Culture

Retracted scientific paper persists in new citations, study finds

image: Information sciences professor Jodi Schneider studied the problem of continued citation of retracted scientific papers. She led workshops for those in the academic publishing community to consider solutions to prevent the spread of retracted research.

Image: 
L. Brian Stauffer

CHAMPAIGN, Ill. -- A small portion of scientific papers are retracted for research that is in error or fraudulent. But those papers can continue to be cited by other scientists in their work, potentially passing along the misinformation from the retracted articles.

Jodi Schneider, a professor of information sciences at the University of Illinois Urbana-Champaign who studies scholarly publications and how information gets used, is considering how scientific journals can better communicate about retracted articles. In a new study published in the journal Scientometrics, she found that a retracted clinical trial report continues to be cited 11 years after its retraction - and that citations actually increased after it was retracted.

Schneider's team reviewed citations of a 2005 paper in the field of respiratory medicine that found omega-3 fatty acids to be helpful in reducing inflammatory markers in patients with chronic obstructive pulmonary disease. The paper was retracted in 2008 for reporting on falsified clinical trial data.

However, it continues to be cited to support the medical nutrition intervention. Schneider's analysis covered 148 direct citations of the paper from 2006-2019 and 2,542 second-generation citations. The retraction was not mentioned in 96% of the 112 direct post-retraction citations for which she was able to study the context of the citation. The example demonstrates problems with how the current digital library environment communicates the retraction status of scientific papers, Schneider wrote.

The number of articles that are retracted "is really, really tiny. It's a regular occurrence that things get retracted, but people publish so much," Schneider said. Since 2012, there have been about four retractions per 10,000 publications, she wrote in her article.

When a new paper is published, most journals don't check the bibliographies for citations of retracted research. "It's really rare for any journal to be scanning reference lists," Schneider said.

Notices of retractions are often hard to find. Some websites and databases, such as PubMed, make retraction notices easily visible, but many others do not, Schneider said. There may be multiple sites where a copy of a scientific paper can be found, and not all will indicate if it is retracted.

In addition, many databases don't have complete information about a retraction. Retractions can occur for a number of reasons, including errors made in the research or misconduct such as reporting fraudulent data. About 10% of retraction notices don't mention the reason for retraction, Schneider said.

"Part of the challenge is understanding the reasons why a particular article was retracted, which often are really vague," Schneider said.

How an article is cited matters - for example, whether authors seem aware of the retraction, whether they use the retracted paper as a foundation to build on with their own work or whether it is cited for a general concept or the history of research on a particular matter. Analyzing the context as well as the number of citations, Schneider found that more than 41% of the post-retraction citations of the respiratory medicine paper that did not mention the retraction also described the paper in detail.

"We looked at whether they were discussing the methods and results of the retracted paper. The more in-depth they are discussing it, the more they are using it as part of an argument for their work," she said.

Unlike with most retracted research articles, the respiratory medicine paper's citations increased substantially after the retraction, Schneider found. One likely factor influencing the number of citations the paper received is that it was the first purported random clinical trial on a research question with very little previous research, she said.
The retraction process can take a long time and involve institutional or governmental investigations, she said. The longer it takes to retract an article that is in error or fraudulent, the more likely it is to be cited in the meantime.
"The current information environment facilitates the spread of research papers, but basic facts about these papers, such as their retraction status, do not spread as swiftly as the PDFs or citations to these papers themselves. Our case study suggests that unknowing and likely unintentional citation of retracted papers could be common, and that post-retraction citation may be correlated with visibility of retraction status," Schneider wrote.

She has led several workshops for people across scholarly publishing to talk about how journals can better check for citation of retracted articles, and the workshop participants are drafting recommendations. Schneider said best practices for journals should include ensuring every retraction notice is publicly available and establishing a convention for how to flag an article that is retracted. Among the suggestions is developing a standard set of metadata regarding retractions that would be attached to articles and use a taxonomy of statuses, such as retraction or expression of concern.

Information sciences students at Illinois built a prototype tool called ReTracker that would automatically check for retractions among the articles that scholars compile in their online libraries, using data from PubMed, and add the retraction status directly into the library. Zotero, a popular reference-management software system used for managing bibliographic data and research materials, also has developed such a tool, Schneider said.

Ensuring that retracted articles don't continue to be cited as reliable research is important not just for scientists but also for public confidence in scientific research, Schneider said.

"A scientific paper that is right is like a brick to build walls of evidence we can rely on," she said.

Credit: 
University of Illinois at Urbana-Champaign, News Bureau

Hotels that promote women perceived as fairer, less discriminatory

Hotel managers have something in common beyond their reputations for charming dispositions and excellent listening skills - they're predominantly men, despite women making up the majority of the accommodations workforce. New research led by the University of Houston Conrad N. Hilton College of Hotel and Restaurant Management suggests hotel companies that promote a woman over an equally qualified man are perceived as fairer and less discriminatory, creating a stronger organizational culture and higher financial performance.

Published in the International Journal of Contemporary Hospitality Management, the study is the first to address gender inequity in promotional opportunities for hotel employees. The researchers surveyed 87 hotel managers to gauge their feelings on gender discrimination and perceived fairness of the promotion process.

Nearly 80% of managerial positions in the hospitality industry are held by men, who are given approximately 30% more promotional opportunities than women. The gender inequity in hotels is even more alarming. Women account for only 12% of all hotel leadership positions, from entry-level supervisor to owner.

"This is important because if women don't believe the promotional process is fair, they're not even going to try to apply for those positions," said Michelle Russen, PhD student and lead study author. "There needs to be more women in these top management positions. How employees perceive the fairness within the process may also directly influence the organizational culture, sales growth and employee productivity of the hotel."

Many organizations may refrain from offering more promotional opportunities to women for fear of reverse discrimination, according to the study authors. While affirmative action requiring a certain quota of female employees and other minorities may be well intentioned, men may feel as though they are discriminated against. But the results of the survey suggest that even hotel managers who believe in reverse discrimination will view promoting a female to management as a fair decision.

Fairness in the process serves as a signal to employees, said Juan Madera, UH professor and study co-author. "If a female applicant is a star, but she sees a management team that's all men, it may signal this is not a good fit for her and the company loses out on a great candidate."

