Culture

On scales too small for our eyes to see, the business of life happens through the making of proteins, which impart to our cells both structure and function. Cellular proteins get their marching orders from genetic instructions encoded in DNA, whose sequences are first copied and made into RNA in a multi-step process called transcription.

A research collaboration at Colorado State University specializes in high-resolution fluorescence microscopy and computational modeling to visualize and describe such stuff-of-life processes in exquisite detail, in real time, at the level of single genes. Now, scientists led by postdoctoral researcher Linda Forero-Quintero have, for the first time, observed early RNA transcription dynamics by recording where, when and how RNA polymerase enzymes kick off transcription by binding to a DNA sequence.

The breakthrough technology, detailed in the journal Nature Communications, has countless possible outshoots; these include sharpening understanding of basic biological processes, to unveiling the genetic underpinnings of certain diseases.

"This is the first time someone has looked at RNA polymerase phosphorylation dynamics in a single-copy gene," said Forero, who is a postdoctoral researcher co-advised by Tim Stasevich, Monfort Professor and associate professor in biochemistry, and Brian Munsky, associate professor in chemical and biological engineering. In the past, such early transcription activity could only be visualized using gene arrays, which are artificial structures composed of hundreds of copies of a gene and not commonly found in the cell nucleus.

Stasevich and Munsky lead a collaboration funded by the W.M. Keck Foundation and the National Institute of General Medical Sciences (through two Maximizing Investigators' Research Awards) that's seeking to unveil and quantify real-time genetic expression in living, single cells. Forero, who works in both labs under the auspices of the collaboration, had previously studied proteins and transporters in cell membranes associated with neurological conditions.

Early transcription activity

As described in Nature Communications, Forero et al. designed a method using an established mammalian cell line, engineered fluorescent antibody fragments, and a custom super resolution microscope to capture the process of early transcription in vivid colors: blue, green and red. More specifically, they observed the start of the transcription cycle that happens when the RNA polymerase II (RNAP2) transcription enzyme becomes phosphorylated, or decorated with phosphate groups, on its amino acid tail.

"The interdisciplinary science here is a fantastic blending of new experimental capabilities and a new approach for mechanistic computational modeling of single-cell dynamics, both of which are very novel in their respective fields," said Munsky, who supervises the computational aspects of the collaboration.

In the lab, the researchers loaded their antibody fragments into an established mammalian cell line containing a reporter gene that when transcribed, is lit up by a fluorescently tagged protein. The antibody fragments, which Stasevich helped develop several years ago, are tagged with fluorescent molecules that light up their specific targets in the RNAP2 tail. Using these tagging technologies together, the researchers could distinguish three distinct steps in the transcription cycle, marked by different colors. The images obtained with this system translate into fluorescent intensity fluctuation. The researchers then used those signals to interpret the spatiotemporal organization of RNAP2 phosphorylation throughout the transcription cycle at a single-copy gene.

New information via computational model

Munsky's team led by graduate student William Raymond took Forero and Stasevich's microscopy data and translated it into a computational model based on stochastic differential equations. By fitting this statistical model to reproduce all the experimental results, the computational team then extended their analyses to glean new mechanistic and quantitative information about the different molecules and their states through the transcription process.

For example, they estimated how many individual RNA polymerase molecules collect to form transient clusters in the region of the DNA's promoter, how long these clusters persist, and how, when and where the polymerases distribute themselves along the DNA. They found, for example, that each burst of transcription activity produces a cluster of between five and 40 RNA polymerases to form around the promoter region of the gene, of which 46% eventually succeed to transcribe RNA. They also found that each RNA takes approximately five minutes to be fully transcribed and processed prior to release.

Forero says the technology has far-reaching potential, especially combined with newer technologies like CRISPR, in which specific genes can be singled out and manipulated. Choosing a certain gene of interest, say one implicated in a disease, and applying the CSU researchers' real-time readout of the transcription cycle, could then allow researchers to watch disease processes happening at the activity level of single genes.

"The ability to resolve the spatial and temporal dynamics of the transcription cycle, in one gene, is the most exciting aspect of this work," Forero said.

SAN ANTONIO (May 27, 2021) — One-fifth of babies who inherit a genetic variant located on chromosome 16 will develop autism spectrum disorder (ASD) by age 3. The variant is called 16p11.2 deletion.

Noboru Hiroi, PhD, of The University of Texas Health Science Center at San Antonio (also referred to as UT Health San Antonio), is studying mice that have this deletion. The team, which includes colleagues from Japan, Ireland and the U.S., is harnessing the power of machine learning to understand which vocalizations of the newborn mouse pups are most predictive of social abnormalities one month later when the pups reach puberty.

“It is essential to identify those very early signs that can predict what is to come, because if we can translate what we discover in mouse pups to human infants and apply therapeutic options earlier, their outcome will be better,” Dr. Hiroi said.

Mice are studied because of the short timeline of their development. The same research in human babies, which is just beginning, will take two to three years of follow-up. In May, collaborators led by Cynthia Blanco, MD, professor of pediatrics and the Greehey Family Foundation Chair in Neonatology Research at UT Health San Antonio, started recording the cries of preterm infants in the University Hospital neonatal intensive care unit. Preterm infants are targeted because of their high risk of developmental issues, including ASD.

Disordered cries

When mouse pups are separated from their mothers, they emit ultrasonic vocalizations in a certain order. Mouse mothers respond to the cries and take care of their offspring.

The cries are abnormal in mice with the 16p11.2 deletion.

“Pups that carry this genetic variation cannot form the correct sequence,” Dr. Hiroi said. “We want to know whether those abnormal sequences or combinations of call types can predict what is to come one month later in their social behaviors.”

Machine learning will enable the team to develop a precise diagnostic algorithm for ASD. “The point is, once we can do this with the mouse vocalizations, we can apply the same algorithm to the cries of human babies,” Dr. Hiroi said.

Earlier intervention

Infants at risk of ASD who are identified in this way can be given desensitization therapy so that they don’t overreact to certain cues they don’t like, he said. And behavioral therapies can be applied to help babies learn how to cope in social situations.

The research is described in a paper published in the journal Molecular Psychiatry.

The authors point out that algorithms developed from infant vocalizations could be used to predict other disorders, such as schizophrenia, which develops 17 to 20 years after birth.

The mice also display abnormality in their responses to social olfactory cues. Normal mice presented with another mouse respond by sniffing. The mutant mice don’t respond to that cue, Dr. Hiroi said.

Acknowledgments

Dr. Hiroi, recruited to UT Health San Antonio in 2019 from the Albert Einstein College of Medicine, is a professor in the departments of pharmacology, cellular and integrative physiology, and cell systems and anatomy within the university’s Joe R. and Teresa Lozano Long School of Medicine.

This research is made possible by a grant (R01DC015776) to Dr. Hiroi from the National Institute on Deafness and Other Communication Disorders, part of the National Institutes of Health. The Department of Psychiatry and Behavioral Sciences at UT Health San Antonio also provided startup funds for this project.

