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Saturday, March 16, 2019

Gene-Edited Oil in Use

Oil made from gene-edited soybeans is already being used in food service in the Midwestern US, the Associated Press reports.
According to the AP, Calyxt CEO Jim Blome has announced that oil from his firm is “in use and being eaten.” Calyxt has edited soybeans to inactivate two genes so that they produce oil that is lower in trans fats and has a longer shelf life. The firm has argued that though its soybeans are gene-edited, its product doesn’t qualify as a genetically modified organism, as the changes made could have also been made through traditional breeding approaches.
The AP adds that, in the US, regulators have decided that gene-edited crops don’t need special oversight. In particular, the Department of Agriculture has said it does not plan to regulate gene-edited crops. Similarly, regulators in Japan have decided not to regulate some types of gene editing. Meanwhile, in Europe, regulators have found that gene editing is a type of genetic modification and falls under the GMO Directive.
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UBS Initiates Coverage of Agilent, Fluidigm, Qiagen

UBS today initiated coverage of Agilent Technologies with a Buy rating and price target of $92; Fluidigm with a  Neutral rating and price target of $14; and Qiagen with a Neutral rating and price target of $42.
In a report to investors, UBS analyst Daniel Brennan noted that for Agilent, the investment bank’s above-consensus 2019 through 2021 organic revenue forecasts are supported by durable high single-digit growth in pharma along with growth tied to the gas chromatography product cycle in the chemical and energy segment.
Agilent “has room to be more aggressive with its balance sheet,” Brennan noted, adding that cell analysis, diagnostics, and genomics are the most likely areas for potential acquisition. Within its diagnostics and genomics business, Agilent has shown interest in biomolecular analysis and next-generation sequencing/genomics workflows, including informatics, Brennan noted.
For Fluidigm, Brennan noted that the product features of its Helios mass cytometry instrument are expected to “yield a significant addressable market opportunity” for the firm. The firm’s instruments are in roughly half of the approximately 70 National Cancer Institute-designated cancer centers in the US, he said, adding, “Our diligence suggests it’s reasonable for every cancer center to adopt a CyTOF/Helios eventually, and it’s not unreasonable to think full penetration by the Hyperion Imaging System can occur.”
Qiagen is executing on four of the growth drivers presented at its last analyst day in 2016, Brennan said. They are QuantiFeron, an in vitro diagnostic test that aids in the detection of M. tuberculosis infection; NGS; personalized health; and the QiaSymphony DNA kits. The firm is also “adding new growth drivers via acquisitions in 2018 and 2019,” Brennan said.
He added that more rapid adoption of recently acquired or soon-to-close platforms, including QiaStat, NeuMoDx, and digital PCR; better-than-expected margin expansion; and better performance in the base business are key levers for upside to the investment bank’s base case for Qiagen.
In afternoon trading, Agilent’s shares on the Nasdaq were up less than 1 percent at $81.36; Fluidigm’s shares on the Nasdaq were down more than 1 percent at $13.62; and Qiagen’s shares on the New York Stock Exchange were up less than 1 percent at $39.95.
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New proof that narcolepsy is an autoimmune disease

Researchers from the University of Copenhagen have discovered autoreactive cells in persons suffering from narcolepsy. This is a new, important proof that the sleep disorder is an autoimmune disease. This knowledge may lead to better treatment of the chronic condition, the researchers behind the new discovery believe.
For many years, scientists have suspected the sleep disorder narcolepsy of being an autoimmune disease, though without being able to prove it conclusively. Now researchers from the Faculty of Health and Medical Sciences at the University of Copenhagen together with the Technical University of Denmark and Rigshospitalet have found a new, important proof that their presumptions were correct. The new research results have been published in the scientific journal Nature Communications.
‘We have found autoreactive cytotoxic CD8 T cells in the blood of narcolepsy patients. That is, the cells recognise the neurons that produce hypocretin which regulates a person’s waking state. It does not prove that they are the ones that killed the neurons, but it is an important step forward. Now we know what the cells are after,’ says Associate Professor Birgitte Rahbek Kornum from the Department of Neuroscience.
