CardioBrief: Eminence-Based Medicine and Cardiac Surgery

I don't want to only pick on interventional cardiologists. Last week I wrote about a breathtaking case of interventional cardiology hubris. In response, a prominent interventional cardiologist shared with me a fascinating anecdote about cardiac surgery. Here's his story:

In the early days of minimally-invasive CABG [coronary artery bypass grafting], a top cardiac surgeon at a top hospital decided to try out the new technique. He then performed many of his cases this way. He meticulously documented the results, obtaining an angiogram on each and every patient immediately after surgery. After about 80 or so cases, he recognized that his results were better with traditional open CABG, he modified his approach, and ultimately, reverted back to standard CABG via a median sternotomy. The surgeon did not seek IRB approval, nor did he seek approval of insurance companies to incorporate an immediate post-operative angiogram, though presumably he explained to the patients that they were going to undergo a new, less invasive operation. As far as my source knew, no one ever raised a question about any of this, though my source said that he couldn't help thinking to himself how different things are on the cardiology side of things. He joked that if he had wanted to demo a new type of surgical glove, he would have been required to get IRB approval.

This case sounds like a nonrandomized, semi-prospective, historically-controlled clinical trial without IRB approval or patient consent. I suspect this sort of thing happens all the time at many hospitals. Do you see anything unusual here?

Should the surgeon have been required to obtain IRB approval with this large a change from the standard operative approach? Should the surgeon have educated his patients and given them a choice?

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CardioBrief: Eminence-Based Medicine and Cardiac Surgery

ACP's View on Newest Doctor-Nurse Battle

The Department of Veterans' Affairs proposal to allow Advanced Practice Registered Nurses (APRNs) to have full and independent practice authority, preempting state laws that hold them back, has triggered another ugly fight between the medical and nursing professions. The American Nurses Association supports it, the AMA opposes it.

The fight over the VA's proposal continues a long-standing battle that plays out regularly in state legislatures, as nurses have sought to expand their "scope of practice" and eliminate existing "physician supervision" requirements, while state medical societies have battled back.

Both sides, of course, frame the issue as being about quality and access, not about who is in control. Physicians argue that being licensed as an MD or DO requires a higher level of education and patient care experience (4 years of medical school and at least 3 years of supervised direct patient care training in residency and fellowship positions) that makes them uniquely qualified to take care of patients, especially those with more advanced conditions, while nurses argue that their different but unique training and skills -- especially those that have been trained as Advanced Practice Registered Nurses -- make them at least as qualified to treat most patients, with equal or better outcomes. Both cite conflicting studies to support their positions.

I have personal experience in how hard it is to find common ground between the two professions or, for that matter, within the medical profession itself. Three years ago, the American College of Physicians published a position paper in the Annals of Internal Medicine, called "Principles Supporting Dynamic Clinical Care Teams: A Position Paper of the American College of Physicians," which I co-wrote with my colleague Ryan Crowley on behalf of ACP's Health and Public Policy Committee. I know Ryan would agree with me that it was one of the more challenging papers we have written. Throughout the 2 years of research and writing the document, we struggled to find positions that would enjoy the support of ACP's own membership, which were themselves not entirely on the same page on how hard to push back against efforts to expand nurses' scope of practice, but also to move closer to finding common ground with the nursing profession.

There was almost universal agreement among ACP's leadership that physicians have unique training and skills that make them especially qualified to exercise advanced clinical leadership responsibilities for team-based care. But there was also recognition that APRNs, NPs, and other nonphysician professionals are essential members of the team, and, in some cases, they may have been held back from practicing to the full extent of their training and skills by overly restrictive internal supervision requirements and overly restrictive state laws. Some of ACP's members favored a more hard-line, physicians-should-always-be-in-charge stance, while others were open to a more nuanced approach that emphasized collaboration and sharing of clinical responsibilities within teams, putting less emphasis on who should run the show. During the process of writing the paper, we engaged in a constructive dialogue with respected members of the nursing profession, seeking to find common ground where possible or, at least, to avoid using words (like physician "supervision") that we learned from them were viewed as offensive, creating rhetorical barriers to achieving agreement.

In the end, I think the paper struck exactly the right balance, affirming that physicians do have unique and more advanced training and skills that make them especially qualified to exercise clinical leadership responsibilities for a team, while supporting the important and essential contributions of highly trained APRNs, NPs, PAs, clinical pharmacists and others in sharing patient care responsibilities, with all members of the team being allowed to practice to the full extent of their training. In other words, we came up with a nuanced approach to the issues of clinical leadership responsibilities within a team rather than defining the issue as being about who is in charge.

