Culture

Journal Name: Nature Methods

Title of the Article: Discovering multiple types of DNA methylation from individual bacteria and microbiome using nanopore sequencing

Corresponding Author: Gang Fang, PhD

Bottom Line:

Bacterial DNA methylation occurs at diverse sequence contexts and plays important functional roles in cellular defense and gene regulation. An increasing number of studies have reported that bacterial DNA methylation has important roles affecting clinically relevant phenotypes such as virulence, host colonization, sporulation, biofilm formation, among others.

Bacterial methylomes contain three primary forms of DNA methylation: N6-methyladenine (6 mA), N4-methylcytosine (4mC) and 5-methylcytosine (5mC). The widely used bisulfite sequencing for DNA methylation mapping in mammalian genomes are not effective at resolving bacterial methylomes. Single molecule real-time (SMRT) can effectively map 6mA and 4mC events, and have empowered the study of >4,000 bacterial methylomes in the past ten years. However, SMRT sequencing cannot effectively detect 5mC methylation.

Results: In this work, we developed a new method that enables nanopore sequencing for broadly applicable methylation discovery. We applied it to individual bacteria and the gut microbiome for reliable methylation discovery. In addition, we demonstrated the use of DNA methylation for high resolution microbiome analysis, mapping mobile genetic elements with their host genomes directly from microbiome samples.

Why the Research Is Interesting:

To battle with bacterial pathogens. Antibiotics resistance poses great risk to public health. To best battle with bacterial pathogens, it is important to discover novel drug targets. Increasing evidence suggests that bacterial DNA methylation plays important roles in regulating bacterial physiology such as virulence, sporulation, biofilm formation, pathogen-host interaction etc. The new method in this work allows researchers to more effectively discover novel DNA methylation from bacterial pathogens, opening new opportunities to discovery novel targets to design new inhibitors.

To better understand microbiome. Despite growing appreciation for the role of microbiome in human health, comprehensive characterization of microbiomes remains difficult. To effectively harness the therapeutic power of microbiome, it is important to understand the specific bacteria species and particular strains in human microbiome. Our new method combines the power of long read sequencing and bacterial DNA methylation to resolve complex microbiome samples into individual species and strains. So, it will also empower higher resolution characterization of human microbiome for medical applications.

The power of methylation based mapping of mobile genetic elements (often encoding antibiotics resistance genes) to their host genomes also helps tracking the transmission of antibiotic resistance genes.

How: By examining three types of DNA methylation in a large diversity of sequence contexts, we observed that nanopore sequencing signal displays complex heterogeneity across methylation events of the same type. To capture this complexity and enable nanopore sequencing for broadly applicable methylation discovery, we generated a training dataset from an assortment of bacterial species and developed a novel method that couples the identification and fine mapping of the three forms of DNA methylation into a multi-label classification design. We evaluated the method and then applied it to individual bacteria and mouse gut microbiome for reliable methylation discovery. In addition, we demonstrated in the microbiome analysis the use of DNA methylation for binning metagenomic contigs, associating mobile genetic elements with their host genomes, and for the first time, identifying misassembled metagenomic contigs.

Said Mount Sinai's Gang Fang of the work:

DNA methylation plays important roles in the human genome, and is widely studied in health and various diseases. DNA methylation is also prevalent in bacteria, but our current understanding is still at a relatively early stage.

An increasing number of studies have reported that bacterial DNA methylation plays important roles in regulating medically relevant phenotypes of pathogenic bacteria, such as virulence, biofilm formation, virulence, sporulation, among others.

Broader and deeper study of bacterial DNA methylation requires reliable technologies, and our new method fills an important gap in that it now enables the use of Nanopore sequencing to make new discoveries from bacterial genomes.

This novel method has broad utility for discovering different forms of DNA methylation from bacteria, assisting functional studies of epigenetic regulation in bacteria, and exploiting bacterial epigenomes for more effective metagenomic analyses.

What The Study Did: A clinical risk assessment tool developed in China was tested with a group of patients in Spain to evaluate its ability to predict critical illness among patients hospitalized with COVID-19 in Europe.

Authors: Oscar Moreno-Perez, M.D., Ph.D., of the Alicante General University Hospital-Alicante Institute of Sanitary and Biomedical Research in Alicante, Spain, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamainternmed.2021.0491)

Editor's Note: The article includes conflicts of interest disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

What The Study Did: Researchers investigated the association of sociodemographic factors and blood group type with the risk of SARS-CoV-2 infection and severity of COVID-19.

Authors: Jeffrey L. Anderson, M.D., of the Intermountain Medical Center Heart Institute in Salt Lake City, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamanetworkopen.2021.7429)

Editor's Note: The article includes conflicts of interest disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

Public trust in the federal Centers for Disease Control and Prevention has fallen during the coronavirus pandemic, with the decline bringing overall population-level trust in the agency to the same lower level of trust long held by Black Americans about the agency, according to a new RAND Corporation study.

Surveys done among a representative group of Americans in May and October of 2020 show about a 10% decline in trust of the CDC over that period.

In contrast, the same research found that public trust in the U.S. Postal Service and the Federal Emergency Management Agency increased significantly over the period, despite those agencies facing their own challenges.

"The Biden administration will have an uphill battle in rehabilitating trust in the CDC at this critical junction in the coronavirus pandemic," said Michael Pollard, lead author of the study and a senior social scientist at RAND, a nonprofit research organization. "A key challenge in the months ahead will be to identify who will be viewed as trusted messengers regarding vaccines and public health policies."

The study found that non-Hispanic white and Hispanic respondents reported significant declines in trust in the CDC, while the changes were not statistically significant for non-Hispanic Black or "other race" respondents.

