Bacteria promote lung tumor development

MIT cancer biologists have discovered a new mechanism that lung tumors exploit to promote their own survival: These tumors alter bacterial populations within the lung, provoking the immune system to create an inflammatory environment that in turn helps the tumor cells to thrive.

In mice that were genetically programmed to develop lung cancer, those raised in a bacteria-free environment developed much smaller tumors than mice raised under normal conditions, the researchers found. Furthermore, the researchers were able to greatly reduce the number and size of the lung tumors by treating the mice with antibiotics or blocking the immune cells stimulated by the bacteria.

The findings suggest several possible strategies for developing new lung cancer treatments, the researchers say.

“This research directly links bacterial burden in the lung to lung cancer development and opens up multiple potential avenues toward lung cancer interception and treatment,” says Tyler Jacks, director of MIT’s Koch Institute for Integrative Cancer Research and the senior author of the paper.

Chengcheng Jin, a Koch Institute postdoc, is the lead author of the study, which appears in the Jan. 31 online edition of Cell.

Linking bacteria and cancer

Lung cancer, the leading cause of cancer-related deaths, kills more than 1 million people worldwide per year. Up to 70 percent of lung cancer patients also suffer complications from bacterial infections of the lung. In this study, the MIT team wanted to see whether there was any link between the bacterial populations found in the lungs and the development of lung tumors.

To explore this potential link, the researchers studied genetically engineered mice that express the oncogene Kras and lack the tumor suppressor gene p53. These mice usually develop a type of lung cancer called adenocarcinoma within several weeks.

Mice (and humans) typically have many harmless bacteria growing in their lungs. However, the MIT team found that in the mice engineered to develop lung tumors, the bacterial populations in their lungs changed dramatically. The overall population grew significantly, but the number of different bacterial species went down. The researchers are not sure exactly how the lung cancers bring about these changes, but they suspect one possibility is that tumors may obstruct the airway and prevent bacteria from being cleared from the lungs.

This bacterial population expansion induced immune cells called gamma delta T cells to proliferate and begin secreting inflammatory molecules called cytokines. These molecules, especially IL-17 and IL-22, create a progrowth, prosurvival environment for the tumor cells. They also stimulate activation of neutrophils, another kind of immune cell that releases proinflammatory chemicals, further enhancing the favorable environment for the tumors.

“You can think of it as a feed-forward loop that forms a vicious cycle to further promote tumor growth,” Jin says. “The developing tumors hijack existing immune cells in the lungs, using them to their own advantage through a mechanism that’s dependent on local bacteria.”

However, in mice that were born and raised in a germ-free environment, this immune reaction did not occur and the tumors the mice developed were much smaller.

Blocking tumor growth

The researchers found that when they treated the mice with antibiotics either two or seven weeks after the tumors began to grow, the tumors shrank by about 50 percent. The tumors also shrank if the researchers gave the mice drugs that block gamma delta T cells or that block IL-17.

The researchers believe that such drugs may be worth testing in humans, because when they analyzed human lung tumors, they found altered bacterial signals similar to those seen in the mice that developed cancer. The human lung tumor samples also had unusually high numbers of gamma delta T cells.

“If we can come up with ways to selectively block the bacteria that are causing all of these effects, or if we can block the cytokines that activate the gamma delta T cells or neutralize their downstream pathogenic factors, these could all be potential new ways to treat lung cancer,” Jin says.

Many such drugs already exist, and the researchers are testing some of them in their mouse model in hopes of eventually testing them in humans. The researchers are also working on determining which strains of bacteria are elevated in lung tumors, so they can try to find antibiotics that would selectively kill those bacteria.

The research was funded, in part, by a Lung Cancer Concept Award from the Department of Defense, a Cancer Center Support (core) grant from the National Cancer Institute, the Howard Hughes Medical Institute, and a Margaret A. Cunningham Immune Mechanisms in Cancer Research Fellowship Award.

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Story Source:

Materials provided by Massachusetts Institute of Technology. Original written by Anne Trafton. Note: Content may be edited for style and length.

