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A large data analysis led by Indiana University School of Medicine Professor Benjamin Gaston, MD, shows a rare respiratory disease called primary ciliary dyskinesia (PCD) is more common than previously thought.
Recently published in The Lancet Respiratory Medicine, the analysis aimed to gauge the global prevalence and genetic variance of PCD, a genetic condition that affects a protective function of the respiratory system. PCD can lead to chronic health issues, including chronic, daily coughing and congestion, recurring respiratory and ear infections and severe lung damage.
Using information from two databases, the group screened the genetic sequences of 180,000 unique people for disease-causing variants of 29 genes that are linked to autosomal recessive PCD. While PCD was previously estimated to occur in only about 1 in 16,000 people, Gaston’s analysis showed that it’s over twice as common at about 1 in 7,500.
“This is very important for clinicians. Since PCD has been thought of as a rare disease, they might not recognize it when they see a patient with PCD symptoms,” said Gaston, who is also the Vice Chair of Translational Research in the Department of Pediatrics. “They may think, ‘Well, it’s unlikely because it’s such a rare disease.’ But actually, it’s not anywhere near as rare as we thought.”
Scientists also looked at disease prevalence among seven ethnic groups, a factor for which previous data were limited. They found that people of African descent had a higher rate of PCD-causing variants than in other populations, followed by non-Finnish European groups and people of Hispanic descent.
Importantly, the data showed that, of the 29 genes studied, the 5 most common genes with PCD-causing variants were different in different ethnic populations. Collectively, these data can help doctors better recognize and diagnose PCD in patients, especially in certain parts of the world or when treating patients from diverse backgrounds.
“My hope is that clinicians will have a much lower threshold for evaluating people who might have PCD,” said Gaston.
Using this type of large-scale analysis to determine disease prevalence is a budding approach in scientific discovery. But it’s not the first time that Gaston “worked backwards,” applying discoveries from his lab to large quantities of genetic data. Gaston said he hopes investigators continue identifying new genes that are associated with PCD — including the ones that this study omitted because of their unknown significance — to continue improving the diagnosis and care of people who have PCD.
For this study, the group used a California-based genetics laboratory, Invitae, and an international sequence database called Genome Aggregation Database (gnomAD). Contributing authors in this study include first-author William B. Hannah, MD, from the University of North Carolina; Duke University School of Medicine’s Bryce A. Seifert,PhD; Rebecca Truty, PhD, and Keith Nykamp, PhD of Invitae; Maimoona Zariwala, PhD from the Marisico Lung Institute, University of North Carolina; University of Utah’s Kristen Ameel, MD; and IU School of Medicine’s Yi Zhao, PhD.

While research has long shown a higher risk of death linked to alcoholism for people with overweight, a new study published in the journal Drug and Alcohol Dependence has found that people with underweight who drink excessively may be at an even higher risk of dying from heart disease, cancer and other causes.
The study was based on data from the National Health Interview Survey (NHIS), which has a nationally representative sample of more than 200,000 U.S. adults aged 35-85, interviewed between Jan. 1, 2001, and Dec. 31, 2011. The researchers analyzed data on mortality risk among drinkers and non-drinkers using the Centers for Disease Control and Prevention (CDC) categories to define “underweight,” “normal weight,” “overweight” and “obesity.”
“The NHIS is like a ‘selfie’ for the U.S. because it is a snapshot of health behaviors of people from every type of background,” said Muntasir Masum, postdoctoral scholar at the Edna Bennett Pierce Prevention Research Center at Penn State. “We expected to see a link between obesity and mortality related to alcoholism, and we were surprised to see that the link was especially pronounced for people with underweight who drink excessively.”
The CDC defines underweight as having a body mass index (BMI) of less than 18.5 using the calculation of person’s weight in kilograms divided by the square of their height in meters. According to the CDC, BMI is a screening tool, but it does not diagnose “body fatness or the health of an individual.”
Further research is needed into how having underweight could contribute to mortality in people who drink excessively. Masum suggested that multiple factors could be at play, such as how people handle stress and whether they have co-occurring health issues or nutritional deficiencies.
“I hope these findings encourage people to eliminate risks that may lead to a life-or-death situation,” said Masum.
Excessive alcohol use is the third most common cause of preventable death in the U.S. and is estimated to cause 1 in 10 deaths among working-age adults in the U.S., according to the Journal of the American Medical Association.
This work was supported by Penn State’s Prevention and Methodology Training program, which is funded by the National Institute on Drug Abuse.