Furthermore, he points out that if employees believe the promotion process is fair, then they will believe the organization will treat them fairly, too, which can affect other attitudes, including overall commitment to the company and plans to stay or move on.

The researchers hope their findings will influence hotel policies and training materials. Whether real or perceived, if there are feelings of inequity, there could be negative consequences.

"Financially there may be discrimination suits, cost of replacement of employee turnover, or reduced firm performance. Therefore, it is essential for hotels to have training and mentoring programs in which employees of both genders are encouraged to participate, to enhance perceived fairness within the organization. These programs must demonstrate the organization's commitment to advancing the careers of both genders," they wrote.

To make the process fairer, the researchers recommend creating a blind review process where initial decisions are made by removing names from employee files and objective third parties review the information and criteria for promotion, thus giving all parties a fair chance without incorporating gender, age or "like-me" biases.

"Owners and operators need to recognize that bias exists and examine how fair they're being in their processes. Beyond just promoting females from within, these findings have implications for bringing in top talent from the outside," said co-author Mary Dawson, associate dean for academic affairs and Donald H. Hubbs Professor at UH's Hilton College. "If I'm a woman doing research about a company that I applied to but only see men in management, then I'd question that company's culture."

Credit: 
University of Houston

COVID-19 unmasked: math model suggests optimal treatment strategies

BOSTON -- Getting control of COVID-19 will take more than widespread vaccination; it will also require better understanding of why the disease causes no apparent symptoms in some people but leads to rapid multi-organ failure and death in others, as well as better insight into what treatments work best and for which patients.

To meet this unprecedented challenge, researchers at Massachusetts General Hospital (MGH), in collaboration with investigators from Brigham and Women's Hospital and the University of Cyprus, have created a mathematical model based on biology that incorporates information about the known infectious machinery of SARS-CoV-2, the virus that causes COVID-19, and about the potential mechanisms of action of various treatments that have been tested in patients with COVID-19.

The model and its important clinical applications are described in the journal Proceedings of the National Academy of Sciences (PNAS).

"Our model predicts that antiviral and anti-inflammatory drugs that were first employed to treat COVID-19 might have limited efficacy, depending on the stage of the disease progression," says corresponding author Rakesh K. Jain, PhD, from the Edwin L. Steele Laboratories in the Department of Radiation Oncology at MGH and Harvard Medical School (HMS).

Jain and colleagues found that in all patients, the viral load (the level of SARS-CoV-2 particles in the bloodstream) increases during early lung infection, but then may go in different directions starting after Day 5, depending on levels of key immune guardian cells, called T cells. T cells are the first responders of the immune system that effectively coordinate other aspects of immunity. The T cell response is known as adaptive immunity because it is flexible and responds to immediate threats.

In patients younger than 35 who have healthy immune systems, a sustained recruitment of T cells occurs, accompanied by a reduction in viral load and inflammation and a decrease in nonspecific immune cells (so-called "innate" immunity). All of these processes lead to lower risk for blood clot formation and to restoring oxygen levels in lung tissues, and these patients tend to recover.

In contrast, people who have higher levels of inflammation at the time of infection -- such as those with diabetes, obesity or high blood pressure -- or whose immune systems are tilted toward more active innate immune responses but less effective adaptive immune responses tend to have poor outcomes.

The investigators also sought to answer the question of why men tend have more severe COVID-19 compared with women, and found that although the adaptive immune response is not as vigorous in women as in men, women have lower levels of a protein called TMPRSS2 that allows SARS-CoV-2 to enter and infect normal cells.

Based on their findings, Jain and colleagues propose that optimal treatment for older patients -- who are likely to already have inflammation and impaired immune responses compared with younger patients -- should include the clot-preventing drug heparin and/or the use of an immune response-modifying drug (checkpoint inhibitor) in early stages of the disease, and the anti-inflammatory drug dexamethasone at later stages.

In patients with pre-existing conditions such as obesity, diabetes and high blood pressure or immune system abnormalities, treatment might also include drugs specifically targeted against inflammation-promoting substances (cytokines, such as interleukin-6) in the body, as well as drugs that can inhibit the renin-angiotensin system (the body's main blood pressure control mechanism), thereby preventing activation of abnormal blood pressure and resistance to blood flow that can occur in response to viral infections.

This work shows how tools originally developed for cancer research can be useful for understanding COVID-19: The model was first created to analyze involvement of the renin angiotensin system in the development of fibrous tissues in tumors, but was modified to include SARS-CoV-2 infection and COVID-19-specific mechanisms. The team is further developing the model and plans to use it to examine the dynamics of the immune system in response to different types of COVID-19 vaccines as well as cancer-specific comorbidities that might require special considerations for treatment.

Credit: 
Massachusetts General Hospital

Dungeness crab fishing industry response to climate shock

image: Researchers found that 71 percent of California Dungeness crab fishing vessels temporarily left the industry and stopped fishing altogether during the delays.

Image: 
Northwest Fisheries Science Center/NOAA Fisheries

Fishermen contend with regulations, natural disasters, and the ups and downs of the stocks they fish, along with many other changes. As a result, fishing communities are quite resilient. That is, they can withstand, recover from, and adapt to change.

But how much pressure can they stand? The 2014-2016 North Pacific marine heatwave, known as the Blob, led to a harmful algal bloom of unprecedented scale. It necessitated substantial delays in the opening of the 2015-16 U.S. West Coast Dungeness crab fishery. The fishery is vital to West Coast communities. It produces around 26 percent of all annual fishing revenue and supports more than 30 percent of all commercial fishing vessels.

Understanding Impacts from Climate Shocks

Previous studies have documented the devastating economic impacts from the 2015-16 event on Dungeness crab fishermen. Members of affected coastal communities attest that these socioeconomic effects rippled through associated industries and coastal communities. But can changes in fishing practices in response to this significant climate shock be quantified?

"We wanted to examine the extent to which the Dungeness crab fishery delays affected participation in other fisheries, and the duration of those changes," said Mary Fisher, a doctoral student at the University of Washington. Fisher did the work as a National Science Foundation Graduate Research Internship Program Fellow at NOAA's Northwest Fisheries Science Center.

