A study led by UT Southwestern and Children’s Health researchers defines parameters for the number of white blood cells that must be present in children’s urine at different concentrations to suggest a urinary tract infection (UTI). The findings, published recently in Pediatrics, could help speed treatment of this common condition and prevent potentially lifelong complications.
UTIs account for up to 7 percent of fevers in children up to 24 months old and are a common driver of hospital emergency room visits. However, says study leader Shahid Nadeem, M.D., assistant professor of pediatrics at UTSW as well as an emergency department physician and pediatric nephrologist at Children’s Medical Center Dallas, these bacterial infections in infants and toddlers can be difficult to diagnose because their symptoms are similar to other fever-causing conditions.
If a diagnosis is delayed, he explains, a UTI can develop into a serious infection that can cause lasting consequences. For example, UTI-related kidney scarring has been linked with hypertension and chronic kidney disease later in life.
To diagnose a UTI, doctors must culture a urine sample and wait for it to grow telltale bacteria in a petri dish containing nutrients. However, says Nadeem, this process can take up to two days, delaying treatment. Consequently, he and other doctors typically rely on testing urine for a white blood cell-linked protein known as leukocyte esterase (LE), then confirm the presence of white blood cells — a sign of immune activity — by looking for them in urine under a microscope.
In children, he adds, the number of white blood cells can be highly variable, with some of this variation potentially due to varying urine concentration. As such, it’s been unknown what white blood cell number threshold should be used to begin treating a suspected UTI based on urine concentration.
To determine these parameters, Nadeem and his colleagues searched medical records of children younger than 24 months old who were brought to the emergency department at Children’s Medical Center between January 2012 and December 2017 with a suspected UTI and had both a urinalysis — in which their urine concentration and the presence of LE and white blood cells were assessed — and a urine culture. The search turned up 24,171 patients, 2,003 of whom were diagnosed with a UTI based on urine culture.
Using their urine’s specific gravity — the density of urine compared with water, a measurement that serves as a surrogate for concentration — and the number of white blood cells present in the field of a high-power microscope, the researchers came up with cutoff points for three urine concentration groups: For low urine concentrations, children needed only three white blood cells to suspect UTI; for moderate concentrations, that number was six; and for high concentrations, it was eight.
For each of these concentration groups, leukocyte esterase remained constant, says Nadeem — suggesting that it’s a good trigger for analyzing urine for the presence of white blood cells.
Knowing how many white blood cells tend to be present in urine samples at different concentrations in children with UTIs could help physicians start treating these infections before they receive urine culture results, he adds, giving relief to patients and their parents and preventing complications.
“The earlier we can start treatment, the better it is for these young patients,” Nadeem says. “Our results add more information to physicians’ toolboxes to make this decision.”
Other UTSW/Children’s Health researchers who contributed to this study include Mohamed Badawy, Oluwaseun Oke, Laura M. Filkins, Jason Y. Park, and Halim M. Hennes.

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A new study of the U.K. and South Africa variants of SARS-CoV-2 predicts that current vaccines and certain monoclonal antibodies may be less effective at neutralizing these variants and that the new variants raise the specter that reinfections could be more likely.
The study was published in Nature on March 8, 2021. A preprint of the study was first posted to BioRxiv on January 26, 2021.
The study’s predictions are now being borne out with the first reported results of the Novavax vaccine, says the study’s lead author David Ho, MD. The company reported on Jan. 28 that the vaccine was nearly 90% effective in the company’s U.K. trial, but only 49.4% effective in its South Africa trial, where most cases of COVID-19 are caused by the B.1.351 variant.
“Our study and the new clinical trial data show that the virus is traveling in a direction that is causing it to escape from our current vaccines and therapies that are directed against the viral spike,” says Ho, the director of the Aaron Diamond AIDS Research Center and the Clyde’56 and Helen Wu Professor of Medicine at Columbia University Vagelos College of Physicians and Surgeons.
“If the rampant spread of the virus continues and more critical mutations accumulate, then we may be condemned to chasing after the evolving SARS-CoV-2 continually, as we have long done for influenza virus,” Ho says. “Such considerations require that we stop virus transmission as quickly as is feasible, by redoubling our mitigation measures and by expediting vaccine rollout.”
After vaccination, the immune system responds and makes antibodies that can neutralize the virus.

