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LA JOLLA--(January 15, 2019) Salk researchers have mapped the genomes and epigenomes of genetically modified plant lines with the highest resolution ever to reveal exactly what happens at a molecular level when a piece of foreign DNA is inserted. Their findings, published in the journal PLOS Genetics on January 15, 2019, elucidate the routine methods used to modify plants, and offer new ways to more effectively minimize potential off-target effects.

"This was really a starting point for showing that it's possible to use the latest mapping and sequencing technologies to look at the impact of inserting genes into the plant genome," says Howard Hughes Medical Institute Investigator Joseph Ecker, a professor in Salk's Plant Molecular and Cellular Biology Laboratory and head of the Genomic Analysis Laboratory.

When a scientist wants to put a new gene into a plant--for basic research purposes or to boost the health or nutrition of a food crop--they usually rely on Agrobacterium tumefaciens to get the job done. Agrobacterium is the bacteria that causes crown gall tumors, large bulges on the trunks of trees. Decades ago, scientists discovered that when the bacteria infected a tree, it transferred some of its DNA to the tree's genome. Since then, researchers have co-opted this transfer ability of Agrobacterium for their own purposes, using its transfer-DNA (T-DNA) to move a desired gene into a plant.

Recently, DNA sequencing technologies had started to hint that when the Agrobacterium T-DNA is used to insert new genes into a plant, it may cause additional changes to the structural and chemical properties of the native DNA.

"Biotech companies spend a lot of time and effort to characterize transgenic plants and disregard candidates with unwanted changes without understanding--from a basic biological perspective--why these changes may have occurred," says Ecker. "Our new approach offers a way to better understand these effects and may help to speed up the process."

"The biggest unknown was whether, and how many copies of, the T-DNA were inserted at the same time as the piece you wanted," says Florian Jupe, a former Salk research associate who now works at Bayer Crop Science. Jupe, Salk Staff Researcher Mark Zander and Research Assistant Angeline Rivkin are co-first authors of the new paper, along with Todd Michael of the J. Craig Venter Institute.

Since the T-DNA approach can lead to an integration of many copies of a desired gene into a plant, it can be difficult to study the final result with standard DNA sequencing, as most technologies struggle to sequence highly repetitive stretches of DNA. But Ecker and his colleagues turned to a new combination of approaches--including optical mapping and nanopore sequencing--to look at these long stretches in high resolution. They applied the technologies to four randomly selected T-DNA lines of Arabidopsis thaliana, a commonly used model plant in biology. (These plants are derived from a large population of T-DNA insertional mutants that were created using an Arabidopsis transformation method, called floral dip, to study gene function.)

Optical mapping revealed that the plants had between one and seven distinct insertions or rearrangements in their genomes, ranging in size by almost tenfold. Nanopore sequencing and reconstruction of the genomes of two lines confirmed the insertions to single-letter resolution, including whole segments of DNA that had been exchanged--or translocated--between chromosomes in one of the selected lines. Gene insertions themselves showed a variety of patterns, with the inserted DNA fragment sometimes scrambled, inverted or even silenced.

"This study was not possible even a year ago," says Michael. "Nanopore sequencing, which some refer to as the 'holy grail' of DNA sequencing, has revolutionized the reading of even the most complex regions of the genome that were completely inaccessible and unknown until now."

Finally, when the researchers studied packets of genetic material called histones they found additional changes. Histone proteins package DNA into structural units, and modifications of these histones mediate whether a gene can be accessed for use by a cell (a level of regulation called epigenetics). Depending on where T-DNA was integrated, certain nearby histone modifications appeared or disappeared potentially changing the regulation or activation of other nearby genes.

"Now we have the first high-resolution insights on how T-DNA insertions can shape the local epigenome environment," says Zander.

In an ideal world, the researchers say, T-DNA would insert one single, functional copy of a desired gene with no nearby side effects on a plant's genome. While their findings show this is rarely the case in Arabidopsis, their methods offer a path to a better understanding and surveillance of the effects.

"This technology is exciting because it gives us a much clearer look at what's going on in some of these transgenic Arabidopsis lines," says Rivkin.

"With Arabidopsis, it's relatively easy because it has such a small genome, but because of continued improvements in DNA sequencing technology, we expect this approach will also be possible for crop plants," adds Ecker, who holds the Salk International Council Chair in Genetics. "Current methods require screening of hundreds of transgenic lines to find good performing ones, such as those without extra insertions, so this technology could provide a more efficient approach."

People with symptoms of Alzheimer's disease (AD), such as cognitive difficulties, behavior changes and mood swings, may wait months or even years to get a definitive diagnosis. That's because doctors lack a simple, accurate and inexpensive test for it. But according to an article in Chemical & Engineering News (C&EN), the weekly newsmagazine of the American Chemical Society, researchers are getting much closer to developing the elusive blood test for AD.

About 5.5 million Americans are living with AD, according to the National Institute on Aging. Most do not seek treatment until their symptoms are well advanced, freelance contributor Jyoti Madhusoodanan writes. By then, substantial and irreversible damage to the brain has already occurred. Current tests for AD, such as positron emission tomography (PET) and lumbar puncture, are invasive, cost thousands of dollars and aren't covered by most health insurance plans in the U.S. For nearly 20 years, researchers have been trying to develop a blood test for AD, but they've been stymied by the low amounts of potential biomarkers in blood.

Recently, new biomarkers and assays have moved a reliable blood test closer to the clinic. For example, instead of measuring the total amount of amyloid -- the protein that forms clumps in the brains of AD patients -- in blood, researchers can more accurately diagnose AD by looking at ratios of different peptides that form when amyloid breaks down. Sensitive new assays can detect smaller amounts of these peptides in blood. These and other developments have made many researchers optimistic that a blood test for AD will be available within the next five years. Such a test would not only aid in diagnosis, but might also help in the search for better AD treatments because it could identify participants for clinical trials.

New research published in The Lancet Neurology journal suggests that frailty makes older adults more susceptible to Alzheimer's dementia, and moderates the effects of dementia-related brain changes on dementia symptoms. The findings suggest that frailty should be considered in clinical care and management of Alzheimer's dementia.