Collaborators on the study included Jeffrey Howard, associate professor of public health at the University of Texas at San Antonio; and Timothy Grigsby, assistant professor in the Department of Social and Behavioral Health at the University of Nevada, Las Vegas.
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Materials provided by Penn State. Original written by Sara P. Brennen. Note: Content may be edited for style and length.

New pose estimation software has the potential to help neurologists and their patients capture important clinical data using simple tools such as smartphones and tablets, according to a study by Johns Hopkins Medicine, the Kennedy Krieger Institute and the University of Maryland. Human pose estimation is a form of artificial intelligence that automatically detects and labels specific landmarks on the human body, such as elbows and fingers, from simple images or videos.
To measure the speed, rhythm and range of a patient’s motor function, neurologists will often have the patient perform certain repetitive movements, such as tapping fingers or opening and closing hands. An objective assessment of these tests provides the most accurate insight into the severity of a patient’s condition, thus better informing treatment decisions. However, objective motion capture devices are often expensive or only have the ability to measure one type of movement. Therefore, most neurologists must make subjective assessments of their patients’ motor function, usually by simply watching patients as they carry out different tasks.
The new Hopkins-led study sought to find whether pose estimation software developed by the research team could track human motion as accurately as manual, frame-by-frame visual inspections of video recordings of patients performing movements.
“Our goal was to develop a fast, inexpensive and easily accessible method to objectively measure a patient’s movements across multiple extremities,” says study lead author Ryan Roemmich, Ph.D., an assistant professor in the Department of Physical Medicine and Rehabilitation at the Johns Hopkins University School of Medicine and a human movement scientist at the Kennedy Krieger Institute.
The research team had 10 healthy subjects between the ages of 24 and 33 record smartphone video of themselves performing five tasks often assigned to neurology patients during motor function assessments: finger taps, hand closures, toe taps, heel taps and hand rotations. The subjects performed each task at four different speeds. Their movements were tracked using a freely available human pose estimation algorithm, then fed into the team’s software for evaluation.
The results showed that across all five tasks, the software accurately detected more than 96% of the movements detected by the manual inspection method. These results held up across several variables, including location, type of smartphone used and method of recording: Some subjects placed their smartphone on a stable surface and hit “record,” while others had a family member or friend hold the device.
With encouraging results from their sample of young, healthy people, the research team’s next step is to test the software on people who require neurological care. Currently, the team is collecting a large sample of videos of people with Parkinson’s disease doing the same five motor function tasks that the healthy subjects performed.
“We want anyone with a smartphone or tablet to be able to record video that can be successfully analyzed by their physician,” says Roemmich. “With further development of this pose estimation software, motor assessments could eventually be performed and analyzed without the patient having to leave their home.”
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How can you mend a broken heart? According to researchers from Japan, in some cases gene replacement therapy just might do the trick.
In a study published in January in Stem Cell Reports, researchers from Osaka University report that heart cells from a patient with an inherited heart disease called arrhythmogenic cardiomyopathy do not contract correctly when grown in the laboratory, and that replacing the mutated gene responsible for this effect fixes this defect.
Arrhythmogenic cardiomyopathy occurs due to mutations in genes involved in desmosomes, which form ‘welds’ between cells that help them communicate and move in a coordinated way. One of these genes, PKP2, encodes a protein known as plakophilin-2 that is crucial to maintaining heart cell structure.
“Previous studies carried out in cardiomyocytes have shown that mutations in PKP2 play a pathological role in arrhythmogenic cardiomyopathy,” says lead author of the study Hiroyuki Inoue. “However, the cells used in those experiments were derived from healthy individuals and were not assessed for contractile function.”
To investigate how cells derived from patients behave in the laboratory, the researchers first took a blood sample from a young patient with arrhythmogenic cardiomyopathy, induced some of the blood cells to become stem cells, and then differentiated these stem cells into heart cells. They then modified this original batch of heart cells into three different cell lines with precisely adjusted PKP2 expression based on how many mutated or intact copies of the gene were present.
“The cells with two mutated copies of PKP2 clearly exhibited reduced contractility and impaired desmosome assembly due to plakophilin-2 deficiency,” explains Shuichiro Higo, senior author. “These effects were also observed in cells with only one mutated copy of PKP2, although they were less severe.”
Replacing the mutated PKP2 with an intact copy of the gene repaired the defects in both cell contraction and desmosome assembly, which the researchers were able to observe using a time-lapse approach and fluorescently labeled desmosomes.
