Culture

The research, led by the University of Plymouth, examined the uptake of nanoparticles by a commercially important mollusc, the great scallop (Pecten maximus).

After six hours exposure in the laboratory, billions of particles measuring 250nm (around 0.00025mm) had accumulated within the scallop's intestines.

However, considerably more even smaller particles measuring 20nm (0.00002mm) had become dispersed throughout the body including the kidney, gill, muscle and other organs.

The study is the first to quantify the uptake of nanoparticles at predicted environmentally relevant conditions, with previous research having been conducted at far higher concentrations than scientists believe are found in our oceans.

Dr Maya Al Sid Cheikh, Postdoctoral Research Fellow at the University of Plymouth, led the study. She said: "For this experiment, we needed to develop an entirely novel scientific approach. We made nanoparticles of plastic in our laboratories and incorporated a label so that we could trace the particles in the body of the scallop at environmentally relevant concentrations. The results of the study show for the first time that nanoparticles can be rapidly taken up by a marine organism, and that in just a few hours they become distributed across most of the major organs."

Professor Richard Thompson OBE, Head of the University's International Marine Litter Research Unit, added: "This is a ground breaking study, in terms of both the scientific approach and the findings. We only exposed the scallops to nanoparticles for a few hours and, despite them being transferred to clean conditions, traces were still present several weeks later. Understanding the dynamics of nanoparticle uptake and release, as well as their distribution in body tissues, is essential if we are to understand any potential effects on organisms. A key next step will be to use this approach to guide research investigating any potential effects of nanoparticles and in particular to consider the consequences of longer term exposures."

Accepted for publication in the Environmental Science and Technology journal, the study also involved scientists from the Charles River Laboratories in Elphinstone, Scotland; the Institute Maurice la Montagne in Canada; and Heriot-Watt University.

It was conducted as part of RealRiskNano, a £1.1million project funded by the Natural Environment Research Council (NERC). Led by Heriot-Watt and Plymouth, it is exploring the effects which microscopic plastic particles can have on the marine environment.

In this study, the scallops were exposed to quantities of carbon-radiolabeled nanopolystyrene and after six hours, autoradiography was used to show the number of particles present in organs and tissue.

It was also used to demonstrate that the 20nm particles were no longer detectable after 14 days, whereas 250nm particles took 48 days to disappear.

Ted Henry, Professor of Environmental Toxicology at Heriot-Watt University, said: "Understanding whether plastic particles are absorbed across biological membranes and accumulate within internal organs is critical for assessing the risk these particles pose to both organism and human health. The novel use of radiolabelled plastic particles pioneered in Plymouth provides the most compelling evidence to date on the level of absorption of plastic particles in a marine organism."

SAN DIEGO -- Mayo Clinic researchers have developed two new strategies that may improve the performance of chimeric antigen receptor therapy (CAR-T cell therapy) in treating cancer. They are presenting results of their preclinical research at the 2018 annual meeting of the American Society of Hematology in San Diego.

Reducing toxicity in CAR-T cell therapy

"While CAR-T cell therapy has proven successful in treating certain cancers, severe toxicities have limited its widespread application," says Rosalie Sterner, an M.D.-Ph.D. student working in the T Cell Engineering Laboratory of Saad Kenderian, M.B. Ch.B., a Mayo Clinic hematologist. Sterner says toxicities associated with CAR-T cell therapy include cytokine release syndrome, in which patients can experience fever, nausea, headache, rash, rapid heartbeat, low blood pressure, and difficulty breathing and neurotoxicity.

Sterner says some patients undergoing CAR-T cell therapy get sick during treatment and require a stay in an ICU. She also notes that deaths related to the side effects of CAR-T cell therapy have been reported. Sterner and her colleagues developed a strategy to reduce the severe toxicities associated with CAR-T cell therapy.

The strategy involves blocking the GM-CSF protein, which is produced by CAR-T cells and other cells using a clinical-grade antibody (lenzilumab).

"When we blocked the GM-CSF protein, we found that we could reduce toxicities in preclinical models, says Sterner. "We also were able to demonstrate that CAR-T cells worked better after the GM-CSF protein was blocked."

Next, researchers used a gene editing technology, called CRISPR, to generate CAR-T cells that did not secrete the GM-CSF protein. Sterner says these modified CART cells were more effective than regular CAR-T cells.

Based on their findings, the research team is proceeding with a phase II clinical trial of the GM-CSF blocking antibody during CAR-T cell therapy. If the trial results are consistent with earlier findings, the therapy could become a standard of care during CAR-T cell therapy at Mayo Clinic.

This research also is published in Blood.

mproving response rates for CAR-T cell therapy in B cell lymphoma

"In CAR-T cell therapy, physicians remove and modify a patient's T cells to recognize and fight cancer," says Reona Sakemura, M.D., Ph.D., a hematologist and a postdoctoral fellow in Dr. Kenderian's laboratory. "Once modified T cells are reinfused into the patient where they seek out and ultimately kill cancer cells."

Dr. Sakemura says response rates for CAR-T cell therapy vary by disease. For example, in B cell acute lymphoblastic leukemia, response rates of more 90 percent have been seen, compared to response rates of 10 to 30 percent for treatment with conventional chemotherapy. In other blood cancers, such as lymphoma and chronic lymphocytic leukemia, the response rates for treatment with CAR-T cell therapy remain low.

To improve the effectiveness of CAR-T cell therapy in these cancers, Dr. Sakemura and his colleagues developed a strategy to combine CAR-T cell therapy with a drug that targets a protein called "AXL." This protein is present on the cancer and within the cancer's environment. The drug, called "TP-0903," not only kills cancer cells, but also it enhances the potency of CAR-T cells in attacking cancer cells and potentially lowers the toxicity associated with CAR-T cell treatment.