"There is remarkable consistency and convergence in reported levels of trust in the CDC across these subgroups after the declines," Pollard said. "Lack of trust among Black Americans has been a well-publicized concern regarding the COVID-19 vaccine rollout, and the convergence in lower levels of trust across race/ethnicity highlights a key challenge that the CDC now faces."

Black Americans have historically held a low level of trust in the CDC and other health institutions, widely seen as a legacy of past racism in the nation's health system.

RAND researchers surveyed a representative sample of more than 2,000 Americans in May 2020, asking to rate their trust of the CDC, the USPS and FEMA on a scale of 0 to 10. Most of the participants were surveyed again in October 2020. All participants were part of the RAND American Life Panel, a nationally representative internet panel.

The survey found that trust in the CDC fell from 7.6 in May to 7 in October. Meanwhile, trust in the Postal Service rose from 6.9 in May to 7.7 in October; trust in FEMA rose from 6.4 in May to 6.7 in October.

Drop in trust of the CDC was particularly significant among people who intended to vote for a candidate other than Joe Biden in the 2020 presidential election or did not intend to vote at all, suggesting that views of the CDC are now strongly politicized. Similar politicization was not observed for FEMA or the USPS.

"The public trust in federal government agencies has never been as important as during the current COVID-19 pandemic, yet public suspicions of scientific experts and distrust of government institutions are increasing for a variety of reasons," said Lois Davis, co-author of the report and a senior policy researcher at RAND. "Reasons for this include a blurring of the line between opinion and fact, and access to more sources of conflicting information."

Researchers say one strategy that may help the CDC rebuild trust and depoliticize the public's views of the agency is to ensure that the public understands the scientific rationale for policy changes and guidance during the COVID-19 pandemic.

New research suggests anxiety among men transitioning into parenthood is significantly higher than reported by the global World Health Organization (WHO) regional prevalence rates.

In a new study published in The Journal of Psychosomatic Obstetrics & Gynecology, researchers from the Colorado School of Public Health on the University of Colorado Anschutz Medical Campus studied the prevalence of anxiety among fathers during the perinatal period, which includes pregnancy through the first year of postpartum.

"The transition to parenthood is a major life event that's often accompanied with new challenges related to financial, relationship, and work-life balance concerns. Despite those changes happening for both men and women, not much is known about the prevalence of anxiety among new fathers," said Jenn Leiferman, PhD, professor at the Colorado School of Public Health. "To our knowledge, our study is the first meta-analysis to explore the prevalence rates of anxiety among both fathers and mothers during the perinatal period."

The researchers reviewed eligible studies representing more than 40,000 participants that have published between 1995-2020. The researchers found that the overall estimate of anxiety among men during the perinatal period was nearly 11 percent, with rates being lower during pregnancy (9.9 percent) than during the first year postpartum (11.7 percent).

These rates are considerably higher than the global WHO regional prevalence rates for anxiety among men that range between 2.2 to 3.8 percent, suggesting the transition into parenthood may increase risk for anxiety in men.

In terms of anxiety among mothers, the researchers found an estimated 17.6 percent of women experience it during the perinatal period. This is also substantially higher than global WHO regional preferences for anxiety among women, but in line with estimates for maternal anxiety from other meta-analyses.

"The prevalence of anxiety and depression among men is talked about less as a society, even though research shows men are more likely to commit suicide or abuse alcohol than women. It's important that we create more transparency around men's mental health issues. Our hope is by creating awareness, we can help people get help earlier when needed," said Leiferman.

The researchers suggest that many men suffer anxiety during the transition to parenthood, starting as soon as the first trimester throughout the first year postpartum. Given this, identifying appropriate support for new fathers as well as early identification and treatment efforts for paternal anxiety are needed.

ORLANDO, April 5, 2021 - A new study from the University of Central Florida suggests that masks and a good ventilation system are more important than social distancing for reducing the airborne spread of COVID-19 in classrooms.

The research, published recently in the journal Physics of Fluids, comes at a critical time when schools and universities are considering returning to more in-person classes in the fall.

"The research is important as it provides guidance on how we are understanding safety in indoor environments," says Michael Kinzel, an assistant professor in UCF's Department of Mechanical and Aerospace Engineering and study co-author.

"The study finds that aerosol transmission routes do not display a need for six feet social distancing when masks are mandated," he says. "These results highlight that with masks, transmission probability does not decrease with increased physical distancing, which emphasizes how mask mandates may be key to increasing capacity in schools and other places."

In the study, the researchers created a computer model of a classroom with students and a teacher, then modeled airflow and disease transmission, and calculated airborne-driven transmission risk.

The classroom model was 709 square feet with 9-foot-tall ceilings, similar to a smaller-size, university classroom, Kinzel says. The model had masked students -- any one of whom could be infected-- and a masked teacher at the front of the classroom.

The researchers examined the classroom using two scenarios -- a ventilated classroom and an unventilated one -- and using two models, Wells-Riley and Computational Fluid Dynamics. Wells-Riley is commonly used to assess indoor transmission probability and Computational Fluid Dynamics is often used to understand the aerodynamics of cars, aircraft and the underwater movement of submarines.

Masks were shown to be beneficial by preventing direct exposure of aerosols, as the masks provide a weak puff of warm air that causes aerosols to move vertically, thus preventing them from reaching adjacent students, Kinzel says.

Additionally, a ventilation system in combination with a good air filter reduced the infection risk by 40 to 50% compared to a classroom with no ventilation. This is because the ventilation system creates a steady current of air flow that circulates many of the aerosols into a filter that removes a portion of the aerosols compared to the no-ventilation scenario where the aerosols congregate above the people in the room.

These results corroborate recent guidelines from the U.S. Centers for Disease Control and Prevention that recommend reducing social distancing in elementary schools from six to three feet when mask use is universal, Kinzel says.