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Journal Reference:

1. Chengcheng Jin, Georgia K. Lagoudas, Chen Zhao, Susan Bullman, Arjun Bhutkar, Bo Hu, Samuel Ameh, Demi Sandel, Xu Sue Liang, Sarah Mazzilli, Mark T. Whary, Matthew Meyerson, Ronald Germain, Paul C. Blainey, James G. Fox, Tyler Jacks. Commensal Microbiota Promote Lung Cancer Development via γδ T Cells. Cell, Jan. 31, 2019; DOI: 10.1016/j.cell.2018.12.040

https://www.sciencedaily.com/releases/2019/01/190131113901.htm

Newly discovered gene governs need for sleep when sick

Humans spend nearly one-third of their lives in slumber, yet sleep is still one of biology’s most enduring mysteries. Little is known about what genetic or molecular forces drive the need to sleep — until now. In a study of over 12,000 lines of fruit flies, researchers from the Perelman School of Medicine at the University of Pennsylvania have found a single gene, called nemuri, that increases the need for sleep. These findings are published today in Science.

The NEMURI protein fights germs with its inherent antimicrobial activity and it is secreted by cells in the brain to drive prolonged, deep sleep after an infection.

“While it’s a common notion that sleep and healing are tightly related, our study directly links sleep to the immune system and provides a potential explanation for how sleep increases during sickness,” said senior author Amita Sehgal, PhD, a professor of Neuroscience and director of Penn’s Chronobiology Program.

Without the nemuri gene, flies were more easily aroused during daily sleep, and their acute need for an increase in sleep — induced by sleep deprivation or infection — was reduced. On the other hand, sleep deprivation, which increases the need for sleep, and to some extent infection, stimulated nemuri to be expressed in a small set of fly neurons nestled close to a known sleep-promoting structure in the brain. Overexpression of nemuri increased sleep in bacteria-infected flies and led to their increased survival compared to non-infected control flies.

In response to infection, NEMURI appears to kill microbes, most likely in the peripheral parts of the fruit fly body, and increases sleep through its action in the brain. Several molecules like NEMURI, which is an antimicrobial peptide (AMP), have multiple functions that help combat infection, but its sleep-promoting role may be just as important for host defense, the researchers suggest, given that increased sleep during sickness promotes survival in the flies.

What’s more, the authors note that cytokines such as interleukin-1 (IL-1), an immune cell molecule, are implicated in human sleep. IL-1 can function in the same pathway as AMPs, and it accumulates after prolonged wakefulness and appears to promote sleep. In mammals, cytokines can induce production of AMPs, but AMPS may also affect the expression of cytokines. Given this interwoven relationship, the researchers conclude that NEMURI is a working link between immune function and sleep.

“The NEMURI protein is a genuine driver of keeping sleep on track under conditions of high sleep need like when we’re sick,” said first author Hirofumi Toda, PhD, a postdoctoral fellow in Sehgal’s lab. “In the next phase of our work, we plan to investigate the mechanism by which NEMURI drives sleep.”

Julie Williams and Michael Gulledge, both from Sehgal’s lab, are also co-authors on this paper. This work was funded by the Howard Hughes Medical Institute and the National Institutes of Health (R01GM123783 402).

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Story Source:

Materials provided by University of Pennsylvania School of Medicine. Note: Content may be edited for style and length.

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Journal Reference:

1. Hirofumi Toda, Julie A. Williams, Michael Gulledge, Amita Sehgal. A sleep-inducing gene, nemuri, links sleep and immune function in Drosophila. Science, 2019 DOI: 10.1126/science.aat1650

https://www.sciencedaily.com/releases/2019/01/190131143335.htm

Ekso Bionics gains after report highlights Boeing use of exoskeletons

Boeing (BA) is equipping mechanics with exoskeletons to increase their strength and speed and help reduce fatigue on repetitive tasks, according to a Reuters report from Eric Johnson and Tim Hepher. In a photo of employee Rob Gross, who “gets a boost from a gas-powered exoskeleton Boeing is using to boost productivity and safety,” an Ekso logo can be seen. Shares of small cap Ekso Bionics (EKSO) have jumped 17c, or 10%, to $1.91 in afternoon trading following the circulation of Reuters’ report.
https://thefly.com/landingPageNews.php?id=2857943

Personalized Medicine: Just Marketing?

“Personalized” medicine sounds appealing. Rather than just guessing at what medication to try, a genetic test can figure out, in advance, which medications will be effective and which medications are more likely to make you sicker.

Except it doesn’t work. It’s mostly marketing and hype.

