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Saturday, December 21, 2019

Lifestyle-related blood lipid profile better predicts type 2 diabetes risk

Using lipidomics, a technique that measures the composition of blood lipids at a molecular level, and machine learning, researchers at Lund University in Sweden have identified a blood lipid profile that improves the possibility to assess, several years in advance, the risk of developing type 2 diabetes. The blood lipid profile can also be linked to a certain diet and degree of physical activity.
Blood contains hundreds of different lipid molecules that are divided into different classes, such as cholesterol and triglycerides.
In healthcare, the total amounts of cholesterol and triglycerides are measured, not the exact composition of the classes. One class consists of several molecules and in our study we can see that it is good to have more of certain blood lipid molecules and less of others, and that these can be linked to lifestyle.”
Céline Fernandez, associate professor of Integrative Molecular Medicine, Lund University
Céline carried out the study in cooperation with the company Lipotype and the National Bioinformatics Infrastructure Sweden (NBIS).
“Lipidomics links imbalances in lipid metabolism at a molecular level to physiological differences – helping us to predict type 2 diabetes”, says Dr Christian Klose, head of the R&D department at Lipotype.
The study involved the analysis of 178 lipids in blood from 3 668 healthy participants in the Malmö Diet and Cancer study. The participants were divided at random into two equally large groups, group A and B. In addition to blood samples, the study is based on self-reported data about physical activity and diet. In a follow-up just over 20 years later, around 250 in each group had developed type 2 diabetes.
Using machine learning, the researchers could draw up a blood lipid profile in group A based on the concentration of 77 lipid molecules linked to the risk of developing type 2 diabetes later in life. The blood lipid profile’s capability to distinguish individuals who develop type 2 diabetes from those who remain healthy was examined and later confirmed in group B.
A risk analysis based on the known risk factors (age, gender, weight, blood sugar, smoking and blood pressure) was carried out to ascertain whether the blood lipid profile could improve the risk assessment. Adding the total amounts of cholesterol and triglycerides did not improve the risk assessment. However, when the researchers added the specific blood lipid profile instead, the risk prediction improved in a statistically significant way.

Furthermore, the blood lipid profile in itself could better predict the risk of developing type 2 diabetes than obesity, which is considered to be the most important risk factor for type 2 diabetes.
“This means that we could produce a better assessment of who had a high risk of developing type 2 diabetes”, says Celine Fernandez.
Nikolay Oskolkov, bioinformatics specialist at NBIS adds: “This shows how machine learning can be used to improve clinical diagnosis”.
The findings also revealed that the blood lipid profile can be linked to lifestyle. The more that participants exercised in their free time, the smaller the amount of harmful blood lipid profile they had. According to the study, coffee was also linked to a reduced amount of the harmful blood lipid profile. Dairy products, sugar-sweetened drinks and processed meat, on the other hand, were linked to larger amounts of the harmful blood lipid profile.
This indicates that it could be possible to modify your blood lipid profile and thereby your risk of developing type 2 diabetes through lifestyle changes, comments Céline Fernandez. However, further research is needed to confirm this.
One strength of the study is that the researchers could repeat the group A results in group B and thereby validate and confirm the results in other individuals. This was possible because the Malmö Diet and Cancer study has many participants and the blood lipid analysis is so robust.
“One weakness, of course, is that all individuals in the cohort have a similar background origin. We don’t know what the results would have been in another cohort, from another part of the world, for example”, concludes Céline Fernandez.
Source:
Journal reference:
Fernandez, C., et al. (2019) Plasma Lipidome and Prediction of Type 2 Diabetes in the Population-Based Malmö Diet and Cancer Cohort. Diabetes Care. doi.org/10.2337/dc19-1199.
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McGill study finds new role of apolipoprotein E4 gene in Alzheimer’s

For years, physicians have been aware that patients carrying the apolipoprotein E4 (APOEε4) gene are at a greater risk of developing Alzheimer’s disease. New research from McGill University has now found the gene plays an even greater role in dementia.
In a study published today in the Journal of the American Medical Association: Neurology, Dr. Pedro Rosa-Neto’s research team from the Douglas Mental Health University Institute’s Translational Neuroimaging Laboratory found that the risk of developing dementia conferred by APOEε4 does in fact involve processes associated to tau aggregation.

