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Applying bioinformatics to resolve biological problems. This is the objective of the research group of the University of Malaga "BI4NEXT", which, in one of its latest studies, developed in the Supercomputing and Bioinnovation Center (SCBI) based on biobank samples, has identified new biomarkers for the diagnosis, prognosis and even treatment of lung cancer.

A discovery published in the scientific journal PeerJ, since it proves that both tumour cell and healthy cell in the repetitive DNA regions, mainly formed by transposon fosils, are consistently, differentially expressed in a controlled way.

"Since 2010, we have worked in the belief that repetitive elements in healthy cells were dormant, and that when the cell becomes cancerous, these regions deregulate, express wildly and cause resistance to treatment", explains Professor Gonzalo Claros of the UMA Department of Molecular Biology and Biochemistry, who asserts that his research supports that this would not be the case, that repetitive sequences both in normal and tumour tissue are specifically expressed and regulated. "What we did evidence is that such control changes when a normal cell becomes cancerous", he says.

Consequently, this research group of the UMA has identified some repetitive regions that behave similarly in all patients and all types of lung cancer studied. This is the case of AluYg6 and LTR18B elements, which are repressed in all lung cancer cells, and HERVK11D-Int and UCON88 elements, which activate specifically in adenocarcinoma and small-cell lung carcinoma, respectively.

A bioinformatic study that is pending on validation at the laboratory, but nevertheless it represents one step closer to the confirmatory diagnosis of lung cancer, as well as a new source of information for specialists, being extendable to all diseases with a genetic component.

New source of biomarkers

The researchers of "BI4NEXT'" propose to study the repetitive elements -more than 50 per cent of the genome- as a new source of biomarkers, still barely exploited. Thus, they highlight the accuracy and cost and time saving that would derive from the analysis of these expression markers, in addition to genome mutations, based on high throughput sequencing.

Translating it into clinical application is the challenge faced by this group of scientists, who, as a potential solution, propose the use of fluid biopsy to find repetitive sequences of transposons, which express consistently as explained above. "Diagnosis robustness would be increased and, moreover, it would take less time and sample portion", points out Claros.

For this study, the researchers have compared for almost 3 years healthy tissue and tumour tissue from the same patient with lung cancer -analysis which is normally performed on tissues of different patients. A biobank sample of 50 patients from Korea and 17 patients from China, based on public databases, which eventually 8 patients from the Regional Hospital of Malaga joined in through the biobank.

"Just by sequencing the eight patients from the biobank of Malaga, using for such purpose the high throughput sequencing platform of SCBI and Picasso supercomputer, we obtained the data we had verified on other thousand patients from other databases", says the Professor of Molecular Biology and Biochemistry, who indicates, moreover, that all this information is available to the scientific community.

Macarena Arroyo, Pulmonologists of the Regional Hospital of Malaga, is the main author of this study, which she started in 2013 as PhD Thesis, under the leadership of Professor Gonzalo Claros, together with Manuel Cabo, Oncologist, and Rocío Bautista, PhD in Biology and Bioinformatics Specialist at the UMA. Nowadays, this study represents the starting point for new research lines like the scientific article recently published in PeerJ.

In a study published in Scientific Reports, a team of international researchers led by University of Hawai'i (UH) at Mānoa postdoctoral fellow Jamie Caldwell used a statistical technique typically employed in human epidemiology to determine the ecological risk factors affecting the prevalence of two coral diseases--growth anomalies, abnormalities like coral tumors, and white syndromes, infectious diseases similar to flesh eating bacteria.

Certain diseases in corals are either endemic, meaning they are consistently found at baseline levels in the environment, or epidemic, meaning there are periods with big outbreaks and then they seem to disappear. Though important to understand, it has been a challenge for researchers to study how those diseases are transmitted because of low rates of occurrence.

The team compared biological, environmental, human-related, and physical disease drivers with observations of healthy and diseased coral colonies.

"We specifically looked at associations between disease occurrence during non-outbreaks periods to understand what conditions allow diseases to persist in the environment at low levels year-round, or in between epidemics," said Caldwell, who is based at the UH Mānoa School of Ocean and Earth Science and Technology's (SOEST) Hawai'i Institute of Marine Biology (HIMB).

They found larger corals had higher disease risk overall. In particular, growth anomalies were more common in reefs with fewer fish, limited water motion and in areas adjacent to watersheds with high fertilizer and pesticide runoff. In contrast, white syndromes were associated with wave exposure, stream exposure, depth, and cooler ocean temperature. 

Healthy coral reefs are culturally important ecosystems and vital to Hawai'i's tourism industry. Disease outbreaks can wreak havoc on coral ecosystems. Because some diseases are rare and hard to observe, it had been difficult in the past to rigorously make inferences about which disease drivers were most impactful.

"The methods we used in this study highlight the power of the experimental design common in epidemiology but rarely, if ever, used in ecological studies," said Megan Donahue, co-author and HIMB associate researcher.

"This study provides information about what specific conditions impact coral health and the results could be used to help improve coastal development plans by considering the downstream effects of different land-use types on the coral community," said Caldwell. "Additionally, this improves our ability to predict future outbreaks based on environmental conditions and mitigate disease drivers like runoff from golf courses to evade outbreaks altogether."