The study found that older adults (59 years and older) with higher levels of frailty were more likely to have both Alzheimer's disease-related brain changes and symptoms of dementia, whilst others with substantial brain changes, but who were not frail, showed fewer clinical symptoms.

"By reducing an individual's physiological reserve, frailty could trigger the clinical expression of dementia when it might remain asymptomatic in someone who is not frail," explains Professor Kenneth Rockwood from Nova Scotia Health Authority and Dalhousie University, Canada, who led the study. "This indicates that a 'frail brain' might be more susceptible to neurological problems like dementia as it is less able to cope with the pathological burden." [1]

"This is an enormous step in the right direction for Alzheimer's research. Our findings suggest that the expression of dementia symptoms results from several causes, and Alzheimer's disease-related brain changes are likely to be only one factor in a whole cascade of events that lead to clinical symptoms. Understanding how individual risk factors work together to give rise to late-life dementia is likely to offer a new way to develop targeted treatment options." [1]

The findings support the idea that late-life dementia (and particularly Alzheimer's disease) is a complex phenomenon rather than a single disease entity marked by genetic risk or single protein abnormalities in the brain. However, the authors caution that this study is a cross-sectional comparison of pathology data from a single database that only includes adults living in Illinois, USA.

Previous research has shown that some people with Alzheimer's disease-related brain changes (eg, amyloid deposition) can have few characteristic symptoms of the disease (cognitive and functional decline), whereas others with few brain changes may have symptoms. These discrepancies suggest that some hidden factors might affect the relationship between Alzheimer's disease-related brain changes and Alzheimer's dementia.

Most people who develop Alzheimer's dementia are older than 65 years and have several other health problems. Frailty - a condition linked with reduced physiological reserve and increased vulnerability to other ailments - is associated with age and higher rates of cognitive deficit and dementia, but little research has explored how these conditions might be related.

In this study, researchers used modelling to assess relationships between frailty, Alzheimer's disease-related brain changes, and Alzheimer's dementia among 456 participants of the Rush Memory and Ageing Project (MAP) who had either no dementia or Alzheimer's dementia, and who subsequently died and underwent brain autopsy. MAP is a longitudinal clinical-pathological study of older adults living in Illinois, USA, which began in 1997 [2].

Every year participants received neuropsychological and clinical evaluations, which included detailed cognitive testing and neurological examinations. Clinical diagnosis of Alzheimer's dementia was based on clinician consensus, with just over half (53%; 242) the participants given a diagnosis of possible or probable Alzheimer's dementia at their last clinical assessment. Brain plaques and tangles were measured after death to quantify Alzheimer's disease-related changes. The researchers also developed a frailty index using a combination of 41 components of health status (eg, fatigue, joint and heart problems, osteoporosis, mobility, meal preparation) obtained at each clinical evaluation.

Overall, 35 participants (8%) had substantial Alzheimer's disease-related brain changes without having been diagnosed with dementia, and 50 (11%) had Alzheimer's dementia but had little disease-related brain changes (table 2).

The analysis revealed that frailty and Alzheimer's disease-related brain changes independently contribute to dementia status, after adjusting for age, sex, and education.

The researchers also found a significant association between frailty and Alzheimer's disease-related brain changes after excluding activities of daily living from the frailty index and adjusting for other risk factors such as stroke, heart failure, high blood pressure, and diabetes.

"While frailty is likely to reduce the threshold for Alzheimer's disease-related brain changes to cause cognitive decline, it probably also contributes to other mechanisms in the body that give rise to dementia, weakening the direct link between Alzheimer's disease-related brain changes and dementia," says Rockwood. [1]

"While more research is needed, given that frailty is potentially reversible, it is possible that helping people to maintain function and independence in later life could reduce both dementia risk and the severity of debilitating symptoms common in this disease." [1]

The authors say that future studies should examine longitudinal relationships between frailty, cognition, and biomarkers of Alzheimer's dementia to establish causation. They also note several limitations, including that a single definition of frailty has not been well established - some definitions are more biological, others are more physical, whilst some combine physical, biological, psychological, and social risk factors. They also note that frailty measurements were taken close to death and might reflect terminal decline, which could result in the relationship between Alzheimer's disease-related brain changes and dementia status among people with high levels of frailty being overestimated.

Writing in a linked Comment, Dr Francesco Panza from the University of Bari Aldo Moro, Italy, discusses how understanding frailty could help predict and prevent dementia. He concludes: "In light of current knowledge on the cognitive frailty phenotype, secondary preventive strategies for cognitive impairment and physical frailty can be suggested. For instance, individualised multidomain interventions can target physical, nutritional, cognitive, and psychological domains that might delay the progression to overt dementia and secondary occurrence of adverse health-related outcomes, such as disability, hospitalisation, and mortality."

A study by UCLA researchers is the first to demonstrate a technique for coaxing pluripotent stem cells -- which can give rise to every cell type in the body and which can be grown indefinitely in the lab -- into becoming mature T cells capable of killing tumor cells.

The technique uses structures called artificial thymic organoids, which work by mimicking the environment of the thymus, the organ in which T cells develop from blood stem cells.

T cells are cells of the immune system that fight infections, but also have the potential to eliminate cancer cells. The ability to create them from self-renewing pluripotent stem cells using the UCLA technique could lead to new approaches to cancer immunotherapy and could spur further research on T cell therapies for viral infections such as HIV, and autoimmune diseases. Among the technique's most promising aspects is that it can be combined with gene editing approaches to create a virtually unlimited supply of T cells able to be used across large numbers of patients, without the need to use a patient's own T cells.

The study, which was published in the journal Cell Stem Cell, was led by senior author Dr. Gay Crooks, a professor of pathology and laboratory medicine and of pediatrics and co-director of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

T cell therapies, including CAR T-cell therapy, have shown great promise for treating certain types of cancer. Current approaches involve collecting T cells from a patient, genetically engineering the T cells with a receptor that helps them recognize and destroy cancer cells, and then infusing the cells back into the patient. But engineered T cells do not always function well, treatment is expensive because it is tailored to each patient, and some people with cancer don't have enough T cells to undergo the therapy.