A tale of two proteins

Of all the genetics risk factors for sporadic Alzheimer’s disease, APOEε4 is the single most important.
Alzheimer’s disease is defined by the aggregation of two proteins in the brain: amyloid plaques and tau tangles, both of which are known to be neurotoxic. APOEε4 has been associated with amyloid plaques, but its association with tau tangles has been controversial. In our study of nearly 500 individuals, we demonstrate this association in living humans.”
Joseph Therriault, PhD student in the McGill’s Integrated Program in Neuroscience under the supervision of Drs. Pedro Rosa-Neto and Serge Gauthier
Therriault and his colleagues assessed two independent populations thanks to data available through the Translational Biomarkers in Aging and Dementia (TRIAD) cohort and the Alzheimer’s Disease Neuroimaging Initiative (ADNI), two research initiatives in which participating patients agreed to complete a variety of imaging and clinical assessments. In both instances, MRIs and PET scans were used to establish a relationship between APOEε4 and tau tangles.

Tau tangles and memory


“For years, we have known that people with the APOEε4 gene have more memory problems,” adds Therriault, who is also the study’s lead author. “We were able to show that carriers of this gene also had greater levels of tau tangles in memory centers of the brain, even after controlling for how much amyloid plaques they had.”
While this study does not identify a biological mechanism for why this association exists, the findings contribute to an evolving framework in which APOEε4 plays a central role in Alzheimer’s disease because of its role in both amyloid plaques and tau tangles.
Dr. Rosa-Neto adds that APOEε4 has an important role in the very early stages of Alzheimer’s disease. “This paper highlights why APOEε4 carriers show early memory deficits that eventually lead to dementia,” he says.
“Our paper is an important step forward because we provide evidence that the substantial increased risk of developing dementia conferred by APOEε4 genotype is related to both of the hallmark pathologies of Alzheimer’s disease,” concludes Therriault.
The team next hopes to determine whether the studied individuals accumulate tau at a faster level through longitudinal imaging to see how subjects evolve over time.
Therriault, Rosa-Neto and Gauthier are hopeful that the research will help clinicians better assess the early signs of Alzheimer’s disease.
Source:
Journal reference:
Therriault, J., et al. (2019) Association of Apolipoprotein E ε4 With Medial Temporal Tau Independent of Amyloid-β. JAMA Neurology. doi.org/10.1001/jamaneurol.2019.4421.
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Marijuana Giant Curaleaf Snags Syndicated Loan in Rare Feat

Marijuana company Curaleaf Holdings Inc. has secured $275 million in financing, one of the first syndicated deals for the cannabis industry.
The senior secured term loan comes as traditional banks have steered clear of pot-linked debt amid regulatory concerns. Curaleaf’s deal, mostly provided by a slate of U.S. institutional buyers including hedge funds and loan-only debt funds, is one of the most sizable financings the cannabis industry has seen in the U.S., according to Boris Jordan, Curaleaf’s executive chairman. One large European party is also taking part in the offering.
“Most of the deals that have been done before have been family-office driven or also included equity warrants,” said Jordan. “This brings cannabis more to the mainstream debt markets.”
Wakefield, Massachusetts-based Curaleaf — the biggest U.S. marijuana company with market value of $2.7 billion — interviewed roughly a dozen investment banks in August to serve as placement agent before narrowing the list down to three and ultimately selecting Seaport Global Securities LLC. A spokeswoman for Seaport declined to comment on the deal beyond Curaleaf’s statement.
“We wanted to pick a bank that could get it done because we understand that we’re charting new territory,” Jordan said.
The financing, priced at 13% and maturing in four years, will be used to refinance existing debt, pay transaction fees and expenses from previously announced acquisitions and to fund capital expenditures. About $150 million of the financing is provided by existing lenders, said Jordan, who declined to disclose the deal’s providers.
The company initially targeted an interest rate of 10% to 12%, but had to sweeten terms after other industry deals priced at higher levels and included warrants, which give the holder the right to purchase equity, Jordan said. To compare, cannabis consumer packaged goods company Green Thumb Industries Inc. earlier this year issued $105 million in pot bonds with a 12% yield, along with warrants.
In the direct lending market, cannabis and hemp accessories company KushCo Holdings Inc. priced a $50 million loan in August at 8.50 percentage points above Libor, and also included warrants.
Curaleaf has tapped institutional financing before. In August 2018, it borrowed $85 million of senior secured debt at 15% from Cetus Investments Ltd., according to Sedar filings. It also completed a $6 million unsecured bridge in June 2017 with an 11% interest rate. Since May 2018, the company has closed a number of unsecured private-placement bridge financings, also with an 11% interest rate, filings show.
In May, Curaleaf purchased the regulated pot business of Cura Partners Inc., which makes the Select brand of vapes. Two months later, it bought Grassroots Cannabis, mainly for its licenses in Illinois and Michigan, which recently legalized recreational weed. Both deals are expected to close early next year.
Despite the high yield on the deal, Jordan said cash generation and the financing give the company enough capital to execute its growth strategy. He said Curaleaf expects to have $300 million of annual Ebitda for 2020.
“This being the landmark debt deal will lead to other cannabis companies financing in the debt markets,” Jordan said.
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Glaxo’s HIV Venture Fails to Get FDA Approval for Monthly Shot