Computational identification of variables in neonatal vocalizations predictive for postpubertal social behaviors in a mouse model of 16p11.2 deletion

Mitsuteru Nakamura, Kenny Ye, Mariel Barbachan e Silva, Takahira Yamauchi, Daniel J. Hoeppner, Amir Fayyazuddin, Gina Kang, Emi A. Yuda, Masako Nagashima, Shingo Enomoto, Takeshi Hiramoto, Richard Sharp, Itaru Kaneko, Katsunori Tajinda, Megumi Adachi, Takuma Mihara, Shinichi Tokuno, Mark A. Geyer, Pilib Ó Broin, Mitsuyuki Matsumoto and Noboru Hiroi

First published: April 15, 2021, Molecular Psychiatry

https://www.nature.com/articles/s41380-021-01089-y

The University of Texas Health Science Center at San Antonio, also referred to as UT Health San Antonio, is one of the country’s leading health sciences universities and is designated as a Hispanic-Serving Institution by the U.S. Department of Education. With missions of teaching, research, patient care and community engagement, its schools of medicine, nursing, dentistry, health professions and graduate biomedical sciences have graduated more than 37,000 alumni who are leading change, advancing their fields, and renewing hope for patients and their families throughout South Texas and the world. To learn about the many ways “We make lives better®,” visit www.uthscsa.edu.

Stay connected with The University of Texas Health Science Center at San Antonio on Facebook, Twitter, LinkedIn, Instagram and YouTube.

To see how we are battling COVID-19, read inspiring stories on Impact.

Journal

Molecular Psychiatry

DOI

10.1038/s41380-021-01089-y

May 27, 2021 - Patients undergoing total hip arthroplasty (THA) show significant reduction in pain and other symptoms and improvement in walking gait biomechanics. However, those improvements do not lead to increased daily physical activity levels, reports a study in The Journal of Bone & Joint Surgery. The journal is published in the Lippincott portfolio in partnership with Wolters Kluwer.

The findings "present a worrying picture that while patients have the opportunity to be more physically active through improvements in functional capacity, their physical behaviors do not change," according to the new research, led by Jasvir S. Bahl of the University of South Australia, Adelaide, in collaboration with the University of Adelaide, Flinders University, and the Royal Adelaide Hospital. The researchers call for additional efforts to help patients get up to a healthy level of physical activity following THA.

Nearly all patients remain sedentary after THA

The prospective study included 51 patients with an average age of 66 years who underwent primary THA at a public hospital in South Australia. All procedures were performed using the same surgical technique and implant type. Prior to the procedure, data were recorded for several patient-reported domains, including hip-related symptoms, function, and quality of life.

In addition, patients underwent gait analysis and musculoskeletal modeling for in-depth analysis of biomechanics and overall walking performance. They also completed 24-hour physical activity monitoring with use of a wrist-worn activity tracker (accelerometer). In a subgroup of patients, gait analysis and activity monitoring were repeated at one and two years postoperatively.

At both follow-up times, patients reported improvements in pain and other hip-related symptoms, hip function, and everyday quality of life. Gait analysis showed improvement in almost every aspect of walking biomechanics, including walking speed and step length.

However, 24-hour activity monitoring showed little or no change in daily physical activity patterns. Both preoperatively and postoperatively, patients were sedentary or asleep for 19.5 hours of the day, on average. This finding remained significant after adjusting for age, body mass index, and occupation.

In fact, there was evidence that sedentary time increased after THA. The percentage of patients who were sedentary for more than 11 hours per day increased from 25 percent preoperatively to 31 percent at one year and 41 percent at two years postoperatively. At all assessment points, patients reported that most of their active time was spent in light physical activity.

Activity monitoring also provided information on the patient sleep time and quality. Average sleep time remained the same, at about nine hours per night. However, sleep efficiency declined year over year, from 84 percent preoperatively to 80 percent at one year and 77 percent at two years postoperatively, with less than 85 percent considered inefficient sleep.

Consistent with many previous studies, these results show that THA leads to "significant and substantial" improvements in pain, function, and quality of life. However, the present study shows that despite these improvements, few patients change their daily physical activity patterns in the two years after THA.

"Evidently, a surgical procedure alone may not enable patients to lead a more physically active lifestyle," Dr. Bahl and coauthors write. Although the study cannot draw conclusions about the reasons why physical activity did not improve, previous reports have suggested that low activity patterns may become "hard-wired" after years of physical disability. The authors also suggest that if patients have to wait several years before THA, they may become used to a more sedentary lifestyle.

Dr. Bahl and colleagues note that patients undergoing hip replacement surgery often have accompanying health conditions such as high blood pressure, obesity, and diabetes that are best managed with increased physical activity and exercise. The researchers conclude: "Health-care providers must consider a multifaceted model of care, which includes patient education on the importance of reducing sedentary behaviors, and addressing a range of barriers and facilitators to increase physical activity postoperatively."

LA JOLLA, CA--Even before the COVID-19 pandemic, most people in the United States already had been sick with a coronavirus, albeit a far less dangerous one. That's because at least four coronaviruses in the same general family as SARS-CoV-2 cause the benign yet annoying illness known as the common cold.

In a new study that appears in Nature Communications, scientists from Scripps Research investigated how the immune system's previous exposure to cold-causing coronaviruses impact immune response to COVID-19. In doing so, they discovered one cross-reactive coronavirus antibody that's triggered during a COVID-19 infection.

The findings will help in the pursuit of a vaccine or antibody treatment that works against most or all coronaviruses, says senior author Raiees Andrabi, PhD, an investigator in the Department of Immunology and Microbiology.

"By examining blood samples collected before the pandemic and comparing those with samples from people who had been sick with COVID-19, we were able to pinpoint antibody types that cross reacted with benign coronaviruses as well as SARS-CoV-2," says Andrabi, who works closely with the laboratory of professor Dennis Burton, PhD.

In later tests, the antibody also neutralized SARS-CoV-1, the coronavirus that causes SARS, or severe acute respiratory syndrome.

"We were able to determine that this type of cross-reactive antibody is likely produced by a memory B cell that's initially exposed to a coronavirus that causes the common cold, and is then recalled during a COVID-19 infection," Andrabi says.

Memory B cells are an essential part of the immune system. They "remember" initial disease threats and can circulate in the bloodstream for decades, ready to be called back into action if the threat emerges again. These cells are responsible for producing targeted antibodies.

The discovery may be an important step in the eventual development of a pan-coronavirus vaccine, which would be able to protect against potential coronaviruses that emerge in the future, says Burton, the James and Jessie Minor Chair in Immunology in the Department of Immunology & Microbiology at Scripps Research.

"Another deadly coronavirus will likely emerge again in the future--and when it does, we want to be better prepared," Burton says. "Our identification of a cross-reactive antibody against SARS-CoV-2 and the more common coronaviruses is a promising development on the way to a broad-acting vaccine or therapy."

