Hopkins Med News Update

NEWS STORIES IN THIS ISSUE:

• Study: Race and Ethnicity May Impact Prevalence and Treatment of Heart Valve Dysfunction
• Johns Hopkins Medicine Suggests Eliminating Nerve Cell Protein May Stop ALS, Dementia
• Researchers Tell Doctors to Avoid Routine Urinary Tests for Older Patients with Delirium
• Johns Hopkins Medicine Researchers Show How Air Pollution May Cause Chronic Sinusitis
• Researchers ID Location on Brain Protein Linked to Parkinson’s Disease Development
• COVID-19 News: The Return of Onsite Schooling — and How to Keep Your Kids Safe from COVID

STUDY: RACE AND ETHNICITY MAY IMPACT PREVALENCE AND TREATMENT OF HEART VALVE DYSFUNCTION

Media Contact: Brian H. Waters, [email protected]

Heart surgery has a history of racial inequities regarding diagnosis, treatment and outcomes. To determine if inequities might exist for one of the more common cardiac procedures — heart valve replacement — Johns Hopkins Medicine researchers looked at patients in Maryland who received diagnoses of faulty valves over a two-year period and then had them replaced.

The researchers say their findings suggest that there may be racial differences in the prevalence or severity of aortic stenosis — when the aortic valve stiffens and becomes less functional — and that cultural or socioeconomic issues may factor into who gets treated for the condition.

In their study published July 15, 2021, in the Journal of the American Heart Association, the researchers found that for aortic stenosis, hospitalized Black patients were diagnosed at half the rate and Hispanic patients at a quarter of the rate of white patients with the condition. Among all patients with aortic stenosis, fewer Black patients had curative procedures.

“We became interested in looking at the demographics of aortic stenosis, because anecdotally, we noticed fewer Black people in our heart valve clinic compared to the population of Baltimore, or even that in Maryland,” says Matthew Czarny, M.D., assistant professor of medicine and an interventional cardiologist at the Johns Hopkins University School of Medicine. “We wanted to make sure we were doing our due diligence and not missing a large population of patients with aortic stenosis, particularly because this condition can be deadly but is completely treatable.”

Czarny adds that a faulty aortic valve can restrict blood flow during exertion, which can result in shortness of breath, chest discomfort, passing out, or over time, even heart failure and death.

After their unexpected finding for aortic stenosis rates, the researchers looked at disease rates in other heart valves, such as the mitral valve — the small flap between the heart’s left-side chambers that prevents blood from flowing backward. Diagnosis rates for a leaky mitral valve, say the researchers, were similar for white and Black patients, but lower by a third for Hispanics.

Czarny says this supports their conclusion that the reduced rate of aortic stenosis they found in Black patients may be due to true racial/ethnic differences in the condition’s prevalence or severity, rather than differences in hospitalization or diagnosis rates.

Czarny says the research team needs to look at larger nationwide datasets and include more races/ethnicities to determine the underlying causes of the differences they observed. This latest study, he explains, shows there is still much unknown about how demographics contribute to heart valve disease risk.

“We know there are differences between the sexes in that women have more scar tissue leading to diseased heart valves, whereas the condition in men is more likely from calcium build up,” says Czarny. “We also know that, generally, Black people have higher levels of lipoprotein (a) — which is traditionally associated with heart disease —yet they seem to have lower rates of aortic stenosis. Both of these show that there is much we still need to explore about what factors into one’s disease risk.”

Czarny is available for interviews.

JOHNS HOPKINS MEDICINE SUGGESTS ELIMINATING NERVE CELL PROTEIN MAY STOP ALS, DEMENTIA

Amyotrophic lateral sclerosis (ALS), commonly known as “Lou Gehrig’s disease,” is a devastating neurodegenerative illness that causes nerve cells in the brain and the spinal cord to atrophy (waste away), usually resulting in dementia. Ninety percent of ALS cases are sporadic, with no known genetic mutation responsible, while the remaining 10 percent are genetically passed from parent to child. Now, Johns Hopkins Medicine researchers have identified a defective cellular pathway that initiates nerve cell breakdown and may be tied to both forms of the disease. They also suggest that eliminating charge multivesicular body protein 7 (CHMP7), the wayward protein responsible for the broken pathway, might provide a future means of treating ALS and dementia.

