Culture

Researchers from the University of Illinois at Chicago are the first to describe why CRISPR gene editing sometimes fails to work, and how the process can be made to be much more efficient.

CRISPR is a gene-editing tool that allows scientists to cut out unwanted genes or genetic material from DNA, and sometimes add a desired sequence or genes. CRISPR uses an enzyme called Cas9 that acts like scissors to cut out unwanted DNA. Once cuts are made on either side of the DNA to be removed, the cell either initiates repair to glue the two ends of the DNA strand back together, or the cell dies.

In a study published in the journal Molecular Cell, the researchers showed that when gene editing using CRISPR fails, which occurs about 15 percent of the time, it is often due to persistent binding of the Cas9 protein to the DNA at the cut site, which blocks the DNA repair enzymes from accessing the cut.

Senior author Bradley Merrill, associate professor of biochemistry and molecular genetics in the UIC College of Medicine, says that before now, researchers did not know why the process randomly failed.

"We found that at sites where Cas9 was a 'dud' it stayed bound to the DNA strand and prevented the cell from initiating the repair process," Merrill said. The stuck Cas9 is also unable to go on to make additional cuts in DNA, thus limiting the efficiency of CRISPR, he said.

Merrill, UIC graduate student Ryan Clarke, and their colleagues also found that Cas9 was likely to be ineffective at sites in the genome where RNA polymerases -- enzymes involved in gene activity -- were not active. Further investigation revealed that guiding Cas9 to anneal to just one of the strands making up the DNA double helix promoted interaction between Cas9 and the RNA polymerase, helping to transform a "dud" Cas9 into an efficient genome editor.

Specifically, they found that consistent strand selection for Cas9 during genome editing forced the RNA polymerases to collide with Cas9 in such a way that Cas9 was knocked off the DNA.

"I was shocked that simply choosing one DNA strand over the other had such a powerful effect on genome editing," said Clarke, the lead author of the paper. "Uncovering the mechanism behind this phenomenon helps us better understand how Cas9 interactions with the genome can cause some editing attempts to fail and that, when designing a genome editing experiment, we can use that understanding to our benefit."

"This new understanding is important for those of us who need genome editing to work well in the lab and for making genome editing more efficient and safer in future clinical uses," Merrill said.

The study findings are also significant because, in the genome editing process, the interaction between Cas9 and the DNA strand is now known to be the "rate-limiting step," said Merrill. This means that it is the slowest part of the process; therefore, changes at this stage have the most potential to impact the overall duration of genome editing.

"If we can reduce the time that Cas9 interacts with the DNA strand, which we now know how to do with an RNA polymerase, we can use less of the enzyme and limit exposure," Merrill said. "This means we have more potential to limit adverse effects or side effects, which is vital for future therapies that may impact human patients."

Dynamic capabilities play a key role in successful key account management, according to a new study by researchers from the University of Eastern Finland, Cranfield University and the University of Portsmouth. The study found that in key account management, companies should invest in market sensing, opportunity creation, continuous improvement of processes and value propositions, as well as capabilities for radical change. The findings were reported in Industrial Marketing Management.

The study developed a framework for key account management, identifying the resources and capabilities needed by companies to gain sustained competitive advantages and profitability.

"We feel that it is vital for companies to develop their key account management schemes, staff and processes with dynamic capabilities in mind, as this can make them stand out from competition and create sustained profitability," says Professor of International Business Mika Gabrielsson from the University of Eastern Finland, one of the study authors.

The study focused on key account management, which is a key aspect of sales management, and a facilitator of increased business profitability. An extensive literature review combined with the authors' consultancy experience served as the foundation for identifying the resources and capabilities that play a key role when striving for sustained competitive advantages and profitability. The study paves way for a new line of research, as the resource-based theory has not been applied to key account management before.

Researchers have developed a 3D map of the gene interactions that play a key role in cardiovascular disease, a study in eLife reports.

The map will help researchers identify the most important genes to focus on for the development of new treatments for heart attacks, heart failure and heart rhythm disorders.