The HIV venture led by GlaxoSmithKline Plc failed to win U.S. approval for a once-a-month injection that aims to free patients from daily doses of medication.
ViiV Healthcare received a complete response letter from the Food and Drug Administration, which cited “chemistry manufacturing and controls,” according to a statement from the HIV unit Saturday. There haven’t been any safety issues reported, ViiV said.
It’s a setback for Glaxo, which has been counting on the monthly therapy to help take on rival Gilead Sciences Inc. in the market for HIV medicines. The British pharma giant and partner Pfizer Inc. are betting that a two-therapy approach will simplify treatment and cause fewer side effects than the traditional three-drug therapies.
ViiV said it will work closely with the FDA to determine the next steps.
The injection combines Johnson & Johnson’s rilpivirine with cabotegravir, which is being developed by ViiV, a venture between Glaxo, Pfizer and Japan’s Shionogi & Co. Studies earlier this year found that the monthly shots worked as well as a standard daily oral combination of three medicines in subduing HIV.
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First-in-human trial for new lung cancer immunotherapy

Cancer Research UK and Vaccitech Oncology Limited (VOLT), today (Wednesday) announce a new partnership to bring a novel immunotherapeutic vaccine strategy to patients with lung cancer.
The vaccine treatment developed by VOLT, a strategic collaboration between Vaccitech Ltd and the Ludwig Institute for Cancer Research, is designed to stimulate the body’s immune system to attack cancer . It will deliver cancer-associated antigens (MAGE A3 and NY-ESO-1) to antigen presenting cells called dendritic cells, causing the immune system to produce cytotoxic T cells, which target and kill cancerous cells expressing the antigens.
This is the first time a viral vaccine program using this platform will be tested in the treatment of non- (NSCLC), the most common type of lung cancer. And separate clinical trials are also ongoing to test similar recombinant virus vaccines to treat people with late-stage prostate cancer.
Cancer Research UK’s Centre for Drug Development (CDD) will sponsor and manage the first clinical trial of the therapeutic vaccine strategy, in combination with current standard of care and first line treatment for NSCLC. The Phase I/IIa trial will investigate whether receiving the immunotherapeutic improves the efficacy of chemotherapy and anti-PD-1 treatment. It will also assess the ability of the therapeutic to provoke a safe and effective anti-cancer immune response in people with NSCLC.
Dr. Nigel Blackburn, Cancer Research UK’s director of , said: “This partnership with VOLT is an important step to help accelerate this promising immunotherapy and could help more people survive lung cancer, which remains very hard to treat. This novel approach using a modified adenovirus to prime the immune system and alert it to the presence of  could offer a completely new way to treat the disease.”
Vaccitech CEO, Bill Enright, said: “We are delighted to enter into a clinical development partnership with two of the world’s most prestigious  institutions. We believe that this partnership is an important validation of our prime boost platform’s utility in oncology as well as infectious disease.”
Jonathan Skipper, executive vice president for technology development, Ludwig Institute for Cancer Research, said: “Previous clinical trials of experimental cancer vaccines targeting MAGE and NY-ESO antigens have demonstrated that these antigens are highly specific to cancer and capable of eliciting strong immune responses. We believe that Vaccitech’s highly effective T cell induction platform should provide a potent immunotherapeutic that, in combination with checkpoint blockade, is capable of inducing sustained levels of cancer antigen-specific CD8+ T cells and the desired therapeutic effect in patients.”
Upon trial completion, VOLT retains the option to undertake further clinical development and commercialization of the immunotherapeutic. If VOLT elects not to exercise its option, Cancer Research UK will have the rights to take the program forward in all cancer indications.
The trial will enroll approximately 80 people who have been diagnosed with NSCLC and is due to start at the end of 2020. It will be conducted across multiple sites in the UK, through the Experimental Cancer Medicine Centre (ECMC) network.
Every year around 41,700 people are diagnosed with NSCLC in the UK, which accounts for around 88% of all lung  cases. New treatments are urgently needed, as only around 5% of people survive  for 10 years or more in the UK.
Explore further
More information: Vaccination in Prostate Cancer (VANCE) clinicaltrials.gov/ct2/show/NCT02390063 Vaccination in Early and Advanced Prostate Cancer (ADVANCE) clinicaltrials.gov/ct2/show/NC … ADVANCE+trial&rank=1
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Study may explain how infections reduce autism symptoms