While more research and clinical trials are needed, Dr. Sakemura says, "We believe the latter effect may eventually be utilized as an innovative approach to augment the efficacy of CAR-T cell therapy and extend its use to other B cell cancers."

Rotaviruses, like all viruses, reproduce inside living cells. Making new viruses requires assembling replication factories via a complex, little known process that involves both viral and cellular components. A report in the Proceedings of the National Academy of Sciences by a multidisciplinary team led by researchers at Baylor College of Medicine reveals that the formation of rotavirus factories depends on a cellular protein called CK1α, which chemically modifies viral component NSP2, thus triggering its localization and assembly into the virus factory, an essential step in the formation of new viruses.

"One of the interests of our labs is to better understand the process of assembling rotavirus factories," said first co-author Dr. Jeanette M. Criglar, staff scientist of molecular virology and microbiology at Baylor College of Medicine and a graduate of the program.

In the process of investigating this, Criglar and her colleagues discovered that a cellular protein called CK1α is required to assemble rotavirus factories.
"When we silenced CK1α in cells before infection with rotavirus, we knocked down the replication of the virus by more than 90 percent, suggesting that CK1α largely controls the formation of rotavirus factories," Criglar said.

CK1α is a enzyme with the ability to modify other proteins and their functions chemically by adding phosphate groups to them. The researchers discovered that CK1α mediates its effect on the formation of rotavirus replication factories by adding a phosphate group to a rotavirus protein called NSP2. This phosphate modification triggers the assembly of NSP2 octameric units into a crystal-like structure and appears to be required for the formation of rotavirus factories.

"CK1α normally takes care of housekeeping tasks within the cell. Rotavirus takes advantage of this protein's activity, 'outsourcing' it to assemble the virus factories," said corresponding author Dr. Mary K. Estes, Cullen Foundation Endowed Professor Chair of Human and Molecular Virology at Baylor College of Medicine and emeritus founding director of the Texas Medical Center Digestive Diseases Center.

In addition, the team discovered that rotavirus protein NSP2 can add phosphate groups to itself, thus modifying its activity and affecting other proteins involved in virus assembly. This is a surprising finding, Estes explains, because this function had not been described before for this viral protein.

"Taken together, our findings suggest that a cascade of phosphate chemical modifications, which is mediated in part by CK1α and NSP2, is essential for the formation of rotavirus factories," said co-author Dr. B V Venkataram Prasad, professor and Alvin Romansky Chair in Biochemistry and Molecular Biology, and member of the Dan L Duncan Comprehensive Cancer Center at Baylor. "These findings provide new insights that could lead to previously unsuspected ways to fight the disease in the future."
"It is possible that our findings may also shed light on the assembly of virus factories for other viruses that also require CK1α, such as hepatitis C, or that also form cytoplasmic virus factories like West Nile and dengue virus," Criglar said. "If we can understand how other viruses assemble their factories, perhaps using similar mechanisms to rotavirus, we could advance the understanding of those diseases as well."

Women who experience domestic violence and abuse (DVA) are more than twice as likely to seek emergency contraception as other women, according to a study by National Institute for Health Research (NIHR)-funded researchers at the University of Bristol and Queen Mary University of London, suggesting that requests for emergency contraception could be an important sign of abuse.

In the study, published in the British Journal of General Practice today [Tuesday 4 December], the researchers analysed medical records of over 200,000 women of reproductive age registered with a GP and found that those who had a record of DVA were 2.06 times more likely to have a consultation for emergency contraception compared to other women, rising to 2.8 times for women aged 25-39.

The researchers also found some evidence that abused women are more likely to seek emergency contraception repeatedly.

DVA is a major public health problem, with devastating consequences for the women who experience it and great financial cost to the NHS. It is known to have a significant impact on women's reproductive health, including an increased risk of unintended pregnancy and abortion, as abusive and controlling partners coerce women to have unprotected sex or rape them.

Although emergency hormonal contraceptive, also known as the morning-after pill, is available from pharmacies, women can also get it from their GP. Up to a third of all emergency contraceptives are prescribed by GPs.

The researchers are calling for this new evidence to be included in existing DVA training programmes for GPs and sexual health practitioners, and for the training to be extended to community pharmacists, to help them identify and refer women who have experienced DVA on to specialist support services. Such programmes are recommended by the National Institute for Health and Care Excellence (NICE) and the World Health Organization (WHO) as part of a multi-sector response to DVA.

Joni Jackson, Research Associate from the NIHR Collaboration for Leadership in Applied Health Research West (NIHR CLAHRC West) and co-lead author of the study, said: "We found a strong positive association between exposure to domestic violence and abuse and requests for emergency contraception. Our findings are in line with evidence from studies in other countries suggesting that women experiencing DVA use more emergency contraception than other women. GPs, pharmacists and sexual health practitioners are at the frontline responding to these requests, with community pharmacists dispensing 50 per cent of all emergency contraceptive pills. This presents an important opportunity to identify women experiencing DVA, signpost them to appropriate support services, and potentially save lives."

Dr Natalia Lewis, from the Centre for Academic Primary Care at the University of Bristol and co-lead author, added: "The negative impact of domestic violence and abuse on health results in higher use of healthcare services by abused women compared to the general population. This means that healthcare services are an important point of contact for DVA victims and survivors. We have already seen improvements in GPs' ability to identify and refer women experiencing DVA through the success of the IRIS (Identification and Referral to Improve Safety) programme. IRIS has recently been adapted for sexual and reproductive health services. Our findings support the case for adapting the IRIS intervention to the community pharmacy setting, although more research is needed to explore if and how this could be done."