More than 500 genetic variants have been linked with increased risk of cardiovascular disease. But most are located in so-called 'non-coding' parts of the genome, which means they don't code for a particular protein molecule. This makes it challenging for researchers to understand the importance of these genetic variants because, until now, there has been no way to study their function.

"The strongest genetic signatures associated with complex human diseases, including many cardiovascular diseases, are actually located outside of genes, scattered throughout the vast 98% of the genome that is 'non-coding,'" explains lead author Lindsey Montefiori, Graduate Student at the University of Chicago, US. "What we think is happening is that these mutations affect the function of the 'switches' of genes, called enhancers, which determine where, when and to what level each gene should be turned on."

These enhancers can be located anywhere in the genome and are often a considerable distance from the genes they control. But because DNA forms loops inside cells, the enhancers can physically connect with the genes they control and fine-tune their activity.

It has recently become possible to map these enhancers to their target genes using a technique called high-resolution promoter capture, which uses the enhancer region as 'bait' to catch its target gene. The team added an extra step to this, so that they only 'captured' a region of the genome that contains coding genes. This enabled them to map each mutation to its target gene in human heart cells and examine the precise wiring of all the potential enhancers controlling each gene.

They looked at more than 10,000 genetic mutations that have been linked to cardiovascular diseases and found that 1,999 of them make physical contact with 347 target genes in heart cells. When they studied the genes further, they found that these were well known for their roles in cardiac function.

Because the three diseases analysed involve different processes, the team next studied the interactions between enhancers with genes in other cell types which may be involved in cardiovascular disease. Here they found that mutations linked to heart attacks captured a target gene involved in cholesterol regulation, and mutations in heart failure pulled out a gene known to be important in coronary artery disease.

"Incomplete understanding of long-range gene regulation is a major roadblock in translating genetic variants into understanding of disease biology," says senior author Marcelo Nóbrega, Professor of Human Genetics at the University of Chicago. "Our 3D map of enhancer-gene interactions in human heart cells will help guide investigators to the most likely causal genes underlying increased cardiovascular disease risk, and could lead to new treatment and prevention strategies."

(Boston)--Intimate partner violence (IPV) is prevalent and has lasting impacts on the health and well-being of the entire family involved. Unfortunately, very little research and guidance about how to address perpetration of IPV in the health care setting, especially among primary care physicians who are in a role to potentially intervene has been available until now.

Researchers from Boston University School of Medicine (BUSM) reviewed the existing literature related to physicians' interactions with male perpetrators of IPV and summarized the recommendations including assessing for lethality, readiness to change and comorbid medical conditions that could impact treatment, such as substance abuse and mental illness.

"Experts agree that referrals to a Batterer Intervention Program should be the primary intervention. If there are none locally available or the patient is unwilling to go, then a physician should refer the abuser to a therapist who has been trained specifically to work with perpetrators of IPV," explained corresponding author Brian Penti, MD, assistant professor of family medicine at BUSM. "In addition, physicians should be prepared to offer education about the negative impact of IPV on the victim, on any children and on the abuser himself," added Penti, a family medicine physician at Boston Medical Center.

According to Penti, physicians should address any untreated substance abuse or mental health issues. Referral to couples' therapy should generally be avoided. Physicians should continue to have regular follow-up with their male patients to support them in changing their behavior.

The researchers believe further research is needed to assess the role the health care system can have in preventing IPV perpetration.

These findings appear in the Journal of American Board of Family Medicine.

Six new species of unique land snails whose shells are covered with what look like scales have been described from the biodiversity hotspot of Malaysian Borneo by scientists Mohd Zacaery Khalik, Universiti Malaysia Sarawak, Kasper Hendriks, University of Groningen, Jaap Vermeulen, JK Art & Science, and Prof Menno Schilthuizen, Naturalis Biodiversity Center. Their paper is published in the open access journal ZooKeys.

Thanks to their conspicuous structures, the mollusks have been added to a brand new species group of land snails to be commonly known as the 'scaly' snails, so that they can be set apart from the rest in the genus Georissa. Why it is that only some of the species in the genus sport the unique 'scales', remains unknown.

