Am J Respir Crit Care Med. 2021 Jan 1;203(1):37-53. doi: 10.1164/rccm.201909-1869OC. PMID: 32667261. https://pubmed.ncbi.nlm.nih.gov/32667261/

Provided by Karolinska Institutet