MRI May Reduce Unneeded Prostate Biopsies

MRI May Reduce Unneeded Prostate Biopsies

Adding two MRI-related variables into a risk calculator with standard clinical measures could reduce the number of unnecessary biopsies in men with elevated prostate-specific antigen (PSA) scores while maintaining a “high rate” of diagnosis of clinically significant prostate cancers, concludes a new study.

The variables are prostate volume (as derived via MRI) and the Prostate Imaging-Reporting and Data System version 2 (PI-RADSv2), a relatively new tool intended to reduce problematic variability among radiologists who read multiparametric MRI scans.

“It has become more common that the results of multiparametric MRI are used to guide clinical decision-making on prostate biopsy,” observe senior study author, Baris Turkbey, MD, from the Molecular Imaging Program, National Cancer Institute (NCI), Bethesda, Maryland, and colleagues.

But it is also “unclear,” they say, whether MRI itself adds value to risk calculators that are based on standard multivariable clinical parameters, such age, race, and PSA score.

So a multi-institutional team led by NCI staff addressed the issue.

Their new analysis was published online February 22 in JAMA Oncology.

All 651 patients in the study, which includes a development cohort and a validation cohort, had a potential warning sign of prostate cancer (elevated PSA or abnormal result on digital rectal exam) and had at least one lesion detected with subsequent MRI. After their MRI, the men’s “index” lesion was assigned a PI-RADSv2 category. The men with a category 3 or higher lesion underwent MRI–transrectal ultrasonography fusion-guided biopsy and a 12-core systematic biopsy.

The development cohort consisted of 400 men with no previous diagnosis of prostate cancer who were seen at the NCI in Bethesda.

The validation cohort consisted of 251 men seen at the University of Chicago Medical Center in Illinois and the University of Alabama, Birmingham.

Overall, 193 (48.3%) of the 400 patients in the development cohort and 96 (38.2%) of the 251 patients in the validation cohort had clinically significant prostate cancer, defined as a Gleason score greater than or equal to 3 + 4. The mean age at biopsy was around 64 years in both groups.

In the two-part study, the “MRI [risk-prediction] model” using standard clinical measures (such as the above-mentioned age, race, and PSA value), plus the two MRI-derived elements, outperformed the “baseline model” (ie, standard clinical measures alone).

In the validation cohort, the area under the curve with the MRI model increased from 64% to 84% compared with the baseline model (P < .001). At a risk threshold of 20%, the MRI model had a lower false-positive rate than the baseline model (46% vs 92%), with only a small reduction in the true-positive rate (89% vs 99%).

The authors explained the importance of the concept of a risk threshold.

“In clinical practice, the threshold for biopsy should be decided after a physician and patient both weigh the relative harm of potentially unnecessary biopsy and benefit of diagnosing clinically significant prostate cancer. Therefore, there is not a single risk threshold that is used to determine who needs to undergo biopsy but rather a range of risk thresholds.”

Thus, in the study’s validation cohort, at the risk threshold of 20%, a total of 38% of biopsies could have been avoided while 89% of clinically significant cancers could still have been identified, the authors say.

Furthermore, at that threshold, in the same cohort, 96 of 251 patients (38.2%) would have avoided a biopsy while 11 of 96 patients with clinically significant disease (11.5%) would have had their cancer missed, write the authors.

The authors also provided findings on net benefit and net reduction in the number of false-positive findings from the study.

They report that the net benefit of the MRI model “was equivalent to performing 27 biopsies per 100 men without negative biopsies, 4 more than the baseline model.”

Additionally, they write, “The net reduction in the number of false-positives based on the MRI model, compared with having to perform a biopsy in all patients with positive MRI results, was equivalent to performing 18 fewer unnecessary biopsies per 100 men, with no increase in the number of clinically significant prostate cancer left undiagnosed.”

“Currently, multiparametric MRI is often considered a singular diagnostic tool in prostate cancer detection. Our study, however, shows that it has to be seen in a broader context,” Dr Turkbey and lead study author, Sherif Mehralivand, MD, also from NCI, told Medscape Medical News in a joint email. “Its main benefit is not the increased detection of cancer but rather the reduction of false-positive results and unnecessary biopsies.”

Its main benefit is not the increased detection of cancer but rather the reduction of false-positive results and unnecessary biopsies.
Dr Baris Turkbey and Dr Sherif Mehralivand

 

Dr Turkbey and Dr Mehralivand believe these attributes represent “an important step towards potential solution of the overdetection and overtreatment issue in the PSA screening era.”

They also explained the importance of the PI-RADSv2.

“We…think that PI-RADSv2 will improve standardization in reporting of multiparametric MRI scans in the near future,” they said.

The authors noted that these guidelines “have been perceived very well by the radiologic and urologic community” and are based on a “broader consensus” than was version 1 of the document, which was mainly a product of European institutions; the version 2 steering committee involves a mix of US and European experts.

“Like many new standardization systems, Pi-RADSv2 has its own limitations, and radiologist experts from all over the world have been working together with urologists to optimize this system,” they added.

Other MRI Research

Other teams have investigated use of MRI in the context of prostate cancer risk assessment, as reported by Medscape Medical News. And multiple prediction models include the imaging.

“The model we propose produces results comparable with those previously reported,” say the current study authors.

One effort (Eur Urol. 2017;72:888-896) was very much akin to the development cohort in the current study. But it suffers from not having been validated in another cohort and not having used the latest version of PI-RADS, the current study authors say.

They also point out a limitation of their own study: that patients with negative MRI results did not undergo biopsies, which could contribute to “verification bias.” But, historically, the likelihood of a clinically significant prostate cancer in patients with negative MRI findings is “low”; thus, those men are unlikely to benefit from a biopsy, they say.

The new MRI risk assessment model should be used in other medical centers, say the authors, for further prospective validation.

The study was funded by the National Cancer Institute. Two investigators report financial ties to corporate divisions of Phillips.

JAMA Oncol. Published online February 22, 2018. Abstract

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Fewer Kidney Problems With IV Balanced Crystalloids vs Saline

Fewer Kidney Problems With IV Balanced Crystalloids vs Saline

Two new trials have tried to answer a long-standing question: which intravenous (IV) fluid is better, normal saline or balanced crystalloids?

The trials, both conducted at Vanderbilt University in Nashville, Tennessee, show that the use of balanced crystalloids in critically ill and noncritically ill hospitalized patients resulted in a lower incidence of major adverse kidney events. The results were presented this week at the Meeting of the Society of Critical Care Medicine and were published online on February 27 in the New England Journal of Medicine.

Although IV fluid administration is one of the most common medical therapies used in hospitals, little is known about how different types of IV fluids affect outcomes. Use of these fluids is based on physiologic principles, rather than hard evidence from clinical trials. None of the different types of IV fluids has been thoroughly evaluated for safety and efficacy.

In the United States, 0.9% normal saline is the most commonly used IV fluid, but it contains higher concentrations of chloride than human blood. That can cause kidney injury and can negatively affect patient outcomes. Some studies have suggested that use of IV saline may result in higher rates of acute kidney injury, renal dialysis, and death compared to use of balanced crystalloids.

On the other hand, crystalloid solutions, such as lactated Ringer’s and Plasma-Lyte A, contain electrolyte concentrations that are closer to what’s found in human blood. Yet even these solutions are not truly “balanced” relative to some body fluids, and their use has been associated with metaboloic alkalosis.

To evaluate the effect of these fluids on patient outcomes, Todd W. Rice, MD, an associate professor of medicine at Vanderbilt University, and colleagues conducted two separate open-label studies in two different groups of patients: critically ill patients in the intensive care unit (ICU), and noncritically ill patients admitted to the hospital from the emergency department (ED).

The first study, called the Isotonic Solutions and Major Adverse Renal Events Trial (SMART), was conducted at five ICUs at Vanderbilt University hospital. The researchers enrolled 15,802 critically ill adults and randomly assigned them to receive either normal saline (n = 7860) or balanced crystalloid (lactated Ringer’s solution or Plasma-Lyte A, n = 7942).

Results showed that significantly fewer patients in the balanced-crystalloids group (n = 1139; 14.3%), compared to the saline group (n = 1211; 15.4%), met the primary endpoint of major adverse kidney events (a composite of death from any cause, new kidney dialysis, or persistent kidney dysfunction) within 30 days of hospital discharge or enrollment in the study (marginal odds ratio, .91; 95% confidence interval [CI], .84 – .99; conditional odds ratio, .90; 95% CI, .82 -.99; P = 0.04).

The authors caution, though, that the study did not include patients with traumatic brain injury, because of concern that balanced crystalloids may increase intracranial pressure. Therefore, the results may not apply to this group.

The second study, called the Saline Against Lactated Ringer’s or Plasma-Lyte in the Emergency Department (SALT-ED) trial, included 13,347 adults who were initially seen in the ED (where 88.3% received balanced crystalloids) and who were then hospitalized outside the ICU. Upon admission, these patients were randomly assigned to receive either balanced crystalloids (n = 6708) or normal saline (n = 6639).

Results showed that for both groups, times to hospital discharge (the primary outcome) were similar; the median was 25 days for both groups (adjusted odds ratio with balanced crystalloids, .98; 95% CI, .92 – 1.04; P = .41).

As in the SMART trial, results also showed that fewer patients in the balanced-crystalloids group (315; 4.7%), compared to the saline group (370; 5.6%), met the secondary outcome of major adverse kidney events within 30 days, also a composite of death, new kidney dialysis, or persistent kidney dysfunction (adjusted odds ratio,.82; 95% CI, .70 – .95; P =.01).

Because more than 95% of patients in the balanced-crystalloids group received lactated Ringer’s, the study cannot determine which is better, lactated Ringer’s or Plasma-Lyte A.