Led by Jeffrey Rothstein M.D., Ph.D., director of the Pedersen Brain Science Institute and the Robert Packard Center for ALS Research, and professor of neurology and neuroscience at the Johns Hopkins University School of Medicine, and senior postdoctoral fellow Alyssa Coyne, Ph.D., the research team studied CHMP7 within an area of a nerve cell known as the nuclear pore. The nuclear pore — a large, highly organized complex of different proteins — serves as the gatekeeper for the nucleus, the cell’s control center, by governing the in-and-out movement of genetic material (RNA) and proteins. Previous studies by Rothstein’s team showed that when this process goes awry — which is said to be dysregulated — it can result in the development of either the familial or inherited forms of ALS and dementias.

However, it has remained unknown why this dysregulation occurs, how it starts the chain of events leading to ALS and if it occurs in the far more common sporadic forms of ALS and dementia.

The Johns Hopkins Medicine study, published July 28, 2021, in the journal Science Translational Medicine, evaluated why the nuclear pore starts to degrade in patients with ALS and dementia, and the role of CHMP7 in that destruction.

The researchers found that CHMP7 protein accumulates specifically within the nucleus of neurons, starting a cascade of events that leads to nuclear pore injury. This, in turn, causes dysregulation of essential proteins in the cell — including one called TAR DNA binding protein 43 (TDP-43), where the dysregulated form is seen in both sporadic and familial ALS — and ultimately, cell death.

“Think of it like an engine that’s starting to lose parts,” Rothstein says. “If CHMP7 is making the nuclear pore start to degrade, what would happen if we took that insult away?”

To find the answer, Rothstein and his colleagues eliminated the CHMP7 protein with antisense technology, a new and promising tool for controlling gene expression (production of a protein) in a cell. Using synthetic antisense oligonucleotides (fragments of genetic material), the researchers targeted the CHMP7 gene at the level of messenger RNA — which codes for CHMP7 protein to be made — rather than changing the DNA — which provides the code. This inhibited the CHMP7 gene from producing its protein, and in turn, the researchers found it prevented nuclear pore degradation, subsequent cellular dysfunction and cell death. With the pore stable, they believe that the conditions potentially leading to ALS cannot be triggered.

“We’re essentially preventing the biological events that give birth to ALS,” Rothstein says.

He says the next steps in the research are to determine if this discovery can be applied to a potential ALS therapy in humans. The team also hopes to learn what causes CHMP7 to become dysregulated in patients with ALS.

Rothstein is available for interviews.

RESEARCHERS TELL DOCTORS TO AVOID ROUTINE URINARY TESTS FOR OLDER PATIENTS WITH DELIRIUM

Based on the results of a new high value health care study, Johns Hopkins Medicine researchers recommend that doctors avoid routine urine testing of older patients with delirium when there are no clinical signs or symptoms of infection.

“Just because it’s an easy test to obtain doesn’t mean it’s an appropriate test,” says study lead author Milad Memari, M.D., senior resident in internal medicine at the Johns Hopkins University School of Medicine. “Our research indicates that patients, who are elderly, delirious and unable to give their medical history, may be more likely to suffer from the consequences of unnecessary testing and treatment. Urine tests are often one of the first that doctors call for in these situations.”

The study was published July 26, 2021, in the Journal of Hospital Medicine.

In their research, Memari and his colleagues reviewed previous studies by others that evaluated the practice of conducting urine tests in hospitals, specifically those for older people with delirium. From one of these studies, Memari’s team learned that 83% of nearly 3,000 patients in hospitals across the nation — including patients age 65 and older — were given antibiotic therapy based on urine cultures positive for bacteria even though the microbes may in fact be harmless. Another investigation showed that more than a quarter (92 out of 343 patients, or 27%) received antibiotics when they did not have clinical signs of urinary tract infections, and they had suffered from harmful long-term consequences of these treatments that may have been unnecessary.

“If elderly, delirious patients are reporting symptoms — including pain or burning with urination, increased frequency of urination and pain in the lower abdomen — or exhibit clinical signs including fevers, low blood pressure, elevated heart rate or an elevated white blood cell count, urine testing may be appropriate,” Memari says.  “If they don’t have symptoms or clinical signs consistent with infection, then their doctors should forego urinary testing to avoid complications from unnecessary antibiotic treatment, and as a result, longer hospitalizations, slower recovery times and poorer outcomes.”

Memari adds that a large number of older patients grow bacteria in urine cultures but may not actually have urinary infections. The focus, he says, should be avoiding unnecessary testing to prevent treatment of bacteria that are a normal, healthy part of a patient’s urinary ecosystem. Also, the more a patient is treated for a urinary infection, the more likely that person will develop a resistance to antibiotics.