DALLAS, December 3, 2018 --Full marathons may significantly raise concentrations of several biomarkers of strain on the heart, according to new research in Circulation, Journal of the American Heart Association.

Investigators in Spain compared levels of cardiac biomarkers, including - troponin I and troponin T- in 21 groups of 3 runners each after each individually ran an endurance race of three different lengths - a full marathon, a half marathon and a 10K race. All of the 63 subjects were amateur runners. They also measured levels of biomarkers for cardiac tissue stress.

Although there was little difference in 10-year risk for cardiovascular events between the runners (average about 3 percent), the strain on the heart muscle, as measured by the biomarker levels, was much greater after a full marathon.

The incidence of cardiac arrests in marathoners is only about 1 in 50,000 runners who compete in races, but a high proportion of all exercise-induced cardiac events occur during marathons, especially in men 35 years of age and older.

The number of subjects in the study was not large enough to accurately assess differences in 10-year cardiovascular risk, but the researchers are planning to examine this in a larger group of runners, said lead investigator Juan Del Coso, Ph.D., director of the exercise physiology laboratory at Camilo José Cela University, in Madrid, Spain.

"We typically assume that marathon runners are healthy individuals, without risk factors that might predispose them to a cardiac event during or after a race. But with the growing popularity of long-endurance races, the exponential increase in the number of participants, and the lack of appropriate training in some cohorts of amateur runners, our findings suggest that running shorter endurance races might reduce the strain imposed on the myocardium during running competition," Del Coso said.

Leading scientists call for action to increase global soil carbon, in advance of the annual climate summit of the United Nations Framework Convention on Climate Change (UNFCCC) in Katowice, Poland (COP24) and World Soil Day (5 Dec).

The amount of carbon in soil is over twice the amount of carbon found in trees and other biomass.

But one-third of the world's soils are already degraded, limiting agricultural production and adding almost 500 gigatons of carbon dioxide to the atmosphere, an amount equivalent to the carbon sequestered by 216 billion hectares of U.S. forest.

Modalities for climate action in agriculture will be addressed 3 December at the first workshop of the Koronivia Joint Work on Agriculture, a breakthrough initiative of the 2017 UNFCCC climate negotiations.

In a commentary piece, Put More Carbon in Soils to Meet Paris Climate Pledges, published today by the journal Nature, climate change and agricultural scientists who serve on the science and technical committee of the organization 4 per 1000 describe a path for recuperating soil carbon stocks to mitigate climate change and boost soil fertility. The scientists suggest that the KJWA formally commit to increasing global soil organic carbon stocks through coordination and activities related to eight steps.

The eight steps are:

1. Stop carbon loss - Protect peatlands through enforcement of regulations against burning and drainage.
2. Promote carbon uptake - Identify and promote best practices for storing carbon in ways suitable to local conditions, including through incorporating crop residues, cover crops, agroforestry, contour farming, terracing, nitrogen-fixing plants, and irrigation.
3. Monitor, report and verify impacts - Track and evaluate interventions with science-based harmonized protocols and standards.
4. Deploy technology - Use high-tech opportunities for faster, cheaper and more accurate monitoring of soil carbon changes.
5. Test strategies - Determine what works in local conditions by using models and a network of field sites.
6. Involve communities - Employ citizen science to collect data and create an open online platform for sharing.
7. Coordinate policies - Integrate soil carbon with national climate commitments to the Paris Agreement and other policies on soil and climate.
8. Provide support - Ensure technical assistance, incentives to farmers, monitoring systems, and carbon taxes to promote widespread implementation.

A joint forum for coordinated action and funding to close research gaps is needed, the scientists argue. The eight steps also inform the KJWA's next workshop (June 2019), which will address soil carbon.

"Taking steps to increase global soil carbon requires multi-stakeholder collaboration at the science-policy interface. 4p1000 initiative, which has 281 partners from 39 countries, is showing how such collaboration can be used to address sustainable development goals in an integrated way," said Cornelia Rumpel, lead author of the commentary and Research Director of the National Research Center at France's Institute of Ecology and Environmental Sciences.

Co-author Farshad Amiraslani, Remote Sensing Specialist and Deputy Dean of Academic Affairs, Faculty of Geography, University of Tehran, is concerned with how lack of coordination among stakeholders and no comprehensive database is hindering the impact of land restoration efforts. We need to apply satellite imagery to capture changes occurring at large scales more frequently and cost-effectively, he said.

"We are amassing a rich body of knowledge on how to increase soil carbon stocks," said Claire Chenu, a Professor of Soil Sciences at AgroParisTech. "But further research is needed. For example, we know root systems make an important contribution to soil carbon stocks, but we are still researching how specific crops with deep roots, vs. cover crops, vs. agroforestry systems differentially contribute to increasing soil carbon. We need more data on the effects of agricultural practices in different ecosystems."

"Challenges to achieving large-scale carbon sequestration include nutrient limits, inadequate farmer incentives and lack of organic matter in some places, but even impacts at lesser scales will benefit the climate and food security," said co-author Lini Wollenberg, Low Emissions Development Leader for the CGIAR Research Program on Climate Change, Agriculture and Food Security (CCAFS) and Research Professor at the University of Vermont's Gund Institute for Environment.

"The potential benefits are too large to ignore," Wollenberg said.

BLOOMINGTON, Ind. - In a new study, Indiana University scientists found toxic flame retardants in newly manufactured children's car seats, sparking concerns about children's health. Of the 18 children's car seats tested, 15 contained new or traditional hazardous flame retardant chemicals.