Further analysis for both studies suggested that use of balanced crystalloids rather than normal saline could prevent major adverse kidney events in 1 of every 94 patients admitted to the ICU and in 1 of every 111 noncritically ill patients.

Although these numbers may seem modest, the authors point out that millions of patients nationwide receive these fluids annually. On a national level, any effects associated with the difference could be substantial.

In a linked editorial, John Myburgh, MD, PhD, of the University of New South Wales, the George Institute for Global Health, and St. George Hospital, Sydney, Australia, urges caution when interpreting the results.

Whereas both studies showed that balanced crystalloids were associated with a reduction in the composite outcome of adverse kidney events, he notes that no significant differences between balanced crystalloids and saline were found for short-term mortality or kidney dialysis.

“What clinicians need to consider is whether the results of an open-label trial conducted in a single, major US medical center can be generalized to the ways in which their own patients survive, feel, and function,” he writes.

He emphasizes that none of the resuscitation fluids are physiologic and that questions about their safety and efficacy remain despite these results.

“[O]utcomes and health economics are fundamental to informing clinicians about their choice of resuscitation fluids in critically ill patients. The trials presented here inform that thinking but do not provide unequivocal clinical direction,” he concludes.

The studies were supported by the Vanderbilt Institute for Clinical and Translational Research and by grants from the National Center for Advancing Translational Sciences. One or more authors report receiving grants, advisory board fees, consulting fees, and/or travel support from one or more of the following: the National Institutes of Health, Vanderbilt Center for Kidney Disease, the Department of Veterans Affairs, Venaxis, Cempra Pharmaceuticals, Ferring Pharmaceuticals, Biotest, Abbott Point of Care, Gilead Sciences, Cumberland Pharmaceuticals, and Avisa Pharma. Dr Myburgh has received nonfinancial grants or other support from the following: Baxter Healthcare, CSL Bioplasma, Fresenius Kabi, and the National Health and Medical Research Council.

N Engl J Med. Published online February 28, 2018. Full text, Editorial

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Old Blood Pressure Drug: Hope for Type 1 Diabetes Prevention?

Old Blood Pressure Drug: Hope for Type 1 Diabetes Prevention?

A drug widely used for over 50 years to control blood pressure may prevent type 1 diabetes and even help treat patients who have the disease by preventing the autoimmune destruction of insulin-producing pancreatic beta cells, suggest US researchers after conducting a search of pre-existing drugs.

Focusing on an immune protein linked to the development of type 1 diabetes present in up to 60% of patients, the team initially identified a candidate molecule for preventing the disease based on its three-dimensional structure and fit with the DQ8 allele.

They then trawled through more than 1500 drugs already approved by the US Food and Drug Administration (FDA) using a sophisticated program to find similar shaped drugs.

Eventually, they identified methyldopa, a well-established antihypertensive drug.

Studying the drug in 20 patients recently diagnosed with type 1 diabetes, the team found that methyldopa not only blocked the immune activity of the DQ8 allele, but also appeared to stabilize disease.

The research was published online February 13 in the Journal of Clinical Investigation.

“This is the first personalized treatment for type 1 diabetes prevention,” said senior author Aaron Michels, MD, Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, in a press release by his institution.

“With this drug, we can potentially prevent up to 60% of type 1 diabetes in those at risk for the disease. This is a very significant development.”

Lead author David A Ostrov, PhD, College of Medicine, University of Florida, Gainesville, noted that the techniques used in the study may also offer opportunities to identify novel treatments for other autoimmune diseases, such as rheumatoid arthritis, celiac disease, and lupus.

In the meantime, the team will build on their findings by conducting a clinical trial of methyldopa for the prevention and treatment of type 1 diabetes funded by the National Institutes of Health (NIH).

Michels told Medscape Medical News that the TN-23 study will be a multicenter, randomized, placebo-controlled crossover trial of children and adolescents at risk of type 1 diabetes who have the immune protein, and will assess the safety, efficacy, and mode of action of methyldopa in preventing antigen presentation.

Proof-of-Concept Trial

Although reduced insulin production in type 1 diabetes is widely believed to be caused by the autoimmune-mediated destruction of pancreatic beta cells, immune therapies tested so far have offered limited clinical benefits.

Research over the past decade has shown, however, that DQ8, a gene in the human leukocyte antigen (HLA) complex linked to autoreactive T-cell responses, is present in 50% to 60% of patients with type 1 diabetes and increases the risk of developing the disease by up to 11-fold.

Hypothesizing that the DQ8 allele may be a novel treatment target, researchers used its three-dimensional structure to screen a library of 139 735 small molecules for those that could bind to structural pockets in the allele and block antigen presentation.

The ability of the top 40 scoring compounds to alter insulin/DQ8-specific T-cell responses was then assessed in vitro using a T-cell bioassay and revealed that one compound, tetraazatricyclododecane (TATD), interacted directly with the peptide/DQ8 complex without causing cell cytotoxicity.

Subsequent administration of TATD to nonobese diabetic mice was found to block major histocompatibility complex (MHC) class II antigen presentation.

Moreover, the compound prevented or delayed diabetes onset, blocked T-/B-cell interactions, reduced tissue-specific destruction, and maintained glucose tolerance in mice with the disease.

To see if an existing drug could have the same effects, the team then screened 1207 small molecule drugs already approved by the FDA to identify those that could potentially occupy the same binding pocket as TATD on the DQ8 allele.

Ten of 39 top-scoring drugs showed promise, of which one, methyldopa, inhibited T-cell responsiveness in vitro. Moreover, the drug blocked antigen presentation by DQ8 in a dose-dependent manner and prevented other peptides binding to the allele without causing cell cytotoxicity.

Having also shown that methyldopa prevented DQ8 antigen presentation in nonobese diabetic mice, the team conducted a single-arm, open-label phase 1b dose-escalation study in 20 patients with type 1 diabetes of less than 2 years’ duration who still produced endogenous insulin and were positive for DQ8.

To prevent hypotension, the patients were given three oral doses of methyldopa over 6 weeks, which was well-tolerated with no serious adverse events.

Low, moderate, and high doses of methyldopa resulted in a significant 40% reduction in DQ8 antigen presentation by peripheral blood mononuclear cells vs baseline levels, and 17 patients responded.

Furthermore, methyldopa was associated with reductions in insulin-specific CD4 T-cell responses in the peripheral circulation.

Glycemic control also remained steady over 3 months, with no changes in total insulin doses, and residual endogenous insulin production remained similar to baseline. This contrasts with findings from natural history studies, which suggest that patients with type 1 diabetes experience a steady decline in insulin production after diagnosis.

Describing the study as a proof-of-concept trial, the team writes: “Although short-term, these results suggest methyldopa treatment may limit beta-cell destruction and preserve function; however, trials with a longer duration and placebo arm are needed to fully evaluate metabolic efficacy.”

Although they acknowledge that there are “several concerns” about using pre-existing drugs to target MHC class II antigen presentation, researchers say that “one advantage of ‘repurposing’ existing drugs is that well-characterized safety profiles indicate potential complications and off-target effects.”

And they note that, with more than 50 years of clinical use, methyldopa “is considered safe,” even in the approximately 10% of the general European-American population carrying the DQ8 allele.

The study was supported by grants from the NIH, Juvenile Diabetes Research Foundation, Children’s Diabetes Foundation, Barbara Davis Center Translational Research Unit, and Colorado Clinical and Translational Science Institute. Michels and Ostrov are inventors on a patent licensed to ImmunoMolecular Therapeutics. Michels and Gottlieb are scientific cofounders of ImmunoMolecular Therapeutics and own shares in the company. Disclosures for the other authors are listed in the article.

J Clin Invest. Published online February 13, 2018. Full text

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Many Mothers May Lack Knowledge About Child Burn Risk, Treatment

Many Mothers May Lack Knowledge About Child Burn Risk, Treatment

(Reuters Health) – Mothers of young children may be largely unaware of the biggest burn risks to their little ones and even what age group is most likely to get burned, Australian researchers say.

The study team surveyed almost 500 mothers of young kids in Queensland, and just one third knew the top cause of burns to young children while only one in 10 knew how long the correct treatment should be applied.

“Hot beverage scalds are the leading cause of childhood burns in Australia and many other developed countries,” lead author Jacqueline Burgess told Reuters Health in an email.

“In Australia, hot beverage scalds account for 20% of all the burns we treat – a figure that has remained constant for the past 15 years,” said Burgess, a researcher at the Centre for Children’s Burns and Trauma Research at the University of Queensland in South Brisbane.

About 75% of these burns occur in children under the age of 24 months, she added. “Our study was undertaken to address this problem.”

The researchers gathered baseline data in advance of testing an app they developed, called Cool Runnings, which is designed to teach burn safety and first aid. Participants were all adult women with at least one child between 5 and 12 months of age at the start of the study. Roughly half of the women were under age 29, and about 40% were first-time mothers.

Researchers scored the participants’ responses on a 19-item questionnaire that measured overall knowledge of burns, first aid for burns and burn risk factors.

Less than half of the women knew that children ages 6 to 24 months are the group most at risk of hot drink scalds, Burgess said.

“This is the age when motor skills are developing, and mobility, curiosity, and a desire to imitate adults are increasing; however, this age group lacks a sense of danger and awareness, and the ability to withdraw from heated objects and liquids,” she said.

Therefore, parents of this age group need to be particularly vigilant when they are preparing and consuming hot drinks that their hot drink is placed out of reach – at the back of the bench, in the middle of the table, not the edge, she noted.

“It is a good idea to keep young children out of the kitchen altogether with a safety gate so children can’t access all the potential hazards found in the kitchen,” Burgess said.

Applying 20-minutes of cool running water to a burn (any type of burn) is the best first aid treatment, resulting in less pain, reduced burn depth, shorter hospital stays and faster healing time, she added.