Therefore, a technique that produces T cells without relying on collecting them from patients is an important step toward making T cell therapies more accessible, affordable and effective.

"What's exciting is the fact that we start with pluripotent stem cells," Crooks said. "My hope for the future of this technique is that we can combine it with the use of gene editing tools to create 'off-the-shelf' T cell therapies that are more readily available for patients."

Other researchers have been only partially successful in their attempts to generate T cells using methods that involve combining pluripotent stem cells with a layer of supporting cells. But the T cells produced in those previous studies did not mature to become fully functional T cells.

Crooks and her team previously demonstrated that the 3D structure of an artificial thymic organoid allowed mature T cells to develop from adult blood stem cells, and hypothesized that they would also support mature T cell production from pluripotent stem cells.

"The 3D structure of the artificial thymic organoid seems to provide the right supportive signals and environment needed for mature T cells to properly develop," she said.

The research demonstrated that the artificial thymic organoids can efficiently make mature T cells from both kinds of pluripotent stem cells currently used in research: embryonic stem cells, which originate from donated embryos, and induced pluripotent stem cells, which are created by reprogramming adult skin or blood cells back to an embryonic-like state.

The researchers also showed they could genetically engineer pluripotent stem cells to express a cancer-targeting T cell receptor and, using artificial thymic organoids, generate T cells capable of targeting and killing tumor cells in mice.

"Once we create genetically edited pluripotent stem cell lines that can produce tumor-specific T cells in artificial thymic organoids, we can expand those stem cell lines indefinitely," said Amélie Montel-Hagen, the study's first co-author and an associate project scientist in Crooks' lab. Having an unlimited supply of T cells capable of fighting various types of tumors would be a major turning point for cancer treatment.

One of the remaining challenges for the UCLA scientists is that the T cells created using the artificial thymic organoids have additional molecules on their surface that are not matched to each individual patient. Those extra molecules could cause a patient's body to reject the transplanted cells, Montel-Hagen said.

"Our next step will be to create T cells that have the receptors to fight cancer but do not have the molecules that cause the rejection of the cells, which would be a major step toward the development of universal T cell therapies," said Dr. Christopher Seet, the study's first co-author and a clinical instructor in the division of hematology-oncology at UCLA.

UCLA and UC San Francisco life scientists have discovered a dramatic pattern of bone growth in female mice -- research that could potentially lead to stronger bone density in women and new treatments for osteoporosis in older women.

The researchers found that blocking a particular set of signals from a small number of neurons in the brain causes female, but not male, mice to build super-strong bones and maintain them into old age. These neurons may play an important role in controlling women's bone density, the researchers said. The study was published Jan. 11 in the journal Nature Communications.

"We think we have identified a new pathway by which the brain regulates bone density that holds great promise because it allows the body to shift new bone formation into overdrive," said co-author Stephanie Correa, a UCLA assistant professor of integrative biology and physiology, and member of UCLA's Brain Research Institute.

More than 200 million people worldwide suffer from osteoporosis, in which bones weaken and can easily fracture. Women are at relatively high risk of osteoporosis after menopause.

Correa said the study highlights the importance of studying females, as well as males. "We would have missed this if we had studied only males," she said. "The differences between what we see in males and females will give us more clues about how these neurons develop, how they work and what they do. The more we understand about how the neurons work, the closer we will get to manipulating them to improve bone health."

The study began when Correa, then a postdoctoral researcher in the UCSF laboratory of study senior author Holly Ingraham, found that genetically deleting the estrogen receptor protein in neurons in a brain region called the hypothalamus caused altered mice to gain a slight amount of weight, and become less active. Correa expected to find that the animals had put on extra fat or gained lean muscle, but neither of these was the case. To learn the source of the extra weight, she used more sensitive laboratory techniques that could reveal changes in bone density. To her surprise, she discovered that the heavy mice were large-boned. Ingraham's laboratory showed that their bone mass had increased by as much as 800 percent.

"I was immediately struck by the size of the effect," Correa said. "We knew right away it was a game-changer and presented a new, exciting direction with potential applications for improving women's health."

In addition, the super-dense bones were exceptionally strong.

"Our collaborators who study bone for a living said they'd never seen bone this strong," said Ingraham, UCSF professor of cellular and molecular pharmacology. "Our current understanding of how the body controls bone growth can't explain this, which suggests we may have uncovered a completely new pathway that could be used to improve bone strength in older women and others with fragile bones."

Ingraham's postdoctoral fellows Candice Herber and William Krause conducted experiments that zeroed in on a specific population of just a few hundred estrogen-sensitive brain cells -- located in a region of the hypothalamus called the arcuate nucleus -- which appeared to be responsible for these dramatic increases in bone density. The authors hypothesized that estrogen must normally signal these neurons to shift energy away from bone growth, but that deleting the estrogen receptors had reversed that shift.

Additional experiments showed that the altered mice maintained their enhanced bone density well into old age. Normal female mice begin to lose significant bone mass by 20 weeks of age, but the altered mice maintained elevated bone mass well into their second year of life, which is considered old for a mouse.

Herber and Krause were even able to reverse existing bone degeneration in an experimental model of osteoporosis. In female mice that had already lost more than 70 percent of their bone density due to experimentally lowered blood estrogen, deletion of arcuate estrogen receptors caused bone density to rebound by 50 percent in a matter of weeks.

The researchers are now studying how this brain-bone communication occurs, and whether drugs could be developed to increase bone strength in post-menopausal women without the potentially dangerous effects of estrogen replacement therapy.

The role of estrogen in the brain is still poorly understood, said Ingraham, whose laboratory studies how the signaling of estrogen in the brain affects female metabolism at different life stages.

The "First international consensus on the diagnosis and management of fibromuscular dysplasia" (FMD) has been published online first today in Vascular Medicine and the Journal of Hypertension. The consensus document was written by a committee of international experts in the field commissioned by the Society for Vascular Medicine (SVM) and the Working Group "Hypertension and the Kidney" of the European Society of Hypertension (ESH). The writing committee was co-chaired by Dr. Heather Gornik (Cleveland, OH, USA) of SVM and Dr. Alexandre Persu (Brussels, Belgium) of ESH and includes leading clinical experts and researchers in the field of FMD.