The problem is that the VA's proposal is anything but nuanced, because it frames the issue as a binary choice: Are you for or are you against allowing APRNs to practice independently, pre-empting any state law licensure laws that hold them back? Presented this way, is it any surprise that it has led to another divisive fight between the medical and nursing professionals?

ACP, for its part, thinks there is a better way. In our comments on the VA proposal, submitted Monday, we offered an alternative to the VA's proposal that tries to move the discussion away from considerations of "independence" and "hierarchy" to how to organize high-functioning, patient-centered clinical care teams that use everyone's skills to the maximum extent of their clinical training and skills, based on the principles in our 2013 paper.

Our alternative offered the following key points:

Tailor care teams to individual patients' needs. While ACP does not support the VA's proposal to broadly preempt state licensing laws to grant full independent practice authority to APRNs, we propose an alternative that matches patients with the healthcare professionals on the team who have the training and skills needed to meet their care needs, modeled on the recommendations in ACP's 2013 position paper.

Maintain access to personal physician. We express support for veterans being able to have access to a personal physician who accepts clinical responsibilities for care of the "whole person," consistent with the Patient-Centered Medical Home model. In a press release that summarizes our recommendations to the VA, ACP President Nitin S. Damle, MD, observed that "While internal medicine physicians have unique training to exercise clinical leadership responsibilities for the team and to care for adults with complex illnesses and diagnostic challenges, patients might appropriately be seen by other members of the clinical care team -- including nurses -- depending on their specific clinical needs and circumstances with physicians being available for referral or consultation as needed."

States should reexamine their laws. Because primary care encompasses various activities and responsibilities, it is simplistic to view primary care as a single type of care that is uniformly best provided by a particular healthcare professional. To illustrate, our letter observes that an advanced practice registered nurse providing primary care commensurate with his or her training may consult with or make a referral to an internal medicine physician, a family physician, or another physician specialist when presented with a patient with significantly complex medical conditions.

Effective clinical care teams allow each member of the team to practice to the full extent of their training and experience, ACP observed. While ACP does not support pre-emption of state licensing laws, it strongly encourages states to examine their laws to ensure that all clinicians are able to practice the full extent of their training and skill while practicing within a dynamic clinical care team.

Access to "virtual" care team. Our letter notes that especially in physician shortage areas, it may be infeasible for patients to have "an ongoing relationship with a personal physician trained to provide first contact, continuous and comprehensive care. They may also be unable to have immediate on-site access to other team members who may be located some distance from where the patient lives and accesses medical care. In such cases, collaboration, consultation, and communication between the primary care clinician or clinicians who are available on site and other out-of-area team members who may have additional and distinct training and skills needed to meet the patient's health care needs are imperative. We suggested the even if a physician and APRN are not physically co-located, the patient should have access to a 'virtual' clinical care team through use of telemedicine, electronic health records, regular telephone consultations, and other technology to enable the on-site primary care clinician and all members of the health care team to effectively collaborate and share patient information. Telemedicine and telehealth technologies can help virtual clinical care teams provide clinical consultation and decision support as well as patient education, remote monitoring, and other services."

I am under no illusion that ACP's approach will be the basis for a truce between the medical and nursing professions on the VA's proposal or, more broadly, over the other raging battles over preserving, changing, or superseding state laws that set limits on what nurses can do independently. These fights will go on, precisely because they present the issue as "either/or" choices. I am hopeful that ACP's nuanced approach of trying to move the discussion towards how both professions can work together, rather than fighting against each other, will eventually bridge some of the differences over leadership, supervision, and scope, especially at the level where care is actually delivered, when teams of clinicians, highly trained in their own disciplines, work closely and collaboratively together while focused solely on what is best for their patients.

Today's question: What do you think of the VA proposal and ACP's alternative?

Bob Doherty is senior vice president of government affairs and public policy at the American College of Physicians and author of the ACP Advocate Blog, where a version of this post originally appeared.

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ACP's View on Newest Doctor-Nurse Battle

Stereotactic Radiosurgery Benefit for Brain Mets: Case Closed? (CME/CE)

Action Points

• The use of stereotactic radiosurgery (SRS) alone on patents with one to three brain metastases results in less cognitive deterioration than when combined with whole brain radiotherapy (WBRT).
• Note that the study suggests that WBRT should not be routinely added to SRS for patients with three or fewer brain metastases, but that WBRT could still have a role to play in the treatment of patients not in that disease category.