Fisher and her colleagues at NOAA Fisheries, University of Washington, and Oregon State University studied the impacts on more than 2,500 vessels across seven California fishing communities. The researchers wanted to see how a climate-related shock (like the heatwave and associated harmful algal bloom) can impact communities' use of ocean resources.

The researchers used 10 years of fishery landings data to map resource use networks for seven California port groups where Dungeness crab is an important revenue source. The networks visualize the portfolio of fisheries that a community harvests and how vessels move between fisheries. The network visualization is similar to a food web, except that the connections represent harvest by fishing vessels rather than predator-prey relationships.

Resilient Fishing Communities

Researchers found that 71 percent of California Dungeness crab fishing vessels temporarily left the industry and stopped fishing altogether during the delays. The two other strategies that fishermen used to cope with the disruption were:

Participating in other fisheries that were not affected by the harmful algal bloom.

Moving out of delayed areas to fish in other more favorable locations.

These strategies significantly changed communities' resource use patterns, but some communities were more affected by the climate shock than others. Researchers could predict which communities would be least sensitive to the shock by looking at their resource use patterns before the 2015-16 season.

These communities, located in central California, were less dependent on Dungeness crab and had shorter fishery delays. In these communities, fishermen had access to more open fisheries during the winter months and were more flexible in how they fished previously. These characteristics provided more options, buffering fishermen from the disruption to the Dungeness crab fishing season.

No matter how central Dungeness crab was to a community's fisheries portfolio, the researchers didn't observe any significant, lasting changes in how vessels participated in fisheries after the closures lifted. This suggests fishing communities may mostly return to "normal" fishing practices relatively quickly after short-term disturbances like climate shocks, provided those changes don't pile up one after the other.

Access to Other Fisheries and Ports Important

The results highlight the importance of nearshore groundfish fisheries like sablefish, rockfish, and lingcod as alternatives to the Dungeness crab fishery. "Most of the crab vessels that stayed out on the water were using pot or hook-and-line gear to fish groundfish," says Fisher. "I think we can expect access to these fisheries to continue to be important during crab season delays."

Fishermen with larger vessels also landed their catch at different ports, a strategy less common among smaller vessels. This was possible in part because regulations only restricted fishing in delayed areas at the district level. In 2018, the California Department of Fish and Wildlife amended these rules, called the Fair Start Provisions. The amendments provide more protection to fishermen at a finer scale than districts in the event of future delays.

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NOAA Fisheries West Coast Region

Understanding disease-induced microbial shifts may reveal new crop management strategies

image: Orange fields and lab work

Image: 
Dr. Nichole Ginnan

While humanity is facing the COVID-19 pandemic, the citrus industry is trying to manage its own devastating disease, Huanglongbing (HLB), also known as citrus greening disease. HLB is the most destructive citrus disease in the world. In the past decade, the disease has annihilated the Florida citrus industry, reducing orange production for juice and other products by 72%. Candidatus Liberibacter asiaticus (CLas) is the microbe associated with the disease. It resides in the phloem of the tree and, like many plant pathogens, is transmitted by insects during feeding events. Disease progression can be slow but catastrophic. Symptoms begin with blotchy leaves, yellow shoots, and stunting, and progress into yield decline, poor quality fruit, and eventually death.

Currently, the only thing citrus growers can do to protect their crops from HLB is control the insect vector. Dozens of researchers are trying to find ways to manage the disease, using strategies ranging from pesticides to antibiotics to CLas-sniffing dogs. Understanding the plant microbiome, an exciting new frontier in plant disease management, is another strategy.

Dr. Caroline Roper and first author Dr. Nichole Ginnan at the University of California, Riverside led a large research collaboration that sought to explore the microbiome's role in HLB disease progression. Their recent article in Phytobiomes Journal, "Disease-Induced Microbial Shifts in Citrus Indicate Microbiome-Derived Responses to Huanglongbing," moves beyond the single-snapshot view of the microbial landscape typical of microbiome research. Their holistic approach to studying plant-microbe interactions captured several snapshots across three years and three distinct tissue types (roots, stems, and leaves). What is so interesting about this research is the use of amplicon (16S and ITS) sequencing to capture the highly intricate and dynamic role of the microbiome (both bacterial and fungal) as it changes over the course of HLB disease progression.

Ginnan et al. surmised that HLB created a diseased-induced shift of the tree's microbiome. Specifically, the researchers showed that as the disease progresses, the microbial diversity increases. They further investigated this trend to find that the increase in diversity was associated with an increase in putative pathogenic (disease-causing) and saprophytic (dead tissue-feeding) microbes. They observed a significant drop in beneficial microbes in the early phases of the disease. Arbuscular mycorrhizal fungi (AMF) were one such beneficial group that the authors highlighted as showing a drastic decline in relative abundance.

The depletion of key microbial species during disease might be opening the door for other microbes to invade. Certain resources may become more or less available, allowing different microbes to prosper. Dr. Roper and Dr. Ginnan hypothesize that when HLB begins, this depletion event triggers a surge of beneficial microbes to come to the aid of the citrus tree. They suspect that the microbes are initiating an immune response to protect the host.

As the disease proliferates, the citrus tree and its microbiome continue to change. Dr. Ginnan, the lead author on this study, found that there was an enrichment of parasitic and saprophytic microorganisms in severely diseased roots. The enrichment of these microbes may contribute to disease progression and root decline, one side effect of HLB.

Survivor trees, or trees that did not progress into severe disease, had a unique microbial profile as well. These trees were enriched with putative symbiotic microbes like Lactobacillus sp. and Aureobasidium sp. This discovery led the researchers to identify certain microbes that were associated with slower disease progression.

Dr. Ginnan says their "aha" moment during the research was in the data analysis. "Originally we were looking for taxa that increased and decreased in relative abundance as disease rating increased," she said. "Our differential abundance analysis ended up revealing clear enrichment patterns replicated in multiple taxa." This is the moment they began to develop the individual patterns they were seeing into a broader disease model.