"If we compare infection probabilities when wearing masks, three feet of social distancing did not indicate an increase in infection probability with respect to six feet, which may provide evidence for schools and other businesses to safely operate through the rest of the pandemic," Kinzel says.

"The results suggest exactly what the CDC is doing, that ventilation systems and mask usage are most important for preventing transmission and that social distancing would be the first thing to relax," the researcher says.

When comparing the two models, the researchers found that Wells-Riley and Computational Fluid Dynamics generated similar results, especially in the non-ventilated scenario, but that Wells-Riley underpredicted infection probability by about 29 percent in the ventilated scenario.

As a result, they recommend some of the additional complex effects captured in Computational Fluid Dynamics be applied to Wells-Riley to develop a more complete understanding of risk of infection in a space, says Aaron Foster, a doctoral student in UCF's Department of Mechanical and Aerospace Engineering and the study's lead author.

"While the detailed Computational Fluid Dynamics results provided new insights into the risk variation and distance relationships, they also validated the more commonly used Wells-Riley models as capturing the majority of the benefit of ventilation with reasonable accuracy," Foster says. "This is important since these are publicly available tools that anyone can use to reduce risk."

WINSTON-SALEM, N.C. - April 5, 2021 - According to the American Cancer Society, a noninvasive breast cancer called ductal carcinoma in situ (DCIS) accounts for approximately one of every four new breast cancer cases in the United States. If left untreated, DCIS has the potential to evolve into invasive cancer, so many patients choose to have breast-conserving surgery or mastectomy after a diagnosis.

However, obtaining clear or negative margins -- no cancer cells in the outer edge of removed tissue -- is critical to mastectomy success as positive margins are associated with higher rates of recurrence.

A new study from Wake Forest School of Medicine suggests removing additional tissue around the tumor cavity, a technique known as cavity shave margin resection, reduces the rate of positive margins in patients with DCIS. The findings are published online in the April 2021 issue of the Journal of the American College of Surgeons.

"Our previous clinical trial showed that this technique can reduce positive-margin rates in invasive disease by at least 50%, but to my knowledge, this is the first analysis involving pure DCIS," said Marissa Howard-McNatt, M.D., director of the Breast Cancer Center at Wake Forest Baptist Health and associate professor of surgical oncology at Wake Forest School of Medicine, part of Wake Forest Baptist.

Researchers randomized 109 patients with pure DCIS (no invasive cancer) from 10 centers across the U.S., and 58 (53.2%) of these patients were randomized for cavity shave margin resection. In this group, researchers noted a nearly 65% reduction in the positive-margin rate.

According to Howard-McNatt, achieving clear margins in patients with DCIS can be difficult due to the continuous and branching nature of the spread of this disease. Clear margins free of cancer are vital in decreasing the chance of recurrence of cancer in the breast.

"Our study shows a significant reduction in positive margins," Howard-McNatt said. "This technique should be considered for DCIS patients."

Scientists create stable nanosheets containing boron and hydrogen atoms with potential applications in nanoelectronics and quantum information technology.

What’s thinner than thin? One answer is two-dimensional materials — exotic materials of science with length and width but only one or two atoms in thickness. They offer the possibility of unprecedented boosts in device performance for electronic devices, solar cells, batteries and medical equipment.

In collaboration with Northwestern University and the University of Florida, scientists from the U.S. Department of Energy’s (DOE) Argonne National Laboratory report in Science magazine a breakthrough involving a 2D material called borophane, a sheet of boron and hydrogen a mere two atoms in thickness.

“We have tackled a significant challenge in determining the atomic structures from scanning tunneling microscopy images and computational modeling at the atomic scale with the help of computer vision.” — Argonne’s Maria Chan, nanoscientist at the Center for Nanoscale Materials.

One of the most exciting developments in materials science in recent decades has been a 2D sheet of carbon (graphene), which is one atom thick and 200 times stronger than steel. A similarly promising and newer material is an atom-thick sheet of boron, called borophene — with an “e.” A multi-institutional team, including researchers in Argonne’s Center for Nanoscale Materials (a DOE Office of Science User Facility), first synthesized borophene in 2015.

While graphene is simply one atomic layer out of the many same layers in the common material graphite, borophene has no equivalent parent structure and is very difficult to prepare. What’s more, the rapid reaction of borophene with air means it is very unstable and changes form readily.

“Borophene by itself has all kinds of problems,” said Mark Hersam, Professor of Materials Science and Engineering at Northwestern University. “But when we mix borophene with hydrogen, the product suddenly becomes much more stable and attractive for use in the burgeoning fields of nanoelectronics and quantum information technology.”

The research team grew borophene on a silver substrate then exposed it to hydrogen to form the borophane. They then unraveled the complex structure of borophane by combining a scanning tunneling microscope with a computer-vision based algorithm that compares theoretical simulations of structures with experimental measurements. Computer vision is a branch of artificial intelligence that trains high performance computers to interpret and understand the visual world.

Even though the borophane material is only two atoms thick, its structure is quite complex because of the many possible arrangements for the boron and hydrogen atoms. “We have tackled a significant challenge in determining the atomic structures from scanning tunneling microscopy images and computational modeling at the atomic scale with the help of computer vision,” said Argonne’s Maria Chan, nanoscientist at the Center for Nanoscale Materials. Given the success in unraveling this complex structure, the team’s automated analytical technique should be applicable in identifying other complex nanostructures in the future.

“What is really encouraging from our results is that we found a borophane nanosheet on a silver substrate to be quite stable, unlike borophene,” said Pierre Darancet, nanoscientist at Argonne’s Center for Nanoscale Materials. “This means it should be easily integrated with other materials in the construction of new devices for optoelectronics, devices combining light with electronics.” Such light-controlling and light-emitting devices could be incorporated into telecommunications, medical equipment and more.