The FDA has officially warned consumers and physicians that genetic tests sold to predict patient responses to medications shouldn’t be used. They’re not FDA approved, and in most cases, there’s no reason to think that these tests can accurately predict how a medication is metabolized or what it’s likely to do when you take it. These tests are being aggressively marketed to the general public and physicians, and they don’t deliver what they promise.

Medicines for conditions like depression, acid reflux, and heart disease have been highlighted by the FDA — though many other medicines have become targets for these tests, too. And these tests do reveal certain genetic “polymorphisms” (variations) that all of us carry, variations that affect the way medicines are metabolized and processed in our bodies.

The problem is that our knowledge about these polymorphisms is rapidly evolving, and it’s far from complete. It turns out that dozens or maybe hundreds of genes can have overlapping functions, and (with few exceptions) we don’t yet know all of the genes involved. And for each gene, there may be hundreds or thousands of variations in the general public. Or maybe, some of us have a unique variant that hasn’t been seen before. These companies have no way to test the gene variants to know their function. They rely on proprietary databases, riddled with incomplete data and assumptions.

Just one example: When the MTHFR gene and its variants were first described, it seemed like MTHFR polymorphisms could have wide-ranging and significant health effects. It turned out that’s completely wrong. MTHFR “variations” are so common in the general public that it’s fair to say we all have polymorphisms, and almost none of these have any clinical importance. Even the 23andMe company, which makes money selling genetic tests, discourages MTHFR testing, saying, “Despite lots of research — and lots of buzz — the existing scientific data doesn’t support the vast majority of claims that common MTHFR variants impact human health.” Still, many families are still relying on misguided MTHFR testing pushed by naturopaths and chiropractors to make health decisions. And this is just one of the hundreds of genes these kinds of tests rely on.

Genetics shows great promise, and I think the future includes a big role for genetic testing. But we don’t have the knowledge to use the results of these tests to better guide therapy. But that doesn’t mean that therapeutic decisions, now, are entirely guesswork. Reviewing a family history and the exact nature of a problem often gives physicians some good clues to help guide decisions. I know, that sounds old-fashioned. But talking and listening remain the best ways for docs and patients to work together to make the best decisions.

Roy Benaroch, MD, is a pediatrician who blogs at the Pediatric Insider. He is also the author of A Guide to Getting the Best Health Care for Your Child and the creator of The Great Courses’ Medical School for Everyone: Grand Rounds Cases.

https://www.medpagetoday.com/blogs/kevinmd/77753

Cath procedure helped women conceive without pills or IVF

A relatively fast outpatient procedure helped infertile women become pregnant – without the need for pills or in vitro fertilization, researchers said here.

Using micro-catheters and a 0.018-inch guide-wire, doctors can perform proximal fallopian tube recanalization in less than the time it takes to watch a feature length movie, reported Jeff Wang, BS, a fourth-year medical student at Chicago Medical School.

At the 2019 International Symposium on Endovascular Therapy, Wang said his review of hospital records found that of 66 women for whom complete records were available, 21 pregnancies occurred, and the median time to pregnancy in these women was 4 months.

“The use of micro-catheters and wires that can be maneuvered in a minimally-invasive manner should make it a first-line use for removing fallopian tube proximal occlusions for women having fertility problems,” Wang told MedPage Today.

His retrospective review overall included 160 patients over the course of 24 years who were treated by Rush Medicine of Chicago. “We have one of the larger datasets out there and it confirms this is a minimally-invasive procedure that has pretty good outcomes. It also shows how obstetricians and gynecologists can work together with interventionalists,” Wang said.

“There is a subset of women – about 30% of the women who report fertility problems — who have proximal occlusions of their fallopian tubes,” he said. “These occlusions can be mucus or debris or a contamination of mucus and debris which build up over time. Which women are at risk for this occurring has not yet been fully explored. It could be they have a history of chronic infection or they could just be unlucky.”

He said the women are all referrals from specialists. “Usually, you have a couple who come to the ob/gyn office with problems of getting pregnant,” he said. “These patients are then referred to a reproductive endocrinologist/fertility specialist.”

In an outpatient procedure, interventionalists employ a micro-catheter to perform hysterosalpingography, and, if necessary, the wire is deployed to remove debris from the tube. “It can take a half hour to 90 minutes, depending on anatomy or whether both tubes need to be opened,” Wang said. “We use a high pressure hysterosalpingogram to determine if contrast is getting into the fallopian tubes. Sometimes this itself will unblock the occlusion. If we can’t see the contrast, we know there is a blockage. The procedure is all done through the vaginal canal. Some women experience some post-procedural pain that can be managed with medication.”