“This treatment is beneficial up to three hours after the burn occurs. Cool the burn but make sure the child doesn’t get too cold. This treatment is fairly readily available, is free, and is the best treatment you can apply.”

While 94% of mothers knew to cool a burn with water only, just 10% realized they should do it for a full 20 minutes, the researchers report online January 31 in Injury Prevention.

The only two factors that seemed to predict whether mothers knew the correct first aid for a burn were training and smoking status – mothers who were smokers tended to score poorly in this category, and mothers who had undergone first aid training in the past 12 months tended to do better than the rest.

The Cool Runnings app was developed to test the efficacy of a smartphone to deliver an injury prevention campaign, Burgess said.

“Specifically, mothers who downloaded the app were able to learn about burn risks and burn first aid by viewing a variety of content – animations, videos and infographics.”

In the trial of the researchers’ app, participants were also rewarded for their engagement with the app. “Each time mothers viewed content, answered pop quizzes, etc., they were awarded points. These points could then be redeemed for tangible prizes such as movie vouchers and supermarket vouchers.”

Burgess and her colleagues plan to publish results of that trial in a separate study. But she noted that mothers who were active on the app showed a significant improvement in burn risk and first aid knowledge at the end of the intervention period. That suggests this method of delivering injury prevention messages is effective in changing participants’ knowledge, Burgess said.

SOURCE: http://bit.ly/2GwsxXI

Injury Prevent 2018.

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Gabon Accuses France's Veolia of Polluting Amid Concession Dispute

Gabon Accuses France's Veolia of Polluting Amid Concession Dispute

LIBREVILLE (Reuters) – Gabon accused French environmental services group Veolia on Tuesday of widespread pollution at SEEG, the power and water utility it operates there, amid a growing dispute over the company’s concession.

Veolia, which has already threatened legal action after the government seized SEEG earlier this month and said it would cancel its concession, rejected the accusations.

Speaking to reporters in the capital Libreville, government spokesman Alain-Claude Bilie By Nze said an environmental inspection of power and water pumping stations discovered “nearly all” SEEG sites were contaminated by petroleum waste.

“This is a very serious situation since, at this stage, aside from the obvious environmental damage, no one knows the consequences this pollution could have had or could have on public health,” he said.

He said that on top of legal penalties of up to 500 million CFA francs ($946,110) for each polluted site, Gabon would force SEEG to shoulder the clean-up costs.

Responding to the accusations, Veolia stated that the water it distributed continued to conform to World Health Organization standards and Gabonese regulations.

“It is surprising that none of the inspections of the public authorities . . . ever highlighted environmental damage,” it said. “The SEEG is subject to regular audits by the Gabonese authorities, more than 10 in the last 10 years.”

Negotiations between the government and Veolia over the concession broke down in October, and authorities seized SEEG earlier this month, citing years of poor service quality.

Veolia in turn blamed the government for failing to live up to its investment obligations, and on Tuesday said the state owed SEEG over 29 billion CFA francs in consumption charges and unpaid value-added tax reimbursements.

Gabon spokesman Bilie by Nze said the government had called for an audit of its 13 billion CFA consumption bill.

He rejected accusations it had neglected SEEG and said the state had invested around 1 trillion CFA francs in the company, around three times more than Veolia.

($1 = 528.4800 CFA francs)

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Freed Salvadoran Woman Vows to Fight for Others Jailed for Abortion Crimes

Freed Salvadoran Woman Vows to Fight for Others Jailed for Abortion Crimes

SAN SALVADOR (Thomson Reuters Foundation) – When Salvadoran Teodora Vasquez was freed this month after more than a decade in prison for a murder she says she did not commit, her thoughts turned to being reunited with her son and to helping other women behind bars.

Vasquez was jailed for 30 years in 2008 for aggravated murder after being convicted of inducing an abortion, which is a crime under any circumstances in El Salvador.

Vasquez said she went into labor in a bathroom at work in 2007, and that the baby was stillborn. Prosecutors said she had strangled the baby after birth.

Earlier this month, Vasquez walked out of the overcrowded Ilopango women’s prison in the capital San Salvador, greeted by her family and crowds of cheering activists, after the Supreme Court reduced her sentence.

“I think that these 10 years and seven months (in jail) have marked my life forever, because I won’t ever forget it,” Vasquez told the Thomson Reuters Foundation.

“The day before gaining my freedom, it was the most exciting and contradictory (thing) at the same time. I had mixed feelings because . . . I was so eager to get out, but at the same time I thought about my cellmates.”

For Vasquez, freedom means spending time with her 14-year-old son. She wants him to get a good education and a job, while she aims to study further and become a lawyer. She also hopes one day to go to the beach.

“For now, I’m enjoying being with my son. We go out, not far, just around the corner from my home because I’m afraid of going far in case I get lost,” the 34-year-old said.

“My son hugs me. He tells me: ‘I’ve waited for you for so long over the years’.”

FREEDOM FOR OTHERS?

Vasquez’s release puts the spotlight on El Salvador’s total ban on abortion as the Central American nation faces mounting international pressure to overturn its strict law.

Abortion has been outlawed in the Catholic-majority nation since 1997 even in cases of rape, incest, when the woman’s life is in danger or the fetus is deformed. Five other countries in Latin America and the Caribbean also have an outright ban.

In 2016, the country’s ruling party introduced a bill to allow abortion in cases of rape or a risky pregnancy, but no date has been set for a vote, and it will likely face tough opposition from the Catholic Church and evangelical groups.

In November, the United Nations urged El Salvador to issue a moratorium on applying its abortion law, and asked authorities to review all such cases in which women had been jailed.

According to the local Citizen Group for the Decriminalization of Abortion (CFDA), which helped campaign for Vasquez’s release, another 27 women are in prison under the country’s abortion law.

The CFDA said they had been accused of inducing abortions, then wrongfully convicted and jailed for murder, when instead they had suffered miscarriages, stillbirths or pregnancy complications.

“It’s totally clear that they haven’t committed any crime, but that they suffered an obstetric emergency which led to the loss of their child and that took them from the hospital to jail,” said CFDA spokesman Jorge Menjivar.

“We will continue to seek different avenues until these women can regain their freedom.”

He said the CFDA had campaigned successfully for the early release of 16 women imprisoned for abortion-related crimes since 2009. Some had their sentences quashed after appeal or were freed after being pardoned.

Vasquez said she would fight for the release of other women jailed for abortion crimes. Like her, most were young, poor single mothers with little education when convicted.

“For them, my leaving prison was an engine that was ignited. They are hopeful that I will fight on their behalf . . . They know I’m going to help them, be with them and for them,” she said.

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Eye Changes May Signal Cognitive Decline

Eye Changes May Signal Cognitive Decline

Signs of damage in the microvasculature of the eye are linked to subsequent cognitive decline, a large prospective study shows.

Using fundus photography, which takes images of the interior surface of the eye, including the retina, investigators at Johns Hopkins Center on Aging and Health in Baltimore, Maryland, found retinopathy was associated with faster cognitive decline over a 20-year period vs no retinopathy.

“One of the reasons we’re so excited about our study is that we think these changes in the very small blood vessels we see in the eye probably mirror the very small blood vessel changes that are going on in the brain,” first author, Jennifer A. Deal, PhD, told Medscape Medical News.

“This lets us get a deeper look at the brain [than we can now] with our standard brain imaging, like MRI, that doesn’t allow us to see blood vessels this small,” she added.

The study was published online February 28 in Neurology.

Accelerated Cognitive Decline

Previous research used fundus photography to examine the relationship between vascular changes in the eyes and cognitive decline. However, the investigators note, these studies are few in number and had limited follow-up, and many were cross-sectional (ie, the participants’ eyes and cognition were assessed simultaneously).

“We can learn a lot from those studies, but we don’t know which came first,” said Deal.

For the current study, investigators used data from the Atherosclerosis Risk in Communities study to determine whether retinal signs were associated with 20-year cognitive decline.

Baseline eye examinations (1993-1995) were conducted in 12,317 participants with an average age of 60 years, and cognition was assessed at three different time points (1990-1992, 1996-1998, and 2011-2013).  

They found 365 participants had mild retinopathy, 256 had moderate-to-severe eye damage, and most — 11,692 participants — had no signs of retinopathy.

In the group with moderate-to-severe retinopathy, neuropsychological test scores dropped 1.22 standard deviations (SDs) over two decades of follow-up.

At the same time, those with healthy eyes experienced a decline of 0.91 SD. Even when researchers took into account the participants who missed some of the periodic cognitive assessments, the difference between these two groups was 0.57 SD.

“We came into the study really expecting to see a strong association. We already had information on the relationship between blood vessels in the eye and blood vessels in the brain,” Deal said.

The research also builds on previous findings reported in a subset of the same cohort with a shorter follow-up (Neurology. 2009;73:862-868).

The fundal examination is routine, noninvasive, and easy to administer, Deal said, and clinicians already use it to screen for eye diseases and adverse effects of other conditions, including diabetes and hypertension.

“However, in terms of being sensitive enough to predict cognitive decline…I don’t think we’re quite there with this test,” she added. “So it would be premature to say we could predict cognitive decline based on this test.”

In the meantime, neurologists who detect microvascular damage in patients without diabetes, high blood pressure, or other relevant conditions might consider the need for tighter control of vascular risk factors, Deal said.

She added that newer technology, such as optical coherence tomography, could prove more sensitive for predicting cognitive decline based on the same microvascular changes in the future, but more research is necessary.

Assessment was performed in only one eye of each participant, a limitation of the study. The research is ongoing, with the investigators continuing to follow the study population over time.

A Window to the Brain?

Commenting on the findings for Medscape Medical News, Christina E. Hugenschmidt, PhD, from Wake Forest University in Winston-Salem, North Carolina, said the longitudinal nature of the study contributes to the literature.