The immune system is designed to recognise viruses and bacteria. When its cells are autoreactive — which is the case in autoimmune diseases — the immune system recognises the body’s own cells and attacks them. That they are cytotoxic means that they are capable of killing other cells. In most narcolepsy patients, the neurons that produce hypocretin and thus regulate our waking state have been destroyed.
‘To kill other cells, e.g. neurons producing hypocretin, CD4 and CD8 T cells usually have to work together. In 2018, scientists discovered autoreactive CD4 T cells in narcolepsy patients. This was really the first proof that narcolepsy is in fact an autoimmune disease. Now we have provided more, important proof: that CD8 T cells are autoreactive too,’ says Birgitte Rahbek Kornum.
Autoreactive Cells Were Also Found in Healthy Individuals
In the study, the researchers studied and analysed blood samples from 20 persons with narcolepsy. In addition, they analysed blood samples from a control group of 52 healthy persons. In nearly all 20 narcolepsy patients the researchers found autoreactive CD8 T cells. But autoreactivity was not only found in persons suffering from the sleep disorder. The researchers also discovered autoreactive cells in a lot of the healthy individuals.
‘We also found autoreactive cells in some of the healthy individuals, but here the cells probably have not been activated. It is something we see more and more often with autoimmunity — that it lies dormant in all of us, but is not activated in everyone. The next big puzzle is learning what activates them’, says Birgitte Rahbek Kornum.
According to Birgitte Rahbek Kornum, the discovery of autoreactive cells in healthy individuals also stresses the theory that something has to trigger narcolepsy and activate autoreactivity. Scientists still do not know what causes the disease. They expect a combination of genetics, autoreactive cells and a form of trigger to bring about the disease, e.g. a virus infection. The disease can be treated medically today, but the new research results may pave the way for even better treatments.
‘Now there will probably be more focus on trying to treat narcolepsy with drugs allaying the immune system. This has already been attempted, though, because the hypothesis that it is an autoimmune disease has existed for many years. But now that we know that it is T cell-driven, we can begin to target and make immune treatments even more effective and precise,’ says Birgitte Rahbek Kornum.
* There are two types of narcolepsy. People suffering from type 1, which is the most common form, lack the transmitter substance hypocretin which regulates the waking state, and they suffer from cataplexy which is brief loss of muscle control.
* Persons with type 2 do not lack hypocretin and do not suffer from cataplexy. Still, they experience the same symptoms as type 1 patients. In this study, the researchers focussed on type 1.
Story Source:
Materials provided by University of Copenhagen The Faculty of Health and Medical Sciences. Note: Content may be edited for style and length.
Journal Reference:
  1. Natasja Wulff Pedersen, Anja Holm, Nikolaj Pagh Kristensen, Anne-Mette Bjerregaard, Amalie Kai Bentzen, Andrea Marion Marquard, Tripti Tamhane, Kristoffer Sølvsten Burgdorf, Henrik Ullum, Poul Jennum, Stine Knudsen, Sine Reker Hadrup, Birgitte Rahbek Kornum. CD8 T cells from patients with narcolepsy and healthy controls recognize hypocretin neuron-specific antigens. Nature Communications, 2019; 10 (1) DOI: 10.1038/s41467-019-08774-1
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Sweat holds most promise for noninvasive testing

The University of Cincinnati developed a sensor that stimulates sweat under a tiny patch even when its wearer is cool and resting. The sensor can provide the same information found in blood except noninvasively and for hours, allowing doctors to track things like illness, dehydration or a medicine’s absorption over time.
Credit: Joseph Fuqua II/UC Creative Services
Making a revolutionary biosensor takes blood, sweat and tears. And saliva, naturally.
University of Cincinnati professor Jason Heikenfeld examined the potential of these and other biofluids to test human health with tiny, portable sensors for the journal Nature Biotechnology.
Heikenfeld develops wearable technology in his Novel Device Lab in UC’s College of Engineering and Applied Science. His lab last year created the world’s first continuous-testing device that samples sweat as effectively as blood but in a noninvasive way and over many hours.
“Ultimately, technological advances in wearables are constrained by human biology itself,” the study said.