This research is the foundation for future projects and collaborations that the authors are excited to continue to develop. They are motivated by the potential function of the microbiome to manage crop diseases. In the near future, they hope that these discoveries and an understanding of beneficial microbes can help establish a microbiome-mediated treatment plan to protect crops from diseases like HLB. In addition, the model they've developed can be applied to understanding diseases of other tree crop systems.

Credit: 
American Phytopathological Society

UC-MSC infusion helps repair COVID-19 damage in severe cases

image: Umbilical cord-derived mesenchymal stem cells naturally migrate directly to the lung where they begin repair to COVID-19 damage.

Image: 
© Dr. Camillo Ricordi

Dr. Camilo Ricordi, director of the Diabetes Research Institute (DRI) and Cell Transplant Center at the University of Miami Miller School of Medicine, and his team of international collaborators are reporting the results of a groundbreaking randomized controlled trial showing umbilical cord-derived mesenchymal stem cell (UC-MSC) infusions safely reduce risk of death and quicken time to recovery for the most severe COVID-19 patients. Dr. Ricordi's peer-reviewed paper has just been published in STEM CELLS Translational Medicine (SCTM) January 2021.

The clinical trial, authorized by the FDA last April, was initiated by The Cure Alliance, a 501(c)(3) non-profit organization of research scientists founded ten years ago by Dr. Ricordi for scientists around the world to share knowledge and accelerate cures of all diseases. At the start of the pandemic, all focus pivoted to ending suffering caused by COVID-19. Dr. Ricordi created a "mini-Manhattan project," the result of which has yielded this important new weapon in the arsenal against COVID-19, especially during this critical time when distribution of the new vaccines is slower than anticipated and the infection rate and death toll are still surging.

The SCTM paper describes findings from 24 patients hospitalized at University of Miami Tower or Jackson Memorial Hospital with COVID-19 who developed severe acute respiratory distress syndrome (SARS), a dangerous and often fatal complication marked by severe inflammation and fluid buildup in the lungs. Each patient received two infusions of either mesenchymal stem cells or a placebo, given days apart.

"It was a double-blind study. Neither doctors nor patients knew who received the treatment, who got the placebo," said Dr. Ricordi, the lead investigator.

At one month,100% of patients (

Dr. Ricordi's team also reports recovery time was faster among those in the treatment arm. More than half of patients treated with the UC-MSC infusions recovered and went home from the hospital within two weeks. More than 80% of the treatment group recovered by day 30, versus less than 37% in the control group.

"It's like smart bomb technology in the lungs to restore normal immune response and reverse life-threatening complications," Dr. Ricordi said.

Just one umbilical cord, donated from a caesarean section, can yield up to 10,000 doses of the COVID-19 treatment.

"Our results confirm the powerful anti-inflammatory, immunomodulatory effect of UC-MSCs. These cells have clearly inhibited the 'cytokine storm', a hallmark of severe COVID-19," said Giacomo Lanzoni, Ph.D, lead author of the SCTM paper.

"The results are critically important not only for COVID-19 but also for other diseases characterized by aberrant and hyper-inflammatory immune responses, such as autoimmune Type 1 Diabetes. We are very much looking forward to applying these cells in clinical trials to halt the progression of Type 1 Diabetes," he added. Dr. Lanzoni is Research Assistant Professor, Diabetes Research Institute, Department of Biochemistry and Molecular Biology at the University of Miami Miller School of Medicine.

Dr. Ricordi's core team included scientists with expertise in stem cells, pulmonary disease and critical care, but it was the diabetes researchers who began to crack the code. At the DRI, Dr. Ricordi and his colleagues had been collaborating with Chinese scientists to study UC-MSCs for the treatment of diabetes Type 1. With the outbreak of the pandemic, he learned those collaborators were now testing the treatment in severely ill COVID-19 patients and reporting success. The researchers in China were soon joined by Israeli researchers, reporting as many as 100% of treated patients surviving and recovering faster than those without stem cell treatment. But none of the studies was a randomized trial, the gold standard in science.

The potential for the treatment was certainly promising. Mesenchymal cells are known to help correct immune and inflammatory responses that go awry. They also have antimicrobial activity and have been shown to promote tissue regeneration.

What's more, when given intravenously mesenchymal stem cells migrate naturally to the lungs. exactly where therapy is needed in COVID-19 patients with life-threatening acute respiratory distress syndrome,

Dr. Ricordi enlisted Dr. Lanzoni and several key collaborators at the Miller School, the University of Miami Health System, Jackson Health System, plus others internationally and across the U.S., including Arnold I. Caplan, Ph.D., of Case Western Reserve University, the first scientist to identify mesenchymal stem cells.

Funding by The Cure Alliance was greatly enhanced by a $3 million grant from North America's Building Trades Unions (NABTU). "North America's Building Trades Unions has been a major supporter of the Diabetes Research Institute since 1984, when they started a campaign to fund, and build, our state-of-the-art research and treatment facility. NABTU has continued to support our work through the years, including our mesenchymal stem cell research that helped lead the way to this clinical trial," Dr. Ricordi said.

Credit: 
The Cure Alliance

Mid-term clinical trial results show similar outcomes in promising cell therapies for CLI

image: The two therapies demonstrated similar mid-term safety and efficacy, while each cell therapy had its unique advantages and are recommended for certain conditions: for example, PBMNCs for patients with 2 or more critical ischemic limbs and PCCs for patients with significant pain.

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AlphaMed Press

Durham, NC - Mid-term results of the first clinical trial designed specifically to evaluate the safety and effectiveness of two cell therapies that are showing early promise in treating angiitis-induced critical limb ischemia were released today in STEM CELLS Translational Medicine. The study, by researchers at Zhongshan Hospital/Fudan University in Shanghai, compared how transplantation of peripheral blood mononuclear cells fared versus transplantation of purified CD34+ cells in treating this condition.

It revealed both therapies yielded satisfactory results and provided evidence for more precise application of cell therapy under different conditions, the researchers say.

Critical limb ischemia (CLI) is a type of peripheral artery disease caused by severe blockage in the arteries of the lower extremities, which markedly reduces blood-flow. Angiitis-induced CLI (AICLI) occurs when the CLI is the result of inflammation of the walls of small blood vessels. This chronic condition results in severe pain in the feet or toes, even while resting. Left untreated, the complications of CLI often result in amputation.