In turn, Memari says, this makes urinary infections harder to treat in future instances, and has contributed to the public health issue of increased antibiotic resistance in a highly vulnerable population.

“When treating older populations, we have to remember the principle of ‘first, do no harm’,” Memari says.  “Our team hopes that this review of existing research will get a conversation started in hospitals across the country about curbing unnecessary urine testing to avoid causing long-term harm to, and provide more precise and individualized care for, elderly patients with delirium.”

Memari is available for interviews.

JOHNS HOPKINS MEDICINE RESEARCHERS SHOW HOW AIR POLLUTION MAY CAUSE CHRONIC SINUSITIS        

Chronic rhinosinusitis (CRS) is a 12 week or longer condition during which the sinuses get infected or irritated, become swollen, are severely congested and secrete mucus into the throat. CRS also can cause facial pain, pressure and loss of smell, and in some cases, it may be associated with depression, anxiety, impaired sleep and low quality of life. Although the factors leading to CRS are unknown, Johns Hopkins Medicine researchers have provided what may be the first evidence that long-term exposure to tiny particulate air pollution is one of them.

A report on the findings was published June 28, 2021, in the American Journal of Respiratory and Critical Care Medicine.

“We assessed patients experiencing chronic rhinosinusitis in areas where exposure to environmental air pollution known as PM2.5 — inhalable, particulate matter less than 2.5 micrometers in size [about 30 times smaller than the diameter of a human hair] —may have been high,” says lead author Murugappan “Murray” Ramanathan, M.D., rhinologist and associate professor of otolaryngology–head and neck surgery at the Johns Hopkins University School of Medicine.

According to the U.S. Environmental Protection Agency (EPA), PM2.5 (the PM stands for “particulate matter”) is the term for a mixture of solid particles and liquid droplets found in the air. PM2.5 consists of many materials that vary with location, including dust, dirt, soot, smoke, organic compounds and metals. It has been linked to cardiovascular disease, lung cancer, decline in cognitive thinking ability, chronic obstructive pulmonary disease, asthma and premature death.

Previous research by Ramanathan and his team linked PM2.5 to loss of smell.

In their latest study, the Johns Hopkins Medicine researchers looked at a population of 6,102 patients age 18 and older, including 2,034 with CRS who did not have the disorder for up to five years before it was diagnosed. Mean PM2.5 exposures were calculated for each patient based on his or her residential address postal code at 12, 24, 36 and 60 months prior to CRS diagnosis.

Air pollution data for the study came from the EPA’s Air Quality System. The researchers fed the data into a complex computer model — incorporating meteorological and satellite-based environmental measurements, land-use information and simulations of airborne chemical movement — to estimate the PM2.5 pollution levels within the participants’ residential ZIP codes. The model was created by study lead author Zhenyu Zhang, a Johns Hopkins Medicine otolaryngology postdoctoral fellow.

The research team found that patients exposed to higher PM2.5 concentrations over a long period of time were more likely to be diagnosed with CRS, regardless of how the exposure occurred. For example, exposure over 60 months was associated with an approximately one-and-a-half-fold increase in developing the disorder. There also was a nearly five times greater risk of developing severe pansinusitis (inflammation in all four sinuses). 

“To our knowledge, this is the first study to report that long-term exposure to fine

particulate matter air pollution increases the odds of developing CRS, particularly the most severe form of the disease,” says Ramanathan.

This research validates a 2017 study by Ramanathan’s team demonstrating that long-term PM2.5 exposure in mice resulted in chronic sinonasal inflammation.

The Johns Hopkins Medicine team is conducting ongoing research to seek a better understanding of how race and socioeconomic status may contribute to air pollution exposure, and in turn, development of chronic rhinosinusitis.

Ramanathan is available for interviews.

RESEARCHERS ID LOCATION ON BRAIN PROTEIN LINKED TO PARKINSON’S DISEASE DEVELOPMENT

Johns Hopkins Medicine researchers say they have pinpointed the section of alpha-synuclein, a protein in the brain, that causes it to latch onto brain cells called neurons and likely drives the development of Parkinson’s disease, a progressively worsening disorder that disrupts movement and neurological functions. The findings may help scientists develop a treatment that curbs the protein’s improper binding, perhaps slowing or stopping the progression of Parkinson’s.

Results of the study, conducted using cell studies and mouse neurons, were published online June 25, 2021, in the Proceedings of the National Academy of Science.