FMD is a nonatherosclerotic arterial disease caused by abnormal cellular proliferation and distorted architecture of the arterial wall, primarily in the renal and extracranial carotid and vertebral arteries. Clinical signs of FMD have recently been expanded to include arterial dissection, aneurysm, and tortuosity, in addition to the classical "string of beads" (multifocal) or focal arterial stenoses. Approximately 80-90% of patients with FMD are women.

This comprehensive review of FMD provides a harmonization and update to two prior European and US scientific statements and covers pathophysiology, nomenclature, differential diagnosis, diagnostic evaluation, management, and longitudinal follow-up as well as the current status of FMD registries and FMD patient advocacy organizations around the world. Physicians will appreciate the point-by-point consensus-based recommendations for managing patients with FMD. Some highlights of the consensus points include:

At least one focal or multifocal arterial lesion on imaging is required to establish the diagnosis of FMD. The presence of aneurysm, dissection, or tortuosity alone is inadequate to establish the diagnosis.

Regardless of initial site of vascular bed involvement, patients with FMD should undergo brain to pelvis imaging, at least once and usually with CTA or contrast-enhanced MRA, to identify other areas of FMD, as well as to screen for occult aneurysms and dissections.

Treatment with antiplatelet therapy (aspirin 75-100 mg/day) is reasonable to prevent thrombotic and thromboembolic complications, in the absence of contraindication.

A standardized consensus-based protocol for renal angiography and angioplasty is proposed, which includes hemodynamic assessment of FMD lesions using translesional pressure gradient measurements.

The writing committee has also identified its top 10 research priorities for FMD. The list includes genetics, pathophysiology, epidemiology and natural history, and treatment. The list is intended to motivate basic, clinical, and translational investigators as well as scientific organizations to focus on FMD research and funding initiatives.

According to writing committee Co-Chair and SVM President, Dr. Heather Gornik, "The coming together of international experts to outline unified, consensus-based standards of clinical care for patients with FMD and an agenda to drive future research into this important but poorly understood vascular disease was our priority. We also hope that this document will provide a single go-to source for both state-of the-art and practice information on FMD for all clinicians, whether they practice in Europe, the United States, or anywhere in the world."

Dr. Persu, Co-Chair of the writing committee and Chair of the Working Group "Hypertension and Kidney" of the ESH adds: "It is an important message for patients suffering from FMD that experts from both sides of the Atlantic and elsewhere in the world stand together and speak with one voice, and that whatever the initially affected vascular bed and the specialty of the caring physician, wherever in the world, a common, comprehensive diagnostic and management strategy can be proposed. Beyond clinical practice, we also hope that this document will stimulate young researchers to engage in the field. We have now all the tools to dig further into the etiology and pathophysiology of FMD. I am convinced that such knowledge will not only help patients with FMD, but also shed light on mechanisms involved in other non-atherosclerotic arterial diseases, which jointly represent a substantial burden in young-middle aged subjects, particularly women".

CHAMPAIGN, Ill. -- By gaining control over shape, size and composition during synthetic molecule assembly, researchers can begin to probe how these factors influence the function of soft materials. Finding these answers could help advance virology, drug delivery development and the creation of new materials.

"We approached this new research concept not by trying to fix a problem, but by asking what is possible when it comes to soft-molecule synthesis," said Damien Guironnet, a chemical and biomolecular engineering professor at the University of Illinois at Urbana-Champaign and lead author of a new study. "What if we can gain control over things like shape, size and composition during molecular synthesis - what does that mean?"

The findings are reported in the Proceedings of the National Academy of Science.

For years, scientists have struggled to clarify how nanoparticle shape and size influence their behavior within living tissue, the researchers said. "The size of the synthetic molecules we are creating correspond to the size of viruses," said Dylan Walsh, a chemical and biomolecular engineering graduate student and study co-author. "Observations made from controlling these factors will allow researchers to probe these types of questions."

The team combined classic chemical synthesis techniques and basic chemical engineering principles. They introduced precise control over the polymer formation sequence via the flow rate of the building blocks used. By altering flow rate, the new process can yield soft matter with unique architectures, the researchers said.

"We use mathematical modeling to predict the shape, size and composition of molecules we create and use computer-guided synthesis in the lab to adjust the flow rate of the mixtures that control the architecture of the polymer," Guironnet said.

The researchers felt it was not enough to simply state that they can do this - they needed to prove it.

"Our mathematical modeling does not include any assumptions so there is really nothing else that can be formed other than what we model, but math is not something you can see," Guironnet said. "Shape is something we can see, and we were able to verify with microscopic imaging that we formed polymers consistent with what we predicted."

The team achieved this with synthetic molecules that are soluble in organic solvents, but the next step will be to move onto water-soluble molecules. "If we truly want to better understand our immune response and improve drug-delivery specificity, we need these to be water-soluble so that they can work in our bodies," Guironnet said.

The researchers view this work as a big step forward in advancement of soft-material synthetic polymer science.

"We have access to new building blocks, and now we can work on figuring out how we can use these blocks to assemble new materials at the molecular level," Walsh said. "We think of it as playing with Legos to see how the shape of the individual building blocks influences the final product."

1. Young-onset diabetes linked to higher risk of hospitalization for mental illness before age 40

Abstract: http://annals.org/aim/article/doi/10.7326/M18-1900

URLs go live when the embargo lifts

Young-onset diabetes, which is defined as onset before age 40, is associated with a higher risk of being hospitalized for mental illness compared with those who develop diabetes later in life. Those with young-onset diabetes also faced increased hospitalizations for any reason across their lifetime. Findings from a population-based cohort study are published in Annals of Internal Medicine.

Young-onset diabetes is a heterogeneous and aggressive phenotype associated with increased risk for death and complications compared with usual-onset diabetes. Its prevalence is increasing rapidly worldwide, especially in Asian populations, where 1 in 5 adults with type 2 diabetes has young-onset disease. Young-onset diabetes is associated with poorly-controlled risk factors, yet its effect on hospitalization rates is not known.