The team is now using the relationships they identified to forecast coral disease outbreak risk across the Indo-Pacific. This is part of a NASA-funded project to develop seasonal and near real-time forecasts of coral disease outbreak risk for all US-affiliated Pacific Islands and the Great Barrier Reef. The forecasts will be publicly available through NOAA Coral Reef Watch.

Life expectancy in the United States has been in decline for the first time in decades, and public health officials have identified a litany of potential causes, including inaccessible health care, rising drug addiction and rates of mental health disorders, and socio-economic factors. But disentangling these variables and assessing their relative impact has been difficult.

Now, a multi-institution study led by the Yale School of Medicine and University of Alabama-Birmingham has attempted to tease out the relative impact of two variables most often linked to life expectancy -- race and education -- by combing through data about 5,114 black and white individuals in four U.S. cities.

The lives and deaths among this group of people -- who were recruited for a longevity study approximately 30 years ago, when they were in their early 20s, and are now in their mid-50s -- shows that the level of education, and not race, is the best predictor of who will live the longest, researchers report Feb. 20 in the American Journal of Public Health. The individuals were part of the Coronary Artery Risk Development in Young Adults (CARDIA) study.

Among the 5,114 people followed in the study, 395 had died.

"These deaths are occurring in working-age people, often with children, before the age of 60," said Yale's Brita Roy, assistant professor of medicine and epidemiology and corresponding author of the paper.

The rates of death among individuals in this group did clearly show racial differences, with approximately 9% of blacks dying at an early age compared to 6% of whites. There were also differences in causes of death by race. For instance, black men were significantly more likely to die by homicide and white men from AIDS. The most common causes of death across all groups over time were cardiovascular disease and cancer.

But there were also notable differences in rates of death by education level. Approximately 13% of participants with a high school degree or less education died compared with only approximately 5% of college graduates.

Strikingly, note the researchers, when looking at race and education at the same time, differences related to race all but disappeared: 13.5% of black subjects and 13.2% of white subjects with a high school degree or less died during the course of the study. By contrast, 5.9% of black subjects and 4.3% of whites with college degrees had died.

To help account for differences in age-related mortality, the researchers used a measure called Years of Potential Life Lost (YPLL), calculated as projected life expectancy minus actual age at death. This measure not only captures numbers of deaths, but also how untimely they were. For example, someone who dies at age 25 from homicide accrues more YPLL than someone who dies at age 50 from cardiovascular disease. It would take two deaths at age 50 to equal the YPLL from a single death at age 25.

Even after accounting for the effects of other variables such as income, level of education was still the best predictor of YPLL. Each educational step obtained led to 1.37 fewer years of lost life expectancy, the study showed.

"These findings are powerful," Roy said. "They suggest that improving equity in access to and quality of education is something tangible that can help reverse this troubling trend in reduction of life expectancy among middle-aged adults."

New Haven, Conn. -- According to the results of a large, global study led by Yale Cancer Center researchers, even a tiny amount of a biomarker known as PD-L1 (programmed death-ligand1) can predict a long-term survival benefit from using pembrolizumab (Keytruda). The drug is one of the first checkpoint inhibitors to be developed and used in cancer treatment. The findings are published online today in the Journal of Clinical Oncology.

"The response that we have seen from pembrolizumab, in a subset of patients years after treatment ended, is remarkable, especially since their chemotherapy had initially failed," said Roy S. Herbst, M.D., Ph.D., chief of Medical Oncology at Yale Cancer Center and Smilow Cancer Hospital and Associate Cancer Center Director for Translational Research at Yale Cancer Center.

The findings come from the phase III KEYNOTE-010 clinical trial, which was conducted in 202 academic medical centers in 24 countries. The study enrolled patients who had previously been treated unsuccessfully with chemotherapy for stage 3 or 4 non-small cell lung cancer (NSCLC), the most common type of lung cancer. The study compared use of pembrolizumab in 690 patients to treatment of docetaxel chemotherapy in 343 patients. In the 79 of 690 patients who received two years of pembrolizumab, overall survival was about 99% one year after discontinuing treatment. Overall, survival in this group three years after the two-year treatment period ranged from 23% to 35%, depending on how much of the PD-L1 biomarker their cancer expressed, compared with 11% to 13% in patients receiving chemotherapy.

Even more surprising, Herbst added, is that some patients whose cancer recurred after an initial two years of treatment responded to pembrolizumab when the drug was offered again.

"Before we had pembrolizumab, survival from advanced lung cancer was measured in months, not years," Herbst said. "It is too soon to say that pembrolizumab is a potential cure for a substantial number of patients whose tumors express PD-L1, and we know that it doesn't work for all patients, but, the agent remains very, very promising. The majority of patients who completed two years of treatment remain in remission and those who had recurrence could be retreated with pembrolizumab at the time of progression and still achieve disease control."

The PD-L1 designation refers to the PD-1 pathway that cancer uses to hide from killer immune cells. Switching on this pathway stops these immune cells from attacking cancer cells, allowing tumors to grow and spread. Checkpoint inhibitors either block the PDL-1 protein that is expressed on the outside of tumor cells, or the PD molecule on immune cells. Pembrolizumab blocks PDL-1, freeing immune cells to target the cancer.