Fascinated with the minute 'scaly' snail fauna of Borneo, the researchers carried out fieldwork between 2015 and 2017 to find out how these curious shells evolved. In addition, they also examined material deposited in museum and private snail collections.

Apart from DNA data, which is nowadays commonly used in species identification, the team turned to yet-to-become-popular modern tools such as 3D modelling, conducted through X-ray scanning. By doing so, the researchers managed to look at both the inner and outer surfaces of the shells of the tiny specimens from every angle and position, and examine them in great detail.

The researchers note that to identify the 'scaly' snails to species level, one needs a combination of both DNA and morphological data:

"Objective species delimitation based solely on molecular data will not be successful for the 'scaly' snails in Georissa, at least if one wishes for the taxonomy to reflect morphology as well."

The six new species are all named after the localities they have been originally collected from, in order to create awareness for species and habitat conservation.

Coral reefs support a quarter of all marine life, feed hundreds of millions of people and contribute vastly to the global economy. But they are dying in mass bleaching events, as climate change warms our oceans and breaks down vital relationships between corals and energy-providing algae.

A new commentary, published in Communications Biology from Nature Research, provides hope that a shift in research focus towards coral immunity will support reef conservation and restoration efforts.

Dr Caroline Palmer, Visiting Research Fellow at the University of Plymouth, has spent more than a decade examining coral health from an immunological perspective.

In particular, she has identified coral immune mechanisms and sought to understand what enables some corals to survive while others die. This led Dr Palmer to discover that corals with higher immune defences are less likely to become diseased or to bleach.

In her latest work, she expands on this observation, drawing on a theory from insects that explains how corals might coexist with specific microorganisms, as a 'holobiont', while resisting infection or other disturbances.

Dr Palmer also presents a model of coral susceptibility, whereby investing in immunity enables coral, with its microorganisms, to tolerate more damage before initiating an immune response. This model describes how coral tolerance may vary among corals indicating their susceptibility to disturbances, such as bleaching events.

"There is no question that climate change is devastating coral reef systems. But if we are to conserve or restore them, we need to understand coral health - what drives tolerance and how can we promote it," Dr Palmer says. "If you have a strong immune system, and the energy to support it, you are more likely to be healthy and to survive adverse conditions."

Dr Palmer first started examining the immune systems of reef-building corals more than a decade ago, and her PhD was the first research to look at the subject in depth. But she says that coral immunity remains an under-studied area of research.

Coral bleaching, on the other hand, has been a research focus for decades, though is often considered distinct from immunity - Dr Palmer, however, suggests it is a component of coral holobiont immunity.

Dr Palmer also proposes an immunological model by which corals may increase their tolerance to adverse conditions - suggesting a way coral may adapt to new, more extreme, conditions.

Dr Palmer, who is currently Lead Scientist on the Seeking Survivors project examining coral health in Costa Rica, added: "Coral biologists are racing to conserve coral reefs before it's too late. There is currently a lot of interest in creating more tolerant corals through genetic engineering and of restoring reefs by targeting more resilient corals. I fully support these approaches, but believe understanding what drives coral health will be key to their success."

ARLINGTON HEIGHTS, IL (July 9, 2018) - Although about 10 percent of school-aged children in the United States have asthma, there are few comprehensive U.S. guidelines for treating pediatric asthma. The Pediatric Asthma Yardstick, a new guideline from the American College of Allergy, Asthma and Immunology (ACAAI), offers a user-friendly "operational document". It helps health care professionals understand which controller treatments are right for which age groups and identifies when a step up is needed.

"There is nothing like the Pediatric Asthma Yardstick in the current literature," says allergist Bradley Chipps, MD, ACAAI president and lead author of the paper. "We created the yardstick because there are many options for treating pediatric asthma. It's a roadmap for how to move forward with kids whose asthma is not under control. The yardstick describes controller treatments at different levels of severity for all ages, the choices available for parents for their child and how to step up therapy."

The diagnosis and management of asthma in children differs from that in adults. Differences also exist between the three age groups addressed in the yardstick - adolescents, 12-18 years old; school-age children, 6-11 years old; infants and young children, 5 years old and under.