He said that all the women in the study were seeking to get pregnant. “But so far we have only been able to gather follow-up data on 66 of the patients, and 21 of them or 32% have gotten pregnant. Our data only tells us that these patients achieved fertilization. We do not yet have data on live births. Live births are part of a different dataset that we haven’t flushed out yet.”

In commenting on the study, Francisco Contreras, MD, an interventional radiologist and associate professor of radiology at Florida State University, University of Central Florida, and Florida Hospital, Orlando, told MedPage Today, “We, as interventional radiologists, have been successful in using these techniques to recanalize the fallopian tubes, and I think as more and more physicians and patients learn of these procedures it is likely that this will be done more frequently.” He suggested that a 32% pregnancy rate as described in the study would be considered a good result.

Contreras noted that undergoing the minimally-invasive procedure would not preclude other attempts at pregnancy down the line, such as in vitro fertilization.

• Prior to the treatment, Wang said 89 women had no patent tubes, but after the procedure 72 of these women achieved bilateral patency; 14 achieved unilateral patency; three women still had no patent tubes.
• In the 67 women who presented with one blocked fallopian tube, bilateral patency was achieved in 61 women; six women remained with one open tube.
• Four women had patent fallopian tubes but underwent the procedure to remove blockages. All still had bilateral patency following the procedure.

Wang said the interventionalists achieved technical success in 319 of 341 tubes they attempted to recanalize.

“We are now seeking to get long-term data and to increase the sample size, and it is important to get live birth outcomes as well,” he said.

Wang and Contreras disclosed no relevant relationships with industry.

• Primary Source

  International Symposium on Endovascular Therapy

  Source Reference: Wang J, et al “Advanced Techniques in Fallopian Tube Recanalization For Infertility treatment: A Single Center Retrospective Analysis” ISET 2019; Abstract 36.

https://www.medpagetoday.com/meetingcoverage/additionalmeetings/77760

Consumer Reports, Industry Square Off Over Metals in Juice

The fruit juice industry hit back at Consumer Reports, the product testing and ratings publication, following its report on Wednesday that many well-known juice products contain enough arsenic, lead, and cadmium that they should be avoided.

Consumer Reports said 21 of 45 juice products it tested had “concerning” levels of at least one of these heavy metals. One such product, Trader Joe’s Fresh Pressed Apple Juice, exceeded 15 parts per billion (ppb) for arsenic — well above a proposed, though not yet official, federal standard of 10 ppb. Two Welch’s products contained lead at more than 5 ppb.

However, the report did not disclose the specific concentrations found for most of the products, nor did it explain what constituted “concerning” levels. In a statement released Thursday, the Juice Products Association seized on those omissions to accuse Consumer Reports of “raising unnecessary alarm.” The publication’s classification of some products as being “potentially harmful” was “without any scientific basis,” the industry group said.

“There is no scientific evidence indicating that the presence of trace levels of heavy metals in juice has caused any negative health outcomes among individuals at any life stage,” the group declared, although it acknowledged that “trace, harmless levels of these substances may exist in juice, and other foods.”

The group cited the FDA’s Total Diet Study to support its assertion that these “trace” levels are harmless. However, that effort merely tests foods for concentrations of various contaminants without determining whether they are unhealthy.

News reports about the dispute pointed out that toxicologists generally accept that no threshold for harm has been established for heavy metals in foods, especially for children. NPR, for example, spoke with an American Academy of Pediatrics committee member, Aparna Bole, MD, of Cleveland’s University Hospitals, who took Consumer Reports’ side: “We know there are no safe levels of exposure to these heavy metals.”

And the director of the National Institute of Environmental Health Sciences told NPR that lead may be harmful at levels below 1 ppb.

https://www.medpagetoday.com/primarycare/dietnutrition/77777

Heart Attack But Not Dementia Reduced With Tight Blood Pressure Control

Target Audience and Goal Statement:

Cardiologists, vascular medicine specialists, neurologists, geriatricians, internists, and family medicine physicians

The goal of the study was to determine whether reducing systolic blood pressure (BP) in older adults, ages 50 and up, who have hypertension but without diabetes or stroke, could reduce risk of dementia and/or mild cognitive impairment (MCI).