For many years, some parents have noticed that their autistic children’s behavioral symptoms diminished when they had a fever. This phenomenon has been documented in at least two large-scale studies over the past 15 years, but it was unclear why fever would have such an effect.
A new study from MIT and Harvard Medical School sheds light on the cellular mechanisms that may underlie this phenomenon. In a study of , the researchers found that in some cases of infection, an immune molecule called IL-17a is released and suppresses a small region of the brain’s cortex that has previously been linked to social behavioral deficits in mice.
“People have seen this phenomenon before [in people with autism], but it’s the kind of story that is hard to believe, which I think stems from the fact that we did not know the mechanism,” says Gloria Choi, the Samuel A. Goldblith Career Development Assistant Professor of Applied Biology and an assistant professor of brain and cognitive sciences at MIT. “Now the field, including my lab, is trying hard to show how this works, all the way from the  and molecules to receptors in the brain, and how those interactions lead to behavioral changes.”
Although findings in mice do not always translate into human treatments, the study may help to guide the development of strategies that could help to reduce some behavioral symptoms of autism or other neurological disorders, says Choi, who is also a member of MIT’s Picower Institute for Learning and Memory.
Choi and Jun Huh, an assistant professor of immunology at Harvard Medical School, are the senior authors of the study, which appears in Nature today. The lead authors of the paper are MIT graduate student Michael Douglas Reed and MIT postdoc Yeong Shin Yim.
Immune influence
Choi and Huh have previously explored other links between inflammation and autism. In 2016, they showed that mice born to mothers who experience a severe infection during pregnancy are much more likely to show behavioral symptoms such as deficits in sociability, , and abnormal communication. They found that this is caused by exposure to maternal IL-17a, which produces defects in a specific brain region of the developing embryos. This brain region, S1DZ, is part of the somatosensory cortex and is believed to be responsible for sensing where the body is in space.
“Immune activation in the mother leads to very particular cortical defects, and those defects are responsible for inducing abnormal behaviors in offspring,” Choi says.
A link between infection during pregnancy and autism in children has also been seen in humans. A 2010 study that included all children born in Denmark between 1980 and 2005 found that severe viral infections during the first trimester of pregnancy translated to a threefold increase in risk for autism, and serious bacterial infections during the second trimester were linked with a 1.42-fold increase in risk. These infections included influenza, viral gastroenteritis, and severe urinary tract infections.
In the new study, Choi and Huh turned their attention to the often-reported link between fever and reduction of autism symptoms.
“We wanted to ask whether we could use mouse models of neurodevelopmental disorders to recapitulate this phenomenon,” Choi says. “Once you see the phenomenon in animals, you can probe the mechanism.”
The researchers began by studying mice that exhibited behavioral symptoms due to exposure to inflammation during gestation. They injected these mice with a bacterial component called LPS, which induces a fever response, and found that the animals’ social interactions were temporarily restored to normal.
Further experiments revealed that during inflammation, these mice produce IL-17a, which binds to receptors in S1DZ—the same brain region originally affected by maternal inflammation. IL-17a reduces neural activity in S1DZ, which makes the mice temporarily more interested in interacting with other mice.
If the researchers inhibited IL-17a or knocked out the receptors for IL-17a, this symptom reversal did not occur. They also showed that simply raising the mice’s body temperature did not have any effect on behavior, offering further evidence that IL-17a is necessary for the reversal of symptoms.
“This suggests that the immune system uses molecules like IL-17a to directly talk to the brain, and it actually can work almost like a neuromodulator to bring about these behavioral changes,” Choi says. “Our study provides another example as to how the brain can be modulated by the immune system.”
“What’s remarkable about this paper is that it shows that this effect on behavior is not necessarily a result of fever but the result of cytokines being made,” says Dan Littman, a professor of immunology at New York University, who was not involved in the study. “There’s a growing body of evidence that the central nervous system, in mammals at least, has evolved to be dependent to some degree on cytokine signaling at various times during development or postnatally.”
Behavioral effects
The researchers then performed the same experiments in three additional mouse models of neurological disorders. These mice lack a gene linked to autism and similar disorders—either Shank3, Cntnap2, or Fmr1. These mice all show deficits in social behavior similar to those of mice exposed to inflammation in the womb, even though the origin of their symptoms is different.
Injecting those mice with LPS did produce inflammation, but it did not have any effect on their behavior. The reason for that, the researchers found, is that in these mice, inflammation did not stimulate IL-17a production. However, if the researchers injected IL-17a into these mice, their behavioral symptoms did improve.
This suggests that mice who are exposed to inflammation during gestation end up with their immune systems somehow primed to more readily produce IL-17a during subsequent infections. Choi and Huh have previously shown that the presence of certain bacteria in the gut can also prime IL-17a responses. They are now investigating whether the same gut-residing bacteria contribute to the LPS-induced reversal of social behavior symptoms that they found in the new Nature study.
“It was amazing to discover that the same immune molecule, IL-17a, could have dramatically opposite effects depending on context: Promoting autism-like behaviors when it acts on the developing fetal brain and ameliorating autism-like behaviors when it modulates neural activity in the adult mouse brain. This is the degree of complexity we are trying to make sense of,” Huh says.
Choi’s lab is also exploring whether any immune molecules other than IL-17a may affect the brain and behavior.
“What’s fascinating about this communication is the immune system directly sends its messengers to the brain, where they work as if they’re  molecules, to change how the circuits work and how the behaviors are shaped,” Choi says.
Explore further
More information: Michael Douglas Reed et al. IL-17a promotes sociability in mouse models of neurodevelopmental disorders, Nature (2019). DOI: 10.1038/s41586-019-1843-6
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Injecting Safety into Supplements — Modernizing the Dietary Supplement Law