The use of stereotactic radiosurgery (SRS) alone on patents with limited (one to three) brain metastases results in less cognitive deterioration than when combined with whole brain radiotherapy (WBRT), investigators have reported.

In a study led by Paul D. Brown, MD, director of the CNS stereotactic radiotherapy program at the University of Texas MD Anderson Cancer Center, researchers determined there was less cognitive deterioration in patients who underwent SRS alone after 3 months (64%), than in patients who underwent SRS plus WBRT (92%).

The results, published online in the Journal of the American Medical Association, showed a "significant difference" in the level of cognitive deterioration, particularly considering the controversy surrounding the role WBRT should play in the treatment of patients with brain metastases, the authors wrote.

The use of WBRT has been associated with cognitive decline, and while previous randomized clinical trials have demonstrated improved intracranial tumor control with the combined use of WBRT and SRS for brain metastases, none have showed any significant survival advantage with adjuvant WBRT.

"Central to this issue is whether tumor progression anywhere in the brain is more detrimental to a patient's well-being than the potential deterioration of cognitive function and quality of life associated with WBRT," Brown and his colleagues wrote. "Because more than 200,000 individuals in the United States alone are estimated to receive WBRT each year, it is important that the potential benefits and risk of adjuvant WBRT be clearly defined."

The study involved 213 patients from 34 institutions in North American who had between one and three brain metastases (all less than 3 cm in diameter); participants were randomized to receive SRS or SRS plus WBRT.

After excluding patients who died, did not return for a 3-month or subsequent evaluation, or did not complete the required baseline tests, 111 patients were available for evaluation.

There was less cognitive deterioration at 3 months after use of SRS alone (40 of 63 patients, 63.5%) than with the SRS-plus-WBRT group (44 of 48 patients, 91.7%). This was a difference of 28.2%; 90% CI, -41.9% to -14.4%).

In addition, quality of life was higher at 3 months with SRS alone (mean change from baseline, −0.1 versus −12.0 points; mean difference, 11.9; 95% CI, 4.8-19.0 points).

The time to intracranial failure was shorter for those in the SRS-alone group compared with those in the SRS-plus-WBRT group (hazard ratio [HR], 3.6; 95% CI, 2.2-5.9), and there was no significant difference in functional independence between the two groups at three months.

Median overall survival was 10.4 months for patients receiving SRS alone and 7.4 months for those given the combined treatments (HR, 1.02; 95% CI, 0.75-1.38).

"In the absence of overall survival, these findings suggest that for patients with one to three brain metastases amenable to radiosurgery, SRS alone may be a preferred strategy," the team concluded.

Limitations to the study included the fact that a majority of the participants had lung cancer and the trial did not attempt to include other types of primary cancers. However, Brown and his colleagues noted that lung cancer is the predominant primary cancer reported in most brain metastases trials and that "there is no obvious biological basis to believe that the quality-of-life and cognitive effects of WBRT would vary between different primary cancers."

The authors also noted that there was significant patient dropout in their trial, mostly due to death, and that clinicians and trial participants were not blinded to treatment.

In an editorial accompanying the study, titled "Whole Brain Radiotherapy for Brain Metastases: Is the Debate Over?," Orit Kaidar-Person, MD, Carey K. Anders, MD, and Timothy M. Zagar, MD, wrote that the trial "confirms previous recommendations that WBRT should not be routinely added to SRS for patients with brain metastases of limited number or size."

But, while there may be little role for WBRT in the type of patient enrolled in the this particular study, the editorial argued that based on the findings, and "until proven otherwise," WBRT could still have an important role to play in the treatment of patients not in that disease category.

"However, the study results cannot be extrapolated to infer that SRS is the standard for patients with four or more metastases or that WBRT no longer has a role in the treatment of brain metastases," Kaidar-Person and his colleagues wrote.

The authors report that there were no commercial sponsors for the study. One co-author reported relationships with Orbus Therapeutics and Bristol-Myers Squibb.

• Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco

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Stereotactic Radiosurgery Benefit for Brain Mets: Case Closed? (CME/CE)

Group Seeks to Close Malpractice Reporting 'Loophole'

Public Citizen has filed suit to close a "corporate shield loophole" that it says undermines the accountability of physicians and the safety of patients.