Remarkably, many of the innovations in the field of biosensors and sweat technology were developed in Cincinnati. The first glucose monitor for diabetes was commercialized in the region. The inventor of the the world’s first antiperspirant, called Odorono, was a Cincinnati physician named Abraham Murphey.
“We have such a strong history in this field here. It’s really fascinating,” Heikenfeld said.
Heikenfeld credits the hard work of his team for his lab’s success.
“We have been able to go far and fast here,” Heikenfeld said. “We resonate with a certain type of student. As much as we have brilliant faculty at UC, if we didn’t have talented students here, this technology wouldn’t exist. We would just be talking theoretically about the potential.”
In the Nature article, Heikenfeld identified four waves of discovery when it comes to testing human health. First, doctors began drawing and shipping blood to labs in an invasive, time-consuming and labor-intensive process that patients still undergo today.
Starting around the 1980s researchers, including pioneering UC engineering professor Chong Ahn, developed point-of-care lab tests that allowed doctors to get immediate results. Instead of shipping samples to a lab, doctors could test samples themselves using tiny self-contained devices.
“Dr. Ahn has been at the forefront of developing these point-of-care devices,” Heikenfeld said.
Now, Heikenfeld said, we’re in the midst of a third wave — continuous health monitoring with wearable devices like those developed at UC. These provide data over time so doctors can track health trends instead of relying on the snapshot that a single blood test provides.
“That’s super powerful because it tells me am I getting better? Am I getting worse?” Heikenfeld said.
Eventually, the field will see devices implanted in the body for long-term diagnosis or monitoring, he said. But first researchers will have to create robust sensors that can provide accurate information over a much longer time frame.
“That’s the big challenge,” Heikenfeld said. “Sensors are chemically reactive themselves. So they don’t last.”
After examining the use of saliva, tears and interstitial fluid, Heikenfeld concluded in the Nature article that sweat holds the most promise for noninvasive testing because it provides similar information as blood and its secretion rate can be controlled and measured.
In his Novel Device Lab at UC, Heikenfeld and his students have been creating new sensors on a wearable patch the size of a Band-Aid that stimulates sweat even when a patient is cool and resting. The sensor measures specific analytes over time that doctors can use to determine how the patient is responding to a drug treatment.
The sensors can be tailored to measure anything from drugs to hormones to dehydration, Heikenfeld said.
Last year the lab created the world’s first continuous-monitoring sensor that can record the same health information in sweat that doctors for generations have examined in blood. The milestone is remarkable because the continuous sensor allows doctors to track health over time to see whether a patient is getting better or worse. And they can do so in a noninvasive way with a tiny patch applied to the skin that stimulates sweat for up to 24 hours at a time.
“This is the Holy Grail. For the first time, we can show here’s the blood data; here’s the sweat data — and they work beautifully together,” Heikenfeld said.
Heikenfeld and his students published their latest experimental findings in December in the journal Lab on a Chip. UC’s study tracked how test subjects metabolized ethanol. The study concluded that sweat provided virtually the same information as blood to measure a drug’s presence in the body.
The latest breakthrough at UC marked the culmination of more than seven years of research, he said.
“For medications, we can use sweat to get an exact measurement of concentrations in the blood,” Heikenfeld said. “That’s important because once we can measure concentrations of therapeutics in blood, we can look at drug dosing. And that could make current dosing look like something from the Stone Age.”
Cincinnati is home to several companies that are turning technologies for drug prescribing, delivery and monitoring into commercial products. The list includes Assurex Health, Enable Injections and Heikenfeld’s Eccrine Systems, where he is co-founder and chief science officer.
Study co-author and computational biologist Tongli Zhang said devices like these will help doctors to provide personalized care. Zhang is an assistant professor in the Department of Pharmacology and Systems Physiology at the UC College of Medicine.
“You don’t give children the same drug dose as adults. Likewise, we can specify a dose based on a patient’s weight,” Zhang said. “But some patients might have liver or kidney failure. And others might metabolize a drug 10 times faster. So the same dose might be ineffective in some patients and toxic in others.”
Zhang said continuous sensors could change treatments in fundamental ways.