Burton's lab is also investigating broadly neutralizing antibodies that can be harnessed to protect against many forms of influenza, which is another virus likely to cause a pandemic in the future.

In the new study, the team used electron microscopy to understand how the cross-reactive antibody is able to neutralize a range of coronaviruses. They saw that it mostly binds to the base of the virus's spike protein, an area that doesn't change much from strain to strain, says first author Ge "Sophie" Song, a graduate student in the Burton laboratory.

"The study highlights how important it is to fully understand the nature of preexisting immunity, especially in regard to coronaviruses," Song says. "Earlier exposure to a coronavirus, even a benign virus that causes colds, impacts the nature and level of antibodies produced when more serious coronavirus threats emerge."

JOHNS HOPKINS MEDICINE RESEARCHERS SHOW HOW AIR POLLUTION MAY CONTRIBUTE TO LOSS OF SMELL

Media Contact: Waun'Shae Blount, wblount1@jhmi.edu

The loss of smell, a condition known as anosmia, can severely impact a person's quality of life, making it extremely difficult to taste foods, detect airborne hazards in the environment and carry out other functions dependent on the sense. Those with anosmia may experience weight concerns, decreased social interaction, depression and general anxiety. In some cases, loss of smell has been linked to death in older adults. Now, Johns Hopkins Medicine researchers have studied one of the known causes of anosmia -- long-term exposure to air pollution -- to better understand how it can rob someone of the ability to smell and taste.

The findings appeared May 27, 2021, in JAMA Network Open.

"We included participants from a variety of areas in our study; however, most lived in urban areas where pollution levels are highest," 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. "We wanted to assess how their exposure to PM2.5 air pollution -- inhalable, particulate matter less than 2.5 micrometers in size or about 30 times smaller than the diameter of a human hair -- might cause them to lose their sense of smell."

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. Depending on location, PM2.5 can consist of many materials, incuding 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 has associated PM2.5 as a likely culprit in loss of smell -- a connection that Ramanathan and his team decided to explore in greater detail.

In their study, the researchers looked at 2,690 people, age 18 and older, who were evaluated by otolaryngologists between January 2013 and December 2016. Of these, 538 were diagnosed with anosmia, with an average age of 54 and with men making up the majority (339 or 63%).

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 Zhenyu Zhang, a Johns Hopkins Medicine otolaryngology postdoctoral fellow.

The researchers found long-term airborne exposure to PM2.5 increases the risk of losing one's smell by nearly twice (a 1.6- to 1.7-fold increase). They believe this may occur because the location of the olfactory nerve -- which contains the sensory nerve fibers relating to the sense of smell -- places it directly in the path of inhaled PM2.5 materials.

"Based on this result, we feel that long-term exposure to high levels of PM2.5 represents a common risk factor for the loss of sense of smell, especially in vulnerable populations such as older people -- but also one that is potentially modifiable if sources of PM2.5 components can be better controlled," says Ramanathan.

Next, the researchers plan to study socioeconomic factors among patients with anosmia to determine if they impact the chances of exposure to PM2.5 air pollution. They also hope to evaluate other air pollution components that may contribute to loss of smell, such as ozone.

Ramanathan is available for interviews.

SIMPLE PROTOCOL CAN IMPROVE USE OF PROVEN MEDICINAL TREATMENT FOR OPIOID DEPENDENCE

Media Contact: Michel Morris, melben1@jhmi.edu

Unintentional overdoses are the leading cause of death for Americans under 50, with many people knowing at least one person who has struggled with drug dependence. In a recent study, Johns Hopkins Medicine researchers found that effective treatments for opioid addiction are underutilized and offer a potential solution to the problem -- increasing access to medical help through a quality improvement project.

The study, published May 18, 2021, in the Journal of Hospital Medicine, details how a team led by Ashish Thakrar, an addiction medicine fellow at the Johns Hopkins University School of Medicine, propose a simple, yet effective awareness and educational program. The protocol increases the use of evidence-based medication -- that is, therapeutic drugs shown by scientific evidence to be useful at treating opioid dependence. There are currently only three evidence-based medications to treat opioid dependence, and Thakrar says they are all underutilized. Thakrar's team focused on increasing the use of one of these drugs -- buprenorphine -- in patients admitted to The Johns Hopkins Hospital, many with substance use-related issues.

Buprenorphine is a drug approved by the U.S. Food and Drug Administration to treat opioid dependence. Experts say that buprenorphine -- which also is an opioid -- can be prescribed alone or as part of a comprehensive treatment plan that includes counseling and other behavioral therapies to provide patients with a whole-person approach.

"Changing practice is hard," Thakrar says. "There are dozens of well-conducted prospective and retrospective studies showing that buprenorphine works. It reduces mortality by 50%, reduces the rate at which patients use opioids, improves the patient's quality of life and helps retain patients in other kinds of medical and dependence care."

Before the project was implemented for the study, Thakrar says only 10% of eligible patients received approved medications for treating opioid dependence. After the project, discharge prescriptions more than doubled to 24%. Thakrar says the increase was due to the use of a one-page, easy-to-use protocol posted in common areas of the hospital; the presentation of the protocol at a conference with a successful patient case study; and the establishment of a novel, resident-led buprenorphine bridge team.

The bridge team consists of a group of residents and attendees who are legally permitted to prescribe buprenorphine prescriptions. This facilitates the use of the drug for treating opioid dependence -- because while any provider can administer it within a hospital, prescriptions require a special waiver from the federal Drug Enforcement Administration.

As part of the quality improvement project tested during the study, 140 internal medicine residents and 16 combined medicine-pediatrics residents received one hour of formal education about opioid use disorder. Additionally, 28 residents who were specializing in urban health primary care spent one month in a clinical rotation focused on dependence medicine. During that rotation, they completed the eight-hour training required to receive the DEA waiver. The training included guidance on selecting patients, shared decision-making around treatment, avoiding precipitated withdrawal, dosing buprenorphine and establishing follow-up.

After learning and implementing the protocol, the majority of residents reported feeling more comfortable and more knowledgeable using the buprenorphine treatment.

"Providers want to give good care to patients with opioid dependence, and are eager for tools that can help them do so," says Thakrar. "Many of the limitations for providing the best care are structural and logistical, so we need multidisciplinary approaches that include nurses and social workers. Collaboration is key."

Thakrar says the buprenorphine bridge team continues to be active at The Johns Hopkins Hospital. Since the team was established in 2019, the hospital also has started a full dependence medicine consult service.

"I hope that other hospitals can see that there are protocols that can improve the quality of care," Thakrar says. "Small changes can make a big difference for patients with opioid dependence."

Thakrar is available for interviews.