"Differences in diagnosis and management of asthma in children reflect differences in development of their respiratory systems, particularly for younger children," says Leonard Bacharier, MD, co-author of the yardstick. "Other factors include challenges related to daily activities and emotional and social concerns, particularly for adolescents. Comorbid conditions and non-adherence with treatment (eg; due to the stigma of having a chronic condition and taking medicine) can affect outcomes for older children."

Although asthma often begins in early childhood, diagnosing asthma in the very young child is challenging because it is based largely on symptoms and is not easily confirmed by objective testing, such as lung function. Additionally, symptoms, notably wheezing and coughing, often are related to, or occur with, common viral infections. Pediatric data for medicines are limited and robust clinical studies attesting to efficacy and safety of asthma medications are few.

"The Pediatric Asthma Yardstick is a practical resource for identifying children with uncontrolled asthma who need a step-up in controller medicine," says Dr Chipps. "It describes how to start and/or adjust controller therapy based on the options that are currently available for children, from infants to 18 years of age. The recommendations are presented around patient profiles, by severity and age, and are based on current best practice strategies according to the most recent data and the authors' clinical experience."

Scientists from The Australian National University (ANU) and overseas have discovered the oldest colours in the geological record, 1.1 billion-year-old bright pink pigments extracted from rocks deep beneath the Sahara desert in Africa.

Dr Nur Gueneli from ANU said the pigments taken from marine black shales of the Taoudeni Basin in Mauritania, West Africa, were more than half a billion years older than previous pigment discoveries. Dr Gueneli discovered the molecules as part of her PhD studies.

"The bright pink pigments are the molecular fossils of chlorophyll that were produced by ancient photosynthetic organisms inhabiting an ancient ocean that has long since vanished," said Dr Gueneli from the ANU Research School of Earth Sciences.

The fossils range from blood red to deep purple in their concentrated form, and bright pink when diluted.

ANU led the research with support from Geoscience Australia and researchers in the United States and Japan.

The researchers crushed the billion-year-old rocks to powder, before extracting and analysing molecules of ancient organisms from them.

"The precise analysis of the ancient pigments confirmed that tiny cyanobacteria dominated the base of the food chain in the oceans a billion years ago, which helps to explain why animals did not exist at the time," Dr Gueneli said.

Senior lead researcher Associate Professor Jochen Brocks from ANU said that the emergence of large, active organisms was likely to have been restrained by a limited supply of larger food particles, such as algae.

"Algae, although still microscopic, are a thousand times larger in volume than cyanobacteria, and are a much richer food source," said

Dr Brocks from the ANU Research School of Earth Sciences.

"The cyanobacterial oceans started to vanish about 650 million years ago, when algae began to rapidly spread to provide the burst of energy needed for the evolution of complex ecosystems, where large animals, including humans, could thrive on Earth."

The research is published in PNAS.

CINCINNATI--Transplanting hepatitis C (HCV)-infected dialysis patients with organs from HCV-positive donors and then treating the infection after transplantation is more effective, costs less and will shorten wait times for donated organs, according to a computer analysis conducted by physician-researchers at the University of Cincinnati (UC) College of Medicine.

The findings are available online in the Annals of Internal Medicine. The study's lead author is Mark Eckman, MD, professor and director of the UC Division of General Internal Medicine.

The model predicts that transplantation with an HCV-infected kidney followed by HCV treatment was more effective and less costly than treating HCV before transplantation, largely because of the longer wait times for HCV-uninfected kidneys, explains Eckman. A typical 57.8 year-old patient receiving hemodialysis would gain an average of six months of additional quality adjusted life years at a lifetime cost savings of $41,591, says Eckman.

A patient receiving a non-infected kidney waits on average more than two years for that organ, while the wait for an HCV-infected kidney is about eight months, says Eckman, a UC Health physician. Also, 15 percent of patients undergoing dialysis for end-stage renal disease are infected with HCV.

"There is a high excess mortality risk for patients receiving hemodialysis and it is associated with a decreased quality of life for some patients," says Eckman. "If you can spend less time on dialysis, you will be better off. The annual cost of hemodialysis is more than $90,000."