Researchers at The Chinese University of Hong Kong examined two large cohorts of Chinese adults with type 2 diabetes to determine the effects of age at onset and modifiable risk factors on hospitalization during the working lifespan, or ages 20 to 75. Using the Hong Kong Diabetes Registry, the researchers computed hospitalization rates for both cohorts. They found that adults with young-onset diabetes, had excess hospitalizations across their lifespan compared with persons with usual-onset diabetes, but also found a previously unknown link between young-onset diabetes and hospitalization for mental illness. According to the researchers, these findings suggest that efforts to prevent diabetes early in life are crucial. In addition, there is an urgent need to find ways to control cardiometabolic risk factors while focusing on mental health.

Media contact: For an embargoed PDF, please contact Lauren Evans at laevans@acponline.org. To interview the lead author, Juliana C.N. Chan, MD, please contact Jackie Chan at jackiechan@cuhk.edu.hk.

2. ACP issues ethical guidance on genetic testing, telemedicine, end-of-life care, human subjects research, and more in its latest Ethics Manual

Abstract: http://annals.org/aim/article/doi/10.7326/M18-2160

Editorial: http://annals.org/aim/article/doi/10.7326/M18-3120

URLs go live when the embargo lifts

The American College of Physicians (ACP) issues ethical guidance on genetic testing, telemedicine, and end-of-life care, human subjects research, and more in its latest Ethics Manual. Published as a supplement in Annals of Internal Medicine, the 7th edition of ACP's Ethics Manual reaffirms ethical tenets of medicine and reexamines their application in changing circumstances.

The Ethics Manual is intended to facilitate the process of making ethical decisions in clinical practice, teaching, and medical research, and to describe and explain underlying principles of ethics, as well as the physician's role in society and with colleagues. New or significantly expanded sections include precision medicine and genetic testing, research and protection of human subjects, telemedicine, electronic communications, social media and online professionalism, electronic health records, and physician volunteerism. The manual also revisits issues that are still very pertinent and in which ACP has maintained long-standing positions, such as on end-of-life care and physician-assisted suicide, physician-industry relations, and complementary and integrative care.

A continuing medical education (CME) quiz and a maintenance of certification (MOC) module are available at http://www.annals.org for ACP members and subscribers to Annals of Internal Medicine. ACP also offers ethics case studies for CME credit and MOC points.

The ACP Ethics Manual is developed primarily for doctors but has been widely used by educators, policymakers, and patients, and is often cited in medical and ethical literature. The first ACP Ethics Manual was published in 1984. This seventh edition is an update of the 2012 sixth edition and was developed by ACP's Ethics, Professionalism, and Human Rights Committee. ACP's Board of Regents reviewed and approved the manual.

Media contact: For an embargoed PDF or to interview someone from ACP, please contact Steve Majewski at smajewski@acponline.org or 215-351-2514.

3. Man's monthly sweating episodes caused by undiagnosed seizures

Abstract: http://annals.org/aim/article/doi/10.7326/L18-0425

URLs go live when the embargo lifts

A man's monthly episodes of excessive sweating were found to be triggered by temporal lobe seizures that were previously undiagnosed. The brief case report is published in Annals of Internal Medicine.

Excessive sweating is common and frequent causes include obesity, anxiety, or hyperthyroidism, among many other common conditions. Cyclic sweating is different because it occurs in cycles that are regularly repeated.

Clinicians from Advocate Aurora Health Care and Ascension Wisconsin saw a 60-year-old man complaining of spontaneous episodes of sweating that had started 3 years earlier. A series of tests ruled out common causes. During an office visit, the patient had an episode of severe sweating observed directly by the clinicians. Altered responsiveness during the sweating event suggested a seizure, so the clinicians scheduled a 7-day ambulatory EEG to begin a few days before his next expected cluster of sweating episodes. The EEG showed left temporal lobe activity suggesting a seizure. After treatment with anti-seizure medications, the patient has only had one episode of sweating in the last year and a half. According to the authors, these findings suggest that seizures should be considered in the differential diagnosis of cyclic conditions with autonomic symptoms, such as sweating or nausea and vomiting.

Media contact: For an embargoed PDF, please contact Lauren Evans at laevans@acponline.org. To interview the lead author, Mark K. Chelmowski, MD, please contact him directly at mchelm81@gmail.com.

Also New in this issue:

Inpatient Notes: Caregiver Engagement in Hospital Medicine--The Next Frontier

Molly J. Horstman. MD, and Eduardo Salas, PhD

Annals for Hospitalists

Abstract: http://annals.org/aim/article/doi/10.7326/M18-3614

Annals Consult Guys - Low Risk for Postoperative Myocardial Infarction: What Do We Really Know?

Geno J. Merli, MD; Howard H. Weitz, MD

Annals Consult Guys

Abstract: http://annals.org/aim/article/doi/10.7326/W18-0028

Annals On Call: Understanding Gout Pathophysiology

Robert Centor, MD

Annals On Call Podcast

Abstract: http://annals.org/aim/article/doi/10.7326/A18-0012

Scientists have created the most comprehensive method yet to predict a woman's risk of breast cancer, according to a study by Cancer Research UK published in Genetics in Medicine.

They have a developed a way of calculating the risk of developing the disease by combining information on family history and genetics with other factors such as weight, age at menopause, alcohol consumption and use of hormone replacement therapy.

Although individually some of these things have a small impact on the likelihood of developing the disease, researchers found that by considering all of them at once, plus family history and genetics, they can identify groups of women who have different risks of developing breast cancer.

Importantly, for the first time, researchers have taken into account more than 300 genetic indicators for breast cancer. This makes calculating the risk much more precise than ever before.

From this, the researchers have created an online calculator for GPs to use in their surgeries.
Some GPs, practice nurses and genetic counsellors are testing this tool before it is considered for wider use. Doctors are prompted to answer a series of online questions about their patient including their medical and family history, whether they have any known genetic alterations linked to cancer, their weight and whether they drink alcohol.

In the future, information like this could help to tailor breast cancer screening depending on an individual's risk. For example, it could help determine what age they are first invited for breast screening or how regularly they are invited to receive it.