Investigators estimate that 75% of NSCLC patients express PD-L1 protein on their cancer cells, and within this group, up to 25% express a high amount. The rest express a lower quantity. The percentage of expression is quantified by a tumor proportion score (TPS) that "pulls" about 100 cancer cells from a tumor and counts the number of cells that express PD-L1. The amount is then described as either cancer that expresses more than 50% PD-L1 or more (TPS ?50) or 1 percent PD-L1 or more (?1).

Pembrolizumab is the first checkpoint inhibitor to test the ability of a biomarker to help determine disease control outcomes, and that biomarker has now been tested for the longest period of any clinical trial. "Currently, the agent is being used in all potential settings," Herbst added, "before any other treatment, after other treatment, and with other treatments."

"Our hope is to find the very best way to use pembrolizumab to treat individual lung cancer patients, assessing how much PD-L1 a tumor expresses, what stage the patient is in, as well as other variables and biomarkers we are working on," Herbst said. "This is the story of tailored therapy."

LOS ANGELES (Feb. 20, 2020) -- When a newborn suffers lack of oxygen before or during birth, doctors have very little time to save precious brain tissue. The only proven effective way to treat babies with hypoxic brain injuries is by reducing body temperature through controlled cooling. In a new study, Children's Hospital Los Angeles neonatologist Tai-Wei Wu, MD, uses leading-edge imaging to measure temperature deep in the brains of these patients. The results demonstrate effective cooling in the deep areas of the brain, which are most often damaged by lack of oxygen.

The study, published in The Journal of Pediatrics this week, provides the foundation clinicians need to personalize this therapy in the future. In order to optimize this neuroprotective technique, the investigators need to understand precisely how therapeutic hypothermia affects a baby's brain temperature.

"First and foremost, we want to make sure we are effectively cooling the center of the brain," says Dr. Wu. "It's usually the core that is hit the hardest by injuries arising from lack of oxygen. These injuries can result in lifelong neurological deficits like cerebral palsy" The results showed that the core of the brain was effectively cooled. Unexpectedly, it was the coldest part of the brain.

"We thought that the core of the brain would be warmer than the outer portions," he says. "This is usually how body temperature works." Dr. Wu explains that the observed effect could be due to cooled blood. The center of the brain receives the cooled blood first, before reaching peripheral parts of the brain, and may get colder for this reason. "Almost every patient showed this pattern," he says, "so the effect is real."

The study represents a critical proof of concept showing that the therapy is reaching the site most likely to be injured.

"Cooling babies after hypoxic injury gives brain cells their best chance at survival," says Dr. Wu. Research found that the brain is in a state of energy failure after hypoxic injury. Multiple clinical trials showed that lowering body temperature several degrees for 72 hours improved neurological outcome. "The cooling of the brain decreased energy demand and prevented energy failure," he says. Therapeutic hypothermia has been standard of care at Children's Hospital Los Angeles for the past 10 years.

Dr. Wu is no stranger to pushing the edge of technology to save babies. Dr. Wu is the Director of the hospital's therapeutic hypothermia program, and also developed the transport protocol that allows doctors to safely conduct imaging studies without interrupting the cooling therapy.

This study marks an important achievement in the field of therapeutic cooling. Measuring temperature in an inaccessible location like the brain is already no easy task. Taking this a step further, Dr. Wu wanted to make temperature measurements for multiple, different brain areas during the cooling therapy.

Fortunately, the radiology department at CHLA has Stefan Bluml, PhD, a magnetic resonance imaging and spectroscopy expert who specializes in adapting these techniques for out-of-the-box experimental questions.

"We were really excited to find out that we could measure temperature in different areas of the brain with great accuracy," says Dr. Wu. The team detected changes as small as 0.2 degrees Celsius between brain regions - all non-invasively and without disrupting treatment.

The findings also show that temperatures were not the same everywhere in the brain. "The fact brain isn't homogenously cooled is important information to have," says Dr. Wu. Knowing how the treatment affects different brain regions could allow investigators to tailor treatments to individual babies and their unique patterns of damage. "The outer portion of the brain is hit harder in about 20% of hypoxic patients," he says. "So, this study shows us how we could better serve individual babies. And better outcomes really are our goal."

DALLAS - Feb. 14, 2020 - An experimental drug already shown to be safe and help some patients with clear cell renal cell carcinoma, a deadly form of kidney cancer, effectively disables its molecular target. The finding from a team of researchers at the UT Southwestern Medical Center's Kidney Cancer Program, published in the Feb. 15 issue of Clinical Cancer Research, reveals a weakness in this cancer that could be further exploited with other targeted treatments in the future.

About 70,000 new cases of clear cell renal cell carcinoma (ccRCC) are diagnosed every year in the U.S. The five-year life expectancy after diagnosis is low compared with other cancers, at about 10-12 percent. Unlike many other forms of cancer, ccRCC doesn't respond to chemotherapy or conventional radiation.

When study lead author James Brugarolas, M.D., Ph.D., professor of internal medicine (hematology/oncology) and director of the Kidney Cancer Program at UT Southwestern, began his career two decades ago, only one medication was approved to treat this cancer. There are now over a dozen approved drugs for ccRCC; however, says Brugarolas, each offers only a modest effect on survival and comes with a host of side effects.