In the United States, an estimated 110,000 patients start dialysis each year. Of the approximately 500,000 patients who received dialysis for end stage renal disease in 2016, only 3.8 percent or 19,060 received kidney transplants, says Eckman.

The computerized decision analytic model pulled data from a variety of sources including the United States Renal Data System (USRDS), medical literature and clinical trials. The model looks at several factors such as sex, age, the degree of liver damage from chronic HCV infection, and treatment costs to predict outcomes that may occur over the lifetime of a patient cohort for each of the clinical strategies studied, explains Eckman.

"While people are waiting for a kidney, there is a risk of dying on hemodialysis, with a mortality rate of approximately 7.5 percent per year," says Eckman. "If you wait a shorter time to get a kidney transplant by accepting an HCV-infected kidney, you can avoid a year-and-a-half or more of time on a waiting list.

"Once you have a transplant, the annual mortality rate is roughly 2 percent per year instead of about 7.5 percent per year. The shorter the period of time waiting for a kidney on dialysis, the better your outcomes will be."

Eckman says the computer model is needed because there are no large clinical trials yet that have addressed this question.

"This isn't something we would have asked or thought about even a year ago," says Eckman. "Now, we have very effective HCV treatments that we didn't have two or three years ago. Some of these new medications can be used in patients on dialysis. The new drugs have much fewer side effects, and the treatment course is a lot shorter. The treatment of HCV has advanced dramatically."

Several clinical trials have shown HCV cure rates as high as 98 percent with the new drugs, says Eckman.

"Secondly, a year ago we didn't have drugs to treat HCV that could be used in patients with end stage renal disease," says Eckman. "While treatment of HCV is very expensive, this cost balances out in our analysis as patients in both strategies are getting treated for HCV."

There are tradeoffs between the two strategies. Patients who get a non-infected HCV kidney have a lower risk of dying from liver disease because HCV is treated earlier, before kidney transplantation, says Eckman. But HCV-infected patients who receive an HCV-infected kidney are able to get off of dialysis sooner and have a lower risk of dying from end stage kidney disease.

"It is better to wait less time for a kidney by getting an HCV-infected kidney followed by treatment after transplantation," says Eckman.

He adds that the supply of HCV-infected kidneys has increased due to the unfortunate deaths of otherwise generally healthy young individuals who suffer opioid overdoses.

"What we hope is that this study will have some impact on policy," says Eckman.

Physicians who work in small, independent primary care practices--also known as SIPs--report dramatically lower levels of burnout than the national average (13.5 percent versus 54.4 percent), according to a study led by researchers at NYU School of Medicine publishing online July 9 in the Journal of the American Board of Family Medicine. The findings indicate that the independence and sense of autonomy that providers have in these small practices may provide some protection against symptoms of burnout.

Physician burnout is a major concern for the healthcare industry. It is associated with low job satisfaction, reduced productivity among physicians, and may negatively impact quality of care. Multiple national surveys suggest that more than half of all physicians report symptoms of burnout.

Research on physician burnout has focused primarily on hospital settings or large primary care practices. The researchers say that this is the first study that examines the prevalence of burnout among physicians in small independent primary practices--practices with five or fewer physicians.

Researchers examined data collected from 235 physicians practicing in 174 SIPs in New York City. The rate of provider reported burnout was 13.5 percent, compared to the 2014 national rate of 54.4 percent. A 2013 meta-analysis of physician surveys conducted in the United States and Europe found that lower burnout rates were associated with greater perceived autonomy, a quality and safety culture at work, effective coping skills, and less work-life conflict.

"Burnout is about the practice culture and infrastructure in which primary care doctors work. So the obvious question is: what is it about the work environment that results in low burnout rates in small practices?" said Donna Shelley, MD, professor of Population Health and Medicine at NYU School of Medicine, and the study's senior author. "It's important to study the group that's NOT showing high burnout to help us create environments that foster lower burnout rates. The good news is that a culture and systems can be changed to support primary care doctors in a way that would reduce the factors that are leading to burnout."