“These findings are an important step in realizing borophane’s incredible potential as a two-dimensional material for nanoelectronics,” Chan said.

A new report by AARP Pennsylvania and Drexel University's College of Nursing and Health Professions highlights how geographic, racial/ethnic and economic factors are combining to restrict access to health care services for many Pennsylvanians, creating disparities that have become more pronounced during the COVID-19 pandemic.

"Disrupting Disparities in Pennsylvania: Retooling for Geographic, Racial and Ethnic Growth" shows that health inequities are most acute among those living in rural and low resourced areas of the state, and among underrepresented populations (particularly Black/African American and Latino), who lack access to health care, experience digital divide and face persistent local healthcare workforce shortages. The study draws on interviews with key stakeholders statewide, a comprehensive literature review and analyses of databases on the health of Pennsylvanians.

"The pandemic is effectively exacerbating inequities for those living in poorer rural and urban areas by limiting their ability to schedule, and get to, COVID-19 vaccine appointments," said Laura N. Gitlin, PhD, dean of Drexel University's College of Nursing and Health Professions. "For years, social conditions that have led to poor health have also combined with limited resources and unequal access to quality care to create significant disparities in underserved areas of Pennsylvania. These disparities persist and have been exacerbated by COVID-19."

"The COVID-19 public health crisis has wreaked havoc on older Pennsylvanians, bringing to the forefront the deep disparities that exist in access to health care and internet connectivity," said AARP Pennsylvania State Director Bill Johnston-Walsh. "Now, more than ever, there is an urgent need to bring about systemic and structural change to promote and assure equitable solutions for older adults across the Commonwealth."

Pennsylvania demographic trends point toward a significant expansion of the number of older adults living in poverty with poor access to health care. Currently, about 40% of Pennsylvanians are 50 and older, with nearly 19% over the age of 65. Those older adults currently live predominately in rural areas and are white with low household income. However, by 2040, the Commonwealth will experience exponential growth in the aging population led by the southeastern part of the state, which is the most populous, racially and ethnically diverse region.

"Our research shows that gaps in access to health care and internet will only continue to grow as Pennsylvania's population becomes older and with the increase in number of low-income adults living in the southeastern part of the state," said Rose Ann DiMaria-Ghalili, PhD, associate dean for Interprofessional Research and Development at Drexel University's College of Nursing and Health Professions.

Geography plays a key role in access to health services and COVID-19 vaccines in other ways. The report finds that each of Pennsylvania's 67 counties has at least one "pharmacy desert," such with few to no pharmacies available. With local pharmacies serving as a key component of Pennsylvania's COVID-19 vaccine distribution plan -- especially in rural areas of the state -- pharmacy deserts directly impact access to vaccines for those at high risk.

The report shows health care costs are also a leading contributor to health inequities. For example, 6% of adults aged 45-64 do not currently have health insurance and 11% report not seeing a doctor because of cost, with the largest percentages coming from counties representing both rural and urban areas of the Commonwealth.

An increased role for telehealth services could represent a significant step toward improving access to quality health care statewide. Unfortunately, the report documents, a digital divide is furthering inequities for those without access to broadband internet and telehealth care. Few Pennsylvania counties are able to support 100% of their population connecting to the internet. In addition, 8% of households in eight counties report no internet access at all.

"Critically, older Pennsylvanians are disproportionately impacted by the digital divide, whether due to lack of access to broadband, internet or smart devices, or due to digital literacy," said Gitlin from Drexel. "The digital divide hampers their ability to access telehealth services and schedule COVID-19 vaccine appointments online."

"During the pandemic many senior centers, adult day services, libraries and other community settings remain closed. This means that older adults, who do not have access to the internet in their homes, remain disconnected," said AARP's Johnston-Walsh. "Without access to the internet, or the know-how to navigate the decentralized system of scheduling a vaccine appointment, older Pennsylvanians are at a disadvantage to protecting themselves from the pandemic."

The report finds additional barriers to accessing health care for many residents, including a significant workforce shortage. An estimated 14% of Pennsylvanians live in a medically underserved area and 22% live in an area that is both medically underserved and designated as having a health professions shortage. Residents of these areas primarily live in rural areas, or are of minority status, poorly educated, live in poverty and have limited access to transportation.

"Not only do we need more health professionals and direct care workers, we need to prepare the health care workforce to be culturally competent and capable of addressing age-related health care issues including preventing and managing chronic conditions and their impact on everyday activities of living and aging in place at home," said Drexel's Gitlin.

"Solutions to help disrupt health disparities impacting the 50-plus population in Pennsylvania are urgently needed," said Angela Foreshaw-Rouse, operations and outreach manager for AARP Pennsylvania. "The time is now to assure that all individuals are able to live long and healthy lives regardless of where they live or their racial/ethnic background."

Highlights of Disrupting Disparities in Pennsylvania: Retooling for Geographic, Racial and Ethnic Growth include:

COVID-19:

Each of the 67 counties in PA have at least one pharmacy desert (which was defined at census tract level). Pharmacy deserts will lead to vaccination deserts with vaccine rollout, causing greater disparities in those areas.

Community-based organizations that provide services for older adults report challenges in delivering virtual services during the pandemic, reporting technology as a barrier.

During the pandemic many senior centers, libraries and other community settings remain closed and older adults who do not have access to the internet in their homes via computer or smartphone remain disconnected.

In addition to access-related challenges, distrust of the health care system, especially among Black Pennsylvanians, and safety concerns may contribute to COVID-19 vaccination hesitancy.