Searching for better pharmaceuticals to fight this cancer, researchers at the Kidney Cancer Program focused on a protein known as hypoxia-inducible factor 2α (HIF-2α), which investigators at UTSW first discovered and described in the late 1990s. HIF-2α is a target of a tumor suppressor protein called von Hippel-Lindau (VHL) that's characteristically inactivated in most cases of ccRCC. When HIF-2α pairs with HIF-1β, it's able to regulate the expression of over 100 genes, including many that play key roles in cancer, such as those that control the formation of blood vessels or maintain stem cell-like qualities.

Although HIF-2α had long been considered undruggable, UTSW researchers identified a vulnerability in the protein structure in 2009 - a pocket that plays a key role in binding to HIF-1β. Eventually, researchers at UTSW identified compounds that bound this pocket, which served as the basis for the founding of Peloton Therapeutics Inc. in the UTSW BioCenter at Southwestern Medical District and the development of the HIF-2 inhibitor drug PT2385. After extensive preclinical testing in animal models, scientists at UTSW and their colleagues performed a phase one clinical trial that showed that this compound was safe, well tolerated, and effective at controlling cancer in 40 percent of patients.

Through an in-depth study of a subset of patients who participated in the phase one study and were willing to undergo extensive testing, the investigators sought to determine how well PT2385 blocked HIF-2α in ccRCC patients, how specific the effect was, and how important HIF-2α was for the cancer.

The researchers performed advanced MRIs to follow blood flow within patients' tumors and took tumor biopsies, as well as blood samples, at different time points.

Their results showed that within two weeks after patients started on the drug, the amount of blood circulating in their tumors decreased by about 29 percent on average. While the cohort of patients tested was relatively small, the results suggested that the drug was starving tumors from blood, says Ivan Pedrosa, M.D., Ph.D., professor of radiology, chief of magnetic resonance imaging at UTSW, and co-leader of the study. Unlike all other drugs that seek to block blood flow to tumors, but do so everywhere, the effect of PT2385 was specific for the cancer.

Within tumors, tests on biopsied tissue showed that PT2385 effectively dissolved the HIF-2α/HIF-1β, blocking the complex from activating cancer-promoting genes. The effect was highly specific, and other related complexes, such as HIF-1α/HIF-1β were unaffected - showing its extreme specificity for HIF-2α.

After more than a year on PT2385, a patient's tumor appeared to develop resistance to the drug, progressing unabated. Further tests revealed the development of a mutation within HIF-2α that prevented access by the drug to the pocket. The same mutation was found in a second patient.

Brugarolas says that the findings, which extend previous discoveries they reported in Nature, offer proof that HIF-2 is critical for ccRCC progression and that HIF-2α inhibitors such as PT2385 offer a novel and powerful weapon against this deadly disease.

"This study exposes the Achilles' heel of ccRCC tumors," says Brugarolas, who leads one of just two National Cancer Institute-designated Specialized Programs of Research Excellence (SPOREs) for kidney cancer in the U.S.

"Short of a cure, which we're still struggling to get to patients, we think this drug and other future drugs in this class could offer a durable way to fight this cancer while preserving quality of life," adds Kevin Courtney, M.D., Ph.D., UTSW associate professor of internal medicine (hematology/oncology) and first author of the study.

The Biophotonics Imaging Lab at the Beckman Institute for Advanced Science and Technology has developed imaging techniques that investigate tissues without using any staining or labels. The researchers created a unique system using a laser source that can capture more information about a tissue compared to traditional imaging techniques. That system provides better visualization of extracellular vesicles -- small packages which are known to increase in number and be associated with cancer -- particularly in connection to breast cancer cells.

"We can acquire information about the structure and metabolism of the living tissue. The imaging system allows us to capture all this information simultaneously, allowing us to see many more details about the tissue, cells, and their functions than the current ways of imaging," said Dr. Stephen Boppart, the Abel Bliss Professor of Engineering with appointments in electrical and computer engineering and bioengineering at the University of Illinois at Urbana-Champaign, who leads the Biophotonics Imaging Lab, and is also a medical doctor.

The paper "Label-Free Visualization and Characterization of Extracellular Vesicles in Breast Cancer" was published in the Proceedings of the National Academy of Sciences, and highlighted on the cover of the journal.

"Cells use these extracellular vesicles to communicate with each other, even under normal conditions. Tumor cells will alter these extracellular vesicles, and release more throughout the body. For this reason, they have the potential to be used as markers for cancer progression," Boppart said.

Traditional visualization techniques are dependent on the use of labels, which involves a lot of effort and can render the tissue unusable for additional investigation. "Our key contribution is that we can visualize these vesicles in living tissues without perturbing the tissues or using any labels. We can see how these vesicles interact with each other and with the tumors," said Sixian You, a bioengineering graduate research assistant in the Boppart lab who is first author on the paper.

The technique used by the lab involves using ultrashort laser pulses which interact with the tissue samples.

"There are two mechanisms involved in imaging," You said. "Some of the tissue components emit different kinds of fluorescence which comes in different colors. The other mechanism involves molecular structures that when aligned in a certain way, will give you an entirely different set of colors."

The researchers have also begun to characterize the contents of the vesicles using this technique.

"We have found that the vesicles which have higher concentrations of NADPH molecules are highly correlated with tumor aggressiveness, and are often located around vessels. By characterizing the vesicles, we have a good shot at detecting cancerous changes at an earlier stage," You said.