“The literature on this idea goes back a few years. The idea is that the vessels in the eyes come from the same blood vessels in the brain at the embryonic stage of development, which is actually pretty cool,” said Hugenschmidt.

“It’s a lot easier to get pictures of the vessels in the eye than the vessels in the brain. So it makes sense that…we might be able to learn about brain health by looking at eye vessels.”

The research adds to the literature by looking at a large number of people over a long span of time, she added.

“The long follow-up period allows you to see how risk plays out during the time when people are most likely to experience dementia and cognitive decline. Seeing eye vessel damage at 60 is actually relatively young. This is reflected in the relatively small numbers of people it affected,” Hugenschmidt said.

“A second point is that while having eye vessel disease increases your risk of developing cognitive decline, not having eye disease does not mean you are free of vascular risk to your brain. Regardless of eye disease, people should take care of their cardiovascular health in order to support their brain health,” she added.

The National Heart, Lung, and Blood Institute and the National Institutes of Health supported the study. Deal and Hugenschmidt have disclosed no relevant financial relationships.

Neurology . Published online February 28, 2018. Abstract

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Too Soon to Celebrate: Obesity Rates Continue Up in US Youth

Too Soon to Celebrate: Obesity Rates Continue Up in US Youth

Obesity rates in American youth continue to rise, with over one third of children and adolescents ages 2 to 19 years now being overweight or obese despite widespread efforts to curb the burgeoning tide of obesity among the young, new research shows.

The study was published online February 26 in Pediatrics.

“About 4 years ago, there was evidence of a decline in obesity in preschoolers,” said lead author Asheley Cockrell Skinner, PhD, associated professor of population health sciences, Duke Clinical Research Institute, Durham, North Carolina, in a statement by her institution.

“It appears any decline that may have been detected by looking at different snapshots in time or different data sets has reversed course,” she added.

“The long-term trend is clearly that obesity in children of all ages is increasing,” Skinner concludes.

As previously reported by Medscape Medical News, obesity rates did appear to be falling among preschoolers, as shown most recently in a study in children aged 2 to 4 years living in low-income households who took part in the Special Supplemental Nutrition Program for Women, Infants, and Children.

That, however, no longer appears to be the case, and particularly not in young children.

Sharp Increase in Class I Obesity in 2 to 5 Year Olds

In the current analysis, researchers from Duke tracked body mass index (BMI) data on 3340 children who were part of the National Health and Nutritional Examination Survey (NHANES) in 2015 and 2016. The database is updated every 2 years.  

Obesity was defined by the Centers for Disease Control and Prevention as a BMI ≥ 85th percentile for age and sex. Class I obesity was defined as a BMI ≥ 95th percentile. Class II obesity was defined as a BMI > 120% of the 95th percentile or ≥ 35 kg/m² (whichever was lower). Class III obesity was defined as a BMI ≥ 140% of the 95th percentile or ≥ 40 kg/m² (whichever was lower).

Investigators tracked BMI data collected in 2-year cycles, starting with the 1999–2000 cycle and ending at the most recent 2015–2016 cycle.

“The prevalence of overweight and obesity increased with age,” they report.

In the most recent NHANES cycle, 35.1% of the cohort was overweight or obese.  

In total, 18.5% of the cohort met the criteria for class I obesity, 6% met the criteria for class II obesity, and 1.9% met the criteria for class III obesity.

However, some age groups were more at risk than others for being overweight or obese.

For example, 41.5% of 16 to 19 year olds in the most recent NHANES cycle met the criteria for obesity and 4.5% of this age group met the criteria for class III obesity, the investigators point out.

Differences between rates of overweight and all classes of obesity in the most recent and previous cycle were not generally very marked.

One exception was a “sharp increase” in class I obesity among 2 to 5 year olds: 13.7% of these children met the criteria for class I obesity in the most recent cycle compared with 9.3% in the previous one.

Black and Hispanic Kids More Likely to Be Obese Than Whites

Regardless of age, both African American and Hispanic children were more likely to be overweight or obese (any class) than other ethnicities.

Indeed, African American and Hispanic girls and boys are two- to fourfold more likely to meet the criteria for class III obesity compared with white children, points out David Ludwig, MD, PhD, Boston Children’s Hospital, Massachusetts, in an accompanying editorial.

In contrast, Asian American and white children had markedly lower rates of overweight or any class of obesity, the authors point out.

And in a related study, 2.1% of children from across the full NHANES survey interlude had severe obesity. The study, led by June M Tester, MD, MPH, from Children’s Hospital Research Center, Oakland, California, and colleagues, was published online February 27 in Pediatrics.

In this select cohort, African American children were 70% more likely to have severe obesity than children of other ethnicities.

Hispanic children in the same NHANES cohort were also more than twice as likely to have severe obesity. They were also more likely to live in homes with lower educational exposure, that were single-parent households, and that were poor.

Being exposed to over 4 hours a day of screen time doubled the risk of severe obesity, and children who were not breastfed were 50% more likely to be obese, Tester and colleagues report.

Current Public Health Approach to Obesity Is Failing

“I think we’ve focused on making healthier foods more available, trying to encourage people to make healthier choices, and teaching healthcare providers how to communicate with families about weight and weight status in a sensitive way,” said senior investigator of the Duke study, Sarah Armstrong, MD, Duke Health, Durham, North Carolina.

“But since we are seeing that these incremental changes really aren’t having much of an impact, particularly among children who already have obesity and severe forms of obesity, we need to look at policies that are going to have a more disruptive impact on our society,” she suggested.

Armstrong also had several practical suggestions to improve family health; for example, avoiding added sugar in beverages and food and incorporating vegetables into every meal, not just dinner.

“Even if your child is a picky eater and wants to eat the same vegetable every day, that is still a good choice,” she observed.

Families also need to be active for an hour every day to help improve health, Armstrong added.  

Commenting further, Ludwig agrees that the current public health approach to the obesity epidemic has failed.

In fact, a recent growth trajectory predicts that most 2-year-old children alive today will be obese by the time they reach age 35 years (N Engl J Med 2017;377:2145-2153).

“The battle against childhood obesity faces many obstacles, most notably entrenched special interests and a ‘business as usual’ mindset,” Ludwig writes.

“But with political will and collaboration across key sectors of society, we can hopefully, soon, begin to end this worsening epidemic,” he concludes.

The study received no outside funding. The authors and editorialist have reported no relevant financial relationships.

Pediatrics. Published online February 26 (Abstract, Editorial) and February 27, 2018 (Abstract).

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Varicose Veins Tied to Higher Risk for Deep Venous Thrombosis

Varicose Veins Tied to Higher Risk for Deep Venous Thrombosis

Adults with varicose veins are five times more likely to develop deep venous thrombosis (DVT), a large retrospective cohort study has found.

“Varicose veins are rarely associated with serious health risks. In contrast, [DVT], pulmonary embolism (PE), and peripheral artery disease (PAD) are vascular diseases that are associated with serious systemic effects. Patients with varicose veins have increased levels of inflammatory and prothrombotic markers,” the authors explain.

Shyue-Luen Chang, MD, from the Vein Clinic, Department of Dermatology, Chang Gung Memorial Hospital, Taoyuan; Chang Gung University College of Medicine, Taoyuan; and the Department of Cosmetic Science, Chang Gung University of Science and Technology, Linkou, all in Taiwan, and colleagues report their findings in an article published in the February 27 issue of JAMA.

The researchers analyzed claims data from Taiwan’s National Health Insurance program from 212,984 adult patients with varicose veins (mean age, 54.5 years; 69.3% women) and 212,984 randomly selected propensity score-matched patients without varicose veins, DVT, PAD, or PE (mean age, 54.3 years; 70.3% women).

With a mean follow-up of 7.3 to 7.8 years, patients with varicose veins had a higher incidence of DVT, at 6.55 per 1000 person-years vs 1.23 for those in the control group.

PE incidence was also higher among those with varicose veins (0.48 per 1000 person-years) compared with participants in the control group (0.28 per 1000 person-years). Similarly, the risk for PAD was elevated in the varicose vein group, at 10.73 per 1000 person-year vs 6.22 for the control group.

The hazard ratios for those in the varicose veins group were 5.30 (95% confidence interval, 5.05 – 5.56) for DVT, 1.73 (95% confidence interval, 1.54 – 1.94) for PE, and 1.72 (95% confidence interval, 1.68 – 1.77) for PAD compared with those in the control group. These results did not differ significantly by sex or age.

Potential limitations of the study include the lack of claims information on patients who did not seek medical care; some patients may have failed to obtain medical care as a result of embarrassment about the appearance of varicosities, which could mean that they may have waited until their varicose veins were severe before seeking care. The study was observational in nature; thus, causal inferences cannot be made.

In addition, because the magnitude of association was smaller for PE and PAD, “the findings for PE and PAD are less clear due to the potential for confounding. Whether the association between varicose veins and DVT is causal or represents a common set of risk factors requires further research,” the researchers conclude.

The authors have disclosed no relevant financial relationships.

JAMA. 2018;319(8):807-817. Abstract

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FDA Rejects Celgene's NDA for Ozanimod in MS

FDA Rejects Celgene's NDA for Ozanimod in MS

The US Food and Drug Administration (FDA) has sent Celgene Corporation a “refusal to file” letter regarding its New Drug Application (NDA) for ozanimod for treatment of patients with relapsing multiple sclerosis (RMS), the company said.

In its preliminary review, the FDA determined that the nonclinical and clinical pharmacology sections in the NDA were insufficient to permit a complete review, the company explained in a news release.

Celgene said it would seek immediate guidance from the FDA to determine what additional information they require to resubmit the NDA.