Questions Addressed:

• Does reducing systolic BP in adults older than age 50 reduce the risk of dementia and/or mild cognitive impairment and if so, by how much?
• Is the reduction of BP in this patient population safe?
• Are there any differences between subgroups in the effects of BP reduction on incident dementia and/or MCI?

Study Synopsis and Perspective:

Aggressively reducing blood pressure in hypertensive older adults reduced dementia risk by 17%, which was not statistically significant, and it reduced MCI by 19%, which was statistically significant, according to the SPRINT MIND study, reported in JAMA.

The SPRINT MIND study, a randomized trial conducted at 102 U.S. and Puerto Rico sites, compared the effects of treating hypertensive adults, ages 50 and up, to reach a systolic blood pressure (SBP) goal of <120 mm Hg, with treating them to a goal of <140 mm Hg. The primary outcome measure was incidence of probable dementia. Although this was reduced by 17% among patients with the lower target, it was not statistically significant (HR 0.83, 95% CI 0.67-1.04) and thus the primary endpoint was missed, according to author Jeff Williamson, MD, MHS, of the Wake Forest School of Medicine in Winston-Salem, North Carolina, and colleagues.

But attaining intensive blood pressure control did show statistically significant benefits in secondary outcomes, including a 19% lower rate for MCI (HR 0.81, 95% CI 0.69-0.95).

The mean SBP at baseline was 139.7 mm Hg, and the median Montreal Cognitive Assessment (MoCA) score was 23 (interquartile range, 20-26). Before the decision to terminate the trial, the mean SBP in the intensive treatment group was 121.6 mm Hg and 134.8 mm Hg in the standard treatment group, for a mean between-group difference of 13.3 mm Hg.

In the study, researchers included 9,361 individuals ages ≥50 who had baseline blood pressure — treated or untreated — from 130 to 180. All participants also had at least one additional cardiovascular risk factor, but not diabetes and no history of stroke; the average age in the study was 67.9. About 30% of the cohort was African American and 10% Hispanic. The median follow-up time was 5.11 years.

During this follow-up time, adjudicated probable dementia occurred in 149 participants in the intensive treatment group vs 176 in the standard treatment group (7.2 vs 8.6 cases per 1,000 person-years). Intensive BP control significantly reduced the risk of MCI (14.6 vs 18.3 cases per 1,000 person-years), as well as the combined incidence of MCI or probable dementia (20.2 vs 24.1 cases per 1,000 person-years; HR 0.85; 95% CI 0.74-0.97).

Participants received anti-hypertensive medications to help achieve their assigned blood pressure target, mostly generic drugs. The trial was not designed to test a specific drug. “SPRINT used a quasi-pragmatic approach with suggestions for treatment choice, but practitioners approached systolic blood pressure control individually, and most participants were taking multiple drugs,” noted Kristine Yaffe, MD, of the University of California San Francisco, in an accompanying editorial.

SPRINT MIND was a substudy of the NIH-funded Systolic Blood Pressure Intervention Trial (SPRINT), which aimed to determine whether aggressively lowering blood pressure could protect the heart, kidney, and brain over 5 years. Initial apparent success of the heart disease portion — although questions were later raised about the trial’s design and conduct and how results should be applied — led to the trial’s early termination at 3.3 years.

This made the study too short to definitively answer the dementia question, Williamson said. As a result, the Alzheimer’s Association announced in late January 2019 that it is funding Williamson’s group for SPRINT MIND 2.0, a 2-year extension.”Because dementia is a much more slowly progressive disease from no impairment to impairment, our hope is that with 2 more years of follow-up, SPRINT MIND will accrue the number of new cases of dementia that we originally planned for so that we can definitively answer this question,” Williamson added.

“The primary outcome was negative in the SPRINT MIND trial, but we’re very encouraged by the positive trend,” Maria Carrillo, PhD, the Alzheimer’s Association chief science officer, told MedPage Today. “And we are incredibly compelled by the secondary outcome of mild cognitive impairment being reduced by 19%. We think that with an extended time frame and an additional opportunity for follow-up, we may very well see that dementia outcome is positive.”

https://tpc.googlesyndication.com/safeframe/1-0-31/html/container.html

The authors noted that the incidence of probable dementia “was likely underestimated in both treatment groups because of incomplete ascertainment.”