The complaint, filed in U.S. District Court in Washington, D.C., asks a federal judge to order the Department of Health and Human Services and the Health Resources and Services Administration to act on a May 2014 citizen petition to close the loophole.

Currently, physicians and other providers are able to evade medical malpractice reporting requirements in the National Practitioner Data Bank, Public Citizen said Tuesday.

Michael Carome, MD, director of Public Citizen's Health Research Group, said NPDB rules are not consistent with the federal statute that established the NPDB.

The loophole allows a physician to avoid being reported to the NPDB if a malpractice plaintiff agrees to dismiss the practitioner from a lawsuit or claim, leaving a hospital or other corporate entity as the sole defendant.

"It is well past time for HHS to issue a rule slamming the door on this loophole, as it should have done when it first acknowledged the problem more than 15 years ago when the agency issued a proposed rule to close the loophole," Carome said in a press release. "The agency later withdrew the proposal, leaving the loophole open."

The NPDB is used by state licensing boards, hospitals, and health maintenance organizations to conduct background checks to learn if a physician or other healthcare providers have been sanctioned for misconduct by a hospital, have had their licenses to practice curtailed, or had malpractice payments made on their behalf.

"The NPDB was created to ensure patient safety by providing a comprehensive, reliable information center concerning the malpractice payment and disciplinary history of physicians and other health care practitioners," Carome said. "The corporate shield loophole makes the NPDB's information less complete, less reliable and less useful."

Organizations must be authorized to access NPDB's reports. Individuals and organizations who are subjects of the reports may access their own information. Otherwise, the reports are not available to the public.

This report is brought to you by HealthLeaders Media.

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Group Seeks to Close Malpractice Reporting 'Loophole'

Tweet of the Week: Poop Chart

Welcome to another edition of the MedPage Today Tweet of the Week! Every Sunday, the editorial team highlights its favorite 140-character contribution from the healthcare twittersphere.

This week's winner is Abraham E. Gracia R. (@Abraham_RMI), an internal medicine physician. Some physicians have stool-color charts for their patients, but this infographic from The BMJ really takes the ... sausage.

What is the best way to manage neurogenic bowel dysfunction? #BMJEducation https://t.co/HBC2B1GIum http://pic.twitter.com/aJfgZjBZEO

— The BMJ (@bmj_latest) July 27, 2016

Thanks for sending your nominations! We want to hear from you. Nominate your favorite tweets by sending an email to editorial@medpagetoday.com.

Past Winners:

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Tweet of the Week: Poop Chart

Mirena IUD Lawsuits Tossed Out

(Reuters) -- A New York federal judge has ruled in favor of Bayer AG against nearly 1,300 lawsuits filed by women who say they suffered internal injuries from the company's Mirena intra-uterine contraceptive device.

U.S. District Judge Cathy Seibel in White Plains said on Thursday that there was no way for the lawsuits to continue after her earlier ruling barring crucial testimony from plaintiffs' experts.

Lawsuits against Bayer over Mirena started to pile up in 2011 and were consolidated in the New York court in 2013.

Mirena -- a small T-shaped plastic device inserted into the uterus -- carries a risk of perforating the uterus during insertion. Bayer warns about this possibility on the product's label.

The plaintiffs in the lawsuits, however, say that Mirena perforated their uteruses after insertion, and that Bayer failed to warn them about this possibility. They sought damages from the company.

Bayer has maintained in court filings that there is no evidence Mirena can perforate the uterus after insertion. It has said that a perforation that occurs during insertion may only be detected later.

In March, Seibel granted Bayer's motion to bar plaintiffs' expert witnesses from testifying that Mirena could cause uterine perforation after insertion. She found that their opinions were not supported by scientific literature and had been developed for the purpose of the litigation.

In Thursday's order, Seibel said that without the expert testimony, no jury would have a sound basis to find in favor of plaintiffs. She ordered that judgment be entered in favor of Bayer in all of the cases.

Attorneys for the plaintiffs and a spokesman for Bayer could not immediately be reached for comment.

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Mirena IUD Lawsuits Tossed Out

PodMed: A Medical News Roundup From Johns Hopkins (with audio)

PodMed is a weekly podcast from Johns Hopkins Medicine. In it, Elizabeth Tracey, director of electronic media for Johns Hopkins Medicine, and Rick Lange, MD, president of the Texas Tech University Health Sciences Center in El Paso, look at the top medical stories of the week.

This week's topics include the cost of physical inactivity, the mortality impact of sedentary behavior, behavioral activation for depression, and skin inspections for skin cancer.