STUDY SHOWS HOSTILE WORK ENVIRONMENTS ARE GLOBAL HEARTACHE FOR CARDIOLOGISTS

Media Contact: Brian Waters, bwaters3@jhmi.edu

In a global survey of nearly 6,000 cardiologists conducted by Johns Hopkins Medicine and the American College of Cardiology, researchers found that as many as 44% of those polled report experiencing a hostile work environment (HWE) at some point in their careers. Based on this finding and others reported in a recent study assessing the survey responses, the researchers suggest that HWE -- characterized by emotional harassment, discrimination, sexual harassment or any combination of the three -- has an adverse effect on professional and patient interactions and relationships, raises concerns about the well-being of those impacted and may threaten the quality of patient care provided.

The study was published May 10, 2021, in the Journal of the American College of Cardiology.

"Unfortunately, we discovered that the problem of HWE is very widespread, with nearly half of the world's cardiologists experiencing some form of it at one time or another," says lead study author Garima Sharma, M.D., assistant professor of medicine at the Johns Hopkins University School of Medicine. "We found HWE in cardiology prevalent across regions, races and ethnicities, and both sexes and all gender identifications."

The 50-item survey in the study was given between September and October 2019 to 5,931 cardiologists in Africa, Asia, the Caribbean, Europe, the Middle East, Oceania, and North, Central and South America. Participants were queried about their demographics, practice environment, academic rank and experiences with discrimination and harassment. Seventy-seven percent of the respondents were men, 54% were white (followed by 17% Asians, 17% Hispanics and 3% Blacks), 73% were age 54 or older and 75% were married.

Cardiologists from the European Union made up the biggest block of respondents (32%), followed by cardiologists from South America (18%); the Middle East, Eastern Europe and Asia (all 9%); Africa (8%); North America (7%); Central America (6%) and Oceania (2%).

"Based on the responses from the survey, we found incidences of HWE were most commonly reported by women [68%], Blacks [53%] and North Americans [54%]," says Roger Blumenthal, M.D., director of the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease and professor of medicine at the Johns Hopkins University School of Medicine. "Gender was the most frequent cause of discrimination [44%], followed by age [37%], race [24%], religion [15%] and sexual orientation [5%]."

Seventy-five percent of survey respondents said HWE adversely affected professional activities with colleagues, while 53% reported a negative impact on relationships with their patients.

Looking at each subset of HWE studied, Sharma says that emotional harassment was experienced by nearly one-third of cardiologists, 30% reported at least one form of discrimination, and women endured more incidences of sexual harassment -- with 44% stating they had experienced multiple types.

"These data come at a crucial time when harassment and the culture of discrimination in medicine are being openly challenged," the study states. "These findings support the need to improve the culture within medicine greatly and raise a call to action to address harassment and discrimination."

Sharma and Blumenthal are available for interviews.

TO CULTURE OR NOT TO CULTURE: NEW TOOL HELPS DECIDE -- AND LOWER ANTIBIOTIC USE IN THE PICU

Media Contact: Michael E. Newman, mnewma25@jhmi.edu

The dictionary defines stewardship as "the job of properly and responsibly taking care of things so that they can be used effectively." Nowhere is that concept -- and the responsibility attached to it -- taken more seriously than in a pediatric intensive care unit (PICU), especially when it involves stewarding the appropriate use of antibiotics. Now, Johns Hopkins Medicine researchers hope to make that high-value health care task simpler and more effective with a new bedside tool that helps clinicians better determine when to test for bacteria in endotracheal tubes being used for critically ill pediatric patients.

The findings were reported in the May 2021 issue of the journal Pediatrics.

To diagnose potentially serious bacterial respiratory infections in a PICU patient receiving invasive mechanical ventilation with an endotracheal tube, physicians and nurses often obtain secretions from inside the tube (known as an endotracheal aspirate) and culture it in the laboratory. The problem with these endotracheal aspirate cultures (EACs) is they may lead to a case of mistaken identity that could do the patient more harm than good, says study lead author Anna Sick-Samuels, M.D., M.P.H., a pediatric infectious disease specialist at Johns Hopkins Children's Center and assistant professor of pediatrics at the Johns Hopkins University School of Medicine.

"The human respiratory tract is far from a sterile environment, so bacteria cultured from aspirated samples may just be part of the body's normal microflora and not be causing an infection that needs antibiotics," says Sick-Samuels. "However, the detection of any bacteria in these cultures is often misinterpreted as a sign of a ventilator-associated infection, which then may result in unnecessary -- and potentially harmful -- antibiotic treatment."

To address the problem, Sick-Samuels and her colleagues developed a clinical decision support algorithm for use in the PICU. The algorithm is a simple flow chart of progressively more definitive, "yes or no" criteria by which clinicians can make an informed, rather than speculative, decision about whether or not an EAC is needed.

"The algorithm standardizes the thought process and makes the clinician carefully consider whether or not to call for an EAC, which in turn, prevents a 'knee-jerk' response to bacteria and the inappropriate use of antibiotics," says Sick-Samuels. "It also helps reduce the problem of clinicians ordering repeated EACs from the same patient, even though the same bacteria typically grow again in repeated cultures."

For a PICU patient with a tracheostomy (a surgically created airway directly into the trachea) or an endotracheal tube in place for more than 48 hours, Sick-Samuels explains that the algorithm asks clinicians to consider obtaining an EAC only if:

The patient has an increased quantity of secretions in the tracheostomy or endotracheal tube over time.

There is at least one additional supporting sign of infection, such as fever greater than 38 degrees Celsius (100.4 degrees Fahrenheit), an increase in white blood cell counts or a chest X-ray that indicates a developing pneumonia.

The patient has not had another EAC within the past 3 days.

To test the effectiveness of their algorithm, Sick-Samuels and her research team put it to work as part of a 12-month quality improvement program at the Children's Center PICU. In the year before the tool was implemented, the researchers documented 557 EACs obtained over 5,092 days of patients on mechanical ventilation (tracheostomy or endotracheal tube). This was equivalent to 10.9 EACs for every 100 ventilator-days.

In the year after the algorithm became part of the regular clinical practice at the Children's Center PICU, the number of EACs dropped to 234 over 3,654 ventilator-days, or 6.5 per 100 ventilator-days -- a 40% reduction. The researchers say the use of the algorithm and the resulting sustained decline in EACs did not change the number of deaths, readmissions or lengths of stay for patients in the PICU. They also estimate that the direct cost savings from obtaining fewer EACs would be approximately $26,000 per year.

What makes this stewardship different from other programs seeking to prevent the inappropriate use or overuse of antibiotics, says Sick-Samuels, is that the "decision tree" process goes to work earlier in the thought process before antibiotics might be started.

"The algorithm makes the early decision for or against microbiological testing the pivotal point, not the choice of whether or not to prescribe antibiotics," she says. "At JHCC, it really did make our staff more mindful and aware of their actions, and it led to a shift in practice that was sustained even through the COVID-19 pandemic."