The risk calculation could also help people to make decisions about preventative therapy - such as identifying women at high risk who may benefit from taking the drug tamoxifen - as well as encouraging women to think about the ways they could reduce the risk themselves, for example trying to keep a healthy weight.

Professor Antonis Antoniou, lead author at the University of Cambridge, said: "This is the first time that anyone has combined so many elements into one breast cancer prediction tool. It could be a game changer for breast cancer because now we can identify large numbers of women with different levels of risk - not just women who are at high risk.

"This should help doctors to tailor the care they provide depending on their patients' level of risk. For example, some women may need additional appointments with their doctor to discuss screening or prevention options and others may just need advice on their lifestyle and diet.
"We hope this means more people can be diagnosed early and survive their disease for longer, but more research and trials are needed before we will fully understand how this could be used."

Breast cancer is the most common cancer in the UK. Nearly 55,000 women are diagnosed with the disease each year. But a large proportion of breast cancer cases occur in people who are at an increased risk. Cancer Research UK has helped to double breast cancer survival over the last 40 years.

Dr Richard Roope, Cancer Research UK's GP expert, said: "Research like this is hugely exciting because in the future it will enable us to offer much more tailored care which will benefit patients and make best use of the services that we have available.

"Although having an increased risk of breast cancer means a woman is more likely to develop the disease - it's by no means a certainty. A woman at high risk may never get breast cancer just as a woman at low risk still could. But any woman with concerns should speak to her GP to discuss the options."

Sea level rise puts coastal areas at the forefront of the impacts of climate change, but new research shows they face other climate-related threats as well. In a study published January 14 in Nature Communications, researchers report that the energy of ocean waves has been growing globally, and they found a direct association between ocean warming and the increase in wave energy.

A wide range of long-term trends and projections carry the fingerprint of climate change, including rising sea levels, increasing global temperatures, and declining sea ice. Analyses of the global marine climate thus far have identified increases in wind speeds and wave heights in localized areas of the ocean in the high latitudes of both hemispheres. These increases have been larger for the most extreme values (e.g., winter waves) than for the mean conditions. However, a global signal of change and a correlation between the localized increases in wave heights and global warming had remained undetected.

The new study focused on the energy contained in ocean waves, which is transmitted from the wind and transformed into wave motion. This metric, called wave power, has been increasing in direct association with historical warming of the ocean surface. The upper ocean warming, measured as a rising trend in sea-surface temperatures, has influenced wind patterns globally, and this, in turn, is making ocean waves stronger.

"For the first time, we have identified a global signal of the effect of global warming in wave climate. In fact, wave power has increased globally by 0.4 percent per year since 1948, and this increase is correlated with the increasing sea-surface temperatures, both globally and by ocean regions," said lead author Borja G. Reguero, a researcher in the Institute of Marine Sciences at the University of California, Santa Cruz.

Climate change is modifying the oceans in different ways, including changes in ocean-atmosphere circulation and water warming, according to coauthor Inigo J. Losada, director of research at the Environmental Hydraulics Institute at the University of Cantabria (IHCantabria), where the study was developed.

"This study shows that the global wave power can be a potentially valuable indicator of global warming, similarly to carbon dioxide concentration, the global sea level rise, or the global surface atmospheric temperature," Losada said.

Understanding how the energy of ocean waves responds to oceanic warming has important implications for coastal communities, including anticipating impacts on infrastructure, coastal cities, and small island states. Ocean waves determine where people build infrastructure, such as ports and harbors, or require protection through coastal defenses such as breakwaters and levees. Indeed, wave action is one of the main drivers of coastal change and flooding, and as wave energy increases, its effects can become more profound. Sea level rise will further aggravate these effects by allowing more wave energy to reach shoreward.

While the study reveals a long-term trend of increasing wave energy, the effects of this increase are particularly apparent during the most energetic storm seasons, as occurred during the winter of 2013-14 in the North Atlantic, which impacted the west coast of Europe, or the devastating 2017 hurricane season in the Caribbean, which offered a harsh reminder of the destructive power and economic impacts of coastal storms.

The effects of climate change will be particularly noticeable at the coast, where humans and oceans meet, according to coauthor Fernando J. Méndez, associate professor at Universidad de Cantabria. "Our results indicate that risk analysis neglecting the changes in wave power and having sea level rise as the only driver may underestimate the consequences of climate change and result in insufficient or maladaptation," he said.

CLEVELAND--Ammonia, a compound first synthesized about a century ago, has dozens of modern uses and has become essential in making the fertilizer that now sustains most of our global food production.

But while we've been producing ammonia at a large scale since the 1930s, it has been accomplished mainly in hulking chemical plants requiring vast amounts of hydrogen gas from fossil fuels--making ammonia among the most energy-intensive among all large-volume chemicals.

A pair of researchers at Case Western Reserve University--one an expert in electro-chemical synthesis, the other in applications of plasmas--are working on fixing that.

Researchers Julie Renner and Mohan Sankaran have come up with a new way to create ammonia from nitrogen and water at low temperature and low pressure. They've done it successfully so far in a laboratory without using hydrogen or the solid metal catalyst necessary in traditional processes.

"Our approach--an electrolytic process with a plasma--is completely new," said Mohan Sankaran, the Goodrich Professor of Engineering Innovation at the Case School of Engineering.

Plasmas, often referred to as the fourth state of matter (apart from solid, liquid or gas), are ionized clouds of gas, consisting of positive ions and free electrons, which give it the unique ability to activate chemical bonds, including the rather challenging nitrogen molecule, at room temperature.

Renner, a Climo Assistant Professor in the Chemical and Biomolecular Engineering Department, added that because this new process doesn't need high pressure or high temperature or hydrogen, it makes it scalable--"the ideal kind of technology for a much smaller plant, one with high potential to be powered by renewable energy."

The results of their two-year collaboration were published this month in the journal Science Advances.

History lesson: The Haber-Bosch process

Virtually all commercial ammonia is made from nitrogen and hydrogen, using an iron catalyst at high temperature and pressure.

German physical chemist Fritz Haber received the Nobel Prize for Chemistry in 1918 for developing this process, which made manufacturing ammonia economically feasible.