Program notes:

0:32 Mortality and physical inactivity

1:33 If you sit for 8 hours increased mortality by 58%

2:33 Looked at over a million individuals

3:31 You have to do 60-95 minutes

3:44 Global economic burden of inactivity

4:44 Physical activity declining worldwide

5:11 Behavioral activation for depression

6:11 Go out to exercise or go out to dinner

7:11 May have applicability widely

7:25 USPSTF recommendations for skin inspection

8:25 Only about 50% with dermatologists

9:12 Inspect even scalp

10:08 End

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PodMed: A Medical News Roundup From Johns Hopkins (with audio)

MRI Findings Match Patients' Experience With RA (CME/CE)

Action Points

• Patient-reported outcomes in rheumatoid arthritis (RA) correlate independently with measures of inflammation and structural damage on MRI scans.
• Note that there was no relationship found between x-ray progression of disease and functional decline, suggesting that MRI may be a better discriminator of functional decline.

Patient-reported outcomes in rheumatoid arthritis (RA) correlate independently with measures of inflammation and structural damage on MRI scans, according to data from a longitudinal study.

For example, at 1 year, the change in MRI-detected synovitis was significantly associated with changes in physical function on the Health Assessment Questionnaire (HAQ) (beta = 0.53, 95% CI 0.029-0.077, P<0.001), according to Joshua F. Baker, MD, of the University of Pennsylvania in Philadelphia, and colleagues.

In addition, change in synovitis at 1 year was associated with pain scores (beta = 0.16, 95% CI 0.058-0.25, P=0.002) and patient global assessment (beta = 0.16, 95% CI 0.066-0.25, P=0.001), the researchers reported in Annals of the Rheumatic Diseases.

The association between longitudinal MRI measures and changes in patient-reported outcomes had not been assessed previously. For this analysis, the researchers used a cohort of 291 patients with MRI scores for synovitis, osteitis, and/or bone erosion from a larger group enrolled in the Go-BEFORE placebo-controlled clinical trial, which randomized methotrexate-naïve patients to golimumab (Simponi), methotrexate, or the combination.

MRIs were obtained at the patient's dominant wrist and second to fifth metacarpophalangeal joints, and the images were scored by two independent readers.

Correlations between the RA-MRI scoring system (synovitis, osteitis, and bone erosion) and physical function, pain, and global patient scores, were determined at weeks 0, 12, 24, and 52. Patients then were followed for an additional year.

MRI measures were associated with scores on the HAQ at all assessments, while MRI measures were increasingly associated with pain and patient global scores at later follow-up time points.

"Improvements in synovitis at 12, 24, and 52 weeks were generally associated with greater improvements in HAQ, pain and patient global scores," wrote Baker and colleagues. Changes in bone erosion were associated positively with changes in pain and patient global at later follow-up times.

In longitudinal regression models, synovitis was significantly associated with HAQ independent of the disease activity score in 28 joints (DAS28) using C-reactive protein (CRP). Synovitis was also associated with pain and patient global scores independent of CRP and swollen and tender joint counts.

Further, longitudinal models demonstrated that progression in bone erosion was associated with worse physical functioning, independent of synovitis and DAS28-CRP. These findings suggest that MRI measures are valid as RA biomarkers, and that the associations are independent of clinical disease activity.

"Thus, for two individuals with similar clinical assessments, the individual with greater synovitis on MRI is likely to have worse pain and function. These data indicate that synovitis and bone erosion are complementary to other clinical parameters in terms of relevance to the patient experience."

"The current study suggests that progression in the MRI erosion score (>0.5) is associated with a change in HAQ of 0.35 at 1 year," the investigators wrote. "In addition, a 4.4-unit change in MRI erosion score would translate into a change in HAQ of 0.2."

There was no relationship found between x-ray progression of disease and functional decline over 1 year, which suggests that MRI may be a better discriminator of functional decline, the authors suggested.

"Of note, we found that changes in synovitis were more strongly correlated with HAQ during the treatment of active inflammation in year 1, while changes in bone erosion were correlated similarly throughout the 2-year period," the authors added.

The correlations between patient-reported outcomes and MRI measures were similar regardless of the treatment received.

They concluded that, "improvements over time in MRI inflammation and deterioration in MRI damage correlate with changes in function, pain and patient global scores, suggesting that these objective measures reflect how patients experience their disease."

Because of the correlation found between patient-reported outcomes and MRI measures, these measures may serve as a reasonable surrogate endpoint in observational and early interventional studies, they noted.