"Cell transplantation, such as purified CD34+ cells (PCCs), which are multipotent hematopoietic stem cells, and peripheral blood mononuclear cells (PBMNCs), which are a mixture of highly specialized immune cells including T cells, NK cells and more, is gradually being used as a promising treatment for AICLI," explained Zhihui Dong, M.D, who along with Weiguo Fu, M.D, led the investigation. "The aim of our trial was to compare the mid-term safety and efficacy between the two groups and determine their respective advantages."

From April 2014 to September 2019, 50 AICLI patients were equally allocated to the two treatment groups. At the 36-month follow-up, 47 patients remained. The endpoints assessed were major amputation-free survival and total amputation-free survival. At six months after treatment these had been 96 percent and 84 percent in the PBMNCs group, and 96 percent and 72 percent in the PCCs group, respectively - rates that remained stable at the 12- and 24-month periods, too. The mid-term trial period focused on in this report - 36 months - once again confirmed stability.

"The PCCs group had a significant higher probability of earlier rest pain relief than the PBMNCs group, while earlier significant improvements in the Rutherford classification (which describes seven stages of peripheral artery disease) were observed in the PBMNCs group. Accordingly, PCCs would be preferred for patients with significant pain, while PBMNCs may be a good option for patients with two or more critically ischemic limbs," Dr. Fu noted.

Additionally the study compared the therapies' cost effectiveness and found that PCCs treatment was less cost-effective compared to PBMNCs treatment, mainly due to the extra cost of the purification process. "This finding is interesting and useful for future clinical trials in which we could consider avoiding purifying PBMNC into PCCs, thus reducing the cost of trials," Dr. Dong said. "The next step should be to verify our outcomes in long-term trials involving larger numbers of patients."

"The outcomes provided in this study of two cell therapies for the treatment AICLI show both to be effective and safe," said Anthony Atala, MD, Editor-in-Chief of STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine. "This finding is promising and useful for the planning of future clinical trials."

Credit: 
AlphaMed Press

3D-printed smart gel changes shape when exposed to light

image: This octopus has color-changing cells, called chromatophores, in its skin, a phenomenon that inspired Rutgers engineers.

Image: 
NOAA Okeanos Explorer Program, Galapagos Rift Expedition 2011

Inspired by the color-changing skin of cuttlefish, octopuses and squids, Rutgers engineers have created a 3D-printed smart gel that changes shape when exposed to light, becomes "artificial muscle" and may lead to new military camouflage, soft robotics and flexible displays.

The engineers also developed a 3D-printed stretchy material that can reveal colors when light changes, according to their study in the journal ACS Applied Materials & Interfaces.

Their invention is modeled after the amazing ability of cephalopods such as cuttlefish, octopuses and squids to change the color and texture of their soft skin for camouflage and communication. This is achieved by the thousands of color-changing cells, called chromatophores, in their skin.

"Electronic displays are everywhere and despite remarkable advances, such as becoming thinner, larger and brighter, they're based on rigid materials, limiting the shapes they can take and how they interface with 3D surfaces," said senior author Howon Lee, an assistant professor in the Department of Mechanical and Aerospace Engineering in the School of Engineering at Rutgers University-New Brunswick. "Our research supports a new engineering approach featuring camouflage that can be added to soft materials and create flexible, colorful displays."

Rutgers engineers developed a 3D printable hydrogel, or smart gel, that senses light and changes shape as a result. Hydrogels, which keep their shape and stay solid despite containing water, are found in the human body, Jell-O, diapers and contact lenses, among many examples.

The engineers incorporated a light-sensing nanomaterial in the hydrogel, turning it into an "artificial muscle" that contracts in response to changes in light. The light-sensing smart gel, combined with the 3D-printed stretchy material, changes color, resulting in a camouflage effect.

Next steps include improving the technology's sensitivity, response time, scalability, packaging and durability.

Credit: 
Rutgers University

Viewing upper gastrointestinal cancers in a new light

image: Left. The spectral characteristics of white fluorescence excited by a laser for white light and the short-wavelength laser. LCI expands and reduces color information simultaneously to intensify shades of red and white. Right. LCI enhances the contrast of red and white colors compared with a white light image.

Image: 
Department of Gastrointestinal Surgery,TMDU

Researchers from Tokyo Medical and Dental University (TMDU) describe an endoscopic modality for detecting upper gastrointestinal tract neoplasms by Linked Color Imaging that innovatively mixes light of different wavelengths to better depict mucosal changes

Tokyo, Japan - Recently there have been significant advances on several fronts in the ongoing war against cancer of the alimentary tract. Now, Japanese researchers report the development of another weapon: Linked Color Imaging (LCI), a novel endoscopic technique that improves detection of cancer by viewing the upper digestive tract mucosa under illumination that combines specific wavelengths of light to intensify subtle color variations indicative of neoplastic change.

Upper gastrointestinal (GI) endoscopy is routinely performed to detect tumorous changes or neoplasia in the pharynx, esophagus, and stomach and is conventionally done under White Light Imaging (WLI). Using the innovative LASEREO system developed by the Fujifilm Corporation, LCI technology balances white light with narrow-band short wavelength light in a specific ratio that deepens and enhances the contrast of red and white hues, thus intensifying nuances of mucosal transformation.

Though earlier studies have described the role of LCI in histological diagnosis of upper GI tract tumors, the research team felt the need for a large-scale, broad-based comparative study to assess its efficacy in neoplasm detection. "Our research was conducted in 19 hospitals across Japan involving 1502 patients with known past or current gastrointestinal cancer, representing a high-risk population" explains Dr Shoko Ono, lead author. "Patients underwent upper GI endoscopy under both WLI and LCI protocols wherein they were grouped according to which modality was performed first. Ingeniously, our study design ensured diagnostic accuracy; not only did each modality serve as a backup and crosscheck on the other, this was further followed by histopathological confirmation."