A second paper, "Real-Time Intraoperative Diagnosis by Deep Neural Network Driven Multiphoton Virtual Histology," was published in Precision Oncology, and it looks at combining the label-free imaging with deep learning techniques.

Currently, when surgeons remove tumors from patients, they analyze the tissue samples from the margins of the tumor to ensure that all the cancer tissue has been removed. Unfortunately, the pathology labs that analyze the samples can take up to a few days to complete their analysis.

"We are trying to use the label-free technique to look at the tissue right away in the surgical room," You said. "After we get the images we use deep learning, which can be used to differentiate between cancerous and normal breast tissue."

"We hope that this technique will be used for medical diagnosis and more clinical applications. The current techniques are useful but outdated and time-consuming. We think that there is a lot of new information that we can gain from this technology," Boppart said.

"The system itself is somewhat expensive, but not unlike other high-end microscopes currently in use, and costs should come down in a few years as the laser technology matures," Boppart said. "The other inherent challenge for us is that if you want high resolution images, you need to focus on smaller areas. However, when we look at the smaller areas, we can still get an adequate picture of what is going on in the tissue."

Children of mothers prescribed macrolide antibiotics during early pregnancy are at an increased risk of major birth defects, particularly heart defects, compared with children of mothers prescribed penicillin, finds a study published by The BMJ today.

The researchers say these findings show that macrolides should be used with caution during pregnancy and if feasible alternative antibiotics should be prescribed until further research is available.

Macrolide antibiotics (including erythromycin, clarithromycin, and azithromycin) are - widely used to treat common bacterial infections. They are often used as alternatives for patients with penicillin allergy.

Previous studies suggest evidence of rare but serious adverse outcomes of macrolide use, especially for unborn babies. The adverse outcomes might be associated with the pro-arrhythmic (heart rhythm problems) potential of macrolides. Policy advice about macrolide use in pregnancy varies.

To address these uncertainties, a team of researchers based at UCL set out to assess the association between macrolide antibiotics prescribed during pregnancy and major malformations as well as four neurodevelopmental disorders (cerebral palsy, epilepsy, ADHD, and autism spectrum disorder) in children.

Researchers analysed data from 104,605 children born in the UK from 1990 to 2016 with a median follow up of 5.8 years after birth. A further 82,314 children whose mothers were prescribed macrolides or penicillins before pregnancy, and 53,735 children who were siblings of children in the study group acted as negative control cohorts.

Major malformations were recorded in 186 of 8,632 children whose mothers were prescribed macrolides at any point during pregnancy and 1,666 of 95,973 children whose mothers were prescribed penicillins during pregnancy.

After taking account of potentially influential factors, the researchers found macrolide prescribing during the first three months (the first trimester) of pregnancy was associated with an increased risk of any major malformation compared with penicillin (28 v 18 per 1000) and specifically cardiovascular malformations (11 v 7 per 1000).

The increased risks were not observed in children of mothers whose macrolides were prescribed in later pregnancy (during the second to third trimester).

Macrolide prescribing in any trimester was also associated with a slightly increased risk of genital malformations (5 v 3 per 1000). No statistically significant associations were found for other system specific malformations or for any of the four neurodevelopmental disorders.

This is an observational study, so can't establish cause, and the researchers point to some limitations, such as being unable to examine treatment exposure during known critical periods for specific malformations and neurodevelopmental disorders.

However, results were largely unchanged after further analyses, suggesting that the findings withstand scrutiny.

If the associations are shown to be causal, the researchers estimate that an additional 4 children with cardiovascular malformations would occur for every 1000 children exposed to macrolides instead of penicillins in the first trimester.

"These findings show that macrolides should be used with caution during pregnancy and if feasible alternative antibiotics should be prescribed until further research is available," they conclude.

What The Study Did: More than 925,000 adults in the National Cancer Database with a new diagnosis of invasive breast, colon or lung cancer were included in this observational study that examined how Medicaid expansion under the Patient Protection and Affordable Care Act (ACA) was associated with insurance status, cancer stage at diagnosis and timely treatment.

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

Authors: Samuel U. Takvorian, M.D., M.S., of the University of Pennsylvania in Philadelphia, is the corresponding author.

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

(10.1001/jamanetworkopen.2019.21653)

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

Researchers at Karolinska Institutet in Sweden have carried out the first randomised trial of civilians with acute conflict-related wounds at two hospitals in areas affected by armed conflict. The study, which is published in The Lancet Global Health, shows that a new, more costly method of wound treatment is not more effective than standard treatment. The researchers hope to inspire new research projects in conflict zones that could improve the care for these vulnerable patients.

The researchers from Karolinska Institutet teamed up with Doctors Without Borders, amongst other entities, to study wound healing in patients injured in the armed conflicts in Syria and Iraq.

"We show that it's possible to conduct a randomised controlled trial of acutely injured civilians in an armed conflict context," says Andreas Älgå, surgeon and researcher at the Department of Clinical Research and Education, Stockholm South General Hospital (Södersjukhuset), Karolinska Institutet. "This patient group does not currently receive optimal care as the treatment generally is based on research with relatively low evidence value or research carried out in high-income contexts."