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Ho and his team found that antibodies in blood samples taken from people inoculated with the Moderna or Pfizer vaccine were less effective at neutralizing the two variants, B.1.1.7, which emerged last September in England, and B.1.351, which emerged from South Africa in late 2020. Against the U.K. variant, neutralization dropped by roughly 2-fold, but against the South Africa variant, neutralization dropped by 6.5- to 8.5-fold.
“The approximately 2-fold loss of neutralizing activity against the U.K. variant is unlikely to have an adverse impact due to the large ‘cushion’ of residual neutralizing antibody activity,” Ho says, “and we see that reflected in the Novavax results where the vaccine was 85.6% effective against the U.K. variant.”
Data from Ho’s study about the loss in neutralizing activity against the South Africa variant are more worrisome.
“The drop in neutralizing activity against the South Africa variant is appreciable, and we’re now seeing, based on the Novavax results, that this is causing a reduction in protective efficacy,” Ho says.
The new study did not examine the more recent variant found in Brazil (B.1.1.28) but given the similar spike mutations between the Brazil and South Africa variants, Ho says the Brazil variant should behave similarly to the South Africa variant.

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“We have to stop the virus from replicating and that means rolling out vaccine faster and sticking to our mitigation measures like masking and physical distancing. Stopping the spread of the virus will stop the development of further mutations,” Ho says.
The study also found that certain monoclonal antibodies used now to treat COVID patients may not work against the South Africa variant. And based on results with plasma from COVID patients who were infected earlier in the pandemic, the B.1.351 variant from South Africa has the potential to cause reinfection.
New study contains comprehensive analysis of variants
The new study conducted an extensive analysis of mutations in the two SARS-CoV-2 variants compared to other recent studies, which have reported similar findings.
The new study examined all mutations in the spike protein of the two variants. (Vaccines and monoclonal antibody treatments work by recognizing the SARS-CoV-2 spike protein.)
The researchers created SARS-CoV-2 pseudoviruses (viruses that produce the coronavirus spike protein but cannot cause infection) with the eight mutations found in the U.K. variant and the nine mutations found in the South African variant.
They then measured the sensitivity of these pseudoviruses to monoclonal antibodies developed to treat COVID patients, convalescent serum from patients who were infected earlier in the pandemic, and serum from patients who have been vaccinated with the Moderna or Pfizer vaccine.
Implications for monoclonal antibody treatments
The study measured the neutralizing activity of 18 different monoclonal antibodies — including the antibodies in two products authorized for use in the United States.
Against the U.K. variant, most antibodies were still potent, although the neutralizing activity of two antibodies in development was modestly impaired.
Against the South Africa variant, however, the neutralizing activity of four antibodies was completely or markedly abolished. Those antibodies include bamlanivimab (LY-CoV555, approved for use in the United States) that was completely inactive against the South Africa variant, and casirivimab, one of the two antibodies in an approved antibody cocktail (REGN-COV) that was 58-fold less effective at neutralizing the South Africa variant compared to the original virus. The second antibody in the cocktail, imdevimab, retained its neutralizing ability, as did the complete cocktail.
“Decisions of the use of these treatments will depend heavily on the local prevalence of the South Africa and Brazil variants,” Ho says, “highlighting the importance of viral genomic surveillance and proactive development of next-generation antibody therapeutics.”
Reinfection implications
Serum from most patients who had recovered from COVID earlier in the pandemic had 11-fold less neutralizing activity against the South Africa variant and 4-fold less neutralizing activity against the U.K. variant.
“The concern here is that reinfection might be more likely if one is confronted with these variants, particularly the South Africa one,” Ho says.