“These findings suggest that our cardiomyocyte cell lines recapitulate the pathology of arrhythmogenic cardiomyopathy and provide a rapid and convenient platform for developing gene-based therapies for this disease,” says Higo.
Given that PKP2 is the most common gene associated with arrhythmogenic cardiomyopathy, and that PKP2 mutations can lead to severe disease, new therapeutic approaches could help halt disease progression. The findings from this study suggest that gene replacement therapy could be a valuable way of treating patients with this condition and the cell lines created in this study are a viable model to test new therapies for arrhythmogenic cardiomyopathy on.
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Materials provided by Osaka University. Note: Content may be edited for style and length.

Social media use has been linked to biological and psychological indicators associated with poor physical health among college students, according to the results of a new study by a University at Buffalo researcher.
Research participants who used social media excessively were found to have higher levels of C-reactive protein (CRP), a biological marker of chronic inflammation that predicts serious illnesses, such as diabetes, certain cancers and cardiovascular disease. In addition to elevated CRP levels, results suggest higher social media use was also related to somatic symptoms, like headaches, chest and back pains, and more frequent visits to doctors and health centers for the treatment of illness.
“Social media use has become an integral part of many young adults’ daily lives,” said David Lee, PhD, the paper’s first author and assistant professor of communication in the UB College of Arts and Sciences. “It’s critical that we understand how engagement across these platforms contributes to physical health.”
The findings appear in the journal Cyberpsychology, Behavior, and Social Networking.
For decades, researchers have devoted attention to how social media engagement relates to users’ mental health, but its effects on physical health have not been thoroughly investigated. Recent surveys indicate social media usage is particularly high for people in their late teens and early 20s, a population that spends about six hours a day texting, online or using social media. And though a few studies have found links between social media usage and physical health, that research relied largely on self-reporting or the effects of usage with exclusively one platform.
“Our goal was to extend prior work by examining how social media use across several platforms is associated with physical health outcomes measured with biological, behavioral and self-report measures,” said Lee, an expert on health outcomes related to social interactions.

With the increase in average life expectancy in many parts of the world, certain age-related diseases have become more common. Alzheimer’s disease (AD), unfortunately, is one of them, being extremely prevalent within aging societies in Japan, Korea, and various European countries. Currently there is no cure or an effective strategy to slow down the progression of AD. As a result, it causes much suffering to patients, families, and caregivers as well as a massive economic burden.
Fortunately, a recent study by a team of scientists at the Gwangju Institute of Science and Technology (GIST) in Korea has just demonstrated that there might be a way to combat AD by using “ultrasound-based gamma entrainment,” a technique that involves syncing up a person’s (or an animal’s) brain waves above 30 Hz (called “gamma waves”) with an external oscillation of a given frequency. The process happens naturally by exposing a subject to a repetitive stimulus, such as sound, light, or mechanical vibrations.
Previous studies on mice have shown that gamma entrainment could fight off the formation of β-amyloid plaques and tau protein accumulations — a standard hallmark of the onset of AD. In this recent paper, which was published in Translational Neurodegeneration, the GIST team demonstrated that it is possible to realize gamma entrainment by applying ultrasound pulses at 40 Hz, i.e., in the gamma frequency band, into the brain of an AD-model mice.
One of the main benefits of this approach lies in the way it is administered. Associate Professor Jae Gwan Kim, who led the study alongside Assistant Professor Tae Kim, explains: “Compared with other gamma entrainment methods that rely on sounds or flickering lights, ultrasound can reach the brain non-invasively without disturbing our sensory system. This makes ultrasound-based approaches more comfortable for the patients.”
As their experiments showed, mice exposed to ultrasound pulses for two hours daily for two weeks had reduced β-amyloid plaque concentration and tau protein levels in their brain. Furthermore, electroencephalographic analyses of these mice also revealed functional improvements, suggesting that brain connectivity also benefits from this treatment. Moreover, the procedure did not cause any type of microbleeding (brain hemorrhages), indicating that it was not mechanically harmful to brain tissue.
Overall, the promising results of this study could pave the way to innovative, non-invasive therapeutic strategies for AD without side effects, as well as help treat other conditions besides AD. Dr. Tae Kim remarked: “While our approach can significantly improve the quality of life of patients by slowing the progression of AD, it could also offer a new solution to other neurodegenerative diseases, such as Parkinson’s disease.”