In high-income countries, negative-pressure wound therapy (NPWT) has been used in the treatment of wounds since the 1990s. Briefly, the technique involves covering the wound with plastic film and applying a negative pressure, aiming to drain excess fluid, reduce wound size, and expedite healing. However, the method is expensive and scientific evidence of its effectiveness is weak, particularly in the case of traumatic injuries. Despite this, NPWT has been introduced in the care of civilian patients with conflict-related injuries, who are often found in areas with scarce resources.

The present study was conducted at two civilian hospitals in Iraqi Kurdistan and Jordan and included patients who had undergone surgery for acute extremity injuries. The patients were randomly assigned to either NPWT or standard treatment, i.e. gauze dressings. The researchers found no difference between the groups regarding time to wound closure or risk of infection.

"This means that the new, more costly form of treatment should not be used for these injuries and that the limited available resources could be better spent on other means, such as hospital staff or medication, which could ultimately lead to improved patient outcomes," says Dr Älgå.

The researchers also hope that the study could inspire new research projects to generate context-specific knowledge with the potential to improve the care of patients in conflict zones.

"Complicated research in an armed conflict setting is associated with a number of challenges, mainly relating to security, practical and ethical issues," Dr Älgå says. "Our study can hopefully demonstrate that it's possible to overcome most of these challenges with a well-conceived, pragmatic study design and a dedicated research team."

More than 10,000 uninsured patients sought care at Texas emergency departments for lifesaving kidney dialysis in 2017, incurring more than $21.8 million in hospital costs, according to researchers from The University of Texas Health Science Center at Houston (UTHealth).

The study, which highlights a common problem in emergency departments across the country, was published today in JAMA Network Open.

The kidneys filter blood by removing waste and excess fluid. Patients with kidneys that no longer function require dialysis, where they are hooked up to a machine that purifies their blood. Each dialysis treatment takes an average of four hours three times a week. For many uninsured patients, waiting until the need becomes life-threatening is the only option because regular treatment is not feasible.

"This is a real problem facing these patients," said Julianna West, a second-year student at McGovern Medical School at UTHealth and lead author of the paper. "They have gone weeks without dialysis, and then they present in life-threatening crisis to the emergency department. This requires many hospital personnel and resources to treat their dire condition, and takes time and resources away from other patients that also need emergent treatment."

"This is a very sick population - the population with the highest morbidity rate in any emergency department," said John Foringer, MD, professor of internal medicine in the Division of Renal Diseases and Hypertension at McGovern Medical School and chief of medicine at Harris Health Lyndon B. Johnson Hospital. "This study is important because there is little data available that really captures the magnitude of the issue. Without data, it is difficult to improve resource utilization to manage these patients."

Emergent dialysis also carries a substantial price tag. Scheduled dialysis in an outpatient clinic costs about $250, while intermittent treatment in the emergency department costs eight times more, about $2,000.

"A system that treats the patient only when gravely ill provides less quality of care and is less cost-effective than investing in a program that schedules the unfunded kidney disease patients with a dialysis slot," said David Robinson, MD, MS, professor of emergency medicine with McGovern Medical School, former chief of emergency medicine of Harris Health LBJ in 2017, and a co-author of the study. "The emergency department, which often serves as the safety net for the indigent, was being used as an acute safety net for a serious chronic disease."

Harris Health System has implemented innovative solutions in the past decade to help connect uninsured patients with scheduled dialysis outside of the emergency department, Foringer said. For example, Harris Health's Riverside Dialysis Center, a chronic dialysis unit, serves nearly 180 patients who would otherwise be receiving intermittent care through hospital emergency services, he said.

Foringer also recently helped Riverside begin a new service offering patients peritoneal dialysis, which involves a surgery to place a catheter in the belly to run sterile cleansing fluid in and out of the abdominal cavity. After the initial surgery, the treatment can be done from home.

"Through the services offered at Riverside and other initiatives we've helped Harris Health implement over the years, now emergent dialysis treatments are half of what they used to be at Harris Health LBJ, from 300 in 2018 to now about 150 a month. We're starting to see the fruits of those efforts," said Foringer, who is a co-author of the study.

Researchers used Texas Emergency Department Data to evaluate adult visits in 2017 with a one-day stay or less.

"The data does not even capture those who were immediately admitted to the intensive care unit, or those that were turned away," said Henry Wang, MD, emergency medicine professor at McGovern Medical School and senior author of the paper. "Because of those limitations, this data really just captures the tip of the iceberg. This study highlights the balancing act emergency room physicians must perform with hospital resources, due to issues with health care that go far beyond the emergency department."

For West, the issue was personal.

"Before medical school, I worked as an EMT and cared for many patients in the final stages of kidney disease," West said. "I witnessed the pain and suffering of patients who went without scheduled dialysis treatment, and I also saw the enormous improvement in quality of life and joy when they did receive their scheduled dialysis. My experience inspired me to advocate for this patient population and begin research to gather more information about this public health problem so that proper solutions could be implemented."

The study, which was led by experts at the University of Nottingham, with collaborators from City, University of London and De Montfort Universities, and was funded by the National Institute for Health and Clinical Excellence, looked at six geographical areas in England.

Findings from the study showed that in a quarter of local maternity services in England, MUs are not available, or women have trouble getting information or access to them.