Geographic Challenges:

About 23% of older adults living in rural communities have cognitive difficulties or difficulties with independent living and lack access to community-based services, such as adult day services, personal care homes and low-income housing, supports that are commonplace in urban areas.

An estimated 14% of Pennsylvanians live in a medically underserved area and 22% live an area that is both medically underserved and designated a health professions shortage area. Residents of these areas primarily live in rural areas, or are of minority status, poorly educated, live in poverty and have limited access to transportation.

Rural communities currently have roughly half the physicians per capita as non-rural areas. There are also less hospital beds compared to urban areas and several rural counties have no hospitals.

Access to Health Care:

In PA, 6% of adults 45-64 years of age report not having health insurance and 11% report not seeing a doctor because of cost. The areas with the highest percentage of adults 45-64 years of age without health care coverage include Pike, Monroe, Susquehanna and Wayne Counties at 13% with Philadelphia at 10%.

The cost barrier is a critical issue: 18% of those 45-64 living in Lackawanna, Luzerne and Wyoming and Erie County, and 15% of those living in Philadelphia County reported not able to see a doctor in the past year because of cost.

Lacking broadband is an impediment to delivering telehealth services in rural areas.

Health and Digital Literacy:

Some 7% of Pennsylvanians 50+ report difficulty in understanding information from a health care professional, and older adults report a slightly higher rate of not being able to understand written information.

Individuals 65+ are less likely to use electronic devices to look for health information, communication with their physician, look up test results and track health charges.

Digital Divide:

Only in Bucks, Chester, Delaware and Montgomery Counties can over 95% of the population use or connect to the internet in their household.

12% of counties (Cameron, Clearfield, Forest, McKeon, Philadelphia, Sullivan, Union and Warren) have 8% of households with no internet access.

Smartphones can lessen the internet access divide by enabling individuals to access the internet on their phone.

During the pandemic, many senior centers, libraries and other community settings remain closed and older adults, who do not have access to the internet in their homes via computer or smartphone, remain disconnected.

Lack of broadband internet is an impediment to delivering telehealth services in rural areas.

Workforce Shortage and Competencies:

Pennsylvania faces a significant workforce shortage in health care professionals including direct care workers, dentists, nurse practitioners, physical therapists, physicians, physician assistants, pharmacists, psychiatrists, registered dietitians, registered nurses, occupational therapists and social workers.

An estimated 14% of Pennsylvanians live in a medically underserved area and 22% live an area that is both medically underserved and designated a health professions shortage area.

Residents of these areas primarily live in rural areas, or are of minority status, poorly educated, live in poverty and have limited access to transportation.

The workforce is unprepared to address complex and co-morbid conditions and lack training in the specialty of geriatrics.

A study at the University of Chicago Medicine found U.S. women experienced increased incidence of health-related socioeconomic risks (HRSRs), such as food insecurity and interpersonal violence, early in the COVID-19 pandemic. This was associated with "alarmingly high rates" of mental health problems, including depression and anxiety. The research was published April 5 in the Journal of Women's Health.

Other studies have found evidence for higher rates of anxiety and depression and related issues, such as alcohol overuse, connected to the pandemic -- but this study is the first to link early pandemic-related changes in HRSRs to mental health effects in women.

"Most national surveys tend to report aggregated findings rather than stratifying by gender," said Stacy Lindau, MD, Professor of Obstetrics and Gynecology and Medicine-Geriatrics at UChicago Medicine. "Those early studies gave us snapshots of the health and behaviors of the whole population, but gave us limited insight on women. Yet, women constitute the majority of the essential workforce, including healthcare workers, and we wanted to make sure that women's experiences were being documented."

The researchers conducted a survey of 3,200 U.S. women over the age of 18 between April 10 and 24, 2020. More than 40% of participants reported experiencing at least one HRSR during the prior year, which included issues such as food insecurity, housing instability, difficulties with their utilities, transportation challenges and interpersonal violence; 22% reported experiencing two or more HRSRs during the year before the pandemic.

But by the first spring of the pandemic, nearly half of all women -- including 29% of those who did not experience pre-pandemic HRSRs -- reported new (incident) or worsening HRSRs. The greatest challenge was an increase in food insecurity. Nearly 80% of those without pre-pandemic HRSRs who reported a new HRSR became food insecure. Almost a quarter experienced interpersonal violence.

"It's incredible and concerning that nearly half of women -- including more than a quarter of those who had no health-related socioeconomic risks -- had experienced incident or worsening conditions," said Lindau. "It's even more striking that more than a quarter of the women who had none of these risks in January or February 2020 now had at least one by April. That points to the likelihood that a large portion of women were already near the edge of vulnerability. When the world shut down, transportation became more difficult, food access became harder, and very soon after the crisis began, many women found themselves struggling to meet basic needs."

Those who experienced socioeconomic risks prior to the pandemic also experienced the greatest increase in insecurity. Three-quarters of women with pre-pandemic HRSRs experienced new or worsening risks during the early pandemic; 38% experienced two or more, with more than half experiencing increased food insecurity.

Significantly, the survey also found that 29% of women reported symptoms of depression and anxiety -- nearly twice the estimated pre-pandemic rates. One in six women screened positive for symptoms of post-traumatic stress, a rate similar to that seen after other significant disasters, such as the SARS and Ebola epidemics. Those who experienced at least one new or worsening HRSR were at significantly higher risk of experiencing anxiety and post-traumatic stress.

"Given very high rates of these problems, we're really concerned about the current capacity of our mental health system," said co-author Marie Tobin, MD, Professor of Psychiatry at UChicago Medicine. "Women are principally responsible for parenting, family caregiving and other essential work -- they are key to managing and recovering from this pandemic, and now are afflicted by very significant socioeconomic risk levels that appear to be drivers of anxiety, depression and traumatic stress. We should be especially concerned that socioeconomically vulnerable women are at high risk for developing pandemic-related psychiatric morbidity."