An analysis of several large studies involving participants from more than 60 countries, spearheaded by researchers from McMaster University, has found that eating oily fish regularly can help prevent cardiovascular disease (CVD) in high-risk individuals, such as those who already have heart disease or stroke.
The critical ingredient is omega-3 fatty acids, which researchers found was associated with a lower risk of major CVD events such as heart attacks and strokes by about a sixth in high-risk people who ate two servings of fish rich in omega-3 each week.
“There is a significant protective benefit of fish consumption in people with cardiovascular disease,” said lead co-author Andrew Mente, associate professor of research methods, evidence, and impact at McMaster and a principal investigator at the Population Health Research Institute.
No benefit was observed with consumption of fish in those without heart disease or stroke.
“This study has important implications for guidelines on fish intake globally. It indicates that increasing fish consumption and particularly oily fish in vascular patients may produce a modest cardiovascular benefit.”
Mente said people at low risk for cardiovascular disease can still enjoy modest protection from CVD by eating fish rich in omega-3, but the health benefits were less pronounced than those high-risk individuals.
The study was published in JAMA Internal Medicine on March 8.
The findings were based on data from nearly 192,000 people in four studies, including about 52,000 with CVD, and is the only study conducted on all five continents. Previous studies focused mainly on North America, Europe, China and Japan, with little information from other regions.
“This is by far the most diverse study of fish intake and health outcomes in the world and the only one with sufficient numbers with representation from high, middle and low income countries from all inhabited continents of the world,” said study co-lead Dr. Salim Yusuf, professor of medicine at the Michael G. DeGroote School of Medicine and executive director of the PHRI.
This analysis is based in data from several studies conducted by the PHRI over the last 25 years. These studies were funded by the Canadian Institutes for Health Research, several different pharmaceutical companies, charities, the Population Health Research Institute and the Hamilton Health Sciences Research Institute.

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A new study from the University of California, Irvine shows that compounds in both green and black tea relax blood vessels by activating ion channel proteins in the blood vessel wall. The discovery helps explain the antihypertensive properties of tea and could lead to the design of new blood pressure-lowering medications.
Published in Cellular Physiology and Biochemistry, the discovery was made by the laboratory of Geoffrey Abbott, PhD, a professor in the Department of Physiology and Biophysics at the UCI School of Medicine. Kaitlyn Redford, a graduate student in the Abbott Lab, was first author of the study titled, “KCNQ5 potassium channel activation underlies vasodilation by tea.”
Results from the research revealed that two catechin-type flavonoid compounds (epicatechin gallate and epigallocatechin-3-gallate) found in tea, each activate a specific type of ion channel protein named KCNQ5, which allows potassium ions to diffuse out of cells to reduce cellular excitability. As KCNQ5 is found in the smooth muscle that lines blood vessels, its activation by tea catechins was also predicted to relax blood vessels — a prediction confirmed by collaborators at the University of Copenhagen.
“We found by using computer modeling and mutagenesis studies that specific catechins bind to the foot of the voltage sensor, which is the part of KCNQ5 that allows the channel to open in response to cellular excitation. This binding allows the channel to open much more easily and earlier in the cellular excitation process,” explained Abbott.
Because as many as one third of the world’s adult population have hypertension, and this condition is considered to be the number one modifiable risk factor for global cardiovascular disease and premature mortality, new approaches to treating hypertension have enormous potential to improve global public health. Prior studies demonstrated that consumption of green or black tea can reduce blood pressure by a small but consistent amount, and catechins were previously found to contribute to this property. Identification of KCNQ5 as a novel target for the hypertensive properties of tea catechins may facilitate medicinal chemistry optimization for improved potency or efficacy.
In addition to its role in controlling vascular tone, KCNQ5 is expressed in various parts of the brain, where it regulates electrical activity and signaling between neurons. Pathogenic KCNQ5 gene variants exist that impair its channel function and in doing so cause epileptic encephalopathy, a developmental disorder that is severely debilitating and causes frequent seizures. Because catechins can cross the blood-brain barrier, discovery of their ability to activate KCNQ5 may suggest a future mechanism to fix broken KCNQ5 channels to ameliorate brain excitability disorders stemming from their dysfunction.
Tea has been produced and consumed for more than 4,000 years and upwards of 2 billion cups of tea are currently drunk each day worldwide, second only to water in terms of the volume consumed by people globally. The three commonly consumed caffeinated teas (green, oolong, and black) are all produced from the leaves of the evergreen species Camellia sinensis, the differences arising from different degrees of fermentation during tea production.
Black tea is commonly mixed with milk before it is consumed in countries including the United Kingdom and the United States. The researchers in the present study found that when black tea was directly applied to cells containing the KCNQ5 channel, the addition of milk prevented the beneficial KCNQ5-activating effects of tea. However, according to Abbott, “We don’t believe this means one needs to avoid milk when drinking tea to take advantage of the beneficial properties of tea. We are confident that the environment in the human stomach will separate the catechins from the proteins and other molecules in milk that would otherwise block catechins’ beneficial effects.”
This hypothesis is borne out by other studies showing antihypertensive benefits of tea regardless of milk co-consumption. The team also found, using mass spectrometry, that warming green tea to 35 degrees Celsius alters its chemical composition in a way that renders it more effective at activating KCNQ5.
“Regardless of whether tea is consumed iced or hot, this temperature is achieved after tea is drunk, as human body temperature is about 37 degrees Celsius,” explained Abbott. “Thus, simply by drinking tea we activate its beneficial, antihypertensive properties.”
This study was supported in part by the National Institutes of Health, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, the Lundbeck Foundation and the Danmarks Frie Forskningsfond.