This is surprising given that there is strong evidence that it is safer and cheaper for healthy women with straightforward pregnancies to give birth in a Midwifery Unit (MU), rather than in an Obstetric Unit (OU) in a hospital.

The Birthplace in England study published in 2011 found that women who planned birth in MUs had around one third the rate of caesarean births and less than half the rate of forceps births, with no difference in safety outcomes for their babies.

Qualitative studies have also shown that families using these services tend to have more positive experiences and satisfaction with their care.

Research from the National Audit Office in 2013 found that if 20% of births occurred in MUs, savings to the NHS maternity budget could be around £85m a year.

Current maternity policy supports choice for women in their maternity care and NICE clinical guidelines recommend MU care for women with healthy pregnancies but there is still a relatively low proportion of women (only 15%) who give birth in MUs, while the vast majority continue to give birth in OUs.

As part of their research, the team studied the current availability of MUs in England to see whether this low use was because they were not available, whether there was a lack of information about them, a lack of interest amongst users of maternity services, or other factors.

Information was collected using individual interviews and focus groups with a range of NHS staff and users of maternity services from six NHS Trusts with varying rates of MU births.

A workshop was held with a range of stakeholders to discuss the research findings and to identify priorities that could increase the availability and use of MUs.

Although there are more MUs now than six years ago, the research identified that:

Some maternity service staff remain unconvinced of their value;

Some believe incorrectly that MUs are more expensive and less safe than OUs and therefore do not encourage pregnant women to use them;

Some women were unaware of such units and were unable to ask providers of maternity care about their use.

Unless the barriers to midwifery units are addressed, including providing women with information about these units, use will remain low and pregnant women's access to midwifery units will continue to be restricted.

Denis Walsh, Associate Professor in Midwifery at the University of Nottingham, said: "'For English maternity services to realise the full benefit of midwifery units, they must be far more proactive in promoting them locally as an equal and complementary provision alongside their standard labour wards."

Christine McCourt, Professor of Maternal Health and lead for the Centre for Maternal and Child health research at City said "This study has highlighted that many services are failing to provide women with full and balanced information about the optimal place for them to give birth. It identifies that a structural shift is needed to locate most maternity care in midwifery settings in the community and to educate professionals as well as the public about the evidence."

A large investment of at least US$3.9 billion needed to meet the World Health Organization's (WHO) target for the elimination of Hepatitis C virus (HCV) in Pakistan could deliver huge benefits in terms of lives saved and reduced ill health, according to University of Bristol led research published in The Lancet Global Health today [19 February].

Pakistan has one of the highest rates of Hepatitis C infection in the world, accounting for over ten per cent of the global HCV infections, so reducing new infections to meet the WHO target is a public health priority. New direct-acting antivirals, or DAAs, are highly effective at curing HCV infection, resulting in WHO recently developing the first Global Health Sector Strategy to eliminate HCV by 2030. Targets have been set to reduce global incidence by 80 per cent and mortality by 65 per cent. However, there is a lack of guidance on how to achieve the WHO elimination targets in low- and middle-income countries (LMICs), and there are no estimates on how much it could cost.

The study, a collaboration between the University of Bristol, Médecins Sans Frontières, the Pakistan HCV Task Force, US Centers for Disease Control and Prevention, Aga Khan University, and the Pakistan Kidney and Liver Institute, used mathematical modelling to provide the first country-level estimates of the screening and treatment needed for achieving the WHO elimination targets for HCV incidence in Pakistan, and the possible the costs of doing so.

The study found that to achieve elimination by 2030, around 36 million people will need to be screened or re-screened annually, and around 660,000 will need to be treated each year. Regular re-screening will also be needed to identify new infections or re-infections, and efforts will need to be made to re-engage individuals lost to follow-up. Success will also depend on achieving high referral rates to ensure that at least 90 per cent of people diagnosed receive treatment.

Achieving the WHO elimination target for incidence could mean preventing 5.8 million new infections and 390,000 HCV-associated deaths that might otherwise occur by 2030. The estimated US$3.9 billion cost - the equivalent of around 9.0 per cent of the current health expenditure of Pakistan or an investment of US$1.50 per person per year - is dependent on using the cheapest drugs and tests, and using a simple testing and treatment algorithm.

Dr Aaron Lim, infectious disease mathematical modeller and lead author from the National Institute for Health Research Health Protection Research Unit at the University of Bristol, said: "Our modelling suggests that Pakistan's HCV epidemic is on the rise, with around 700,000 new infections occurring each year, rapidly adding to the current 7.5 million people, or about four per cent of the population, who are chronically infected by HCV. The situation is expected to get worse if interventions are not scaled up. With fewer than 14 per cent of infected people aware of their infection status, and even fewer having been treated, it is clear that any global HCV elimination effort will need to seriously address Pakistan's large epidemic."

Professor Saeed Hamid, Professor and Department Chair of Medicine at Aga Khan University in Karachi, added: "The amount of investment needed to reduce new HCV infections to WHO elimination levels will be substantial, but equally so are the benefits to patients and the community. Improving access to DAAs along with reductions in costs means that now is the time to push for HCV elimination. This will require cooperation across both public and private sectors to ensure the best pathways of care which will bring the biggest impact."