These results, the investigators say, should help spur healthcare providers and policy makers to address the underlying and modifiable health-related socioeconomic risk factors in order to prevent these negative outcomes.

"We can't change a person's gender, but we can act to ensure that all people have the basic nutrition and shelter they need to survive," said Lindau. "We can intervene on transportation barriers, we can pass policies to delay or offset rent or utilities payments. These are modifiable factors that can be addressed by leveraging the humanitarian resources of our communities and implementing policies that ensure everyone can live independently with their basic needs met. Ensuring equitable access to the basics would be a powerful buffer against mental illness in general and could help mitigate costly and painful mental health crisis among women and everyone who depends on us in the context of this and other public health emergencies."

RIVERSIDE, Calif. -- A team led by a biomedical scientist at the University of California, Riverside, has developed a new RNA-sequencing method-- "Panoramic RNA Display by Overcoming RNA Modification Aborted Sequencing," or PANDORA-seq -- that can help discover numerous modified small RNAs that were previously undetectable.

RNA plays a central role in decoding the genetic information in DNA to sustain an organism's life. It is generally known as the intermediate molecule used to synthesize proteins from DNA. Cells are full of RNA molecules in complex and diverse forms, two main types being ribosomal RNA, or rRNA; and transfer RNA, or tRNA; which are involved in the synthesis of proteins.

Small RNAs play essential roles in health and diseases, including cancer, diabetes, neurological diseases, and infertility. Examples of small RNAs are microRNA; piwi-interacting RNA, or piRNA; and tRNA-derived small RNA, or tsRNA. Small RNAs can get modified by chemical groups and thus acquire new functions.

The development of high-throughput RNA sequencing technologies -- useful for examining the quantity and sequences of RNA in a biological sample -- has uncovered an expanding repertoire of small RNA populations that fine-tune gene expression and protect genomes.

"PANDORA-seq can be widely used to profile small RNA landscapes in various physiological and disease conditions to facilitate the discovery of key regulatory small RNAs involved in these conditions," said Qi Chen, an assistant professor of biomedical sciences in the UCR School of Medicine, who led the study published today in Nature Cell Biology. "Modified small RNAs wear an 'invisibility cloak' that prevents them from being detected by traditional RNA-sequencing methods. How many such modified RNAs are there? What is the origin of their sequences? And what exactly is their biological function? These are questions PANDORA-seq may be able to answer."

PANDORA-seq employs a stepwise enzymatic treatment to remove key RNA modifications, which then takes off the invisibility cloak used by the modified small RNAs.

"PANDORA-seq has opened Pandora's box of small RNAs," said Tong Zhou, a bioinformatician at the University of Nevada, Reno School of Medicine and a co-corresponding author of the study. "We can now dance with these once invisible partners in the RNA ballroom."

According to Chen, PANDORA-seq uncovers a surprising small-RNA landscape that is dominated by tsRNAs and rRNA-derived small RNAs, or rsRNAs, rather than microRNAs, which were previously believed to dominate many mammalian tissues and cells.

"With PANDORA-seq, we found unprecedented microRNA/tsRNA/rsRNA dynamics when somatic cells are reprogrammed to induced pluripotent stem cells, which are generated by adult cells and have properties similar to those of embryonic stem cells, making them capable of differentiating into all cell types of the body," said Sihem Cheloufi, an assistant professor of biochemistry at UCR and a co-corresponding author of the paper. "Some tsRNAs and rsRNAs can impact protein synthesis and even affect lineage differentiation in embryonic stem cells."

Chen explained the current best-studied classes of small RNAs in mammals are microRNAs, which are abundant in mammalian somatic cells and control the kind and amount of proteins the cells make; and piRNAs, which are mainly expressed in the testis and modulate germ cell development.

"Currently, these small RNAs can be comprehensively profiled by high-throughput methods such as RNA sequencing," he said. "However, the widely used small RNA sequencing protocols have intrinsic limitations, which prevent certain modified small noncoding RNAs from being detected during RNA sequencing. PANDORA-seq overcomes these limitations."

Junchao Shi, a doctoral student working in Chen's lab and the research paper's first author is enthusiastic about the use of PANDORA-seq.

"The new method could revolutionize the view of small RNA landscapes," he said. "Frankly, all previous studies using traditional RNA-sequencing may now need to be revisited."

Cheloufi said the team now wants to understand how tsRNA/rsRNA are generated, how they function in stem cells, and how they orchestrate cell fate decisions during development.

"Answers to these questions are timely to develop diagnostic tools, identify therapeutic targets, and advance regenerative medicine," she said.

While developing PANDORA-seq, Chen was reminded of the parable of the blind men and the elephant, which teaches truth is only revealed when various parts come together.

"We sometimes forget the big picture, being focused on just a small part of it," he said. "Perhaps the only way to arrive at total truth -- the big picture -- is to push against our boundary of knowledge and confirm the revealed truth with newly devised technology."

"It is fascinating to observe down the lenses of a microscope in the lab the profound cell fate change during cellular reprogramming and differentiation," said Reuben Franklin, a doctoral student in Cheloufi's lab and a coauthor on the study. "But PANDORA-seq allows us to eavesdrop on the molecular players during these processes."

Researchers from North Carolina State University have developed an exosome-coated stent with a "smart-release" trigger that could both prevent reopened blood vessels from narrowing and deliver regenerative stem cell-derived therapy to blood-starved, or ischemic, tissue.