How the Study Was Conducted

Researchers analyzed data as part of the HealthyHearts NYC (HHNYC) trial, which is funded by the Agency for Healthcare Research and Quality's (AHRQ) EvidenceNOW national initiative. AHRQ is a division of the U.S. Department of Health and Human Services. The HHNYC trial evaluates how practice coaching or facilitation helps SIPs adopt clinical guidelines for the treatment and prevention of cardiovascular disease.

Each physician answered a multiple choice question with response options indicating various levels of burnout. Options ranged from no symptoms of burnout, to feeling completely burned out and questioning whether or not to continue practicing medicine. The question was validated against the Maslach Burnout Inventory, a nationally recognized measure that identifies occupational burnout. Physician respondents were categorized as burned out if they checked one of the last three options in the multiple choice question.

As part of the HHNYC trial, physician respondents were also asked a number of questions about the culture of their practices. The tool used specifically measures "adaptive reserve," or a culture where individuals have opportunities for growth, and the ability to learn from mistakes by talking and listening to each. Physicians that described this kind of culture in their practice reported lower levels of burnout. According to Dr. Shelley, practices where employees feel that they are included in decisions and have control over their work environment are referred to as having 'high adaptive reserve."

Dr. Shelley is careful not to minimize the challenges that physicians working in solo practices or SIPs face. She cites that even though burnout rates are lower, many of these practices are struggling financially, and many of these physicians are on call all of the time.

"The more we can understand what drives low rates of burnout, the more likely it is that we'll find solutions to this problem," said Dr. Shelley. "The hope is that our research can inform ways for larger systems to foster autonomy within practices so that there is space to carve out a work environment that is aligned with doctors' needs, values and competencies."

Dr. Shelley lists a number of the study's limitations. Since the findings are representative of physicians working in small practices in New York City, the study does not capture burnout rates in other cities across the country. It is also possible that the researchers underestimated the number of hours worked by physicians, since hours worked is associated with burnout. Shelley also cited the lack of data linking physician burnout to patient outcomes.

New peer-reviewed research published today in the Harm Reduction Journal shows that flavours play a critical role in attracting - and retaining - smokers into the vaping category, directly contributing to tobacco harm reduction.

"The results show that non-tobacco flavours, especially fruit based flavours, are being increasingly preferred to tobacco flavours by adult vapers who have completely switched from combustible cigarettes to vapour products," said Dr Christopher Russell, Deputy Director of CSUR, who led the research.

The survey, one of the largest of its kind to focus on flavours, conducted by the Centre for Substance Use Research (CSUR) and funded by Fontem Ventures, assessed the first flavour and current e-vapour product flavour used by over 20,000 adult frequent vapers in the United States. The majority of frequent e-vapour product users, who had completely switched from smoking cigarettes to using vaping products, are shown to have increasingly likely initiated vaping with non-tobacco flavours, and to have transitioned from tobacco to non-tobacco flavours over time.

Of the 20,836 adult frequent e-vapour product users in the survey, nearly 16,000 had completely switched to from smoking to vaping, while 5,000 were dual users who were smoking and using e-vapour products.

In the study the most popular currently used e-vapour flavours in the US were fruit/fruit beverage, where up to 82.9% of sampled users reporting regular purchase and use of vape liquids in this category, with dessert/pastry flavours next at 68.5%. Tobacco and menthol flavours ranked as the 5th and 6th most popular currently used flavours, respectively. "The data suggest that U.S. vapers' journeys towards quitting smoking are increasingly likely to start with, progress to, or be sustained by frequent use of vaping devices containing non-tobacco flavours", said Dr Russell.

Commenting on the new research, Dr Grant O'Connell, Corporate Affairs Manager at Fontem Ventures said "The declining popularity of tobacco flavours among adult vapers strongly suggests that flavour bans like the one recently passed in San Francisco*, could see vapers return to cigarette smoking and discourage other adult smokers from switching."

The study also looked at the flavour first time users typically used when starting to vape. The proportion of first vaping product purchases that were fruit-flavoured increased from 17.8% of first purchases made before 2011, to 33.5% first purchases made between June 2015 and June 2016. Tobacco-flavoured first purchases almost halved during this time from 46.0% pre-2011, to 24.0% between 2015-2016.