Next, the researchers plan to introduce diagnostic stewardship of EACs at 15 pediatric centers across the United States, validate its effectiveness and show that the stewardship program can be adapted for use in other PICUs. They also hope their efforts will serve as a model for EAC decision-making tools that can be used in other clinical settings.

Sick-Samuels is available for interviews.

Nearly three years after the Trump administration's "Zero Tolerance" policy went into effect, more than 445 children remain separated from their families, largely due to insufficient identifying paperwork and U.S. immigration officials' failures to plan, track and reunite separated families. In a Policy Forum, Elizabeth Barnert and colleagues - an interdisciplinary group of physicians, scientists and human rights advocates - argue that a well-defined, replicable, scalable, and sustainable framework to collect and manage sensitive DNA data is urgently needed in order to play a part in helping reunite separated migrant families safely and ethically. "We recognize that no technology - including DNA analysis - is capable of reuniting all families; however, this inherent limitation cannot and should not serve as a rationale to avoid applying scientific tools to support the prompt reunification of parents and children whose whereabouts are unknown," write Barnert et al. The authors' call to action is particularly timely considering the upcoming release of the Biden Administration's Family Reunification Task Force's initial report, due on June 2, 2021. "Given the Biden Administration's executive order to reunite migrant children separated from their families by previous administrations, it is imperative that scientists and human rights advocates develop an international protocol that sets out guidelines and best practices for a DNA-led approach for family reunification," write the authors. While protocols and standards already exist for using DNA technology to identify the deceased, a global protocol for using DNA to reunite the living has yet to be established. Here, Barnert and colleagues provide an overview of how DNA-based strategies have been used in the past to identify the unknown and outline how a DNA-led framework for family reunifications could be established. They address scientific rigor, rights protection, ethical processes, trauma-informed protocols, and more.

A cutting-edge digital tool that will make it cheaper, safer and faster for pharmaceutical companies to predict protein stability - a vital step in the development of new medicines - is being rolled out by scientists from the UK's University of Bath through their spin-out company, BLOC Labs.

The tool, launched this week, will help researchers identify the most promising protein molecules for drug development. It has the potential to play an important role in the creation of monoclonal antibodies (mAbs). The market for these therapeutic antibodies is worth over £70 bn.

Monoclonal antibodies are a type of protein derived from natural antibodies and then refined and mass produced in the lab. They are steadily transforming the way we treat and prevent diseases, from cancer and conditions affecting the immune system to viral infections. The coronavirus pandemic has triggered particular interest in mAbs, as a number of protein candidates are showing great promise as therapies to treat Covid-19, and are currently being trialled in humans.

STABILITY IS KEY

Only mAbs that are known to be stable (that is, they neither break down easily nor clump together to form toxic compounds) are suitable for development, and finding a stable candidate adds massively to the cost and time of finding new drugs.

Until now, the process of determining protein stability has been a big headache for drug companies, with researchers testing vast libraries of molecules in their search for proteins with medicinal properties. However, the tool developed in Bath - called Quantitative Understanding of Bio-molecular Edge-Shift (QUBES) - is able predict the stability of proteins with startling speed and accuracy.

Dr Chris Pudney from the University's Department of Biology & Biochemistry and developer of QUBES, said: "We're really excited by the potential of QUBES because it can be used immediately in the biopharmaceutical industry in quality assurance, formulation and development."

He added: "Proteins are notoriously unstable for a good reason - the body wants to recycle them constantly. But with a therapeutic product, you need stability - if a protein breaks down and aggregates, it becomes toxic. Finding stable proteins is hugely expensive for pharmaceutical companies, but using our tool to find the best molecule possible will cut down on the time and cost of development massively."

QUBES FINGERPRINTING

QUBES works by allowing researchers to accurately 'fingerprint' a protein's structure and predict stability under nearly any condition of concentration or formulation. The technique uses fluorescence to map protein structure and then applies a mathematical algorithm, based on the position and type of the protein's atoms, to calculate stability. Thanks to an online suite of software - also developed in Bath - laboratories can interpret their fluorescent data from anywhere in the world, using equipment found in most biochemistry labs without modifications.

Elaborating on the fingerprinting technique, Dr Pudney said: "Proteins contains tryptophan - an amino acid that emits fluorescent light. Every protein molecule has a unique fluorescent signature, and QUBES leverages this optical phenomenon, applying mathematical techniques to analyse and interpret the fluorescence.

"The software suite takes this academic work and makes it incredibly easy for people to use. You can run it on any machine - even on your mobile phone. It's ultra-rapid and ultra-easy, and it offers an incredibly high level of security - in fact, we have a grade of security that's normally reserved for the financial service industry."

What sets QUBES apart from its competitors is the quality of its readings and its extreme flexibility. Dr Pudney explains: "Not only is our approach faster, more accurate and more sensitive than anything else on the market, but it can also predict stability at any concentration and in any formulation - unlike other tools on the market, which require set conditions."

Dr Pudney's team have recently conducted a validation study of the QUBES technology with the National Physical Laboratory (NPL) under the government backed 'Measurement for Recovery Scheme' scheme, which provides independent validation of technology by the country's leading analytical facility.

Dr Alex Jones, who led the study at NPL, said: "We tested the QUBES approach using a range of analytical methodologies and found that it tracks subtle changes in protein structure and stability with remarkable sensitivity when compared to established methodologies. The approach is fast and simple to implement."

PULLMAN, Wash. - For decades, wealthy nations have transported plastic trash, and the environmental problems that go with it, to poorer countries, but researchers have found a potential bright side to this seemingly unequal trade: plastic waste may provide an economic boon for the lower-income countries.

In a study published in the Journal of World Systems Research, Yikang Bai of Washington State University and Jennifer Givens of Utah State University analyzed 11 years of data on the global plastics trade against economic measures for 85 countries. They found that the import of plastic waste was associated with growth in gross domestic product per capita in the lower-income countries.

"Our study offers a nuanced understanding of the global trade in plastic waste," said Bai, a recent WSU Ph.D. graduate and lead author on the study. "Media coverage often has a narrative that developed countries shift environmental harms to less developed countries. There's another layer of the story: plastic waste could be used as a resource first, even though ultimately it could still add to the environmental burdens of less-developed countries."

The authors emphasized that plastic waste is still a big problem, especially for developing countries, as most does not get recycled and even plastics that are recycled still ultimately end up negatively affecting the environment. This study only indicates that some plastic waste is being purchased and repurposed before being thrown away.

For the study, Bai and Givens analyzed data from the United Nations and the World Bank looking at several economic variables as well as trade information on common plastic wastes such as polyethylene and polystyrene, also known as #1 and #2 plastics respectively. They analyzed data on 45 high-income countries mostly found in the Global North, including European countries and the United States - and 40 lower income countries which are mostly found in the Global South such as Botswana, El Salvador and Vietnam.