Let us hope future studies will cement ultrasound-based gamma entrainment as an effective treatment option, and provide a much-needed relief to AD patients and their families.
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Materials provided by GIST (Gwangju Institute of Science and Technology). Note: Content may be edited for style and length.

A new study shows that living in a neighbourhood socioeconomic disadvantage is a risk factor for adverse weight development in children under school age. Researchers studied the connection between neighbourhoods’ socioeconomic status and children’s weight development from data covering over 11,000 Finnish children.
A new study conducted at the University of Turku, Finland, examined the association between the neighbourhood socioeconomic disadvantage and the development of children’s body mass index and the risk of overweight from birth to school age. The children’s growth data was acquired from a national register of well-baby clinics.
Information on the socioeconomic status of the neighbourhood was linked to the participants with address coordinates using the national grid database of Statistics Finland. The database contains information that is based on all Finnish residents on social and economic characteristics at the level of 250 m x 250 m grids.
– The socioeconomic status of the neighbourhood was measured with education level, household income, and unemployment rate. The results were independent of the education level, economic situation, marital status and health of the children’s parents, says lead author, Docent Hanna Lagström from the Department of Public Health of the University of Turku.
Living in a less prosperous neighbourhood posed a major risk for children to develop overweight by school age in the population-based data, even when the researchers considered factors that can increase the risk of overweight in childhood. These included e.g. mother’s type 2 diabetes, mother’s smoking, and child’s high birth weight. In neighbourhoods with a higher socioeconomic status, children weighted more at birth, but their weight development stabilised already by the age of four.
– This could implicate that neighbourhoods can offer very different types of development environments for children, and that the risk of overweight grows before school age in neighbourhoods with lower socio-economic status. The results of our research are an important factor to take into consideration in e.g. city planning to ensure that inequality is stopped right from the childhood, says Lagström.
The study is based on 2008-2010 data from the Southwest Finland Birth Cohort (SFBC). The Birth Cohort consists of all children born in the Hospital District of Southwest Finland during those three years. In this study, the participants consisted of the first children born to the mothers during this this time.
The research was funded by the Academy of Finland and Juho Vainio Foundation as well as the Hospital District of Southwest Finland.
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A newly developed test to screen for three rare genetic disorders simultaneously in newborns was feasible, reliable and scalable, according to a new study.
The research, led by the Murdoch Children’s Research Institute (MCRI), reported that screening for Prader Willi, Angelman and Dup15q syndromes using the new type of test would open new avenues for earlier diagnosis and treatment, paving the way for the three chromosome 15 imprinting disorders to be added to newborn bloodspot screening programs (heel prick test) for the first time.
The study, published in The Journal of the American Medical Association Network Open, was the first to validate the use of a low-cost, specialised screening method called Methylation Specific-Quantitative Melt Analysis (MS-QMA), developed by MCRI researchers, for these disorders at a large scale.
The one-step test can be used to screen for the three conditions simultaneously, by looking at the number of chemical modifications or marks called methylation added to affected genes, which are not present at such high or low levels in children without these disorders.
The Victorian State Government provided a $100,000 grant to MCRI as part of the 2018 Victorian Medical Research Acceleration Fund to support the development of the new screening method for the rare disorders. Medical Research Minister Jaala Pulford visited MCRI recently to see how the test worked and to learn more about its potential.
The study first checked for accuracy, with the test correctly distinguishing most of the 167 samples from people who had one of the disorders. It was then tested on 16,579 newborns in Victoria with the test identifying two with Prader Willi, two with Angelman and one with Dup15q.

LMU neuroscientists have shown that breathing coordinates neuronal activity throughout the brain during sleep and quiet.
While we sleep, the brain is not switched off, but is busy with “saving” the important memories of the day. To achieve that, brain regions are synchronized to coordinate the transmission of information between them. Yet, the mechanisms that enable this synchronization across multiple remote brain regions are not well understood. Traditionally, these mechanisms were sought in correlated activity patterns within the brain. However, LMU neuroscientists Prof. Anton Sirota and Dr. Nikolas Karalis have now been able to show that breathing acts as a pacemaker that entrains the various brain regions and synchronizes them with each other.
Breathing is the most persistent and essential bodily rhythm and exerts a strong physiological effect on the autonomous nervous system. It is also known to modulate a wide range of cognitive functions such as perception, attention, and thought structure. However, the mechanisms of its impact on cognitive function and the brain are largely unknown.