Dr Kenro Kawada, co-lead author, describes the results. "With LCI, lesions were detected in 8% of the patients but the detection rate was only 4.8% with WLI. Conversely, with WLI 3.5% of patients had a lesion overlooked but this rate was only 0.67% with LCI. This shows a clear superiority of LCI over conventionally illuminated endoscopic screening for discerning mucosal changes related to upper GIT neoplasia as it detected neoplasia 1.67 times more frequently."

Professor Mototsugu Kato, senior and corresponding author, explains the implications of their research. "Combined with previous studies that show the efficacy of LCI in detecting large intestinal neoplasia, our findings make a strong case for wider adoption of this modality in surveillance of the entire endoscopically accessible digestive tract. However, we need further research to confirm its efficacy in the hands of general clinicians for upper GI screening of an average population."

Credit: 
Tokyo Medical and Dental University

Dental experts discover biological imbalance is the link between gum and kidney disease

image: Research into link between gum and kidney disease

Image: 
University of Birmingham

An imbalance of the body's oxygen producing free radicals and its antioxidant cells could be the reason why gum disease and chronic kidney disease affect each other, a new study led by the University of Birmingham has found.

Periodontitis - or gum disease - is a common, inflammatory disease which causes bleeding gums, wobbly or drifting teeth and can eventually result in tooth loss.

Previous studies have shown a link between the severe oral inflammation caused by gum disease and chronic kidney disease (CKD) which demonstrated that those with worse inflammation of the gums have worse kidney function.

Previous research also showed that patients with CKD and periodontitis experience a drop in survival rates, similar in magnitude to if they had diabetes instead of gum inflammation, suggesting that gum inflammation may casually affect kidney function.

In this latest study, led by researchers at the University of Birmingham, over 700 patients with chronic kidney disease were examined using detailed oral and full-body examinations including blood samples. The aim was to test the hypothesis that periodontal inflammation and kidney function affect each other and to establish the underlying mechanism that may facilitate this.

Results showed that just a 10% increase in gum inflammation reduces kidney function by 3%. In this group of patients, a 3% worsening in kidney function would translate to an increase in the risk of kidney failure over a 5 year period from 32%-34%. Results also showed that a 10% reduction in kidney function increases periodontal inflammation by 25%.

In contrast to current beliefs that inflammation is the link between periodontitis and other systemic diseases, researchers found for the first time, that in this group of patients, the effect was caused by a biological process called 'oxidative stress' - or, an imbalance between reactive oxygen species and the body's antioxidant capacity which damages tissues on a cellular level.

Lead author Dr Praveen Sharma, from the Periodontal Research Group at the University of Birmingham's School of Dentistry, said: "This is the first paper to quantify the casual effect of periodontitis on kidney function and vice-versa as well as the first to elucidate the pathways involved.

"It showed that even a modest reduction in gum inflammation can benefit renal function. Given the relative ease of achieving a 10% reduction in gum inflammation, through simple measures like correct brushing techniques and cleaning between the teeth, these results are very interesting.

"We hope that this research paves the way for further studies to see if improvements in kidney function, following periodontal care, translate to longer, healthier life for patients with chronic kidney disease. We would also hope that the hypothesis we have identified could be tested in other groups."

Credit: 
University of Birmingham

Looking forwards rather than backwards safeguards wellbeing during Covid-19 lockdowns

Practicing gratitude and looking to the future will help safeguard our mental wellbeing during Covid-19 lockdowns, a new study in the Journal of Positive Psychology reports.

In the first study of its kind, researchers from the University of Surrey investigated the effectiveness of three psychological interventions -- nostalgia, a sentimentality for the past; gratitude, recognising the good things currently in our life; and best possible self, thinking about positive elements of the future -- and how they each affect wellbeing during lockdowns.

Personal characteristics such as emotion regulation (the ability to respond to and manage an emotional experience) and attachment orientations (how a person views their relationships to others) were also examined. It is believed that such traits may be an indicator of how an individual responds to lockdowns.

Investigating which intervention was the most effective, researchers worked with 216 participants who were each assigned to one of four groups, each one practicing either nostalgia, gratitude or best possible self, plus a control group.

Those practicing a nostalgic approach were instructed to think of a sentimental memory in their life that occurred before the lockdown; for gratitude, participants were encouraged to list three things that went well in their day and why this was; and for best possible self those involved were asked to think about where they imagine themselves in the future after lockdown has lifted. Those in the control group were each asked to recall the plot of a recent television or film they had viewed. Participants were then asked about their thoughts and feelings.

Researchers found that those who participated in the best possible self and gratitude interventions reported higher levels of social connectedness than those who practiced nostalgia. Those in the best possible self group were also found to experience significantly more positive emotion than those in the nostalgia group. Researchers believe that gratitude and best possible self direct attention towards positive aspects of a person's life by giving them hope and prevent individuals from dwelling on their current situation.

Amelia Dennis, a postgraduate researcher at the University of Surrey, said: "All three interventions have proven beneficial to people experiencing a difficult time in their life. However, as lockdowns have continued people have been presented with unusual challenges and many have struggled. We found that looking to the future and appreciating what is positive in our lives currently is more psychologically beneficial than reminiscing about the past.

"The current restrictions and any future lockdowns have removed our sense of control of our lives. For the sake of our wellbeing, we need to acknowledge what we do have rather than regretting what we have lost."

Participants were also surveyed on their personal characteristics regarding attachment and emotion regulation. Researchers found that those with low attachment anxiety (i.e. believe they are worthy of love) and those with lower attachment avoidance (i.e. inclined to feel others are trustworthy) were most likely to experience greater wellbeing during lockdown. Those with higher emotion regulation were also found to be more resilient to their current circumstances, which protects their overall wellbeing.

Jane Ogden, Professor of Health Psychology at the University of Surrey, said: "The two lockdowns last year dramatically affected our mental and emotional wellbeing and it is likely any future ones will have the same affect. Reports of increased levels of depression and anxiety are worrying because these can negatively impact upon our physical health. It is important that we understand which psychological techniques can most benefit and support people during unsettling and difficult times."