A new type of CAR T-cell therapy more than triples the expected length of remission for multiple myeloma patients who have relapsed several times, according to an international clinical trial with UT Southwestern as the lead enrolling site.
Results of the trial, published recently in the New England Journal of Medicine, were significantly better than those seen with other therapies available to heavily relapsed and refractory myeloma patients who had already received the three main classes of treatment. Nearly three-quarters of the patients had at least a partial response to the therapy. About a third achieved a complete remission, with the disappearance of all traces of cancer.
Median time without the disease worsening was 8.8 months with this new treatment, but Larry D. Anderson Jr., M.D., Ph.D., associate professor of internal medicine and co-first author of the journal article, points out that patients who received the trial’s maximum dose of engineered T-cells experienced longer remissions, bringing the average to more than 12 months. Previously, similar patients treated with currently available therapies following multiple relapses have only had an average of three to four months of remission before their disease returned.
“We have patients that are over two years out from their single infusion of CAR T-cells and still in remission despite having no other treatment options when they were enrolled in this trial,” says Anderson, a member of the Harold C. Simmons Comprehensive Cancer Center who cares exclusively for patients with plasma cell disorders, mostly myeloma patients. “The results mark a true breakthrough with unprecedented depth and duration of remissions from what we hope will be the first cellular therapy option to become available for myeloma patients. Even though we don’t yet know if some of these patients may be cured, and many relapse within one to two years, it can at least buy many patients time until other treatment options become available. Most patients also have good quality of life with relatively low risk of severe CAR T-cell-related side effects.”
Multiple myeloma, the second most common blood cancer, is a cancer of plasma cells, a white blood cell important in the immune system. The disease’s attack on bone marrow puts patients at risk of life-threatening infections. It is diagnosed in more than 32,000 people a year, and African Americans are twice as likely as the general population to be diagnosed with this disease.
Three main classes of treatment are available now for multiple myeloma: drugs called proteasome inhibitors, drugs to modulate the immune system, and antibody treatments. Among more than a dozen new therapies for myeloma approved by the Food and Drug Administration over the past decade, most offer only a few months of remission for patients with multiple relapses. Until now, most treatments induce responses in only a third of patients, and complete remissions are rare.