But the process became more economically profitable when industrial chemist Carl Bosch (who also won a Nobel Prize in 1931) brought the method into a large-scale system. The process was further propelled by a second innovation: the development of steam methane reforming that made hydrogen more accessible and less expensive.

So, what became known as the Haber-Bosch process became the go-to global method for fixing nitrogen and hydrogen to make ammonia.

But Haber-Bosch was never the only approach to nitrogen fixation, it was just the turn-of-the-century winner.

A new, old method rises

Renner and Sankaran have resurrected an element from a little-known Norwegian method that predated Haber-Bosch (the Birkeland-Eyde process) which reacted nitrogen and oxygen to produce nitrates, another chemical that can be used in agriculture. That process lost out to Haber-Bosch mostly because it required even more energy in the form of electricity, a limited resource in the early 20th century.

"Our approach is similar to electrolytic synthesis of ammonia, which has gained interest as an alternative to Haber-Bosch because it can be integrated with renewable energy," Sankaran said. "However, like the Birkeland-Eyde process, we use a plasma, which is energy intensive. Electricity is still a barrier, but less so now, and with the increase in renewables, it may not be a barrier at all in the future.

"And perhaps most significantly, our process does not produce hydrogen gas," he said. "This has been the major bottleneck of other electrolytic approaches to forming ammonia from water (and nitrogen), the undesirable formation of hydrogen."

The Renner-Sankaran process also does not use a solid metal catalyst that could be one of the reasons ammonia is obtained instead of hydrogen.

"In our system, the ammonia is formed at the interface of a gas plasma and liquid water surface and forms freely in solution," Sankaran said.

So far, the "table-top batches" of ammonia produced by the duo have been very small and the energy efficiency is still less than Haber-Bosch. But with continued optimization, their discovery and development of a new process could someday lead to smaller, more localized ammonia plants which use green energy.

Emergency and urgent hospitalizations are associated with an increased rate of cognitive decline in older adults, report researchers at Rush University Medical Center. Results of their study, published in the Jan. 11, 2019, online issue of Neurology, the medical journal of the American Academy of Neurology, shows that hospitalization may be a more of a major risk factor for long-term cognitive decline in older adults than previously recognized.

"We found that those who have non-elective (emergency or urgent) hospitalizations and who have not previously been diagnosed with dementia or Alzheimer's disease had a rapid decline in cognitive function (i.e., thinking abilities) compared to the prehospital rates," said Bryan James, PhD, an epidemiologist and in the Rush Alzheimer's Disease Center and an assistant professor in the Rush Department of Internal Medicine. "By comparison, people who were never hospitalized and those who had elective hospitalizations did not experience the drastic decline in cognitive function."

In 2017, James and colleagues presented a preliminary version of their study results at the Alzheimer's Association International Conference in London.

Study compares hospitalization data and cognitive assessments for 777 older adults

The data emerged from a study of 777 older adults (81 years old on average, 75 percent of them women) enrolled in the Rush Memory and Aging Project (MAP) in Chicago. The study involved annual cognitive assessments and clinical evaluations.

Information on hospitalizations was acquired by linking records of 1999 to 2010 Medicare claims for these participants with their MAP data. All hospital admissions were designated as elective, emergency, or urgent. The latter two were combined as non-elective for analysis.

Of the 777 participants, 460 were hospitalized at least once over an average of almost five years of observation. Of those who were hospitalized, 222 (29 percent of the total study population) had at least one elective hospital admission, and 418 (54 percent) had at least one non-elective hospital admission. These groups included 180 participants (23 percent) who had both types of hospitalizations.

Non-elective hospitalizations were associated with an approximately 50 percent acceleration in the rate of cognitive decline from before hospitalization, and a rate of cognitive decline that was more than double the rate in persons who were not hospitalized. Elective hospitalizations, however, were not associated with acceleration in the rate of decline at all.

'Elective admissions do not necessarily carry the same risk'

"We saw a clear distinction: non-elective admissions drive the association between hospitalization and long-term changes in cognitive function in later life, while elective admissions do not necessarily carry the same risk of negative cognitive outcomes," James said. "These findings have important implications for the medical decision making and care of older adults.

"While recognizing that all medical procedures carry some degree of risk, this study implies that planned hospital encounters may not be as dangerous to the cognitive health of older persons as emergency or urgent situations."

It is unknown why emergency and urgent hospitalizations carry a higher risk of long-term cognitive decline than elective hospitalizations, but it could be due to differences in levels of sickness (though the authors controlled for health status), stress, or hospital procedures involved. The authors plan to explore these reasons in future research.

This work expands upon previous research which has shown that after being hospitalized, older adults are at high risk for memory and other cognitive problems, including both transient (temporary) delirium and long-term changes in cognition, including dementia. According to the Healthcare Cost and Utilization Project in October 2010, 40 percent of all hospitalized patients in U.S. are age 65 and older. Therefore, hospitalization may be an under-recognized risk factor for cognitive decline and dementia for a large number of older adults that deserves more attention.

Detection of dementia at the earliest stages has become a worldwide priority, because drug treatments, prevention strategies and other interventions will likely be more effective very early in the disease process, before extensive brain damage has occurred.

UCLA researchers led by Dr. Donald Kohn have created a method for modifying blood stem cells to reverse the genetic mutation that causes a life-threatening autoimmune syndrome called IPEX. The gene therapy, which was tested in mice, is similar to the technique Kohn has used to cure patients with another immune disease, severe combined immune deficiency, or SCID, also known as bubble baby disease.

The work is described in a study published in the journal Cell Stem Cell.

IPEX is caused by a mutation that prevents a gene called FoxP3 from making a protein needed for blood stem cells to produce immune cells called regulatory T cells. Regulatory T cells keep the body's immune system in check; without them, the immune system attacks the body's own tissues and organs, which is known as autoimmunity.

The approach adds a normal copy of the FoxP3 gene to blood stem cells, which can produce all types of blood cells. In the study, the approach corrected the genetic mutation in mice with a version of IPEX that's similar to the human version of the disease, and it restored proper immune regulation.