More than 25 years have passed since one of us helped draft the law that redefined the U.S. regulatory landscape for vitamins, minerals, botanicals, live microorganisms, and many other health products. The law, known as the Dietary Supplement Health and Education Act of 1994 (DSHEA), created a new category of products termed “dietary supplements.”1
Today, this law does not adequately protect the public. Since it was written, the supplement industry has been reshaped by Internet sales and an increasingly complex global supply of new substances. What was a $4 billion market in 1994 with a few thousand products has grown into a more than $40 billion market with tens of thousands of dietary supplements.
We have become particularly concerned about the risks associated with newly discovered, sophisticated, and potentially potent biologic and botanical ingredients that are routinely introduced as new ingredients in supplements. The great majority of these ingredients are never reviewed by the Food and Drug Administration (FDA), even though review is mandated by the New Dietary Ingredients provision in DSHEA.
We believe the time has come to reform this law. For the first time, members of Congress, many manufacturers of dietary supplements, and the scientific community recognize that the law requires changes to enhance public safety.
We recommend reforming DSHEA such that all new ingredients, rather than only a small subset, are reviewed by the FDA and effective systems are implemented to track the safety of all supplements. This approach would provide an enhanced safety net for consumers while limiting the ability of unscrupulous companies to profit from the introduction of dangerous products that have bypassed FDA scrutiny.
The New Dietary Ingredients provision was designed to address the safety of newly introduced ingredients in supplements. For every new ingredient introduced into the market after 1994, manufacturers were expected to provide the FDA with a 75-day advance notice containing safety data establishing that the ingredient “will reasonably be expected to be safe.”1 Instead, a number of loopholes, vague language in the law, and lack of industry compliance have led to the majority of new ingredients being introduced without any safety evaluation by the FDA.
The FDA has also failed to enforce this provision2 — a failure that has led to even less industry compliance with the law and has contributed to the creation of the current supplement market. An estimated 75,000 new supplement products have been introduced since 1994, while the FDA has received adequate safety data for fewer than 250 new ingredients. The agency has no system for determining how many new ingredients are contained in the tens of thousands of new products on the market.
The safety risks associated with the current system are illustrated by the case of 1,3-dimethylamylamine (DMAA), a pharmaceutical stimulant, which was introduced into hundreds of workout and weight-loss products without being vetted by the FDA.3 By 2011, experts at the Department of Defense (DOD) had grown concerned that DMAA might increase troops’ risk of hemorrhagic stroke and sudden death. The DOD took the unusual step of prohibiting the sale of the stimulant on military bases and, under pressure, the FDA banned DMAA nationwide.
Many supplement manufacturers responded by reformulating their products with alternative stimulants. One replaced DMAA with a new combination of aegeline, higenamine, and caffeine, including synthetic versions of botanical constituents not traditionally consumed together. The firm did not notify the FDA of this change, nor did it provide safety data to the agency. Within a year of being introduced, the product, OxyELITE Pro, had been linked to an outbreak of severe hepatitis affecting 69 people; 32 of them were hospitalized, 3 required liver transplants, and 2 died.4