Angioplasty - a procedure that opens blocked arteries - often involves placing a metal stent to reinforce arterial walls and prevent them from collapsing once the blockage is removed. However, the stent's placement usually causes some injury to the blood vessel wall, which stimulates smooth muscle cells to proliferate and migrate to the site in an attempt to repair the injury. The result is restenosis: a re-narrowing of the blood vessel previously opened by angioplasty.

"The inflammatory response that stents cause can decrease their benefit," says Ke Cheng, corresponding author of the research. "Ideally, if we could stop smooth muscle cells from over-reacting and proliferating, but recruit endothelial cells to cover the stent, it would mitigate the inflammatory response and prevent restenosis." Cheng is the Randall B. Terry Jr. Distinguished Professor in Regenerative Medicine at NC State and a professor in the NC State/UNC-Chapel Hill Joint Department of Biomedical Engineering.

There are drug-eluting stents currently in use coated with drugs that discourage cell proliferation, but these anti-proliferative drugs also delay stent coverage by endothelial cells - which are the cells healthcare providers want to coat the stent.

To solve this problem, Cheng and his team developed a stent coating composed of exosomes derived from mesenchymal stem cells. Exosomes are tiny nano-sized sacs secreted by most cell types. The idea behind the coating was two-fold: first, since the exosomes are composed of materials not much different from cell membranes they 'camouflage' the stent to trick smooth muscle cells and the body's immune system. Second, the exosomes promote coverage of the stent by endothelial cells and, in the case of injury, travel downstream to the site to promote tissue repair.

To prevent premature depletion of the therapy, the stent releases exosomes when it encounters reactive oxygen species (ROS) - which are more prevalent during an inflammatory response.

"Think of it as a smart release function for the exosomes," Cheng says. "Ischemic reperfusion injuries, which occur when blood flow is diminished and then reestablished, create a lot of ROS. Let's say the heart is damaged by ischemia. The enhanced ROS will trigger the release of the exosomes on the stent, and regenerative therapy will travel through the blood vessel to the site of the injury."

The research team performed in vitro testing to ensure biocompatibility and test the release mechanism. They found that in the presence of ROS, the exosomes released up to 60% of their secretions within 48 hours post-injury.

In a rat model of ischemic injury, the researchers compared their exosome-eluting stent (EES) to both a bare metal stent (BMS) and a drug-eluting stent (DES). They found that in comparison to the BMS, their stent performed better in both decreasing stenosis and promoting endothelial coverage. While the DES performed similarly to the EES in preventing restenosis, the EES was less injurious to the vessel wall and had better endothelial coverage overall. In addition, the exosomes released from EES promoted muscle regeneration in rats with hind limb ischemia. The researchers plan to test the stent in a large animal model with an eye toward eventual clinical trials.

"This bioactive stent promotes vascular healing and ischemic repair, and a patient wouldn't need additional procedures for regenerative therapy after the stent is in place," Cheng says. "The stent is the perfect carrier for exosomes, and the exosomes make the stent safer and more potent in tissue repair."

BOSTON - Addiction is associated with social exclusion, loss of access to resources, and general disengagement from civic life. Now, a study recently published in the journal Psychology of Addictive Behaviors and led by David Eddie, PhD, of the Massachusetts General Hospital's Recovery Research Institute has found that the majority of Americans who have resolved an alcohol or other drug problem report achievements related to self-improvement, family engagement, and civic and economic participation since resolving their addiction. Additionally, it appears these achievements accumulate with time in addiction recovery.

Incorporating data from the Recovery Research Institute's landmark 2017 National Recovery Study, which indicated for the first time that 23.3 million Americans consider themselves to have resolved a significant alcohol or other drug problem, this study is the first to report the national prevalence of personal, civic, and economic achievements among people in addiction recovery.

"Individuals in addiction recovery face numerous challenges, yet in spite of this, findings from this study show that most individuals are able to rebuild important aspects of their lives," says Eddie. "And perhaps more importantly, we saw that these achievements were associated with greater happiness, well-being and quality of life."

These study results challenge commonly held beliefs about the nature of substance use disorders as constantly recurring disorders with little room for improvement. "The fact of the matter is that addiction is a good-prognosis disorder with significant improvement over time in recovery," says co-author John Kelly, PhD, director of the Recovery Research Institute. "With more years in recovery, individuals achieved an increasing number of achievements, which are then supportive of ongoing remission and recovery."

The study authors also note that there are certain individual factors associated with accrual of achievements, including (but not limited to) race, education level, age of initiation of regular substance use, and co-occurring psychiatric disorders. However, Eddie cautions that this shouldn't be taken to mean there are some who can't accomplish significant personal achievements after resolving an addiction: "Recovery is achievable for everyone, and the majority of Americans who resolve their substance use problem go on to accrue numerous life achievements. At the same time, there are many individuals who face greater barriers and hardships as they attempt to rebuild their lives, and as a society we should be addressing the barriers that hamper their rebuilding efforts."

A new study by Stanford University biologists finds an explanation for the idea that physical characteristics such as skin pigmentation are "only skin deep." Using genetic modeling, the team has found that when two populations with distinct traits combine over generations, traits of individuals within the resulting "admixed" population come to reveal very little about individuals' ancestry. Their findings were published March 27 in a special edition of the American Journal of Physical Anthropology on race and racism.

"When two founding groups first come together, a visible physical trait that differed between those founders initially carries information about the genetic ancestry of admixed individuals," says Jaehee Kim, a postdoctoral research fellow in biology at Stanford and first author of the study. "But this study shows that after enough time has passed, that's no longer true, and you can no longer identify a person's genetic ancestry based only on such traits."

A diminishing correlation

Working with Stanford biology professor Noah Rosenberg and others, Kim built a mathematical model to better understand genetic admixture - the process by which two populations that have long been separated come together and create a third admixed population with ancestral roots in both sources. They specifically studied how the relationship between physical traits and genetic admixture level changes over time.