They also observed that there has been controversy surrounding the benefits and risks associated with lowering SBP to below 150 mm Hg, such as the possibility of hypotension and cerebral hypoperfusion resulting in negative effects on the brain. The authors stress that their trial “demonstrates no such negative effect; specifically, these results importantly show that intensive BP control did not result in harm to cognition after a median intervention period of 3.34 years and an overall median follow-up of 5.11 years.” To the contrary, they view this trial as evidence, the first in any study, of benefit for reducing SBP in the reduction of MCI occurrence, a known risk factor for dementia.

Study limitations include early termination of the study which reflects a probable loss of power to detect an effect on dementia beyond that point. As well, patients with common comorbidities including type 2 diabetes, previous stroke, advanced kidney disease, or heart failure were excluded. The study did not adjudicate baseline cognitive status, and there was no way to determine the relative effect of specific anti-hypertensive medications on MCI or dementia.

There was also limited power to detect differences among race/ethnic groups; a recent study mentioned by Yaffe reported that older black adults may show greater effects of SBP control on cognitive outcomes. “This finding requires further investigation,” she observed.

Source References: JAMA 2019; DOI:10.1001/jama.2018.21442

Editorial: JAMA 2019; DOI:10.1001/jama.2019.0008

Study Highlights: Explanation of Findings

The study found that aggressively reducing blood pressure in hypertensive older adults reduced dementia risk by 17%, which was not statistically significant, and it reduced MCI by 19%, which was statistically significant. Many observational studies have linked hypertension to dementia, Yaffe pointed out in her editorial.

“How does one interpret a secondary endpoint in a trial that fails to win on the primary endpoint? With great circumspection,” observed Sanjay Kaul, MD, of Cedars-Sinai Medical Center in Los Angeles, who was not involved in the research.

“Hence the caveat from the investigators: ‘There was no adjustment of the significance threshold for the secondary or other endpoints; because of the potential for type I error, the findings from these analyses should be considered exploratory,'” Kaul told MedPage Today.

But even if the dementia results are positive, how that will translate into clinical practice is up for debate. “The relation of blood pressure — and in particular level and change in blood pressure — to brain function is complex,” noted Zoe Arvanitakis, MD, of Rush University Medical Center in Chicago.

While SPRINT MIND adds important information to this puzzle, more research needs to be done across a range of blood pressures, in a range of ages, using different outcomes beyond diagnostic dementia classification, Arvanitakis told MedPage Today.

A recent study of nearly 1,300 older people at autopsy showed that faster declining systolic blood pressure was associated with an increased number of brain infarcts and more severe cerebral vessel pathologies, she noted, and much research is needed to “better understand the potential benefits of intensive blood pressure treatment, as well as the potential risks.”

Like any other clinical trial, the results of SPRINT MIND should be interpreted in the context of the population it studied, added Behnam Sabayan, MD, PhD, of Northwestern University in Chicago.

“SPRINT excluded individuals who had diabetes, history of stroke, and those who are residing in nursing homes,” Sabayan told MedPage Today. “This means that frail individuals with highest burden of cerebrovascular pathologies were not necessarily a part of this study, and intensive blood pressure reduction in those subjects should be exercised with caution since it can put them at risk for brain hypoperfusion, falls, kidney impairment and might introduce further risk for subsequent strokes.”

The MCI finding in SPRINT MIND also needs a more careful look, Kaul suggested. “In a sensitivity analysis that accounts for multiple imputation for missing data for time to first mild cognitive impairment, the difference was not significant,” he said.

“And even if we were to take the results at face value, it is unproven whether lowering the risk of mild cognitive impairment will translate into reduced risk of progression to dementia or Alzheimer’s disease,” Kaul added.

Primary Source

JAMA

Source Reference: SPRINT MIND Investigators for the SPRINT Research Group “Effect of intensive vs standard blood pressure control on probable dementia: a randomized clinical trial” JAMA 2019; DOI:10.1001/jama.2018.21442.

Secondary Source

JAMA

Source Reference: Yaffe K “Prevention of cognitive impairment with intensive systolic blood pressure control” JAMA 2019; DOI:10.1001/jama.2019.0008.

Additional Source

MedPage Today

Source Reference: George J “SPRINT MIND: What Have We Learned?” 2019.

https://www.medpagetoday.org/neurology/dementia/77780