The data ranged from 2003 to 2013, allowing the researchers to conduct a longitudinal analysis--showing change over time--which can reveal a strong connection among the measures. While they found an association between economic benefits and plastic waste imports in the lower income countries, for the high-income countries there was no association between importing waste and economic growth.

While the study did not assess exactly how the plastic waste was being used in the developing countries, the authors note that it is likely they are recycling some of the plastic for use in industry and manufacturing. There was also some evidence that the lower-income countries were trading the plastic waste among themselves regionally.

"Most plastic doesn't get recycled - that's important to keep in mind," said Givens, a USU assistant professor of sociology. "A lot of plastic waste ends up in landfills or in the environment, so maybe it's a silver-lining that importing plastic waste is associated with economic development in developing countries. At least they are recycling some of it and not using virgin materials because plastics are made from fossil fuel chemicals."

The researchers emphasized that there is a lot of complexity in global trading of plastic waste. In the future, they plan to investigate the regional trade among countries as well as changes in more recent years, especially in light of the fact that China stopped taking plastic waste imports in 2018.

Even with the economic benefits of importing plastic waste, reducing environmental harm from plastics would still likely require changes from both high-income countries and lower-income countries, especially high-income countries, said Bai.

"Some people might argue that developed countries need to create more ways to better process plastic waste domestically, instead of looking for other destinations for plastic waste overseas," he said. "The way we recycle plastic waste varies greatly across the United States. Some communities may do it well, but in others, there is still room for improvement. Producing and using less plastic would be another way to reduce environmental harms."

Oysters' exposure to plastics is concerning, particularly because these materials can accumulate and release metals which are then absorbed by the molluscs. According to a recent study published in the journal Chemosphere, the combined presence of nanoplastics and arsenic affects the biological functions of oysters. This study was conducted by the Institut national de la recherche scientifique (INRS) in Québec City and the French National Centre for Scientific Research (CNRS) at the University of Bordeaux in France.

The international research team chose to study arsenic, since it is one of the most common metals absorbed by the plastic debris collected from the beaches of Guadeloupe. "Oysters easily accumulate metals from the environment into their tissues. We therefore wanted to test whether the combined exposure to nanoplastics and arsenic would increase the bioaccumulation of this contaminant," reported Marc Lebordais, the Master's student in charge of the research.

The scientists proved that the bioaccumulation of arsenic does not increase when nanoplastics are also present. However, it remained higher in the gills of the Canadian Crassostrea virginica oyster than in the Isognomon alatus oyster, found in Guadeloupe. These results are the first to highlight the diverging sensitivity of different species.

Gene deregulation

In addition to bioaccumulation, the team also observed an overexpression of genes responsible for cell death and the number of mitochondria--a cell's energy centres--in C. virginica. In I. alatus, the expression of these same genes was less significant.

"Evaluating the expression of genes involved in important functions, such as cell death and detoxification, gives us information on the toxicity of nanoplastics and arsenic on a cellular level," explained the young researcher, who is co-directed by Professors Valérie Langlois of INRS and Magalie Baudrimont of the University of Bordeaux.

The food chain

The next step, after characterizing the presence of nanoplastics and arsenic in oysters, would be to study how these contaminants are transferred through the food chain.

"Analytical tools are currently being developed to quantify the presence of nanoplastics in biological tissues," said Marc Lebordais. "Understanding the amount of nanoplastics in farmed oysters currently boils down to a technical issue." ?

Research shows that poor sleep health may disproportionately affect children of color from families of low socioeconomic status and place them at risk for behavior problems and lower academic performance. However, few sleep studies utilize standard measures of both classroom behavior and academic achievement.

A new longitudinal study examined the relation between sleep, classroom behavior, and academic achievement scores among primarily Black children growing up in historically disinvested neighborhoods. Disinvested refers to neighborhoods in which public and private funding, city services, or other necessary resources have been denied or withheld, and which are often segregated along racial and economic lines as a result. The findings showed that sleep is related to observed classroom behavior and may predict future academic achievement.

The findings were published in a Child Development article, written by researchers at the NYU Grossman School of Medicine, Harvard Medical School, and University of Texas at Austin.

According to the study, higher teacher-reported child sleepiness was associated with lower observed adaptive behaviors (defined as active engagement in learning in the classroom), and higher classroom behavior problems in first grade. Higher teacher-reported child sleepiness also predicted lower academic achievement as assessed one year later, in second grade. Parent-reported bedtime resistance and disordered breathing also predicted lower achievement in second grade.

"Our study, the first to examine the ways in which sleep is related to observed engagement in learning and academic test scores among primarily Black children growing up in disinvested neighborhoods, highlights the importance of educating both parents and teachers about fostering positive sleep habits in young children for their school success," said Alexandra Ursache, assistant professor in the department of population health at NYU Grossman School of Medicine. "The study indicates that encouraging teachers to share their observations of children's sleepiness with parents, in a collaborative and culturally-affirming manner could help make them aware of its interference with learning."

The study included 572 predominantly Black first grade girls and boys with over half coming from immigrant families. The children came from 10 schools located in historically disinvested neighborhoods in New York City. Children in first and second grade (approximately ages 6 and 7), were assessed on:

Sleep health and sleep disorder symptoms: Parents used a questionnaire to report on their children's bedtime resistance, sleep duration, disordered breathing, daytime sleepiness, and sleep onset delay. Teachers reported on their students' daytime sleepiness.

Classroom behavior (adaptive and problem behaviors): Observers from the research team used a coding system to assess students' adaptive behaviors (non-verbal actively engaged learning such as listening, nodding, sitting up, working on an assigned task) and problem behaviors (behavioral or emotional problems).

Academic achievement: A standardized academic achievement assessment was administered by trained research assistants to assess reading, math and writing ability in second grade.

"Sleep is an essential component of healthy development for children, and children of color are at elevated risk for poor sleep health and undetected sleep disorders," said Alicia Chung, assistant professor in the department of population health at NYU Grossman School of Medicine. "This can set the stage for sleepiness in school, increased problem behavior, decreased engagement in learning activities and lower academic achievement."

"The findings raise the possibility that developing a sleep health curriculum may help engage teachers and parents to promote sleep health," said Rebecca Robbins, instructor in medicine at Harvard Medical School.

The authors acknowledge that the measures of sleep used in this study were reported by parents and teachers rather than objective, standardized assessments (for example, collected through activity monitors). The authors also recognize that the measures provided by teachers and parents may include inherent bias involving Black children or African American children being incorrectly rated as sleepy. Although the authors controlled for several important covariates and examined longitudinal relations with academic achievement, they cannot make strong causal claims about the relations between sleep health and classroom behavior or achievement without a research design that intentionally manipulates sleep behavior, for example by randomly selecting some families to participate in an intervention to promote sleep health. This work may also not be generalized to Latinx children or other populations of children of color.

Highlights

Among patients receiving dialysis in the Southeastern United States, those at for-profit dialysis facilities were less likely to be referred for kidney transplantation than those at non-profit facilities.