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The phase 2 trial involved 128 patients, ages 18 and older, who previously had been given regimens from the three main classes of treatment. The patients received a median of six previous antimyeloma regimens; 120 formerly had undergone stem cell transplantation.
The clinical trial included nine sites in the U.S., one in Canada, and 10 sites in five European countries. Several patients traveled from as far away as Michigan and Minnesota to UT Southwestern’s Dallas campus to be part of the trial.
Study participants had their T-cells engineered to target a molecule called B-cell maturation antigen, or BCMA, which is only found in plasma cells and myeloma cells. This new T-cell therapy for myeloma patients is called idecabtagene vicleucel, or ide-cel. It is also known as bb2121.
The infusions of the engineered cells started a two-week hospitalization period during which doctors watched for possible side effects such as anemia; neutropenia, a drop in a type of white blood cells; and thrombocytopenia, a drop in blood platelets. Although low blood counts were common, they were manageable, and other severe side effects were uncommon.
“One of the nice things we saw in this study was that the rates of severe CAR T-cell-related toxicities — called neurotoxicity and cytokine release syndrome — were very low in multiple myeloma compared to what we have seen with lymphoma CAR T-cell infusions,” Anderson says. “The majority of people had some side effects, but most were low level and manageable, and I would say this therapy is often much better tolerated than a stem cell transplant, which most of these patients had already gone through.”
Pioneered in the late 1980s, CAR T-cell therapy is a promising and still emerging treatment for blood cancers. CAR, which stands for chimeric antigen receptor, takes part of its name from the chimera, the mythical animal with the tail of a serpent and head of a lion. In modern medicine’s version of the chimera, the head is an antibody, and the tail is a T-cell receptor. CAR T-cell therapy involves harvesting a patient’s own T-cells by withdrawing blood, reengineering them in a lab to have this cancer-fighting chimera, and then growing hundreds of millions of them to put back into the patient by infusion.
CAR T-cell therapy is currently approved for use only in lymphoma and leukemia. Several different CAR T-cell treatments for myeloma are in clinical trials, but this CAR T-cell treatment is the first to complete and publish data from an FDA registration trial. Based on these results, the pharmaceutical companies Bristol Myers Squibb and bluebird bio are seeking FDA approval of ide-cel as a standard therapy for relapsed myeloma with a decision expected by the end of March.
The trial was funded by bluebird bio and Celgene, a Bristol Myers Squibb company. Anderson is a consultant who serves on an advisory board for Celgene and has other consulting activities disclosed in the manuscript.

Deep learning is a potential tool for scientists to glean more detail from low-resolution images in microscopy, but it’s often difficult to gather enough baseline data to train computers in the process. Now, a new method developed by scientists at the Salk Institute could make the technology more accessible — by taking high-resolution images, and artificially degrading them.
The new tool, which the researchers call a “crappifier,” could make it significantly easier for scientists to get detailed images of cells or cellular structures that have previously been difficult to observe because they require low-light conditions, such as mitochondria, which can divide when stressed by the lasers used to illuminate them. It could also help democratize microscopy, allowing scientists to capture high-resolution images even if they don’t have access to powerful microscopes. The findings were published March 8, 2021, in the journal Nature Methods.
“We invest millions of dollars in these microscopes, and we’re still struggling to push the limits of what they can do,” says Uri Manor, director of the Waitt Advanced Biophotonics Core Facility at Salk. “That’s the problem we were trying to solve with deep learning.”
Deep learning is a type of artificial intelligence (AI) in which computer algorithms learn and improve by studying examples. To use deep learning to improve microscope images — either by improving the resolution (sharpness) or reducing background “noise” — the system would need to be shown many examples of both high- and low-resolution images. That’s a problem, because capturing perfectly identical microscopy images in two separate exposures can be difficult and expensive. It’s especially challenging when imaging living cells that might be moving around during the process.
That’s where the crappifier comes in. According to Manor, the method takes high-quality images and computationally degrades them, so that they look something like the lowest low-resolution images the team would acquire.
Manor’s team showed high-resolution images and their degraded counterparts to the deep learning software, called Point-Scanning Super-Resolution, or PSSR. After studying the degraded images, the system was able to learn how to improve images that were naturally poor quality.
That’s significant because, in the past, computer systems that learned on artificially-degraded data still struggled when presented with raw data from the real world.
“We tried a bunch of different degradation methods, and we found one that actually works,” Manor says. “You can train a model on your artificially-generated data, and it actually works on real-world data.”
“Using our method, people can benefit from this powerful, deep learning technology without investing a lot of time or resources,” says Linjing Fang, image analysis specialist at the Waitt Advanced Biophotonics Core Facility, and lead author on the paper. “You can use pre-existing high-quality data, degrade it, and train a model to improve the quality of a lower-resolution image.”
The team showed that PSSR works in both electron microscopy and with fluorescence live cell images — two situations where it can be extraordinarily difficult or impossible to obtain the duplicate high- and low-resolution images needed to train AI systems. While the study demonstrated the method on images of brain tissue, Manor hopes it could be applied to other systems of the body in the future.
He also hopes it could someday be used to make high-resolution microscopic imaging more widely accessible. Currently, the most powerful microscopes in the world can cost upwards of a million dollars, because of the precision engineering required to create high-resolution images. “One of our visions for the future is to be able to start replacing some of those expensive components with deep learning,” Manor says, “So we could start making microscopes cheaper and more accessible.”

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