In Parkinson’s disease, the alpha-synuclein protein can misfold and take an abnormal shape, enabling it to bind and clump onto a neuron’s surface. Clumps of misfolded alpha-synuclein, known as alpha-synuclein fibrils, spread to other healthy neurons and ultimately kill these cells as the fibrils pile up.

“These findings are significant because we determined what part of alpha-synuclein fibrils is important in the binding process and how it leads to Parkinson’s progression,” says study co-author Xiaobo Mao, Ph.D., assistant professor of neurology at the Institute for Cell Engineering of the Johns Hopkins University School of Medicine. 

Through several molecular and cell studies, the research team focused on a region at the tip of the misfolded alpha-synuclein fibrils called the C terminus, along with the addition of p129, a chemical group near the end of the fibril. The researchers knew from previous studies that both of these characteristics enable the fibrils to bind to neurons and cause cell death.

Mao and his Johns Hopkins Medicine colleagues — including study co-author and Parkinson’s disease researcher Ted Dawson, M.D., Ph.D., who is director of the Institute for Cell Engineering and professor of neurology at the Johns Hopkins University School of Medicine — determined the C terminus can bind receptors on the neurons due to the receptors’ positive electrical charges. When the receptors were removed, the C terminus could not clump to neurons and spread to other healthy cells.

In healthy alpha-synuclein, the C terminus is covered and cannot bind to neurons.

The researchers also investigated p129, a group of molecules in alpha-synuclein fibrils that have an extra chemical group, and are present in about 95% of people with Parkinson’s and other Lewy body neurodegenerative diseases, such as Lewy body dementia. When the alpha-synuclein fibrils with p129 and the C terminus were injected into mouse neurons, researchers found that those fibrils bound with neuron receptors and spread faster. This contributed to quicker cell death and disease progression.

To slow the progression of clumping alpha-synuclein fibrils, the researchers hope to develop treatments that target the binding process.

“If the spreading of alpha-synuclein fibrils can be blocked by preventing the C terminus from binding, it would be a good therapeutic strategy,” says Mao.

Mao is available for interviews.

This news story was researched and written by Johns Hopkins Medicine science writing intern Haley Wasserman.

COVID-19 NEWS: THE RETURN OF ONSITE SCHOOLING — AND HOW TO KEEP YOUR KIDS SAFE FROM COVID

School will soon begin for children and adolescents around the United States, and for many, that means returning to classes in-person for the first time since the start of the pandemic. So, what do parents need to know to help ensure their kids stay safe from coronavirus infection?

The most current advice comes from the Centers for Disease Control and Prevention (CDC) and the American Academy of Pediatrics (AAP), which both recently released guidelines on preventing coronavirus spread in schools. At the top of the CDC and AAP lists — and heartily supported by Johns Hopkins Children’s Center (JHCC) experts — is getting vaccinated.

“For any adolescent age 12 and older, getting fully vaccinated against COVID-19 is essential,” says JHCC infectious diseases specialist Aaron Milstone, M.D. M.H.S, professor of pediatrics at the Johns Hopkins University School of Medicine. “While kids don’t often come down with serious cases of COVID-19, they can pass it on to others, which can cause serious consequences.”

The CDC calls for children who aren’t vaccinated to wear properly fitting face masks at school, while the AAP recommends universal masking for students in class.

“Wearing face masks will not only help prevent the spread of COVID-19 but also will help reduce the spread of other viruses with similar transmission routes,” says Milstone. “In turn, this will reduce absenteeism and disruption in schools.”

All children — no matter the vaccination status — also should wash their hands frequently and maintain proper respiratory etiquette, such as sneezing or coughing into a tissue or the crook of their elbow. Sending kids to school with hand sanitizer, the experts add, may help if they are unable to frequently wash their hands.

JHCC experts emphasize that keeping the school community safe means keeping children at home if they’re sick. If a student is diagnosed with COVID-19, parents should follow the guidance of their local public health agency, pediatrician and child’s school regarding when return to class can occur.

“Resuming in-person schooling is so important for our kids’ educational success and overall wellbeing,” says JHCC pediatrician Kate Connor, M.D., M.S.P.H., assistant professor of pediatrics at the Johns Hopkins University School of Medicine. “It’s imperative to keep COVID-19 safety precautions in place to make sure everyone has a safe and healthy school year.”

Along with heeding the new CDC and AAP back-to-school guidelines, Milstone, Connor and others at JHCC recommend that parents learn and follow the COVID-19 prevention policies of their child’s school and check with their child’s pediatrician for more tips on how to stay COVID-19 free.

Milstone and Connor are available for interviews.