Rates of starting medical evaluations soon after referral and placing patients on a waitlist after evaluations were similar between the groups.

Washington, DC (May 26, 2021) -- New research indicates that patients with kidney failure who receive care at for-profit dialysis facilities are less likely to be referred for kidney transplants that those receiving care at non-profit facilities. The findings will appear in an upcoming issue of CJASN.

Kidney transplantation is the optimal therapy for most patients with kidney failure. Many patients first initiate dialysis and are referred for a transplant by kidney specialists through dialysis facilities. Previous studies have reported that patients treated at for-profit dialysis facilities are less likely than those treated at non-profit facilities to be placed on a transplant waitlist and to receive a transplant. Little information is available concerning earlier steps in the process, however--namely, referrals and medical evaluations for transplantation.

To investigate, a team led by Rachel E. Patzer, PhD and Laura J. McPherson, MPH (Emory University) examined referral and evaluation data from all 9 transplant centers in the Southeastern United States (Georgia, North Carolina, and South Carolina), as well as information from the United States Renal Data System.

The analysis included 33,651 patients with kidney failure who initiated dialysis in the Southeast from 2012 to 2016. Eighty-five percent of patients received dialysis treatments at for-profit facilities, and 15% were treated at non-profit facilities. A total of 44% of patients were referred for transplant during the 4-year study period. After adjustments, patients at for-profit facilities were 16% less likely to receive a referral than patients at non-profit facilities. Rates of starting medical evaluations within 6 months of referral and placing patients on a waitlist within 6 months of evaluations did not meaningfully differ between the groups.

"Our study offers insight into the practice patterns related to referral for transplantation, start of the transplant evaluation at the transplant center, and placement on the national deceased donor waiting list, but our study does not have detailed information about the mechanisms and reasons for these differences in referral between for profit and non-profit facilities," said Dr. Patzer. "The reasons for these differences in referral could be due to differences in patients' health status that are not measured in our dataset, or they could be due to other unmeasured factors such as limited time to educate or refer patients for transplant, or unconscious bias. Future research is still needed to better understand these mechanisms, such as through focus groups and interviews with patients and care provider team members."

An accompanying editorial notes that "the early steps in transplant access remain frustratingly opaque, indicating the ongoing need to address long-standing disparities and ensure equity in treatment options for patients with kidney failure."

Jodi Karnell and colleagues have developed a monoclonal antibody, VIB7734, that reduces symptom severity in people with cutaneous lupus by targeting and depleting plasmacytoid dendritic cells (pDC) in blood and skin. In two phase I clinical trials involving a total of 67 people with autoimmune diseases such as lupus, treatment with VIB7734 was as safe as a placebo and significantly reduced pDC frequencies, the researchers found. The antibody also reduced the activity of a group of key immune proteins called type 1 interferons in skin. Both pDCs and type 1 interferons are suspected to play a role in autoimmune conditions including lupus, so the new antibody may be an effective treatment option against autoimmunity if these initial results are supported in further clinical trials. VIB7734 targets a molecule on the surface of pDCs to deplete them, often halving the number of these cells after just one dose in non-human primates and patients with autoimmune diseases. In patients with cutaneous lupus treated with a high dose (150 milligrams) of VIB7734, 87.5% had clinically meaningful reductions in their symptoms one month after treatment, compared with 37.5% for those treated with a 50-milligram dose and 28.6% for those treated with a placebo. Karnell et al. also note that VIB7734 seems to work best in people with high concentrations of type 1 interferons circulating in the blood, suggesting that baseline type 1 interferon concentrations could predict patient responses.

UNIVERSITY PARK, Pa. -- One of the most important and widespread reef-building corals, known as cauliflower coral, exhibits strong partnerships with certain species of symbiotic algae, and these relationships have persisted through periods of intense climate fluctuations over the last 1.5 million years, according to a new study led by researchers at Penn State. The findings suggest that these corals and their symbiotic algae may have the capacity to adjust to modern-day increases in ocean warming, at least over the coming decades.

Cauliflower corals -- which are in the genus Pocillopora -- are branching corals that provide critical habitat for one-quarter of the world's fish and many kinds of invertebrates, such as lobsters, sea urchins and giant clams. They are common throughout the Indo-Pacific -- the region extending from eastern Africa, north to India and Southeast Asia, across Australia and encompassing Hawaii -- and are capable of long-range dispersal and rapid growth, making them among the first species to repopulate reefs damaged by typhoons and events of mass coral bleaching and mortality.

"We found that Pocillopora has maintained a close relationship with certain species of algae in the genus Cladocopium over repeated oscillations in Earth's climate," said Todd LaJeunesse, professor of biology, Penn State. "Our findings reinforce how stable and resilient these relationships are over deep time."

LaJeunesse explained that corals comprise hundreds to hundreds of thousands of individual animals, called polyps. Tiny, single-celled algae, known as dinoflagellates, live inside these polyps' tissues, giving the corals their color and providing the animals with up to 90% of their energy needs through the products of photosynthesis. These dinoflagellates significantly influence the capacity of corals to deal with environmental stressors.

For two decades, LaJeunesse and his colleagues have been collecting coral samples from around the world, using molecular-genetic techniques to identify the coral and algal species, documenting the specificity of the partnerships (some species of algae are highly specific to certain species of coral, whereas others are generalists and can associate with many different types of coral) and determining how these partnerships have changed through evolutionary history.

"Important biological discoveries are more likely when working with accurate species resolution -- in this case, for both coral and dinoflagellate," said LaJeunesse. "Research on the biology of photosynthetic corals has been hampered by a lack of good taxonomic resolution. Our work on resolving these species is highly detailed and currently among the most sophisticated."

The team used a combination of genetic, ecological and morphological -- the outward appearance of an organism -- techniques to examine Cladocopium that associate with Pocillopora. Specifically, they relied on a variety of genetic markers -- or DNA sequences with known locations on chromosomes -- to determine the genetic identities of the species. They also used a microscope to visualize and image the Cladocopium cells. The findings published on May 20 in the ISME Journal, the official journal of the International Society for Microbial Ecology.

"With this research, we now know that Cladocopium, the most common genus of coral symbionts, comprises hundreds of species," said Kira Turnham, graduate student in biology, Penn State. "We were able to identify and describe two species, which we named Cladocopium latusorum and Cladocopium pacificum, and with this resolution, were able to deduce the age of their partnerships and unique importance to specific host corals."

Next, the team investigated whether Cladocopium from geographically dispersed populations of Pocillopora were reproductively isolated or displayed connectivity. They found that populations of both species, like their Pocillopora hosts, are genetically well-connected across the tropical and sub-tropical Pacific Ocean, indicating a capacity for long-range dispersal.

For instance, Turnham said, "Cladocopium latusorum spans the Indian and Pacific Oceans -- from the eastern shores of Tanzania to the Coral Triangle, Great Barrier Reef in Australia and Panama. This connectivity between populations in different locations may contribute to the resiliency of these species to endangerment or extinction threats."