"New replacement flame retardants, often marketed as safer alternatives, are lurking in children's products without rigorous safety testing and may pose risks for children's health," said Marta Venier, associate scientist at IU's School of Public and Environmental Affairs and principal investigator on the study. "The abundance of emerging flame retardant chemicals in children's car seats and the key role these products play as potential sources of chemical exposure is a cause for concern."

The research was conducted in conjunction with the Ecology Center, an independent nonprofit organization in Ann Arbor, Michigan. The car seats tested in this study were purchased by the Ecology Center and shipped to Indiana University for analyses. All of the car seats were newly manufactured between January 2017 and February 2018 and were made in China, Canada, or the United States. In total, the researchers tested 36 different fabric and foam samples from 18 car seats.

For the first time, two cyclic phosphonate esters (PMMMPs) were measured at high levels in North America, suggesting their use as a replacement flame retardant for compounds that are known to be harmful. PMMMPs were found in 34 of the 36 car seat sampled at levels much higher than those of traditional flame retardants. Little is known about their health effects. Two other emerging flame retardants (tris(2,4-di-t-butylphenyl) phosphate (TDTBPP) and resorcinol bis(diphenyl phosphate) (RDP)) were also measured in baby products for the first time.

Polybrominated diphenyl ethers (PBDEs) were observed in 75 percent of the samples tested, despite being phased out of use in the United States in 2013 over health concerns. However, PBDEs were detected at such low levels that it is unlikely they were added intentionally. They may have been impurities or found in parts containing recycled materials. Conversely, decabromodiphenyl ethane (DBDPE) was detected in four samples at high levels, suggesting that it was intentionally used. DBDPE is a brominated flame retardant known to cause oxidative stress, hormone disruption and thyroid problems.

Unlike other baby products, children's car seats are required to meet the flammability standards for car interiors outlined in the Federal Motor Vehicle Safety Standard 302, which was created in 1971 by the National Highway Traffic Safety Administration. Flame retardants are routinely used as a cost-effective way to meet this standard. However, flame retardants have been linked to a variety of negative health effects, including hormone disruption, impaired brain development, liver damage and cancer. Children are more susceptible to these effects than adults because of their smaller size and their tendency to put their hands and objects in their mouths.

Children can be exposed to flame retardants in car seats by breathing in chemicals that leach into the air out of fabrics and foam. This is especially problematic for children during the summer months, when heat increases the rate at which flame retardants enter the poorly ventilated, semi-closed car environment. Children can also be exposed to flame retardants by ingesting the dust which accumulates inside the vehicle, through skin contact or by chewing on their car seats.

"We found that car seat manufacturers are intentionally moving away from certain toxic chemicals compounds that they know to be harmful, which is good news," said Yan Wu, a postdoctoral researcher at Indiana University and the lead author of the study. "However, we know very little about the replacement chemicals they're using. Car seats are vital for protecting children during a vehicle crash, but more research is needed to ensure that those seats are chemically safe as well."

A follow-up analysis of patients enrolled in a Phase I/II multi-center trial for diffuse large B-cell lymphoma (DLBCL) reported 51 percent of patients receiving an anti-CD19 chimeric antigen receptor (CAR T) called axi-cel were still alive two years post-treatment. Axi-cel was approved by the U.S. Food and Drug Administration for treatment of DLBCL in October 2017 and by the European Commission in August 2018.

The study, co-led by Sattva Neelapu, M.D., professor of Lymphoma & Myeloma at The University of Texas MD Anderson Cancer Center, reported its findings in the Dec. 2 online issue of The Lancet Oncology and during a presentation at the 60th American Society of Hematology Annual Meeting & Exposition in San Diego.

"This two-year assessment demonstrates that axi-cel can induce durable remissions in a substantial proportion of patients with an acceptable long-term safety profile," said Neelapu. "There also is evidence of gradual B-cell recovery in most patients with refractory large B-cell lymphoma who otherwise have limited treatment options."

With a median follow-up of 27.1 months for 101 patients enrolled in Phase II, the study found that 83 percent of patients achieved a reduction in cancer activity tied to treatment, known as an objective response; 58 percent had no detectable cancer or a complete response, and 39 percent reported ongoing responses. Median overall survival was not reached, and no axi-cel related adverse effects were reported after the 12-month period.

The results mirrored findings of a previously reported median follow up of 15.4 months at which time objective response rate was 82 percent, complete response rate was 58 percent, with 42 percent of patients reporting ongoing responses.

In addition, exploratory analyses were performed to assess CAR T-cell persistence and B-cell recovery in patients with ongoing remission, and at 24 months, persisting CAR gene-marked cells were observed in 66 percent of patients with evaluable biomarker samples. Peripheral blood B-cells were measurable in 75 percent of patients.

'Real-world' outcomes support ZUMA-1 findings

A subsequent "real-world" assessment of 274 patients who received axi-cel, post FDA-approval of the therapy revealed similar results to the overall ZUMA-1 study. The real-world retrospective study included 17 centers that contributed data independent from the manufacturer-funded trial.

Findings from the study, led by Loretta Nastoupil, M.D., assistant professor of Lymphoma & Myeloma, were presented Dec. 1 at the ASH Annual Meeting & Exposition. By day 90, the real-world assessment reported 81 percent of patients had an objective response and 57 percent had a complete response.

"Although limited by a relatively short follow up, 90-day responses in the real-world setting are comparable to the best responses observed in the pivotal ZUMA-1 clinical trial," said Nastoupil. "Importantly, safety appears comparable to the ZUMA-1 trial despite nearly half of patients failing to meet ZUMA-1 eligibility criteria."

People with epilepsy living in high crime neighborhoods in Chicago had three times as many seizures as those living in neighborhoods with lower crime rates according to new research from the University of Illinois at Chicago presented at the American Epilepsy Society 2018 conference in New Orleans.