Dr Huma Qureshi, national lead for the prevention and control of viral hepatitis in Pakistan and former executive director of the Pakistan Health Research Council, said: "Alongside screening and treatment, we also need to raise public awareness on viral hepatitis and educate people on the risk factors and how hepatitis can be spread. These prevention efforts can help speed up our elimination efforts."

Professor Peter Vickerman, Professor of Infectious Disease Modelling at the University of Bristol and principal investigator of the study, said: "Achieving HCV elimination is not just about reducing the number of people who are infected. Crucially, it is also about improving quality of life and population health through averting new infections and preventing cases of advanced liver disease, liver cancer, and liver-related deaths. Our study provides policy guidance on how to scale-up HCV screening and treatment to achieve HCV elimination and what the costs are likely to be. This is relevant not only to Pakistan, but also to other low- and middle-income countries formulating national plans for achieving HCV elimination."

Hepatitis C is a blood-borne virus infecting 71 million people worldwide (about one per cent of the world's population) and causes 400,000 deaths each year.

In complex surgery, does a correlation exist between the volume of services provided per hospital or per surgeon and the quality of the treatment results? This is the question addressed in eight commissions on minimum volumes awarded in Germany by the Federal Joint Committee (G-BA) to the Institute for Quality and Efficiency in Health Care (IQWiG). The IQWiG report is now available for the fourth indication investigated, the surgical treatment of breast cancer.

According to the findings, a positive correlation exists between the volume of services provided and the quality of treatment results in the surgical treatment of primary breast cancer: In hospitals with larger case numbers and with medical teams who perform many breast cancer operations, the overall survival chances are higher for breast cancer patients who underwent surgery. In addition, further surgery on the operated breast is less common.

Breast cancer is the most common cancer in women

At around 69,000 new cases per year, breast cancer is the most common cancer in women in Germany. In rare cases, breast cancer can also occur in men (about 1% of all new cases). The relative 10-year survival rate in 2016 was 82% for women and 72% for men.

In 2014, doctors performed 74,224 surgical procedures due to a suspected diagnosis of breast cancer in 817 hospitals throughout Germany. In general, a distinction can be made between the surgical treatment of breast cancer, which involves a breast-conserving procedure, and breast removal. The choice of treatment depends not only on the characteristics of the tumour but also on the individual physical, psychological and social situation as well as on age, concomitant diseases and patient preferences.

In Germany, there is currently no binding minimum volume for hospitals with regard to surgical procedures for the treatment of breast cancer. The German Cancer Society, however, requires minimum case numbers as part of its certification system for breast centres. For example, at least 100 primary cases per centre and 50 breast cancer operations per surgeon and year are required as proof of certification as a breast centre. In 2018, 280 sites were certified as breast centres, in which 55,715 primary cases were treated.

Positive correlation between volume and quality

On the basis of 10 studies included in the assessments, IQWiG sees a positive correlation between the volume of services provided and the quality of treatment results for the surgical treatment of breast cancer. Above all, the IQWiG researchers state in their report that a lower overall mortality rate can be assumed if such procedures are performed more frequently; the same applies to disease-related mortality. Correlations between the case numbers and mortality can be derived for both the hospital and surgeon level.

Likewise, for both levels, they conclude that with an increasing number of breast cancer operations, the number of follow-up operations that may become necessary decreases.

The IQWiG researchers were unable to identify any meaningful studies investigating the correlation between the volume of services and the quality of treatment results with regard to other outcomes such as "adverse effects of the therapy", "local recurrences", "disease-free survival" and "health-related quality of life".

Likewise, there are no meaningful studies investigating the effects of specific minimum case numbers introduced into health care.

Process of report production

In December 2018, the Federal Joint Committee (G-BA) commissioned IQWiG to prepare the report on the correlation between the volume of services and the quality of treatment results in the surgical treatment of primary breast cancer in an accelerated procedure as a so-called rapid report. Interim products were therefore not published or made available for a hearing. The work on this rapid report started in April 2019 and after completion it was sent to the contracting agency, the G-BA, in January 2020.

An English extract of this rapid report will be available soon. If you would like to be informed when it is published, please contact info@iqwig.de

Leesburg, VA, February 19, 2020--Two MRI findings--joint capsule edema and thickness at the axillary recess, specifically--proved useful in predicting stiff shoulder in patients with rotator cuff tears, according to an ahead-of-print article in the May issue of the American Journal of Roentgenology (AJR).

Studying 106 patients with small to large (

Tear size and location were determined by MRI findings and operative report, while associations between MRI findings and preoperative passive range of motion (ROM) were evaluated with simple and multiple linear regression analyses and proportional odds logistic regression analysis.

As Kim and colleagues wrote: "There was a significant, negative linear correlation between limited ROM at forward elevation and thickness of the joint capsule in the glenoid portion of the axillary recess (p = 0.018), external rotation and joint capsule edema in the humeral portion of the axillary recess (p = 0.011), and internal rotation and joint capsule edema in the glenoid portion of the axillary recess (p = 0.007)."

Fatty degeneration (p = 0.003) was an independent predictor of limited ROM on internal rotation. Meanwhile, male sex (p = 0.041) and posterosuperior rotator cuff tear (p = 0.030) were independent predictors of shoulder ROM on external rotation.

"This study is important," Kim et al. noted, "because it is the first to highlight joint capsule abnormality on MRI as a factor associated with stiff shoulder in patients with full-thickness rotator cuff tears."