“Personalized or individualized medicine is becoming a bigger deal. We realize it’s important. If we can understand what’s going on in the body, we can tailor the treatment accordingly,” he said.
UC is at the forefront of developing new biosensors that Heikenfeld thinks will revolutionize the way we track disease and wellness.
“UC continues to build on our rich regional history in revolutionizing diagnostics through this third wave of continuous biochemical sensing,” he said.
Story Source:
Materials provided by University of Cincinnati. Note: Content may be edited for style and length.
Journal Reference:
  1. Jason Heikenfeld, Andrew Jajack, Benjamin Feldman, Steve W. Granger, Supriya Gaitonde, Gavi Begtrup, Benjamin A. Katchman. Accessing analytes in biofluids for peripheral biochemical monitoring. Nature Biotechnology, 2019; DOI: 10.1038/s41587-019-0040-3
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Abnormal Blood Sugar, Cholesterol Common in Middle School

More than one third of middle school students who underwent cardiovascular screening at school had abnormal blood sugar levels or high cholesterol, a pilot study of 45 students found. For two of those children, hemoglobin A1c(HbA1C) levels were “solidly in the range that would be concerning for diabetes in children without symptoms or diagnosis of diabetes,” the researchers write.
They say the findings demonstrate the importance of cardiovascular screening in this age group and that conducting such screening in middle schools is a feasible alternative to medical visit screenings, particularly for communities with limited access to primary pediatric care.
Robert M. Siegel, MD, director of the Center for Better Health and Nutrition in the Heart Institute at Cincinnati Children’s Hospital in Ohio, and colleagues reported their findings in a study published online March 15 in the Journal of Pediatrics.
“What our study demonstrates is that this type of screening is very important. You do pick up a number of kids with lipid abnormalities, and there will be some kids that have borderline hemoglobin A1c levels,” Siegel told Medscape Medical News.
“Ideally, these screenings should be done in the medical setting, but if that’s not happening, this is a reasonable alternative,” he added.
The American Academy of Pediatrics, the American Heart Association, and the American Diabetes Association recommend routine screening of school-age children for hypertension, lipid abnormalities, and diabetes.
However, “that’s not happening anywhere as much as it should,” Siegel said. He and his colleagues designed their pilot study to see whether it was practical to conduct screenings “in a school setting as a backup for those kids being missed by their medical providers.”
Among 290 seventh and eighth grade students at a middle school who were invited to participate, parents returned consent forms for 45 students (16%), who then took part the study. During two 4-hour morning screening sessions, those 45 students reported in small groups to the nurse’s office for assessment of height, weight, blood pressure, percent body fat, and nonfasting HbA1C, total cholesterol, high-density lipoprotein, and triglyceride levels. Screening is recommended for persons aged 9 to 11 years; these students were 12 to 14 years old.
Among the 45 children, 26 (57.8%) had a normal or low body mass index (BMI), and 19 (42.2%) had a BMI in the overweight or obese range. High triglyceride levels were identified in 23.2% of all students screened, including 12.5% of the students with a normal or low BMI. Overall, 34.8% of the students — including a quarter of those with normal or low BMI — had elevated lipid or HbA1c levels.
None of the lipid abnormalities were in ranges that indicated a need for medication, Siegel said. “They were all in the lifestyle intervention range,” he said.
The researchers found that 42% of the students had a high percentage of body fat (more than 25% for girls and more than 35% for boys), including 8% of those with a normal or low BMI.
In addition, the researchers were surprised to find two children with HbA1C values in the diabetes range, yet neither child had symptoms or had been diagnosed with diabetes. After follow-up at a diabetes clinic, one was diagnosed with type 2 diabetes, and the other with maturity-onset diabetes of youth type 1.
Siegel said he did not expect that the discovery of these two undiagnosed cases means that widespread school screenings would uncover a high percentage of children with unrecognized diabetes. However, these findings do underscore the importance of ensuring that screenings occur, regardless of the setting, he explained.
The screenings cost approximately $20 per student, Siegel said. Although that would be a significant amount with respect to school populations, he noted that “the savings can be large on the back end, especially with some of the results we saw.”