Epilepsy is a chronic neurological disorder characterized by abnormal brain activity and seizures that affects more than 65 million people worldwide. About one-third have difficulty controlling their seizures even with medication. Seizures can interfere with work, relationships, and the ability to live independently. Previous research has shown that living in neighborhoods with high rates of crime have significantly higher levels of the stress hormone, cortisol. Stress is also a factor that is commonly reported to trigger seizures in people with epilepsy.

The UIC study included 63 adults with epilepsy living within the city limits of Chicago who were participating in a larger study testing the efficacy of a tablet-based educational tool that provides tailored information about epilepsy. That study, called PAUSE, involves patients at the University of Illinois Hospital's epilepsy clinic and in the Chicagoland community and is facilitated by the Epilepsy Foundation of Greater Chicago.

The researchers determined the levels of crime in neighborhoods of the 63 participants by mapping their zip codes to specific neighborhoods and then cross-referencing those neighborhoods with local crime rates available through the City of Chicago Police data portal. Participants self-reported the number of seizures they had in the past month and in the past three months.

"We found that people living with epilepsy who live in high-crime neighborhoods experienced significantly more seizures," said Jessica Levy, a research coordinator in the UIC department of neurology and rehabilitation who presented the findings. "On average, people in high-crime neighborhoods had three seizures versus one for people living in low-crime neighborhoods when we looked back over the last 30 days. Over the course of 90 days, people in high-crime neighborhoods had seven seizures on average compared to three for those living in low-crime neighborhoods, so the link between crime and seizure activity is significant."

The researchers found no overall association between neighborhood crime status and the duration of epilepsy or between crime status and poverty.

Having more seizures can significantly lower quality of life. Seizures that result in falls can cause bruising or even broken bones. There can also be a stigma associated with having a seizure in public.

"Understanding the impact of violence and crime as potential triggers for seizures underscores the need for further research that might allow clinicians to make better-informed recommendations for self-management education and stress management skills," said Dr. Dilip Pandey, associate professor of neurology and rehabilitation at UIC and an investigator on the study.

Sunday, Dec. 2, 2018, SAN DIEGO: At the American Society of Hematology (ASH) Annual Meeting, Cleveland Clinic medical hematologist and oncologist Aziz Nazha, M.D., will present results of a personalized prediction model that surpassed current prediction models for Myelodysplastic Syndromes (MDS).

Dr. Nazha and colleagues report the model outperformed current prognostic scoring systems, such as the Revised International Prognostic Scoring System (IPSS-R), in predicting an MDS patient's risk of mortality and transformation to acute myeloid leukemia (AML), a more aggressive type of bone marrow cancer. "A Personalized Prediction Model to Risk Stratify Patients with MDS" will be presented Monday, Dec.3, at 2:45 p.m. in Grand Hall A at ASH.

Patients with MDS have survival outcomes that can range from months to decades. Although several prognostic scoring systems have been developed to risk stratify MDS patients, survival varies even within distinct categories, which may lead to over- or under-treatment. Researchers hypothesized that discrepancies may be due to analytic approaches or lack of incorporation of molecular data.

"Determining prognosis in oncology is one of the most important parts of our job. All oncology patients want to know how long they are going to live," said Dr. Nazha. "Too often we find a significant gap between what we predicted, based on existing prediction models, and what actually happened to our patients."

The new model designed by Dr. Nazha and team incorporates individual patient genomic and clinical data using a machine-learning algorithm to better predict survival probabilities and outcomes. Patients' clinical and mutational variables are entered into a web application that runs the personalized prediction model and provides overall survival and AML transformation probabilities at different time points that are specific for a patient. Patient data used to test the model came from Cleveland Clinic and Munich Leukemia Laboratory and was validated in a separate collection of patient data from Moffitt Cancer Center.

In a comparison using medical records, the new model predicted a patient's likelihood of surviving for a given period of time 74 percent of the time, compared to IPSS-R accuracy of 67 percent. The model accurately predicted a patient's risk of AML 80 percent of the time, compared to IPSS-R accuracy of 73 percent.

Dr. Nazha's next step is to build a website where clinicians can input a patient's clinical and genetic characteristics and get back the patient's probability of surviving at different time points such as six months, 12 months, and 18 months.

"Understanding a patient's prognosis allows us to more appropriately develop a treatment plan and counsel patients," Dr. Nazha said. "We are optimistic an improved prediction will lead to more personalized care."

Dr. Nazha also presented "A Personalized Prediction Model for Outcomes after Allogeneic Hematopoietic Stem Cell Transplant in Patients with MDS: On Behalf of the CIBMTR Chronic Leukemia Committee" at ASH on Saturday, Dec. 1.

In this study, Dr. Nazha and colleagues developed a personalized prediction model for outcomes after allogeneic hematopoietic cell transplant (HCT) in patients with MDS. In allogeneic HCT a person receives blood-forming stem cells from a genetically similar donor. HCT remains the only potentially curative option for MDS, and previous research has shown genetic alterations have an impact on outcomes after HCT in MDS.

Investigators used data from MDS patients enrolled in the Center for International Blood and Marrow Transplant Research Registry and built a web application where patients' genomic and clinical data are computed to predict survival probability after HCT at 6,12 and 24 months. The application identified several clinical and molecular variables that impacted overall survival and the hazard of relapse. This information may aid physicians and patients in their decision prior to HCT.

"Because of the risks of transplant-related mortality and relapse, identifying patients who may or may not benefit from HCT is clinically important," said Dr. Nazha. "Understanding survival probability at different points in time may aid physicians and patients in their approach, prior to HCT."