SAN DIEGO, CA - Young patients who underwent surgery for isolated meniscus tears between 1990 and 2005 showed positive long-term clinical results, according to new research presented today at the American Orthopaedic Society for Sports Medicine's Annual Meeting in San Diego. The study represents one of the largest long-term follow-up cohorts describing clinical outcomes of meniscus repair in pediatric patients to date.

"The patients we observed at a long-term follow up had an average IKDC score of 92.3, continuing increases from the pre-operative average of 65.3 and mid-term average of 90.2," noted corresponding author Aaron Krych, MD, from the Mayo Clinic in Rochester, Minnesota. "These numbers show a significant, lasting improvement in functional outcomes for those involved in this study."

Researchers examined 32 patients (and 33 knees) at an average follow-up of 17.6 years after surgery. At the time of repair, the average age of patients was 16.1 years. Of the 33 knees included in the study, none had a failed repair since the previous follow-up in 2008. The average Tenger activity score was 6.53, lower than pre-operative 8.33 and mid-term scores of 8.39, though the authors indicated decreasing sports activity with age may be an independent risk factor and not indicative of poorer surgical outcomes.

"Finding the best treatment options for these meniscus tears is important not only to the patient's immediate recovery, but for long-term health and wellness," commented Krych. "Our research team believes the data from this study shows the promise of surgery for young patients with these types of injuries."

Limitations of the work include no MRI data or radiograph images available, and a relatively small patient population despite being one of the largest group studied. Future studies to assess the progression of knee osteoarthritis are recommended.

Young athletes with shoulder instability are considered to be a high-risk group of patients following arthroscopic shoulder stabilization given the high recurrence rates and lower rates of return to sport, which have been reported in the literature. However, according to researchers presenting their work today at the American Orthopaedic Society for Sports Medicine's (AOSSM) Annual Meeting in San Diego outcomes may be improved by proper patient selection and reserving arthroscopic stabilization for athletes with fewer incidents of pre-operative instability.

The senior author of this study, Frank A. Cordasco, MD, MS and his colleagues from the Hospital for Special Surgery in New York City presented a series of patients with shoulder instability between the ages of 14 and 20 who were treated with arthroscopic anterior stabilization performed in the beach chair position by a single surgeon. The primary outcomes were the rates of revision surgery and return to sport at a minimum follow-up of 2 years. Sixty-seven athletes were included in the study with 19 females and 48 males who averaged 17 years of age. There was a low rate of revision surgery of 6% and 82% percent of the athletes returned to sport at an average of 7 months following surgery.

"Our study highlights the importance for young athletes with shoulder instability, undergoing a thorough preoperative evaluation to determine the number of instability events and to obtain appropriate advanced imaging when significant bone loss is suspected. Each pre-operative instability episode can result in greater degrees of bone loss, which results in higher failure rates following arthroscopic shoulder stabilization. This pre-operative approach can determine the best procedure to select from the menu of operations we use to manage shoulder instability," said Cordasco. "This menu includes arthroscopic stabilization, open stabilization and bone augmentation such as the Latarjet reconstruction. Providing the young athlete with the appropriate selection from the menu will to lead to the best outcomes in this high-risk group and will allow them to predictably and reproducibly get back in the game.

Forty-two of the 67 (63%) athletes in this study were indicated for surgery after their first dislocation and only a few had more than two instability episodes. "We found a gender-specific difference in that all of the six recurrences occurred in males. This study demonstrates that when the high-risk young athlete with fewer episodes of pre-operative instability is treated with an arthroscopic stabilization, the revision surgery rate is low and the return to sport rate is high. Arthroscopic shoulder stabilization may offer the best outcomes in this group when it is performed after the first dislocation. Additional research needs to be performed to continue to improve the outcomes for this challenging group of young, active high-risk athletes," said Cordasco.

Artificial intelligence (AI) holds real potential for improving both the speed and accuracy of medical diagnostics. But before clinicians can harness the power of AI to identify conditions in images such as X-rays, they have to 'teach' the algorithms what to look for.

Identifying rare pathologies in medical images has presented a persistent challenge for researchers, because of the scarcity of images that can be used to train AI systems in a supervised learning setting.