To get the normal copy of the FoxP3 gene to the proper place within the blood stem cells, the researchers used a tool called a viral vector -- a specially modified virus that can carry genetic information to a cell's nucleus without causing a viral infection. The UCLA team engineered the viral vector used in the study so that the gene is turned on only in regulatory T cells, but not in other types of cells.

"It's exciting to see how our gene therapy techniques can be used for multiple immune conditions," said Kohn, a professor of pediatrics and microbiology, immunology and molecular genetics at the David Geffen School of Medicine at UCLA and member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. "This is the first time we've tested a technique that targets an autoimmune disorder, and the findings could help us better understand or lead to novel treatments for other autoimmune conditions such as multiple sclerosis or lupus."

The name IPEX stands for immune dysregulation, polyendocrinopathy, enteropathy, X-linked. The syndrome can affect the intestines, skin and hormone-producing glands such as the pancreas and thyroid, as well as other parts of the body. It is typically diagnosed within the first year of life and can be life-threatening in early childhood. IPEX can be treated with a bone marrow transplant, but finding a matched bone marrow donor can be difficult, and the transplant procedure is often risky because people with IPEX can be very sick.

In the new study, the UCLA researchers used viral vectors to deliver normal copies of the FoxP3 gene to the genome of the mice's blood stem cells so that they produced functional regulatory T cells. All of the mice in the study were virtually free of IPEX symptoms shortly after the treatment.

"It's incredibly important that we only create regulatory T cells that have the non-mutated FoxP3 gene," said Katelyn Masiuk, a student in the UCLA physician-scientist degree program and the study's first author. "We found that if the FoxP3 protein is turned on in blood stem cells, the whole blood system functions abnormally. We realized that we needed a vector that only made FoxP3 in the regulatory T cells made from the blood stem cells, but not in the blood stem cells themselves or other types of blood cells they make."

The researchers also put their IPEX-targeting vector into human blood stem cells and then transfused those cells into mice without immune systems. The human blood stem cells were able to produce regulatory T cells that turned on the vector.

Kohn, who also is a member of the UCLA Children's Discovery and Innovation Institute and the UCLA Jonsson Comprehensive Cancer Center, said the results are promising and the researchers hope to test the approach in human patients.

Kohn said that to treat humans with IPEX, blood stem cells would be removed from the bone marrow of patients with IPEX. Then, the FoxP3 mutation would be corrected in a lab using the IPEX-targeting vector. The patients would receive a transplant of their own corrected blood stem cells, which would produce a continuous life-long supply of regulatory T cells.

An unusual supernova studied by multiple telescopes, including the SOAR telescope and other telescopes at the National Science Foundation's (NSF) Cerro Tololo Inter-American Observatory (CTIO) and NSF's Kitt Peak National Observatory (KPNO), is thought to herald the birth of a new black hole or neutron star, caught at the exact moment of its creation. Observations made with facilities ranging from X-rays to optical and radio wavelengths were used to understand this remarkable event. These multi-messenger observations give astronomers a rare glimpse into the physics at play during the creation of a black hole or neutron star.

A Mysterious Bright Glow

On June 16, 2018 a sky survey telescope in Hawai'i alerted the astronomical community to the sudden appearance of a new object in the sky. It was similar to a supernova, except that it brightened, and then faded, faster than a typical supernova, and was intrinsically brighter at its peak. A supernova (from nova meaning "new" star) is a sudden explosion of a massive star which has reached the end of its lifetime, leading to the formation of a black hole or neutron star. The transient object, assigned the designation AT2018cow, was immediately nicknamed "the Cow" based on the final 3 letters of its name. "The Cow" is located in a relatively nearby galaxy - only 200 million light years away from our own Milky Way galaxy in the direction of the constellation Hercules.

It Takes a Team

Immediately after receiving the alert, an international research team led by Raffaella Margutti (Northwestern University) leapt into action and began observing the unusual source across the electromagnetic spectrum - at X-ray, optical, infrared and radio wavelengths. Telescopes around the world contributed to the effort using spectroscopy to decode the nature of the source. Among the telescopes that contributed was the Southern Astrophysical Research Telescope (SOAR) in Chile whose instruments obtained spectra of the Cow. With spectra, which spread out the light in the form of a rainbow, astronomers could quickly confirm that matter was expanding from the object at up to 10% the speed of light.

Régis Cartier, who made the SOAR observations, said, "Almost from the very start I realized that this transient was special. It was fast, blue and bright, different from any supernova seen before. I dropped everything else I was working on to focus on understanding this event." In addition to the SOAR telescope, other telescopes at NSF's CTIO and KPNO imaged the object and contributed to a broader picture as the Cow faded away.

A Nearly Naked Cow

Because the collapsed star was surrounded by a relatively small amount of debris, the team was able to peer through the debris and get a glimpse of the object's "central engine." This rare event will help astronomers better understand the physics at play within the first moments of the creation of a black hole or neutron star. The results were presented today at this week's meeting of the American Astronomical Society in Seattle, Washington.

"We think that 'The Cow' is the formation of an accreting black hole or neutron star," said Giacomo Terreran (Northwestern University), who led the CTIO observations. "We know from theory that black holes and neutron stars form when a star dies, but we've never seen them right after they are born." This event may represent a new class of objects within the category known as fast luminous transients.

A Whole New World of Transients

Although a supernova like the Cow has never been seen before, Cartier expects that astronomers will detect larger numbers of such rare events in the future. Now that surveys are searching for sources that vary on a wider range of timescales, "we've already discovered a whole family of fast transients that we didn't know existed," noted Cartier.

The SOAR telescope is gearing up to help us understand these new events. Said Dr. Jay Elias, Director of SOAR, "The SOAR telescope was designed from the start to provide flexible instrument configurations, allowing it to respond quickly to events like this. There are many astronomical surveys observing interesting transient events, as well as other events, such as last year's kilonova detected by LIGO, which was also observed at SOAR. Very soon, there will be even more interesting transient events from the Large Synoptic Survey Telescope (LSST) and other large-scale survey telescopes." The LSST is a new telescope being built on the same mountaintop as the SOAR telescope with major funding from NSF: it will conduct a 10-year survey of the sky with special emphasis on transient events.