CINCINNATI - A daily hydroxyurea pill may finally bring some relief for young children living with the painful and deadly blood disease sickle cell anemia (SCA) in resource-challenged sub-Saharan Africa, where the disease is prevalent and health care availability is suboptimal.

This is what a large multinational clinical trial called REACH discovered when it tested daily hydroxyurea treatment in 606 children between the ages of 1 and 10 years old. The children took a pill each day for six months, followed by increases in the daily dosages based on their health status and weight. Initial doses varied between 15-20 mg/kg a day.

The treatment improved their health by controlling SCA symptoms and, in an expected finding, giving them some protection from malaria that is also prevalent in the region, according to the study's lead physicians at Cincinnati Children's Hospital Medical Center and Centre Hospitalier Monkole in Kinshasa, in the Democratic Republic of the Congo.

Study results are published today online by The New England Journal of Medicine in conjunction with being presented at the American Society of Hematology's annual meeting in San Diego.

The clinical trial determined that hydroxyurea therapy is feasible to use and safe for children in sub-Saharan Africa. Compared to pre-treatment levels, hydroxyurea use was linked to reduced rates of sickle cell pain by an average of 55 percent, infections by 38 percent, malaria by 51 percent, transfusions by 67 percent, and death by 70 percent.

"Hydroxyurea was safe and offered many benefits to these young patients, including improved anemia, fewer sickle cell pain events, less malaria, and better survival," said Russell Ware, MD, PhD, the study's senior investigator and a physician-scientist at the Cincinnati Children's Cancer and Blood Diseases Institute.

Also leading the clinical trial was Leon Tshilolo, MD, PhD, at the Centre Hospitalier Monkole. Investigators named the study REACH, an acronym for Realizing Effectiveness Across Continents with Hydroxyurea. According to Tshilolo, the clinical trial lived up to its name.

"The study shows the importance of research partnerships between the US and Africa to improve clinical care," he said. "Even in an African setting hydroxyurea is feasible to use, accepted by patients and families, well-tolerated, and safe for children with sickle cell anemia. Almost all of the children had clinical improvements, and the older patients were well enough to attend school."

SCA's Heavy Burden

Caused by a genetic mutation and most prevalent in people of African ancestry, SCA is a painful disease where blood cells turn sickle-shaped and become stuck in the vascular system where they block blood flow. This can damage vital organs and cause death. Hydroxyurea works by significantly increasing both hemoglobin and fetal hemoglobin in the blood, which helps reduce sickling, anemia and other impacts on patients.

Available therapies to treat SCA effectively are limited, although numerous studies in recent years--almost all in developed countries--show that hydroxyurea is a safe and effective drug for managing the disease and improving quality of life.

SCA affects more than 90,000 people in the United States and millions of people worldwide, with 75 percent of the disease's burden in sub-Saharan Africa. Other nations with high incidence rates are India, nations in the Caribbean, Central America, and South America.

Because of the lack of detailed medical records, the best available estimates are that 50 to 90 percent of infants with SCA born in sub-Saharan Africa die before the age of 5, according to a 2017 paper published by Cincinnati Children's researchers that included Ware. The paper also reported that efforts to help people in the region with SCA have been stagnant because most affected people lack access to basic diagnostics and clinical care.

Institutions like Cincinnati Children's are working with ASH and the National Heart, Lung, and Blood Institute (part of NIH) to invest in research and clinical programs and address the global burden of SCA in limited-resource settings, especially sub-Saharan Africa.

The Phase 1-2 multi-center open-label REACH clinical trial treated children in four sub-Saharan countries: the Democratic Republic of Congo, Uganda, Kenya and Angola. Researchers plan to follow children in the study long-term to get additional data about growth and development and to look for any possible effects on organ function and fertility.

Breast cancer survivors who used a smartphone app created at Houston Methodist consistently lost weight, largely due to daily, real-time interactions with their health care team via the mobile app. Few clinically-tested mobile apps exist today with clear measurable goals to support continued care of cancer survivors and patients.

There is increasing evidence that reducing obesity also reduces the risk of cancer recurrence and the frequency of hospital readmission. A meta-analysis of 82 studies evaluating the relationship between body weight and breast cancer in more than 213,000 women found a 35 percent increase in breast cancer mortality.

A Nov. 30 paper in JCO Clinical Cancer Informatics focused on the benefits of using the Methodist Hospital Cancer Health Application specifically designed for breast cancer survivors to interact with their clinical dietitian and reinforce healthier lifestyle choices, especially between appointments.

Of the 33 breast cancer survivors enrolled, 25 women actively used the app over a four-week period. During this pilot study, 56 percent of enrolled patients lost an average of 3.5 pounds. Also, the more the study participants used the app, the more likely they were to lose weight.

"Some breast cancer medications slow down metabolism, but one of the biggest hurdles for a survivor is finding the support needed to maintain a healthy lifestyle," said Tejal A. Patel, M.D., co-senior author and breast medical oncologist at Houston Methodist Cancer Center. "We tell our patients that losing weight reduces the risk of cancer recurrence, but don't usually provide them with structured tools to achieve and maintain this weight loss. The mobile application provides a link to the physician's office so that real-time changes can be made."

Unlike popular consumer health apps, the Houston Methodist app incorporated a clinical dietitian who actively communicated with patients and provided direct feedback and guidance. For example, if a breast cancer survivor logged her daily meals, the nutritionist reviewed it and made comments and suggestions in real time.

Studies show that fewer than 35 percent of all breast cancer survivors follow recommended levels of physical activity. Stephen T.C. Wong, Ph.D., P.E., chair and professor of the Department of Systems Medicine and Bioengineering at Houston Methodist Research Institute, and his informatics development team helped create the mobile application as a way for Houston Methodist health care providers to actively support their patients after treatment and to provide continued care beyond hospital walls.