“We remain confident in ozanimod’s clinical profile demonstrated in the pivotal program in relapsing forms of multiple sclerosis,” Jay Backstrom, MD, chief medical officer and head of global regulatory affairs for Celgene, said in the release. “We will work with the FDA to expeditiously address all outstanding items and bring this important medicine to patients,” he added.

Ozanimod is an oral once-daily immunomodulator that selectively targets sphingosine 1-phosphate 1 (S1P) and 5 receptors, in development for several immune-inflammatory indications, including RMS, ulcerative colitis, and Crohn’s disease.

Ozanimod was recently found to be safe and effective in patients with RMS in the phase 3 SUNBEAM and RADIANCE trials. 

Full data from both multicenter, randomized controlled trials were presented at the  Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2017 meeting, and reported by Medscape Medical News.

In SUNBEAM, which included more than 1300 patients, those who received once-daily ozanimod 0.5 mg or 1 mg for 1 year had significantly greater reductions in annualized relapse rate (ARR, the primary endpoint) than did patients who received weekly 30-µg intramuscular injections of interferon β-1a (IFN; Avonex, Biogen).

MRI findings showed that the ozanimod group also had greater reductions in gadolinium-enhancing lesions and new or enlarging T2 lesions.

In RADIANCE part B, which also included more than 1300 patients with RMS, the groups receiving 0.5 or 1 mg of ozanimod daily had greater ARR reductions at 2 years than the group receiving IFN.

In addition, the number of new or enlarging T2 lesions was reduced by 34% and 42% for the two doses, respectively, compared with IFN, and the number of gadolinium-enhancing lesions was reduced by 47% and 53%.

In both trials, there were few serious adverse events, which did not differ significantly between treatment groups. No serious cardiac-related adverse events, serious opportunistic infections, or treatment-related deaths occurred.

Ozanimod is an investigational compound that is currently not approved for any use in any country.

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FDA Serotonin Syndrome Warning Erroneous?

FDA Serotonin Syndrome Warning Erroneous?

New data cast doubt on the validity of a US Food and Drug Administration (FDA) advisory against coprescribing triptans and antidepressants due to an increased risk for serotonin syndrome.

In 2006, the US Food and Drug Administration (FDA) warned that coadministration of a triptan and selective serotonin reuptake inhibitors (SSRIs) or selective norepinephrine reuptake inhibitor (SNRIs) has an additive effect on serotonin levels that can lead to serotonin syndrome, a potentially life-threatening condition.

The FDA advised health providers prescribing a triptan, SSRI, or SNRI to consider that triptans are often used intermittently and that drugs from all three classes may be prescribed by different clinicians.

They further advised that clinicians weigh the potential risk for serotonin syndrome against the potential benefit of using a triptan with an SSRI or SNRI.

But Yulia Orlova, MD, PhD, Department of Neurology, University of Florida College of Medicine, Gainesville, and colleagues say results of their research “cast doubt on the validity of the FDA advisory and suggest that it should be reconsidered.”

Serotonin syndrome is “rare when triptans are coprescribed with SSRI/SNRI antidepressants, and patients with coexisting migraine and depression can be safely managed with this combination,” Orlova told Medscape Medical News.

The study was published online February 26 in JAMA Neurology.

No Cases

Using the Partners Research Data Registry, investigators identified 47,968 patients who were prescribed triptans over the 14-year study period (2001 to 2014), including 19,017 who were coprescribed a triptan and SSRI or SNRI.

“In this large population-based study with more than 30 000 person-years of exposure to coprescription of these drugs, we found no cases of life-threatening serotonin syndrome and no cases in which triptan use was unequivocally implicated as a cause,” the investigators report.

Serotonin syndrome was suspected in 17 patients, but only 2 patients were classified as having definite serotonin syndrome (incidence rate, 0.6 cases per 10,000 person-years of exposure; 95% confidence interval [CI], 0.0 – 1.5).  Five patients were classified as having possible serotonin syndrome (incidence rate with these 5 cases added to the 2 definite cases, 2.3 cases per 10,000 person-years of exposure; 95% CI, 0.6 – 3.9).

“Thus, our estimates suggest that the incidence of serotonin syndrome among patients coprescribed triptans and SSRI or SNRI antidepressants ranged from 0 to 4 cases per 10 000 person-years of exposure,” the authors write.

Orlova noted that the 2006 FDA advisory was based on a small number of clinical cases and doubt exists as to whether they meet diagnostic criteria for serotonin syndrome.

The current study applied two sets of diagnostic criteria of serotonin syndrome to all cases where it was suspected (Sternbach and Hunter criteria).

“Based on our results, we believe triptans do not add to the risk of serotonin syndrome beyond the one already associated with SSRI/SNRI antidepressants. Taken together, we believe that FDA advisory should be reconsidered,” Orlova said.

The study also shows that coprescription of a triptan and SSRI/SNRI antidepressant did not decline after the 2006 FDA advisory. During the entire study period, the proportion of patients with triptan prescriptions who were coprescribed these drugs was relatively stable, ranging from 21% to 29%.

Advisory Harms Patients

This study demonstrating a “low risk of serotonin syndrome with SSRIs and SNRIs and the triptans is actually very important,” Jennifer Payne, MD, director, Women’s Mood Disorders Center, Johns Hopkins School of Medicine, Baltimore, Maryland, told Medscape Medical News.

“Since both antidepressants and triptans are commonly used medications, knowing that there is a low risk of an adverse reaction is reassuring. Also, being able to quote the risk when prescribing for patients is helpful from a clinical management point of view,” said Payne.

Stewart J Tepper, MD, professor of neurology, Geisel School of Medicine at Dartmouth in Hanover, New Hampshire, noted that there doesn’t appear to be a “legitimate” pathophysiologic mechanism to explain an increased risk for serotonin syndrome (also called serotonin toxicity) when triptans are added to SSRIs and SNRIs.

“Serotonin toxicity is mediated by the serotonin 2a receptor, and triptans are not 2a agonists. It doesn’t matter how high you take the dose on triptans — they don’t become 2a agonists. So there is no rational reason to think that adding triptans to an SSRI or SNRI would increase serotonin syndrome. There is a fixed rate of serotonin syndrome with SSRIs and SNRIs by themselves,” Tepper told Medscape Medical News.

In a position paper published in 2010 , the American Headache Society concluded that the available evidence does not support limiting the use of triptans with SSRIs or SNRIs.

“They pronounced the level of evidence as level U — equivocal — and I think that is being generous. I think the evidence is against this,” Tepper said.

He said it’s “inexplicable” why the FDA doesn’t go back and look at this issue and rescind the advisory because it “hurts patients.”

“It is very common to see patients with comorbid depression, anxiety and migraine; at least 20% of the time, patients need coprescriptions for triptans and SSRI or SNRI antidepressants” and doctors may be reluctant to coprescribe these medicines.  The advisory also has a deleterious effect on clinical research, he said.

The study had no commercial funding. Orlova, Payne, and Tepper have disclosed no relevant financial relationships.

JAMA Neurol. Published online February 26, 2018. Abstract

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Misuse of Opioids, Biologics Emphasized at AAOS 2018

Misuse of Opioids, Biologics Emphasized at AAOS 2018

NEW ORLEANS – The surgeon’s role in the opioid crisis will be underscored at the upcoming American Academy of Orthopaedic Surgeons (AAOS) 2018 Annual Meeting. And budding problems with misuse of biologics will also be debated.

“The two hottest topics are going to be opioids and biologics,” said James Huddleston, MD, from Stanford University in California, who chairs the instructional course committee for the meeting.

Studies will be presented on prescribing patterns and alternatives to opioids that are accompanied by adverse effects, such as addiction and nausea.

I’ve been using multimodal pathways and my use of opioids has gone way down.

The effectiveness of oxycodone, ibuprofen, and acetaminophen in the management of pain after carpal tunnel or stenosing tenosynovitis release will be examined by researchers from the Rothman Institute in Philadelphia. All 23 carpal tunnel release and 7 stenosing tenosynovitis release surgeries were performed under local anesthesia, without sedation. Of the 30 study participants, 10 received oxycodone, 12 received ibuprofen, and 8 received acetaminophen.

“I’ve been using multimodal pathways and my use of opioids has gone way down,” Huddleston told Medscape Medical News. “You want to try to block the pain signals at the various points from the site of the injury back to brain. You can use local anesthetics and peripheral nerve blocks to numb the nerves that are supposed to send the signal, and epidermal and spinal anesthetics for neuraxial analgesia.”

The team from the Rothman Institute also tested the effect of preoperative opioid counseling on opioid consumption after hand surgery, looking at pill consumption, pain levels, and adverse reactions. The more than 40 study participants were randomized to receive or not receive counseling, and all surgeries were performed with the same mini-open carpal tunnel release technique.

The use of stem cells in orthopedic surgery will be explored in many of the studies presented.

Stem Cells

In one presentation — a survey of 317 American centers that offer stem cell therapies for musculoskeletal conditions — researchers from the Cleveland Clinic will look at cost and efficacy.

“The Holy Grail for stem cells, at least in regard to osteoarthritis, would be for us to have an injection we could give that grows cartilage back,” said Huddleston. “The current challenge is that we can grow the cells, but getting them to stay where we want them to stay hasn’t been as successful as we’d like. There is a lot of research in this field, there are clinical trials going on, and there are also a lot of treatments by practitioners that are not evidence-based.”

The first clinical trial of an intratendinous injection of autologous adipose tissue-derived mesenchymal stem cells for the treatment of rotator cuff disease will be presented by researchers from the SMG-SNU Boramae Medical Center in Seoul, South Korea.

To get a one-stop overview of biologics, conventioneers can attend a 2-hour symposium, entitled Use and Misuse of Biologics in Orthopaedic Surgery: Platelet-Rich Plasma and Stem Cells.

Several other studies will shed light on ongoing controversies in orthopedics.