Credit: 
University of Surrey

Integrator: A guardian of the human transcriptome

image: RNA polymerase II (RNAPII) initiates transcription at a multitude of positions in the human genome. However, only a fraction of these sites is associated with genes that give rise to functional RNA. The 'Integrator' complex by default terminates RNAPII shortly after its initiation (top), unless specific gene-defining elements are present allowing for transition to productive elongation (bottom). In the latter case, transcription is typically terminated by the 'Cleavage & Polyadenylation' Complex that recognizes specific 'terminator' sequence elements in the genome (bottom, red box). In the former case the produced short RNA is by default rapidly degraded by the RNA exosome, whereas snRNAs constitute a special case that avoids degradation.

Image: 
Søren Lykkke-Andersen

In a joint collaboration, Danish and German researchers have characterized a cellular activity that protects our cells from potentially toxic by-products of gene expression. This activity is central for the ability of multicellular organisms to uphold a robust evolutionary 'reservoir' of gene products.

Manufacturing processes need quality control systems in order to ensure proper assembly of functional products. Moreover, space-consuming, and perhaps even toxic, by-products of such processes need to be properly discarded or recycled by efficient waste handling systems.

By analogy, transcription of our genome is an imperfect process that produces large quantities of non-functional and potentially harmful transcripts both from within and outside of conventional genes. The RNA polymerase II enzyme transcribes the majority of our genes, and it also generates pervasive transcripts from multiple non-genic regions. Over the past decade, it has become increasingly clear that the enzyme is relatively promiscuous when it comes to where it starts, and there are transcription initiation sites scattered everywhere in the genome. However, not all these sites are associated with a 'proper' gene, and this requires the presence of specific gene-defining elements.

Discovery of new activity of the protein complex 'Integrator'

In a new article published in the international journal Molecular Cell, a Danish-German research team has now demonstrated that the multi-protein complex 'Integrator' - which was previously described as the transcription termination factor for a specific class of genes encoding small nuclear (sn)RNAs - is in fact a default 'early' termination factor for most, if not all RNA polymerase II initiation events (Figure, top panel).

The resulting short transcripts are in most cases rapidly degraded by the ribonucleolytic RNA exosome. This mechanism is also at play to varying degrees inside conventional genes, but these have evolved elements, counteracting such early termination, to facilitate productive transcription elongation, which eventually produces functional transcripts such as protein-coding 'messenger' (m)RNA (Figure, bottom panel).

Through this newly discovered mechanism of action, Integrator ensures that production of wasteful transcripts remains limited, while at the same time allowing maintenance of thousands of transcription start sites under neutral selection in the human genome. These provide a reservoir of transcription units that may turn into functional genes over time, exemplified by the evolution of the currently known functional RNAs of our genome. As a curious example, snRNA genes appear to be a special case, taking advantage of the general early termination activity of Integrator and fend off the ensuing RNA exosome activity to allow production of stable functional RNAs (Figure, top panel).

Inactivating mutations in Integrator subunits lead to severe neurodevelopmental disorders, and elevated expression of some integrator subunits is associated with increased epithelial-to-mesenchymal transition - a key step in tumor metastasis. This duality highlights the need for a tight control of the Integrator activity. Moreover, the realization that Integrator is a general attenuator of nonproductive transcription may inform the molecular characterization and potential treatment of such ailments.

Credit: 
Aarhus University

Bedside EEG test can aid prognosis in unresponsive brain injury patients

Assessing the ability of unresponsive patients with severe brain injury to understand what is being said to them could yield important insights into how they might recover, according to new research.

A team at the University of Birmingham has shown that responses to speech can be measured using electroencephalography, a non-invasive technique used to record electrical signals in the brain. The strength of these responses can be used to provide an accurate prognosis that can help clinicians make the most effective treatment decisions.

Significantly the assessments can be made while the patient is still in intensive care and does not require any conscious response from the patient - they do not have to 'do' anything.

In the study, published inAnnals of Neurology, the team assessed 28 patients with acute traumatic brain injury (TBI) who were not under sedation, and who failed to obey commands. The patients were assessed within just a few days of their injury. They were played streams of sentences and phrases made up of monosyllabic words while their brain activity was monitored using EEG.

In healthy individuals, EEG activity only synchronises with the rhythm of phrases and sentence when listeners consciously comprehend the speech. The researchers assessed the level of the unresponsive patients' comprehension by measuring the strength of this synchronicity.

The researchers were able to follow up 17 of the patients three months following their injury, and 16 of the patients after six months. They found the outcomes significantly correlated with the strength of the patients' response to speech measured by the EEG.

Patients with traumatic brain injury are commonly assessed by their behaviour or by a CT scan, but some patients who remain unresponsive pose a significant challenge. Recent studies have shown that TBI patients can be shown to 'imagine' themselves following commands. This activity can also be tracked using EEG. However, this approach requires a fairly sophisticated response from the patient, so patients with lower brain capabilities may be overlooked.

Lead author Dr Damian Cruse is based at the University of Birmingham's School of Psychology and Centre for Human Brain Health. He explains: "The strength of our approach is that we can measure a scale of comprehension without needing any other sort of response from the patient. This insight could significantly reduce prognostic uncertainty at a critical point. It could help clinicians make more appropriate decisions about whether or not to continue life-sustaining therapy - and also ensure rehabilitation resources are allocated to patients who are most likely to benefit."

Credit: 
University of Birmingham

Increase in pleasurable effects of alcohol over time can predict alcohol use disorder

A new study out of the University of Chicago Medicine following young adult drinkers for 10 years has found that individuals who reported the highest sensitivity to alcohol's pleasurable and rewarding effects at the start of the trial were more likely to develop an alcohol use disorder (AUD) over the course of the study.

Moreover, when retested on their responses 10 years later, those who became alcoholics had the highest levels of alcohol stimulation, liking and wanting - and these were heightened compared to their baseline with no signs of tolerance to these pleasurable effects.

The research, published on Jan. 5 in the American Journal of Psychiatry, followed a cohort of 190 young adults in a laboratory-based binge-drinking scenario at three regular intervals over the course of 10 years.

These results indicate that individuals developing an AUD are more likely to be sensitized to the effects of alcohol -- that is, they experience a stronger positive response -- rather than habituated to the substance with a lower level of response. In these same individuals, alcohol was less sedating for them from the beginning and this did not change over time.