"We are a mobile society, so digital innovations like smartphone health care apps must be made in a way that empower our patients and deliver patient-centric care," said Wong, co-senior author on the paper. "More than 90 percent of the study patients found our app easy to navigate, and they wanted to use it daily for real-time feedback and support. The app helped breast cancer patients change daily behaviors and successfully meet their personal goals."

Houston Methodist dietician Renee Stubbins said the mobile health app allowed her to interact with more patients in one day than she normally would in person, something she believes can be adapted by other registered dietitians and health care providers. Not only did she provide recommendations for diet and exercise, but she also motivated the study participants to provide virtual support to each other.

"Maintaining a healthy weight is difficult enough for the average person, let alone for those who've survived breast cancer, so being able to empower and support these women made a difference," said Stubbins, one of the paper's co-first authors.

The app is currently accessible to study patients, but the goal is to widely offer this mobile application on the App Store and Google Play. Houston Methodist will broaden the use of this app in multi-center studies and focus on long-term behavioral changes to reduce health issues most common in cancer survivors. One study will include active breast cancer patients undergoing chemotherapy or other treatment. A second study will include all cancer survivors and monitor exercise, wellness and diet over a 12-week period.

A study recently published in Translational Psychiatry, a Nature journal, has shown how using cultured cells from patients with psychotic disorders, such as schizophrenia, to investigate abnormalities in nerve connections in the brain could lead to new treatments. Strong correlations were observed between the findings in the cells in culture--grown outside the body in a controlled environment--and findings from brain imaging performed on the very same human participants.

"The findings are important, because if the health of cells in culture reflects the health of the same cells in a human brain, we may be able to create a better model for studying psychotic disorders," said the study's senior author, Bruce M. Cohen, MD, PhD, director of McLean Hospital's Program for Neuropsychiatric Research (PNPR). Cohen said such a model could give researchers a greater capacity to find genetic and biochemical targets in the brain. Using these targets, he said, "could enable us to develop novel and more effective interventions for psychotic disorders."

For their work, Cohen and his colleagues, including first author Donna L. McPhie, PhD, director of the Cellular Neuropsychiatry Laboratory in the PNPR, drew on studies showing that altered pathways of brain development can be found across most cases of schizophrenia and that inaccurate connections and "leaks" in signaling between nerve cells are a feature of many psychotic disorders. A substance called myelin, produced by cells called oligodendrocytes, serves as a kind of insulation to prevent these leaks. In studies at McLean Hospital by co-author Dost Öngür, MD, PhD, chief of the Psychotic Disorders Division at McLean, and his colleagues, myelin was measured and found to be reduced in the brain in patients with schizophrenias.

Based on this prior research, Cohen and his colleagues drew on a repository of cell lines they had obtained from patients with psychiatric disorders. These samples were reprogrammed from skin cells into brain-like cells in the laboratory. The reprogrammed cell lines, taken from both ill and healthy patients, produced nerve cells and support cells called glia, including oligodendrocytes, in laboratory cultures. Investigations into these cells revealed significant abnormalities in the development of oligodendrocytes grown from subjects with psychotic disorders.

The research also revealed a strong correlation between the number of oligodendrocytes in culture and the amount of myelin made by these cells in the brains of the same subjects who provided the cells. This finding, Cohen explained, "means that we can now study the causes of the abnormality of myelin that we have observed in living brain tissue in a laboratory setting."

For Cohen and his colleagues, the prospect of using lab cultures to examine differences in the brains of individuals with psychotic illnesses is "an exciting development." For example, Cohen said, researchers have observed that not all genes and proteins necessary to make oligodendrocytes are affected in these cells, and they can now begin to identify exactly what genes and proteins are different in these cells. It would be impossible, he said, to do these detailed studies in living brain tissue.

Such studies, the researchers believe, could lead to better treatment approaches for individuals with psychotic conditions. "Using in vitro cell cultures to study these abnormalities could help us identify specific genetic and biochemical targets that might be addressed by novel drug treatments, cell transplantation, or other interventions," Cohen said.

Heart attacks reoccurred more frequently in younger patients with several modifiable risk factors, including smoking and high blood pressure. Researchers on the new study, presented at the American College of Cardiology Asia Conference 2018 in Shanghai, suggested secondary preventive programs for younger patients should target modifiable risk factors.

"When treating younger patients with a history of heart attack, clinicians should emphasize better control of high blood pressure, high cholesterol and diabetes," said Joanne Karen Recacho-Turingan, MD, a Cardiology Fellow at The Medical City in Manila, Philippines. "Other modifiable risk factors to highlight in patient history and address with these patients include smoking habits and obesity."

Researchers analyzed 133 young patients admitted at The Medical City for a heart attack between 2013 and 2016. During the study period 22 patients had a reoccurrence. All patients who experienced a second heart attack were male with an average age of 40.9 years. Patients who did not experience a reoccurrence were 90.1 percent male and 9.9 percent female with an average age of 39.6 years.

Risk factors such as smoking, high blood pressure, family history of heart disease and chronic kidney disease were more prevalent among the patients who experienced a reoccurrence. In these patients, chest pain was the most common presenting symptom at 81.8 percent while 90.9 percent had unstable vital signs at the time of admission.

"Heart attack in young patients can cause disability and even death at the prime of life," Recacho-Turingan said. "There are often serious consequences for these patients, their families and the health system, which can lead to an increased economic burden. We must make sure to work with these patients on their modifiable risk factors to reduce their risk not just for a second heart attack, but hopefully, even preventing the first."