This product and similar ones were introduced by companies that often claimed their products were exempt from safety notification under DSHEA. The law provides an exemption for ingredients that have been “present in the food supply as an article used for food in a form in which the food has not been chemically altered,” and manufacturers have used this provision to justify not submitting safety data to the FDA. The law was written with the expectation that this exemption would be used infrequently, but its language is not sufficiently clear. The exemption was not meant to apply to new chemicals, combinations, or synthetic compounds. Nonetheless, the FDA has appeared to condone the use of this loophole to permit countless substances to be introduced in the absence of submitted safety data.
The loophole has grown into the exemption that swallowed the law: industry developed, and the FDA accepted, an approach whereby manufacturers convene sympathetic food-safety experts to affirm that a new, nontraditional ingredient is “generally recognized as safe.” The firm then incorporates the new ingredient into an energy bar or drink. After the ingredient has been in the “food supply” for a few months, the manufacturer claims that it can market the new ingredient, at any dose, in dietary supplements.
Fortunately, momentum is building from many stakeholders to reform the law by closing this loophole and ensuring that all new ingredients are reviewed for safety by the FDA before products are sold. The solution we propose addresses the inherent tension between maximizing consumer access and protecting consumer safety and attempts to balance these interests. We believe that thoughtful reform is practical, can be passed by Congress, and should include three basic principles.
First, manufacturers should be required to submit all product labels to the FDA so that the agency is aware of, and can track, what products are on the market. Mandatory submission of product labels would enhance transparency and advance the FDA’s ability to use its authority under DSHEA to regulate products. The agency could be required to provide each product with a unique bar code or quick response (QR) code and could use these codes to track adverse effects, manufacturing problems, and adulteration.5 With this system in place, the FDA could determine whether a labeled ingredient is new and lacking adequate evidence of safety before a product appears on the market. The agency could flag products containing such ingredients in the label database so that retailers would be able to easily confirm that a product was properly listed with the FDA before making it available in retail stores or online.
Second, we believe that manufacturers should be required to submit basic safety data for all new ingredients to the FDA. The definition of “new” or “novel” ingredient should be changed so that exemptions apply only to extracted ingredients formulated in the same quantity and form as they are consumed in botanicals or food — for example, bioflavonoids extracted from citrus fruit. For all other new ingredients, regardless of their origin, firms would be required to submit evidence of safety to the FDA before selling their products.
Finally, for mandatory listing and safety screening of new ingredients to have meaningful effects on consumer safety, the FDA would need to aggressively enforce the law. New legislation will need to clearly delineate the FDA’s responsibilities and ensure that the agency receives adequate budgetary resources for necessary reorganization and increased enforcement.
With stronger safeguards incorporated into a thoughtful reform of DSHEA, we believe it is possible to create a modern regulatory framework for supplements that would achieve Congress’s original intent of providing consumers with access to a wide variety of safe vitamins, minerals, botanicals, and other dietary supplements.

Disclosure forms provided by the authors are available at NEJM.org.

Author Affiliations

From Harvard Medical School, Boston (P.A.C.); and Global Life Sciences, Sidley Austin, New York (S.B.).
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