An “eye-opening” study looking at fluoroscopy field radiation scatter in patients with orthopedic hardware will be presented by a team from the Hand Center of Southwestern Ohio in Dayton, said Marc Safran, MD, from Stanford University in Palo Alto, California, who is program chair for the meeting.

And a long-term follow-up of patients whose acetabular labral tears showed up on MRI, but did not cause any symptoms, and who did not undergo surgery, will be presented by Matthew Schmitz, MD, from San Antonio.

Two studies presented will explore concerns raised by a report published in the Boston Globe about surgeons operating on multiple patients concurrently. “There was concern about complications in patients undergoing spine surgery when the surgeon was involved in another surgery in another room,” Safran told Medscape Medical News. The studies measure complication rates to see if the patients are adversely affected by concurrent surgeries.

Other studies explore whether hip surgery can alleviate back pain, whether most randomized controlled trials of orthopedic surgery are statistically underpowered, and the effects of clavicle fracture nonunion on functionality.

Follow Medscape Orthopedics on Twitter @MedscapeOrtho and Laird Harrison @LairdH

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Off-label Cochlear Implantation Common

Off-label Cochlear Implantation Common

YORK (Reuters Health) – Cochlear implantation is commonly performed for indications beyond those included in device labeling, according to a survey of American Neurotology Society (ANS) members.

Label indications for cochlear implantation were issued more than 17 years ago. They include:

– adults who score 50% or lower in the ear to be implanted, and 60% or lower in the best-aided listening condition, on recorded open set sentence recognition; and

– children at least 12 months old with bilateral profound sensorineural hearing loss (SNHL) who gain limited benefits from appropriately fitted hearing aids.

Many practitioners find these candidacy guidelines to be too restrictive, and increasing numbers of centers perform cochlear implantation for off-label or nontraditional indications.

To examine practice variation in cochlear implant candidacy assessment and off-label indications, Dr. Matthew L. Carlson from Mayo Clinic School of Medicine, Rochester, Minnesota, and colleagues distributed a 26-item web-based survey to 627 ANS members, 81 of whom completed and returned them.

The findings were published online January 1 in Otology and Neurotology.

More than three-quarters of respondents (78%) reported performing cochlear implantation for at least one of the following off-label and/or nontraditional indications within the past 2 years:

– profound hearing loss in children younger than 12 months (43%);

– children with asymmetrical hearing loss where at least one ear scored better than performance cutoff for age (31%);

– adults with asymmetrical hearing loss where at least one ear scored better than performance cutoff for adult criteria (60%);

– single-sided deafness (46%); and

– ipsilateral vestibular schwannoma (35%).

According to the survey results, the areas most likely to provide the greatest immediate opportunity for program growth would be FDA approval of cochlear implantation for single-sided deafness (44%), FDA approval for implantation in patients with greater degrees of residual hearing (27%), and greater access to patients who meet existing/current candidacy criteria (29%).

In evaluating candidacy for cochlear implantation, 100% of respondents routinely used AzBio sentences, 56% used consonant-nucleus-consonant word scores, and 35% used a hearing in noise test (HINT).

Overall, 19% of respondents performed only unilateral implantation in the Medicare population and 28% considered bilateral implantation in the second ear only if both the implanted and hearing aid ears score below the candidacy cutoff, whereas 53% considered implantation of the second ear without regard to performance of the implanted ear.

“The high percentage of surgeons performing implantations for off-label or nontraditional indications reflects the overly restrictive and dated status of current implant guidelines,” the researchers conclude. “With greater adoption of more difficult speech perception testing in noise, careful clinical judgment is needed to maintain a favorable risk-benefit balance for prospective implant candidates.”

Dr. P.J. Govaerts from The Ear Group, Antwerp-Deurne, Belgium, who has previously argued that cochlear implantation selection criteria are out-of-date and should be abandoned, told Reuters Health by email, “Even 30 years after the introduction of this new medical option/technique, huge variation exists between different cochlear implantation (CI) centers in the U.S., and even more when considering global practice. This holds for the audiological tests used to select and evaluate candidates, as well as for the ultimate indications.”

“There is no consensus on GCP (good clinical practice),” he said. “Although this cannot be avoided for emerging treatments, it means that the choices patients get offered really depend on the center they visit and the knowledge available in that center. The fact that so many specialists go off-label indicates that the regulatory bodies are too conservative and fail to follow the pace of the real world. A consequence is that many patients are refused access to” available treatments that the specialists consider beneficial.

“Medicine remains an art,” Dr. Govaerts said. “It is the duty of a medical professional to analyze his/her own results and to offer treatments that will improve the patient’s outcome, not based on literature statistics, but based on his/her own individual statistics. This justifies some differences between centers/clinicians, and the world should live with it.”

“At the same time, excellence should remain the driving force, and regulatory bodies should base their restrictions, if any, on recommendations by excellent experts rather than on democratic consensus,” he said. “This is essential to keep space for progress.”

Dr. Carlson was unavailable for comment.

SOURCE: http://bit.ly/2EMLgO5

Otol Neurotol 2018.

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U.S. to File 'Statement of Interest' in Lawsuits Against Opioid Makers, Distributors

U.S. to File 'Statement of Interest' in Lawsuits Against Opioid Makers, Distributors

WASHINGTON (Reuters) – The U.S. Justice Department will argue the federal government deserves reimbursement for costs it has borne stemming from the opioid crisis in a “statement of interest” it plans to file in a lawsuit against drug manufacturers and distributors, U.S. Attorney General Jeff Sessions said on Tuesday.

“I am announcing today that the department will file a statement of interest in a lawsuit against a number of opioid manufacturers and distributors for allegedly using false, deceptive, and unfair marketing of opioid drugs,” Sessions told reporters.

“The hard-working taxpayers of this country deserve to be compensated by any whose illegal activity contributed to these costs. And we will go to court to ensure that the American people receive the compensation they deserve,” Sessions added.

Sessions also said he had appointed a federal prosecutor to lead the government’s battle against the crisis and had created a task force to help.

In 2016, the last year with publicly available data, 42,000 people died from overdoses for the class of drugs, according to the U.S. Centers for Disease Control and Prevention.

Consequently, hundreds of U.S. states, counties and cities have filed lawsuits against drug manufacturers and wholesale distributors, accusing them of promoting the addictive painkillers with misleading marketing and failing to report suspicious orders.

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U.S. Subpoenas Mallinckrodt for Information on Opioid Painkillers

U.S. Subpoenas Mallinckrodt for Information on Opioid Painkillers

(Reuters) – Pharmaceutical company Mallinckrodt Plc said on Tuesday it had received a grand jury subpoena from federal prosecutors in Florida seeking documents related to generic drugs it produces that contain the opioid painkiller oxymorphone.

The drugmaker disclosed in a U.S. Securities and Exchange Commission filing that it received a subpoena on January 27 seeking documents related to the company’s distribution, marketing and sale of oxymorphone generic products.

The disclosure came on the same day that the United Kingdom-based company reported earnings. The company reported $792.3 million in net sales in the fourth quarter of 2017, down 4.5%.

The subpoena came from the U.S. Attorney’s Office for the Southern District of Florida. Drugmaker Endo International Plc disclosed on January 11 that it received a grand jury subpoena from the same office related to its own oxymorphone products.

Mallinckrodt had no immediate further comment on the subpoena.

There has been a growing number of lawsuits by state and local governments accusing drugmakers including Mallinckrodt of contributing to the national drug addiction epidemic through their marketing and promotion of opioids.

The U.S. Justice Department said on Tuesday it would side with plaintiffs in the litigation as it seeks reimbursement for costs the federal government has borne from the opioid epidemic.

Mallinckrodt in July resolved a federal investigation into allegations that it failed to notify the U.S. Drug Enforcement Administration of suspicious orders of drugs like oxycodone for $35 million.

The drugmaker disclosed in August that it had received a subpoena from the U.S. Justice Department related to its promotional practices and sales involving opioid products including Exalgo and Xartemis XR.

The company says it faces 281 lawsuits seeking damages related to its opioid products and faces investigations by several state attorneys general.

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Twenty U.S. States Sue Federal Gov't Seeking End to Obamacare

Twenty U.S. States Sue Federal Gov't Seeking End to Obamacare

(Reuters) – A coalition of 20 U.S. states sued the federal government on Monday over Obamacare, claiming the law was no longer constitutional after the repeal last year of its requirement that people have health insurance or pay a fine.

Led by Texas Attorney General Ken Paxton and Wisconsin Attorney General Brad Schimel, the lawsuit said that without the individual mandate, which was eliminated as part of the Republican tax law signed by President Donald Trump in December, Obamacare was unlawful.

“The U.S. Supreme Court already admitted that an individual mandate without a tax penalty is unconstitutional,” Paxton said in a statement. “With no remaining legitimate basis for the law, it is time that Americans are finally free from the stranglehold of Obamacare, once and for all,” he said.

The U.S. Justice Department did not immediately respond to a request for comment on whether the Trump administration would defend the law in court.

The individual mandate in Obamacare was meant to ensure a viable health insurance market by forcing younger and healthier Americans to buy coverage.

Republicans have opposed the 2010 law formally known as the Affordable Care Act, the signature domestic policy achievement of Trump’s Democratic predecessor Barack Obama, since its inception.

Paxton and Schimel, both Republicans, were joined in the lawsuit by 18 states including Arizona, Florida, Georgia, Utah and West Virginia. It was filed in U.S. District Court in the Northern District of Texas.

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'Artificial Pancreas' Is Far From Perfect, but Holds Promise

'Artificial Pancreas' Is Far From Perfect, but Holds Promise

The MiniMed 670G hybrid closed-loop insulin delivery system (Medtronic) offers the potential for improved blood glucose control for people with type 1 diabetes, but clinicians should anticipate the need for close monitoring, frequent adjustments, and ongoing patient and family education, particularly in the first month. 