Previous studies have defined young heart attack patients as less than 45 years old while some used a less than 40-year old cut-off. Prior research has found these patients have a high prevalence of smoking, family history and high cholesterol.

MANHATTAN, KANSAS -- Along with a warming climate and intensified human activities, recent water storage in global landlocked basins has undergone a widespread decline. A new study reveals this decline has aggravated local water stress and caused potential sea level rise.

The study, "Recent Global Decline in Endorheic Basin Water Storage," was carried out by a team of scientists from six countries and appears in the current issue of Nature Geoscience.

"Water resources are extremely limited in the continental hinterlands where streamflow does not reach the ocean. Scientifically, these regions are called endorheic basins," said Jida Wang, a Kansas State University geographer and the study's lead author.

"Over the past few decades, we have seen increasing evidence of perturbations to the endorheic water balance," said Wang, an assistant professor of geography. "This includes, for example, the desiccating Aral Sea, the depleting Arabian aquifer and the retreating Eurasian glaciers. This evidence motivated us to ask: Is the total water storage across the global endorheic system, about one-fifth of the continental surface, undergoing a net decline?"

Using gravity observations from NASA/German Aerospace Center's Gravity Recovery and Climate Experiment, or GRACE, satellites, Wang and his colleagues quantified a net water loss in global endorheic basins of approximately 100 billion tons of water per year since the start of the current millennium. This means a water mass equivalent to five Great Salt Lakes or three Lake Meads is gone every year from the arid endorheic regions.

Surprisingly, this amount of endorheic water loss is double the rate of concurrent water changes across the remaining landmass except Greenland and Antarctica, Wang said. Opposite to endorheic basins, the remaining regions are exorheic, meaning streamflow originating from these basins drains to the ocean. Exorheic basins account for most of the continental surface and are home to many of the world's greatest rivers, such as the Nile, Amazon, Yangtze and Mississippi.

Wang noted that the signature of water storage changes in exorheic basins resembles some prominent oscillations of the climate system, such as El Niño and La Niña in multiyear cycles. However, the water loss in endorheic basins appears less responsive to such short-term natural variability. This contrast may suggest a profound impact of longer-term climate conditions and direct human water management, such as river diversion, damming and groundwater withdrawal, on the water balance in the dry hinterlands.

This endorheic water loss has dual ramifications, according to the researchers. Not only does it aggravate water stress in the arid endorheic regions, but it could also contribute to a significant factor of global environmental concern: sea level rise. Sea level rise is a result of two main causes: thermal expansion of sea water as a result of increased global temperature, and additional water mass to the ocean.

"The hydrosphere is mass conserved," said Chunqiao Song, researcher with the Nanjing Institute of Geography and Limnology, Chinese Academy of Sciences, and a co-lead author of the study. "When water storage in endorheic basins is in deficit, the reduced water mass doesn't disappear. It was reallocated chiefly through vapor flux to the exorheic system. Once this water is no longer landlocked, it has the potential to affect the sea level budget."

Despite an observation period of 14 years, the endorheic water loss equals an additional sea level rise of 4 millimeters, the study found. The researchers said this impact is nontrivial. It accounts for approximately 10 percent of the observed sea level rise during the same period; compares to nearly half of the concurrent loss in mountain glaciers, excluding Greenland and Antarctica; and matches the entire contribution of global groundwater consumption.

"We are not saying the recent endorheic water loss has completely ended up in the ocean," said Yoshihide Wada, deputy director of the water program at the International Institute for Applied Systems Analysis in Austria and a co-author of the study. "Instead, we are showing a perspective of how substantial the recent endorheic water loss has been. If it persists, such as beyond the decadal timescale, the water surplus added to the exorheic system may signify an important source of sea level rise."

By synergizing multi-mission satellite observations and hydrological modeling, Wang and his colleagues attributed this global endorheic water loss to comparable contributions from the surface -- such as lakes, reservoirs and glaciers -- as well as soil moisture and aquifers.

"Such comparable losses are, however, an aggregation of distinct regional variations," Wang said. "In endorheic Central Eurasia, for instance, about half of the water loss came from the surface, particularly large terminal lakes such as the Aral Sea, the Caspian Sea and Lake Urmia, and retreating glaciers in High Mountain Asia."

While glacial retreat was a response to warming temperature, water losses in the terminal lakes were a combined result of meteorological droughts and long-term water diversions from the feeding rivers.

The net water loss in endorheic Sahara and Arabia, on the other hand, was dominated by unsustainable groundwater withdrawal, according to the researchers. In endorheic North America, including the Great Basin of the U.S., a drought-induced soil moisture loss was likely responsible for most of the regional water loss. Despite a lesser extent, the surface water loss in the Great Salt Lake and the Salton Sea was at a substantial rate of 300 million tons per year, which was partially induced by mineral mining and diversion-based irrigation.

"The water losses from the world's endorheic basins are yet another example of how climate change is further drying the already dry arid and semi-arid regions of the globe. Meanwhile, human activities such as groundwater depletion are significantly accelerating this drying," said Jay Famiglietti, director of the Global Institute of Water Security, Canada 150 research chair in hydrology and remote sensing at the University of Saskatchewan, Canada and co-author of the study.

Wang said the team wants to convey three takeaway messages from their research.

"First, water storage in the endorheic system, albeit limited in total mass, can dominate the water storage trend in the entire land surface during at least decadal timescales," Wang said. "Second, the recent endorheic water loss is less sensitive to natural variability of the climate system, suggesting a possible response to longer-term climate conditions and human water management.

"Third, such a water loss in the endorheic system has dual ramifications, both to regional water sustainability and to global sea level rise," he said. "These messages highlight the underrated importance of endorheic basins in the water cycle and the need for an improved understanding of water storage changes in the global hinterlands."