He acknowledged that an in-school cardiovascular screening program would likely need a “medical champion,” such as a school nurse, because the cost and time investment does not end with initial screenings. “They require follow-up phone calls, tracking kids down, and making sure parents get educated and plugged into the proper care,” Siegel told Medscape Medical News.
The city where the study occurred has a population of 19,207. There are no practicing pediatricians in town, which is 86.6% white, 7.6% black, and 5.1% Latino. The racial/ethnic breakdown of the participating students was similar to the town’s (71% white, 16% black, 9% Latino). The researchers did not have adequate data to directly compare demographics or characteristics between the 45 participating students and the students whose parents did not return consent forms for the study.
Siegel acknowledged that selection bias was therefore likely, but it is unclear in what direction that bias might take. It is possible that the parents who returned the consent forms were more concerned about their children, perhaps suggesting that those screened were more vulnerable to cardiovascular risk factors or had a relevant family history. On the other hand, participating students’ parents could be more attentive in general, and the students screened could be at lower risk than their peers, he explained. Overall, the BMI of those screened did not substantially differ from the school population’s BMI, he added.
The researchers also lacked data on students’ previous screenings, health histories, and potential barriers to screening, nor did they have data on screening rates in the city. The researchers “assumed that [the rates] are <30% based on published surveys and screening data and that few if any students had been previously screened for lipid abnormalities and diabetes.
“Barriers previously reported to screening such as concerns over adherence to lifestyle recommendations, inability to pay for testing, and lack of knowledge by physicians and families are very likely to be at play in this community as well,” they add.
Identifying potential harms of screening were beyond the scope of the study, but Siegel noted that BMI screenings already occur in many schools and that such screenings may be upsetting to some students with higher BMIs.
“By including BMI in a more comprehensive cardiovascular screen with less emphasis on weight, children with a high BMI may feel less stigmatized,” the researchers write.
The research was funded by Ethicon Corporation. The authors have disclosed no relevant financial relationships.
J Pediatr. Published online March 15, 2019. Full text
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Big Jump in Success for Sickle Cell Transplants

Doubling the dose of total-body irradiation (TBI) led to a near-doubling of the engraftment rate for patients with severe hemoglobinopathies undergoing haploidentical transplants, a small clinical trial showed.
All but one of 17 patients had successful engraftment after receiving 400 cGy TBI as part of a nonmyeloablative conditioning regimen. Following successful engraftment, 15 of 16 patients remained transfusion independent, and 14 of 16 discontinued immunosuppression.
Four patients developed grade 2 acute graft-versus-host disease (GVHD) and one developed grade 3, but GVHD had resolved in all cases at the most recent follow-up, Javier Bolaños-Meade, MD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, and co-authors reported online in The Lancet Haematology.
“These results suggest that engraftment after haploidentical bone marrow transplantation for hemoglobinopathies is possible, and primary graft failure — the main problem previously reported — might be addressed by this strategy,” the authors concluded. “Therefore, this curative approach should no longer be restricted to patients with HLA-matched donors.”
The author of an accompanying commentary said the findings represent a “substantial advance” in making potentially curative therapies more broadly available to patients with sickle cell disease and β-thalassemia.
“The relatively simple condition regimen, without the need for donor graft engineering, should allow further validation of this approach in a larger cohort of patients who are ineligible for standard myeloablative transplantation, either because of the absence of an HLA-matched sibling donor or the presence of end-organ complications that exclude them from these traditional approaches,” wrote John Tisdale, MD, of the National Heart, Lung, and Blood Institute in Bethesda, Maryland.
“Additionally, haploidentical transplantation now takes its place as another broadly available curative approach for sickle cell disease and β-thalassemia, alongside approaches such as gene addition and gene editing, which are under development.”
Two decades ago, hematologists learned that bone marrow transplants offered potentially curative therapy for sickle cell disease and β-thalassemia. However, use of the procedure remained limited by the need for HLA-matched donors, either related or unrelated. Additionally, allogeneic blood or marrow transplantation required myeloablative conditioning to facilitate engraftment, which carried a high risk of severe morbidity and mortality, the authors noted.