The new findings, from 31 patients with type 1 diabetes aged 14 to 26 years who wore the 670G for 3 months as outpatients, were published online February 14 in Diabetes Care by Laurel H Messer, RN, MPH, CDE, of the Barbara Davis Center for Diabetes, Aurora, Colorado, and colleagues.

The 31 “emerging adult” study participants were among 124 patients aged 14 to 75 years in the pivotal trial that led to approval of the 670G system by the US Food and Drug Administration (FDA) in September 2016.

In this deeper dive into transitioning young patients to the 670G from stand-alone insulin pumps, with or without continuous glucose monitoring, adjustments in carbohydrate-to-insulin ratio and active insulin time settings were frequently required.

In addition, “auto mode exits”, whereby the system switches back into open-loop mode for safety reasons, were common in the beginning but diminished as patients more closely adhered to system instructions, including bolusing before meals. 

“The 670G is like a 1990s cell phone. It’s not an iPhone 6.0. It’s a giant leap forward in automation of insulin delivery, but it’s not a plug-and-play system,” study coauthor Gregory P Forlenza, MD, assistant professor of pediatrics at the Barbara Davis Center, told Medscape Medical News.

The authors chose to focus on adolescents and young adults for the current analysis, as these populations tend to be among the most challenging in terms of glycemic variability and stand to gain the greatest long-term benefit from automated insulin delivery.

However, the lessons learned from using the 670G system are relevant to all users, Messer and colleagues note in their article.

“There is a rather steep learning curve for both the provider and patient. If you don’t anticipate that, you’ll say this doesn’t work. But if you anticipate and address that, it works beautifully,” Forlenza said.

With Adjustments, Time in Range Improved

In the substudy group of emerging adults, participants were a mean age 17.8 years, and had a mean duration of type 1 diabetes of 9.3 years and mean baseline HbA_1c of 7.8%. By the end of the 3-month study, HbA_1c dropped by 0.75 percentage points (P < .0001).  

Over the same period, the carbohydrate-to-insulin ratios used to determine meal boluses, which users must still direct the system to initiate, needed to be strengthened by about 10% to 20%. This was necessary because the 670G system — unlike stand-alone insulin pumps — dials back basal insulin delivery following a meal bolus. (Traditional pumps only consider the amount of insulin “on board” when calculating correction doses.) 

Because of that, the ratios needed to be significantly decreased for more insulin to be delivered. At breakfast, the carbohydrate-to-insulin ratios decreased from 7.9:1 at baseline to 7.4:1 at week one, and leveled off at 6.9:1 for months 2 and 3 (P ≤ .001 for all time points from baseline). Similar adjustments were required for lunch and dinner. 

“Most patients won’t get any auto-basal after a meal bolus. That’s part of the reason we had to make the ratio more aggressive. Providers and patients need to know that’s the case,” Forlenza explained.

With those adjustments, the percentage of time in the target glucose range of 70 to 180 mg/dL significantly increased with auto mode use, from 55.3% at baseline to 68.4% within the first 7 days (P < .001), and the 15% improvement was sustained through the remainder of the trial.

“Small variations are what it’s very good at catching up on…If you underestimated meal carbs by 10%, the [system] will minimize that, and blood glucose levels won’t be as high for as long as with an open-loop. But you can’t skip a meal bolus,” he noted.

By the same token, the system will decrease basal insulin to prevent hypoglycemia if too much insulin is given (10% to 20%), he added. 

Still a “First-Generation System,” but Improvements Being Made 

One of the challenges — which may disappear in future iterations of the hybrid closed-loop system — is the “auto mode exit,” which can be performed intentionally by the user or automatically by the 670G under certain circumstances.

Prolonged hyperglycemia (> 300 mg/dL for 1 hour or > 250 mg/dL for 3 hours), which can be caused by a pump or infusion-set malfunction, will automatically cause the system to switch back to open-loop (manual) mode.    

Other situations can trigger a “safe basal” mode, in which the system calculates basal delivery but doesn’t modulate it based on sensor readings.

This can happen when the system’s internal checks detect a problem with the sensor, which can often be resolved by entering an extra fingerstick blood glucose for calibration (in addition to the usual two per day). If the user doesn’t enter that value, the system reverts to manual mode after a 90-minute “safe basal time-out.”

Auto mode was active for 87% of the time during the first 7 days of 670G use, dropping to 80% at the end of the first month, and 72% by 3 months. Most of the system-initiated “auto mode exits” were because of “safe basal time-outs.”

“It’s very nuanced…As this moves into the real world, we need to manage expectations,” Forlenza said.

But changes are happening. On February 26, 2018, Medtronic received FDA approval for use of the Guardian Sensor 3 on the upper arm. The move is expected to increase both convenience and accuracy, according to a company statement.

Overall, Forlenza said, “We’ve shown that patients are doing better. They’re improving their time in range by about 15% from before. That’s huge. That’s about 3 hours a day more time that people are in target range.”

“They still have to work, and they still have high and low blood sugars, but this improves it. And once you learn the system, it improves it with less work. It’s a first-generation system and there’s a lot of learning required for both providers and patients. But once you get over that, people generally find it’s worth it.”  

The study was funded by Medtronic MiniMed. Forlenza reported receiving research grants from Medtronic MiniMed, Insulet Corporation, Tandem Diabetes Care, and Dexcom, is a consultant for Abbott Diabetes Care, and advisory board member for Dexcom. Messer has reported no relevant financial relationships.

Diabetes Care. Published online February 14, 2018. Abstract

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Shine a Healing Light: Circadian-Based Lighting in Hospitals

Shine a Healing Light: Circadian-Based Lighting in Hospitals

The harsh lighting common to most hospitals and other healthcare settings has been developed with energy consumption and economics in mind. It provides constant low illumination for healthcare staff and helps patients feel safe, particularly at night.

However, these efficiencies disturb innate circadian rhythms linked to overall health, say researchers.

Using special circadian lighting can help patients to get a good night’s sleep and may speed healing and recovery, they point out. It should be available to every patient staying in a healthcare setting for 2 weeks or longer, they argue.

“We’re designed to be exposed to high amounts of light during the day, not the constant dim lighting found in most hospitals 24 hours a day,” Mariana Figueiro, PhD, director of the Lighting Research Center at Rensselaer Polytechnic Institute in Troy, New York, said in an interview. “In the last 15 to 20 years, we’ve learned a lot about the impact of light on health.”

For just about any patient who receives institutionalized care for 2 weeks or longer, constant, low-level room lighting can inhibit melatonin production during the day and suppress its sleep-inducing release at night. When sleep/wake cycles get turned around, the resulting insomnia, fatigue, and daytime sleepiness may increase the risk for depression and the need for pain medication, and it may even extend recovery time.

Automatic circadian lighting changes from early morning to late night are part of post-stroke patient care at the Central Hospital in Karlstad, Sweden.Source: Chromaviso

“Without this synchronization, research has shown that we may experience long-term decrements in physiological function, neurobehavioral performance, and sleep and are put at a higher risk for cardiovascular disease, diabetes, and certain forms of cancer,” Figueiro told Medscape Medical News. “Giving hospital patients a robust light/dark lighting pattern is the most logical thing to do to promote synchronization of the body’s biological clock, and we’re seeing many health benefits.”

Studies of circadian lighting show that recreating changes in natural light over a 24-hour period works well in a wide variety of clinical settings, from nursing homes to neonatal intensive care units (ICUs). For example, clinical benefits have been observed in patients with myeloma following bone marrow transplant, in patients with Alzheimer’s, and in those undergoing rehabilitation after acute stroke.

“I think the science is pretty robust,” said Figueiro. “Staying in the hospital makes sleep worse. We now have enough scientific knowledge about the impact of a robust light/dark lighting pattern on health to do better than what we’re doing in healthcare facilities. There is no reason not to deliver cycled light to any patient in any facility.”

Although the body’s circadian system is sensitive to short-wave blue light, conventional lighting standards are designed for the body’s visual systems, which are sensitive to longer-wave blue light. A robust 24-hour circadian lighting system provides subtle morning light followed by bluish-white hues that simulate bright sunlight on a cloudless day.

Unlike conventional hospital lighting, which is usually set at around 147 lux, circadian lighting delivers about 2000 lux of short-wave blue light at “mid-day,” stimulating melatonin production and promoting alertness.

In the evening, circadian systems provide a soft yellow light that doesn’t shut down the release of sleep-inducing melatonin. This is then followed by lighting corresponding to that of a dark night.

Since 2010, studies in patients with Alzheimer’s disease have demonstrated “extreme success” with circadian lighting in restoring normal sleep patterns, said Figueiro. Not only is fatigue reduced, but depression and agitation scores drop significantly.

Too often, patients spend their days and nights in dimly lit rooms and spend little or no time outdoors, she noted. “When you have patients confined to an environment where you can control the 24-hour light exposure, you can see a very strong positive effect on depression and agitation.”

Any kind of lighting can be used to develop circadian systems, but LED lighting is the most versatile because it allows users to tune the emission of light to whatever part of the spectrum is desired, she explained.

Studies in US Hospitals

Recently, Figueiro and colleagues partnered with Mount Sinai Hospital, New York City, to investigate the impact of circadian-based light on recovery in patients with myeloma who had undergone bone marrow transplant. Preliminary data show that patients confined to hospital for 2 to 3 weeks reported better sleep and less fatigue.

The research group is also partnering with researchers at Yale University, New Haven, Connecticut, to determine whether circadian light can reduce delirium in patients admitted to the intensive care unit after cardiac surgery. “They completely lose track of night and day,” Figueiro said. “If we give them a robust light/dark pattern, it will help them sleep.”