The researchers considered several scenarios. In one, individuals within the admixed population mated randomly. In others, they were more likely to seek out partners with similar genetic admixture levels or who had similar levels of a trait, in a process known as assortative mating.

The study found that over time, traits that might have initially been indicative of an individual's genetic ancestry ultimately no longer carried that information. While this decoupling of ancestry and traits occurred more slowly if mating was assortative rather than random, decoupling still happened in all scenarios.

"In the model, if assortative mating depends on a genetically inherited trait, a correlation between the trait and genetic ancestry would last longer than if mating had occurred randomly, but the correlation would still disassociate eventually," said Rosenberg, senior author of the paper, who holds the Stanford Professorship in Population Genetics and Society in the School of Humanities and Sciences.

The team's research was inspired in part by a study conducted by a different team in Brazil, a country with much genetic admixture in its history. After sampling individuals and studying their genomes, the biologists from the 2003 study hypothesized that decoupling occurred between physical traits and genetic admixture and claimed that over time traits such as skin pigmentation revealed little about the fraction of a person's ancestors originating from European, African or Native American origins. The Stanford team found that their model largely supported this hypothesis.

Only skin deep

To understand the decoupling, the researchers say, consider a trait such as skin pigmentation that is due in part to variations among a series of genes. If a person happens to receive most of their genetic ancestry from one population but the key genetic variants that determine their skin pigmentation from another, their skin pigmentation may appear to be a "mismatch" to their genetic ancestry. The reshuffling of genetic variants that occurs in every generation increases the probability of such mismatches.

The researchers recognize that there are limitations to their modeling approach. The model didn't consider environmental conditions that also play a role in trait development. A person's height, for example, has some genetic basis, but also depends on factors like nutrition. The model also focused only on scenarios in which the initial admixture happened all at once, and didn't explore the role of new members of the source populations entering the admixed population over time. In the future, Rosenberg plans to add some of these features into the initial model.

According to Kim, the new findings have important implications for understanding the social meaning of physical traits.

"When societies attach social meaning to a trait like skin pigmentation, the model suggests that after admixture has been ongoing for enough time, that trait is not going to be telling us much about genetic ancestry - or about other traits that are based in genetics," she said.

Even before the pandemic made telehealth a hot topic, people with minor urgent health needs had started to turn to companies that offer on-demand video chats with physicians that they don't normally see.

Insurers and employers even started buying access to this direct-to-consumer form of virtual care, hoping it might reduce in-person care, including emergency department visits.

But a new University of Michigan study casts some doubt on whether that will actually happen.

Published in the April issue of Health Affairs, the study finds that patients who had an on-demand virtual care visit for an upper respiratory infection in the three years before the pandemic began were slightly more likely to receive additional follow-up care than similar patients who had their first visit in person.

The study compared data from more than 28,700 virtual visits with data from more than 57,400 in-person visits for acute respiratory infections in 2016 through 2019. Those visits, and any follow-up care, were all covered by a large insurer. All the virtual visits were done through a direct-to-consumer telehealth company that the insurer had partnered with.

The authors say it's important to note that the vast majority of the patients did not require any further care for their infections, which included ear infections, bronchitis, laryngitis, sore throat and pneumonia.

But 10.3% of the patients first seen through a direct-to-consumer telehealth visit ended up having an in-person visit in the next week, compared with 5.9% of those who had their first visit in person. This includes second telemedicine visits or visits to clinics, urgent care centers and emergency rooms.

Less than 1% of all the patients in the study visited an emergency department after their initial visit, and the percentage was only slightly lower among people whose first visit was through a direct-to-consumer virtual provider compared with those who started with an in-person visit.

Kathleen Li, M.D., M.S., is the first author of the paper and an alumna of the IHPI Scholars program at the U-M Institute for Healthcare Policy and Innovation, and conducted the study as part of the institute's telehealth research effort.

She notes that direct-to-consumer telehealth providers usually don't have access to patients' electronic health records, so they may not know the patient's full medical history or underlying conditions.

As an emergency physician at Michigan Medicine, Li notes that often patients will come to the ED after trying to reach their primary care physician and not being able to get an appointment quickly.

Li was a co-author on a recent National Poll on Healthy Aging report from IHPI that found that 1 in 8 older adults had gone to the ED after not being able to get a timely appointment with their regular provider.

"If an appointment with a patient's regular provider isn't available right away, or the patient isn't able to get to the clinic in person during standard business hours, on-demand virtual care does offer convenience," she says. "But things have changed so much with the pandemic, and more primary care providers are now offering telehealth visits with themselves or members of their teams. It remains to be seen how primary care-based telehealth models will affect downstream use and cost of care."

Senior author Chad Ellimoottil, M.D., M.Sc., who directs IHPI's Telehealth Research Incubator, says that while the insurance claims data in the study were available to the IHPI team, that may not be the case for most direct-to-consumer telehealth, especially if the patient pays directly rather than using insurance.

"As more companies enter the marketplace of direct-to-consumer telehealth, it's going to be important to understand the outcomes for patients, and the broader implications for the health care system," says Ellimoottil, a urologist and telehealth researcher. "Data transparency is essential. We need to be able to directly compare outcomes of patients seen by direct-to-consumer telehealth companies with in-person care and with telemedicine provided by the patient's own primary care provider."

For employers that offer a direct-to-consumer telehealth option through their benefits package, Li says, the bottom line comes down to balancing how much the instant access may result in an increase in visits or additional follow-up care, against the benefit of less time spent away from work and a potential reduction in inappropriate emergency department visits.

"We need to optimize both the use of telehealth and of in-person emergency care," she says.