"Prior longitudinal studies have looked at young drinkers' response to alcohol and focused primarily on the fatiguing and impairing effects of alcohol," said lead author Andrea King, PhD, professor of psychiatry and behavioral neuroscience at UChicago Medicine. "The thinking that alcoholics do not like the effects of alcohol over time is based on ad-hoc reports of patients entering treatment. Only by testing the same people over a substantial amount of time to see if alcohol responses change over time were we able to observe this elevated response to alcohol compared with placebo, and in participants who did not know the contents of the drinks, so expectancy effects were minimized."

The study showed that higher sensitivity to the euphoric and rewarding effects of alcohol can predict who will go on to have an AUD as they progress through their 20s and 30s.

"These pleasurable alcohol effects grow in intensity over time, and do not dissipate, in people progressing in excessive drinking," said King. "This tells us that having a higher sensitivity to the rewarding effects of alcohol in the brain puts such individuals at higher risk for developing addiction. It all fits a picture of persistent pleasure-seeking that increases the likelihood of habitual excessive drinking over time. Alcoholics were thought to need to drink more to finally get their desired effect when they drink, but these well-controlled data do not support that contention. They get the desirable alcohol effect early in the drinking bout and that seems to fuel wanting more alcohol."

While it may seem relatively intuitive that individuals who experience alcohol's pleasurable effects most intensely are at the greatest risk for developing drinking problems, King's findings run counter to current prominent addiction theories.

"Our results support a theory called incentive-sensitization," said King. "In response to a standard intoxicating dose of alcohol in the laboratory, ratings of wanting more alcohol increased substantially over the decade among the individuals who developed more severe AUD. Additionally, the hedonic response -- essentially, how much a person liked the effects -- remained elevated over this interval and didn't go down at all. This has traditionally been the crux of the lore of addiction - that addicts don't like the drug (alcohol) but can't stop using it."

The participants were regular light or heavy social drinkers in their mid-20s at the start of the trial from 2004 to 2006. They were brought back for repeated testing of alcohol responses in the laboratory five and 10 years later as they approached middle adulthood. In between testing periods, participants were interviewed at near-annual intervals to track their drinking patterns and symptoms of AUD over time.

King hopes that these results can help improve our understanding of how some individuals have more vulnerability to developing AUD, while others remain social drinkers over their lifespan. She also points out that the results can help to develop better treatments for AUDs and inform earlier interventions for individuals who may be at high risk for developing an addiction.

"I'm already using this information to inform how I talk about addiction with my therapy clients," King said. "It can be frustrating for them to see other people who can have a couple drinks and just stop there. They can't understand why they repeatedly seem unable to do that, too, and I tell them, it may be because your brain responds differently to alcohol that makes it harder to stop drinking once you start. Knowing that information can empower a person to make different decisions. Even with our current pandemic, a person may drink to cope with stress or reduce negative feelings, but that doesn't mean that they don't also experience the buzz, or pleasurable effects from drinking. This is most concerning for at-risk drinkers as those responses may intensify as they progress with heavier drinking."

Based on this research, King sees the potential for a sort of "personalized medicine" approach for treating AUDs, describing how sharing an individual's "thumbprint" response to alcohol can make a difference in how they think about their consumption.

"This could be an opportunity for early intervention, comparable to how someone may get their cholesterol tested and then may be more motivated to change their diet, exercise more or start a medication to rein it in," King said. "Similarly, knowing one's acute response to alcohol and how it may indicate a person's future risk for drinking problems, one may decide to change their drinking on their own or seek help to avoid the progression to addiction."

Credit: 
University of Chicago Medical Center

Eurasian eagle owl diet reveals new records of threatened giant bush-crickets

image: Male specimen of the Big-Bellied Glandular Bush-Cricket (Bradyporus macrogaster)

Image: 
Dragan Chobanov

Bird diets provide a real treasure for research into the distribution and conservation of their prey, such as overlooked and rare bush-cricket species, point out scientists after studying the diet of the Eurasian Eagle Owl (Bubo bubo) in southeastern Bulgaria.

In their paper, published in the open-access, peer-reviewed journal Travaux du Muséum National d'Histoire Naturelle "Grigore Antipa", Dr Dragan Chobanov (Institute of Biodiversity and Ecosystem Research, Bulgaria) and Dr Boyan Milchev (University of Forestry, Bulgaria) report the frequent presence of the threatened with extinction Big-Bellied Glandular Bush-Cricket (Bradyporus macrogaster) in the diet of Eurasian Eagle Owls, and conclude that the predatory bird could be used to identify biodiversity-rich areas in need of protection.

While the Balkan Peninsula has already been recognised as the area with the highest diversity of orthopterans (grasshoppers, crickets and bush-crickets) in Europe and one of the generally most biologically diverse areas in the whole Palearctic realm, it is also home to a worrying number of threatened species. Additionally, a thorough and updated country assessment of the conservation status of the orthopterans found in Bulgaria is currently lacking. This is why the Bulgarian team undertook a study on the biodiversity of these insects by analysing food remains from pellets of Eurasian Eagle Owls, collected from 53 breeding sites in southeastern Bulgaria.

As a result, the scientists reported three species of bush crickets that have become a significant part of the diet of the studied predatory birds. Curiously enough, all three species are rare or threatened in Bulgaria. The case of the Big-Bellied Glandular Bush-Cricket is of special concern, as it is a species threatened by extinction. Meanwhile, the local decline in mammals and birds that weigh between 0.2 and 1.9 kg, which are in fact the preferred prey for the Eurasian Eagle Owl, has led the highly opportunistic predator to increasingly seek large insects for food. The researchers even suspect that there might be more overlooked species attracting the owls.

Taking into account the hereby reported interconnected inferences of conservation concern, as well as the vulnerability of the Big-Bellied Glandular Bush-Cricket, a species with a crucial role in the food chain, the scientists call for the newly provided data to prompt the designation of a new Natura 2000 site. Additionally, due to the species' requirements for habitats of low disturbance and high vegetation diversity, and its large size and easy location via singing males, they point out that it makes a suitable indicator for habitat quality and species community health.

Credit: 
Pensoft Publishers