Almost 50 patients have been enrolled so far: 25 control patients, who received conventional, dim lighting of a warm color, and 25 patients who received circadian-effective light. After 14 days, researchers say patients who received light/dark-patterned light reported better sleep and reduced fatigue.

Figueiro predicts that in the future, circadian lighting will be standard in most buildings, including homes and offices. “It will become more personalized and customizable, with the goal of improving human health and well-being,” she said.

Last December, researchers at the University of Minnesota’s Masonic Children’s Hospital in Minneapolis launched a pilot study to assess the impact of circadian lighting systems on delirium and quality of sleep in the pediatric ICU. It is estimated that delirium or some state of confusion is linked to sleep disruption in about 23% of children admitted to ICUs and in up to 80% of adults in ICUs.

“Sleep is an important part of the healing process, and disruption can affect cognition, pain, hormonal balances, and immune processes,” lead researcher Helena Molero, MD, assistant professor of pediatrics at the University of Minnesota, told Medscape Medical News. “We discovered that in the ICU rooms, light pollution at night from the hallways was high, and light during the daytime was not as bright since patients weren’t facing the windows, resulting in lack of typical day and night light changes.”

Molero anticipates that by using circadian lighting to regulate patients’ hormonal and immune functions associated with sleep, patients will need less sedation and pain medication and will show clinical improvement faster.

“Any attempt to improve sleep, whether by minimizing sleep interruptions associated with care or by strengthening the circadian cycle, can result in benefits and the patient’s return to a healthy state,” said Molero. “We hope our study will identify new avenues to improve patient health,” she said.

Unlike conventional overhead hospital lighting, the pediatric ICU system features about 10 lights placed in an array across the ceiling and along the walls, including on either side of the patient’s bed. The lighting is automatically calibrated to adjust to the time of day, but manual controls can be used to override standard settings.

Studies in Denmark

In Denmark, a clinical trial in patients admitted to the Copenhagen University Hospital following acute stroke has also shown benefits from circadian-based lighting, according to Anders Sode West, MD, clinical associate professor of neurology. The prospective, longitudinal controlled trial compared outcomes in 45 patients who were randomly assigned to receive circadian lighting and 39 patients who received standard lighting during stroke rehabilitation.

Depression was quantified using the Hamilton Rating Scale for Depression (HAM-D6) and the Major Depression Inventory scale (MDI). Fatigue was measured using Epworth Sleepiness Scale.

In the Plejecentret Albertshøj care facility in Albertslund, Denmark, circadian lighting has been installed to assess the impact of such lighting on quality of life in elderly patients in comparison to regular lighting. Source: Chromaviso

Even when the use of antidepressant medication was included as a confounder, the study showed that at discharge, HAM-D6 and MDI scores were significantly lower in patients who received circadian lighting during stroke rehabilitation compared to control patients (-2.25, P = .018, and -4.71, P=1.74, respectively). Patients given circadian lighting also had lower sleepiness scores compared to control persons (P = .17 vs P = .183).

A report on the study findings was presented at the International Stroke Conference 2017 in Houston, Texas, on February 22, 2017.

“This knowledge encourages new ways of thinking by embracing light as a significant contributor to our health,” West told Medscape Medical News. Circadian lighting is “a relevant investment as an additional medical treatment for depression and fatigue during long-term hospitalization,” he added. He noted that the study was confined to patients who had undergone acute stroke. “This study should pave the way for new clinical light studies in patients,” he said.

Two evidence-based lighting protocols customized to patients in ICUs at Aarhus University Hospital in Denmark and at the neurology clinic at Rigshospitalet, Copenhagen, are also being studied. Both clinically validated protocols were developed in collaboration with the Danish lighting technology company Chromaviso.

At Rigshospitalet, West and colleagues are measuring circadian biomarkers as well as sleep/wake cycles, sleep quality, anxiety, and cognitive performance in 73 neurology patients.

Exterior view of patient rooms with circadian and noncircadian lighting at the Plejecentret Albertshøj care facility in Albertslund, Denmark. Source: Chromaviso

At the Psychiatric Center Copenhagen, a research team led by Klaus Martiny, MD, PhD, clinical associate research professor at the University of Copenhagen, has been studying at the impact of customized circadian lighting technology on patient care since 2014. A study of a circadian lighting system called Room-light is currently underway in 150 patients hospitalized for depression. Martiny and colleagues will measure the impact of circadian lighting on depression, sleep, duration of inpatient stay, the use of medication, circadian rhythm, and well-being. “We hope to be able to demonstrate a connection between therapeutic light and a swifter recovery from depression, leading to earlier discharge and a reduction in drug therapy,” said Martiny in a statement.

Change to Circadian Lighting in Hospitals Is “Long Overdue”

When asked to comment, Richard G. Stevens, PhD, professor of cancer epidemiology at the University of Connecticut Health Center in Farmington, said in-hospital circadian lighting could have physical as well as emotional benefits for most patients, regardless of why they are hospitalized.

Dimming conventional hospital lighting at night isn’t enough to prevent this, said Stevens, who is one of the world’s leading experts on circadian rhythms. “The constant harsh lighting that is still so pervasive in most hospitals is to nobody’s benefit. Even at short wavelengths, night-time exposure to light in the blue spectrum can affect optimal health.”

Fortunately, the realization that a robust circadian rhythm can generally improve the effectiveness of therapies is growing, Stevens confirmed.

“The change to circadian-friendly lighting in a small but growing number of hospitals, particularly in the Nordic countries, is long overdue,” he told Medscape Medical News. “We now have the technology to light hospitals and other buildings in a way that accommodates circadian rhythms, thereby promoting healing in patients and better maintaining health for the rest of us. I hope and believe it is the coming thing for patients in hospitals everywhere.”

Dr Figueiro has received funding from the National Institute on Aging, the National Institute for Occupational Safety and Health, the Centers for Disease Control and Prevention, the US General Services Administration, and the Office of Naval Research. She also has collaborated with companies in the lighting industry, including Acuity Brands, Cree, Current by GE, Ketra, OSRAM, Philips Lighting, and USAI Lighting. Dr West has a nonfinancial relationship with Chromaviso. Dr Molero has a partnership with Phillips Lighting. Dr Stevens has disclosed no relevant financial relationships.

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Have You Retired From Medicine?

Google's AI Uses Retinal Images to Reveal Cardiovascular Risk

Google's AI Uses Retinal Images to Reveal Cardiovascular Risk

Deep machine learning can extract and quantify several risk factors for cardiovascular disease (CVD) from photographs of the retinal fundus, according to findings published online February 19 in Nature Biomedical Engineering.

Traditional risk factors for CVD include age, sex, smoking status, blood pressure, body mass index, and blood glucose and cholesterol levels. However, a major limitation in considering these risk factors is that many people do not know all of their values, particularly serum cholesterol, for which body mass index is sometimes used as a substitute.

However, another way to assess CVD risk may be from retinal images, which are easily obtained in an outpatient setting. Retinal anatomy may reveal cardiovascular status through the presence of cholesterol emboli, hypertensive retinopathy, and details of blood vessel caliber, bifurcation and further branching patterns, and tortuosity.

Ryan Poplin, from Google Research, Mountain View, California, and colleagues applied deep learning to assess retinal images. Deep learning is a type of machine learning that can transcend the “round up the usual suspects” approach of seeking only what experts prespecify, and instead forms algorithms that recognize predictive features from dense data. The approach has been applied to images to diagnose melanoma and diabetic retinopathy.

The deep-learning models were trained to recognize elevated CVD risk on data from 284,335 patients (48,101 from the UK Biobank and 236,234 from EyePACS) and were validated using two independent datasets of 12,026 patients (from the UK Biobank) and 999 patients (from EyePACS). The UK Biobank represents the general population; the EyePACS group is mostly Hispanic individuals being screened for diabetic retinopathy. The mean ages were similar, at 56.9 ± 8.2 years for UK Biobank participants and 54.9 ± 10.9 years for EyePACS participants.

The strategy identified predicted CVD risk factors that were not known to be quantifiable from images of the retina, including age, with a mean absolute error of less than 3.5 years for both validation datasets. The algorithm also accurately predicted systolic and diastolic blood pressure, body mass index, and HbA1c.

Moreover, the presence of diabetic retinopathy did not alter the identification of CVD risk factors, Poplin and colleagues note.

The researchers also trained a model to predict the onset of major adverse cardiovascular events within 5 years. The endpoint was only available for the relatively healthy UK Biobank group. The researchers identified 631 events among the 48,101 individuals, with 150 of those in a validation subset.

“Despite the limited number of events, our model achieved an area under the receiver operating characteristic curve (AUC) of 0.70 (95% [confidence interval (CI)]: 0.648 to 0.740) from retinal fundus images alone, comparable to an AUC of 0.72 (95% CI: 0.67 to 0.76) for the composite European SCORE risk calculator,” the authors write.

The trained deep-learning models zeroed in on particular anatomical structures that made sense in terms of the predictions, and were validated by ophthalmologists blinded to the prediction task viewing 100 randomly chosen retinal images. The models trained to detect standard risk factors (age, smoking, and systolic blood pressure) highlighted vasculature, whereas those trained to predict HbA1c indicated the perivascular areas. Models trained to predict sex highlighted predominantly the optic disc, blood vessels, and macula.

The researchers, referring to the detected structures and anatomical regions, conclude “we demonstrate not only that these signals are present in the retina, but that they are also quantifiable to a degree of precision not reported before.” They suggest that existing diabetic retinopathy screening programs could be used to also assess cardiovascular disease risk factors.

Limitations of the study include only using images with a 45° field of view, a data set smaller than average for deep learning investigations, and inconsistent availability of lipid data and diabetes diagnoses.

The authors are employees of Google and Verily Life Sciences.

Nat Biomed Eng. Published online February 19, 2018. Abstract

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