In 2012, Bolaños-Meade and colleagues reported successful engraftment of haploidentical (half-matched) bone marrow transplants, facilitated by the use of a nonmyeloablative conditioning regimen, followed by posttransplant treatment with cyclophosphamide. Still, engraftment was unsuccessful in about half of cases.
In an effort to improve engraftment without increasing risk, investigators modified the nonmyeloablative conditioning regimen by increasing the low dose of TBI used to date (200 cGy). The researchers evaluated the modified regimen in 12 patients with sickle cell disease and five with β-thalassemia. None of the patients had a prior transplant, and the study population had a median age of 16 (range 6 to 31).
All patients received conditioning that consisted of rabbit-derived anti-thymocyte globulin, fludarabine, cyclophosphamide, and 400 cGy administered in a single fraction. Following infusion of unmanipulated bone marrow, patients received GVHD prophylaxis with cyclophosphamide. The trial had a primary objective of engraftment, as assessed by chimerism.
The authors reported that the one patient who did not achieve successful engraftment had recovery of host hematopoiesis. All but three of the patients who had successful engraftment achieved full donor chimerism, and the remaining three had mixed donor-host chimerism.
In addition to the five cases of grade 2-4 acute GVHD, three patients developed chronic GVHD. At last follow-up visit, no patient was receiving systemic therapy for GVHD. After a median follow-up of 705 days, all patients remained alive.
“These results are really exciting as we’re approaching a 90% cure rate for sickle cell and beta-thalassemia,” senior author Robert Brodsky, MD, also of Johns Hopkins, said in a statement. “Bone marrow transplants are not just for patients with a perfectly matched donor. A half-match is definitely good enough.”
The study was supported by the Maryland Stem Cell Research Fund and the National Institutes of Health.
Bolaños-Meade disclosed a relationship with Incyte. Several co-authors disclosed relationships with pharmaceutical companies and other commercial interests.
Tisdale reported having no relevant relationships.
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Medtronic Evolut Low Risk Trial Meets Primary Endpont

Medtronic plc (NYSE:MDT) today announced first-ever clinical data from the landmark Evolut Low Risk Trial comparing the minimally invasive Evolut(TM) transcatheter aortic valve replacement (TAVR) system to the gold standard of open-heart surgery in characteristically younger, healthier aortic stenosis patients. The randomized trial, which met its primary non-inferiority endpoint of all-cause mortality or disabling stroke at two years compared to surgery (5.3 percent versus 6.7 percent; posterior probability of non-inferiority >0.999), was presented today at the American College of Cardiology 68th Annual Scientific Session (ACC.19) and published simultaneously in The New England Journal of Medicine (NEJM)(1).
Key Data Highlights:
* The prespecified 30-day safety composite of all-cause mortality, disabling stroke, life-threatening bleeding, major vascular complications or acute kidney injury was significantly lower for TAVR as compared to open heart surgery (5.3 percent versus 10.7 percent), as was the rate of the composite endpoint of all-cause mortality or disabling stroke at 30 days (0.8 percent versus 2.6 percent). The pacemaker rate was greater in the TAVR treatment arm.
* TAVR demonstrated excellent hemodynamic (blood flow) performance with significantly lower mean aortic valve gradients (8.6 mm Hg versus 11.2 mm Hg) and larger EOAs (effective orifice area) than surgery (2.3 vs. 2.0) at 12 months.
* The TAVR treatment arm also showed statistically lower rates of heart failure hospitalizations (3.2 percent versus 6.5 percent) and disabling stroke (0.8 percent versus 2.4 percent) compared to surgery at 12 months.
Analyst and Investor Briefing
Medtronic will host a webcast to highlight its Cardiac and Vascular Group from 2:30-3:30 p.m. CDT, Sunday, March 17. The webcast will feature remarks from Medtronic management, including comments on Medtronic’s clinical data and product pipelines. The live audio webcast can be accessed by clicking on the Investor Events link at http://investorrelations.medtronic.com on March 17.
Within 24 hours of the webcast, a replay will be available on the same webpage. This event is not part of the official ACC Scientific Sessions.
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