Professor Shahrokh Valaee and his team have designed a new approach: using machine learning to create computer generated X-rays to augment AI training sets.

"In a sense, we are using machine learning to do machine learning," says Valaee, a professor in The Edward S. Rogers Sr. Department of Electrical & Computer Engineering (ECE) at the University of Toronto. "We are creating simulated X-rays that reflect certain rare conditions so that we can combine them with real X-rays to have a sufficiently large database to train the neural networks to identify these conditions in other X-rays."

Valaee is a member of the Machine Intelligence in Medicine Lab (MIMLab), a group of physicians, scientists and engineering researchers who are combining their expertise in image processing, artificial intelligence and medicine to solve medical challenges. "AI has the potential to help in a myriad of ways in the field of medicine," says Valaee. "But to do this we need a lot of data -- the thousands of labelled images we need to make these systems work just don't exist for some rare conditions."

To create these artificial X-rays, the team uses an AI technique called a deep convolutional generative adversarial network (DCGAN) to generate and continually improve the simulated images. GANs are a type of algorithm made up of two networks: one that generates the images and the other that tries to discriminate synthetic images from real images. The two networks are trained to the point that the discriminator cannot differentiate real images from synthesized ones. Once a sufficient number of artificial X-rays are created, they are combined with real X-rays to train a deep convolutional neural network, which then classifies the images as either normal or identifies a number of conditions.

"We've been able to show that artificial data generated by a deep convolutional GANs can be used to augment real datasets," says Valaee. "This provides a greater quantity of data for training and improves the performance of these systems in identifying rare conditions."

The MIMLab compared the accuracy of their augmented dataset to the original dataset when fed through their AI system and found that classification accuracy improved by 20 per cent for common conditions. For some rare conditions, accuracy improved up to about 40 per cent -- and because the synthesized X-rays are not from real individuals the dataset can be readily available to researchers outside the hospital premises without violating privacy concerns.

"It's exciting because we've been able to overcome a hurdle in applying artificial intelligence to medicine by showing that these augmented datasets help to improve classification accuracy," says Valaee. "Deep learning only works if the volume of training data is large enough and this is one way to ensure we have neural networks that can classify images with high precision."

Our bodies consist of many different kinds of cells, each with their own role. The Japanese scientist Shinya Yamanaka had made earlier the discovery, earning the Nobel Prize in 2012, that cells from adult skin can be converted to cells typical of early embryos, so-called induced pluripotent stem cells (iPSC). This process is called reprogramming.

Up till now, reprogramming has only been possible by introducing the critical genes for the conversion, called Yamanaka factors, artificially into skin cells where they are not normally active at all.

Professor Timo Otonkoski at the University of Helsinki and Professor Juha Kere at Karolinska Institutet and King's College London, with their teams of researchers, have now for the first time succeeded in converting skin cells into pluripotent stem cells by activating the cell's own genes. This was achieved by using gene editing technology - called CRISPRa - that can be directed to activate genes. The method utilizes a blunted version of the Cas9 'gene scissors' that does not cut DNA and can therefore be used to activate gene expression without mutating the genome.

"CRISPR/Cas9 can be used to activate genes. This is an attractive possibility for cellular reprogramming because multiple genes can be targeted at the same time. Reprogramming based on activation of endogenous genes rather than overexpression of transgenes is also theoretically a more physiological way of controlling cell fate and may result in more normal cells. In this study, we show that it is possible to engineer a CRISPR activator system that allows robust reprogramming of iPSC", tells Professor Otonkoski.

An important key for the success was also activating a critical genetic element that was earlier found to regulate the earliest steps of human embryo development after fertilization. "Using this technology, pluripotent stem cells were obtained that resembled very closely typical early embryonal cells", Professor Kere says.

The discovery also suggests that it might be possible to improve many other reprogramming tasks by addressing genetic elements typical of the intended target cell type.

"The technology may find practical use in bio banking and many other tissue technology applications", says PhD student, MSc Jere Weltner, the first author of the article published in Nature Communications. "In addition, the study opens up new insights into the mechanisms controlling early embryonic gene activation."