The scientists performed large-scale in vivo electrophysiological recordings in mice, from thousands of neurons across the limbic system. They showed that respiration entrains and coordinates neuronal activity in all investigated brain regions — including the hippocampus, medial prefrontal and visual cortex, thalamus, amygdala, and nucleus accumbens — by modulating the excitability of these circuits in olfaction-independent way. “Thus, we were able to prove the existence of a novel non-olfactory, intracerebral, mechanismthat accounts for the entrainment of distributed circuits by breathing, which we termed “respiratory corollary discharge,” says Karalis, who is currently research fellow at the Friedrich Miescher Institute for Biomedical Research in Basel. “Our findings identify the existence of a previously unknown link between respiratory and limbic circuits and are a departure from the standard belief that breathing modulates brain activity via the nose-olfactory route,” underlines Sirota.
This mechanism mediates the coordination of sleep-related activity in these brain regions, which is essential for memory consolidation and provides the means for the co-modulation of the cortico-hippocampal circuits synchronous dynamics. According to the authors, these results represent a major step forward and provide the foundation for new mechanistic theories, that incorporate the respiratory rhythm as a fundamental mechanism underlying the communication of distributed systems during memory consolidation.
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Many future gene and cell therapies to treat diseases like cancer, rare genetic and other conditions could be enhanced in their efficacy, persistence, and predictability by so-called “genomic safe harbors (GSHs).” These are landing sites in the human genome able to safely accommodate new therapeutic genes without causing other, unintended changes in a cell’s genome that could pose a risk to patients.
However, finding GSHs with potential for clinical translation has been as difficult as finding a lunar landing site for a spacecraft — which has to be in smooth and approachable territory, not too steep and surrounded by large hills or cliffs, provide good visibility, and enable a safe return. A GSH, similarly, needs to be accessible by genome editing technologies, free of physical obstacles like genes and other functional sequences, and allow high, stable, and safe expression of a “landed” therapeutic gene.
Thus far, only few candidate GSHs have been explored and they all come with certain caveats. Either they are located in genomic regions that are relatively dense with genes, which means that one or several of them could be compromised in their function by a therapeutic gene inserted in their vicinity, or they contain genes with roles in cancer development that could be inadvertently activated. In addition, candidate GSHs have not been analyzed for the presence of regulatory elements that, although not being genes themselves, can regulate the expression of genes from afar, nor whether inserted genes change global gene expression patterns in cells across the entire genome.
Now, a collaboration of researchers at Harvard’s Wyss Institute for Biologically Inspired Engineering, Harvard Medical School (HMS), and the ETH Zurich in Switzerland, has developed a computational approach to identify GSH sites with significantly higher potential for the safe insertion of therapeutic genes and their durable expression across many cell types. For two out of 2,000 predicted GSH sites, the team provided an in-depth validation with adoptive T cell therapies and in vivo gene therapies for skin diseases in mind. By engineering the identified GSH sites to carry a reporter gene in T cells, and a therapeutic gene in skin cells, respectively, they demonstrated safe and long-lasting expression of the newly introduced genes. The study is published in Cell Reports Methods.
“While GSHs could be utilized as universal landing platforms for gene targeting, and thus expedite the clinical development of gene and cell therapies, so far no site of the human genome has been fully validated and all of them are only acceptable for research applications,” said Wyss Core Faculty member George Church, Ph.D., a senior author on the study. “This makes the collaborative approach that we took toward highly-validated GSHs an important step forward. Together with more effective targeted gene integration tools that we develop in the lab, these GSHs could empower a variety of future clinical translation efforts.” Church is a leader of the Wyss Institute’s Synthetic Biology Platform, and also the Robert Winthrop Professor of Genetics at HMS and Professor of Health Sciences and Technology at Harvard University and the Massachusetts Institute of Technology (MIT).
Sifting the genome for GSHs
The researchers first set up a computational pipeline that allowed them to predict regions in the genome with potential for use as GSHs by harnessing the wealth of available sequencing data from human cell lines and tissues. “In this step-by-step whole-genome scan we computationally excluded regions encoding proteins, including proteins that have been involved in the formation of tumors, and regions encoding certain types of RNAs with functions in gene expression and other cellular processes. We also eliminated regions that contain so-called enhancer elements, which activate the expression of genes, often from afar, and regions that comprise the centers and ends of chromosomes to avoid mistakes in the replication and segregation of chromosomes during cell division,” said first-author Erik Aznauryan, Ph.D. “This left us with around 2,000 candidate loci all to be further investigated for clinical and biotechnological purposes.”