To determine how old the partnerships are, the researchers used a "molecular clock" -- an analysis that assesses DNA sequence divergence over time -- to estimate when the two Cladocopium species diverged from their common ancestor. They found that the species arose during the late Pliocene to early Pleistocene epochs, at a time when their coral host was also forming new species.

"There has been considerable talk about corals' ability to shuffle their dinoflagellate species to improve their ability to withstand global warming," said LaJeunesse. "While some of this may be true, most corals have a very limited assortment of species with which they are able to associate. We have shown that with this limited number of compatible symbionts, Pocillopora have been able to deal with major changes in climate every 100,000 years for the past 1-to-2 million years."

Turnham noted that despite their persistence through time, the strict nature of the relationship between Pocillopora and Cladocopium may limit their ability to evolve in response to increased warming compared to corals that can associate with more thermally tolerant dinoflagellates.

"Ultimately," she said, "the broad geographic distributions and geological age of these and other coral-algal combinations must be considered in forecasting their response to ocean warming, and guide decisions when planning for their conservation."

To help patients manage their mental wellness between appointments, researchers at Texas A&M University have developed a smart device-based electronic platform that can continuously monitor the state of hyperarousal, one of the signs of psychiatric distress. They said this advanced technology could read facial cues, analyze voice patterns and integrate readings from built-in vital signs sensors on smartwatches to determine if a patient is under stress.

Furthermore, the researchers noted that the technology could provide feedback and alert care teams if there is an abrupt deterioration in the patient's mental health.

"Mental health can change very rapidly, and a lot of these changes remain hidden from providers or counselors," said Dr. Farzan Sasangohar, assistant professor in the Wm Michael Barnes '64 Department of Industrial and Systems Engineering. "Our technology will give providers and counselors continuous access to patient variables and patient status, and I think it's going to have a lifesaving implication because they can reach out to patients when they need it. Plus, it will empower patients to manage their mental health better."

The researchers' integrated electronic monitoring and feedback platform is described in the Journal of Psychiatric Practice.

Unlike some physical illnesses that can usually be treated with a few doctor visits, people with mental health needs can require an extended period of care. Between visits to a health care provider, information on a patient's mental health status has been lacking. Hence, unforeseen deterioration in mental health has a limited chance of being addressed. For example, a patient with anxiety disorder may experience a stressful life event, triggering extreme irritability and restlessness, which may need immediate medical attention. But this patient may be between appointments. On the other hand, health care professionals have no way to know about their patients' ongoing struggle with mental health, which can prevent them from providing the appropriate care.

Hence, patient-reported outcomes between visits are critical for designing effective health care interventions for mental health so that there is continued improvement in the patient's wellbeing. To fill in this gap, Sasangohar and his team worked with clinicians and researchers in the Department of Psychiatry at Houston Methodist Hospital to develop a smart electronic platform to help assess a patient's mental wellbeing.

"The hospital has the largest inpatient psychiatry clinic in the Houston area," said Sasangohar. "With this collaboration, we could include thousands of patients that had given consent for psychiatric monitoring."

Sasangohar's collaborators at Houston Methodist Hospital were already using an off-the-shelf patient navigation tool called CareSense. This software can be used to send reminders and monitoring questions to patients to better assess their wellbeing. For instance, individuals at risk for self-harm can be prompted to take questionnaires for major depressive disorder periodically.

Rather than solely relying on the patients' subjective assessment of their mental health, Sasangohar and his team also developed a whole suite of software for automatized hyperarousal analysis that can be easily installed on smartphones and smartwatches. These programs gather input from face and voice recognition applications and sensors already built in smartwatches, such as heart rate sensors and pedometers. The data from all of these sources then train machine-learning algorithms to recognize patterns that are aligned with the normal state of arousal. Once trained, the algorithms can continuously look at readings coming from the sensors and recognition applications to determine if the individual is in an elevated arousal state.

"The key here is triangulation," said Sasangohar. "Each of these methods on their own, say facial sentiment analysis, show promise to detect the mental state, albeit with limitations. But when you combine that information with the voice sentiment analysis, as well as physiological indicators of distress, the diagnosis and inference become much more powerful and clearer."

Sasangohar noted that both the subjective evaluation of mental state and the objective evaluation from the machine-learning algorithms are integrated to make a final assessment of the state of arousal for a given individual.

While their technology's prototype is ready, the researchers said they still need to improve the battery life of smartphones carrying their software since the algorithms guzzle a lot of power. Further, they noted that they have to address usability issues, that is, any issues that prohibit patients from using their technology, such as difficulty in navigating their application.

"Because of the stigmatization that surrounds mental illness, we wanted to build a mental health monitoring device that was very discreet," said Sasangohar. "So, we chose off-the-shelf products, like smartphones, and then build sophisticated applications that operate within these devices to make monitoring mental health discreet."

Up to half of patients with head and neck squamous cell carcinoma will experience tumor recurrence or new tumors--tumors that often spread and are difficult to treat.

A team of scientists led by the University of Michigan School of Dentistry identified a mechanism by which head and neck cancer cells subvert adjacent normal tissue, allowing small clusters of cancer cells to burrow beneath the healthy tissue.

The team decided to look at this particular mechanism in head and neck cancer because a specific gene, DMBT1, appeared on a screen of genes that are silenced during oral cancer, said principal investigator Nisha D'Silva, the Donald A. Kerr Endowed Collegiate Professor of Oral Pathology.

Researchers from the D'Silva lab found that when DMBT1 was suppressed in head and neck cancer cells, it promoted aggressive invasion and metastasis in laboratory studies
and was associated with metastasis in patients.

They also found that two proteins secreted by head and neck cancer cells suppress DMBT1 in nearby ?healthy tissue, subverting it to promote invasion of a small amount of cancer cells, which burrow under healthy tissue.

Researchers looked at this mechanism in mice, chick embryos and cultures of human cancer cells. ??In the chick embryos, none of the tumors that overexpressed DMBT1 metastasized, whereas most of the control tumors that had low DMBT1 metastasized, D'Silva said.

"The importance of this paper is that loss of DMBT1 in cancer cells and adjacent normal tissue benefits cancer cells, allowing them to travel in tiny groups away from the main tumor," she said. "That is why cancer cells enlist the help of the adjacent tissue. Finding ways to interrupt this communication and enhance DMBT1 expression could help improve outcome."

The findings, published in the Journal of Experimental Medicine, could open possibilities for new therapeutics that target proteins in cancer cells that regulate DMBT1 and could have implications for other cancers in which DMBT1 expression is altered, D'Silva said.

"We are familiar with cancer cells enlisting the help of other cell types to grow and spread," she said. "Our research demonstrated that cancer cells also communicate with healthy cells of their own cell type to facilitate spread."

Head and neck cancer is the sixth most common cancer in the world, with 600,000 new cases annually.