The findings of this analysis may not be entirely generalizable beyond the study population, according to the authors. The study also was limited in the patient-reported outcomes that were available as part of the randomized trial. Furthermore, there have been advances in MRI since the study was undertaken some 10 years ago, which may improve visualization of inflammation and structural changes.

Authors report financial relationships with AbbVie, Abbott, BMS, Janssen, Eli Lilly, Novartis, UCB, Roche, Merck, Boehringer Ingelheim, Celgene, Centocor, GSK, Mundipharma, Novo Nordisk, Schering-Plough, Takeda, Pfizer, and Wyeth. One author is an employee of Janssen Biotech.

The study was supported by a Veterans Affairs Clinical Science Research and Development Career Development award.

• Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco

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MRI Findings Match Patients' Experience With RA (CME/CE)

What's in an Earworm: That's Improbable!

Why do we get specific songs stuck in our head? In this 2015 study, Lassi A. Liikkanen and colleagues took to Twitter to study the psychology of earworms based on thousands of earworm-related tweets.

Why does popcorn jump around when it's popping? One scientist explains in this video (and study).

A recent analysis found that colons (the punctuation) may increase readership of academic papers.

Can you count things that don't exist but could? One philosopher ponders this possibility in a new paper.

"It helps to imagine under what conditions a man would be swimming at, say, the same Reynolds number as his own sperm," according to Edward M. Purcell. Learn more about the Reynolds number in Purcell's 1977 paper.

That's Improbable! is MedPage Today's weekly roundup of clinically, um, relevant finds at Improbable Research, which awards the Ig Nobel Prizes.

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What's in an Earworm: That's Improbable!

What We Heard This Week

"This ship has already sailed." Sam Chang, MD, responding to data from the first-ever randomized trial of robotic versus open surgery for localized prostate cancer.

"I predicted the robot would prove to show no meaningful advantage over the open approach. A decade later, this paper proves my conviction. Herbert Lepor, MD, also responding to results of the randomized comparison of robotic versus open prostatectomy.

"When you feel as a Republican that you've been running on 'repeal and replace the Affordable Care Act' for like 6 or 8 years, and your only criticism was, 'I didn't have the person in White House to sign it,' and then you don't do it [when a Republican is elected]? You know, people tell me it's not a big deal -- this is a big deal." -- Chris Jennings, former healthcare adviser to presidents Clinton and Obama, talking about what Republican lawmakers will do about the Affordable Care Act after the election.

"The epidemic of inactivity is sending a powerful reminder about our roots. It is time for action, through physical activity." -- Richard Becker, MD, Director at the University of Cincinnati Heart, Lung and Vascular Institute, commenting on a new study about the health risks of binge-watching.

"While the authors' prior study found that there is an increase in morbidity, these new findings will allow us to offer reassurance to our RA patients with regard to the potential effects in their children." -- Jennifer Murphy, MD, of Low Country Rheumatologists in North Charleston, S.C., commenting on a study that found overall childhood mortality was elevated in the offspring of parents with rheumatoid arthritis (RA).

"There have been lots of hints in the literature that some children with trisomy 13 and trisomy 18 can survive longer, but we haven't been able to look at these children surviving into their second decade of life from a population standpoint...this was the first time we've been able to identify a group of them within the population." -- Katherine E. Nelson, MD, of Hospital for Sick Children in Toronto, commenting on a study on survival rates in children with severe birth defects.

"Having administratively worked on this issue myself, it makes one happy to see education and public health campaigns translate into actual broad epidemiologic changes." -- David Hackney, MD, University Hospitals in Cleveland, on the declining number of early term birth interventions in the U.S.

"A vaccine is the ultimate female prevention tool ... you put it in your arm and it works in your vagina." Glenda Gray, MBChB, president of the South African Medical Research Council, commenting on a new HIV vaccine trial at the International AIDS Conference.

"After a century of trying, we declared that healthcare in America is not a privilege for a few; it's a right for everybody." -- President Obama at the Democratic National Convention, discussing one of the major accomplishments of his presidency, the enactment of the Affordable Care Act.

"We have to do things that nature has never before done" in order to find a cure for HIV. Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, commenting on cure research on the eve of the International AIDS Conference.

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What We Heard This Week

Friday Feedback: Alzheimer Drug Flop Frustrates Field

A drug for Alzheimer's disease targeting tau protein pathology failed to demonstrate a benefit in the primary analysis from phase III trial reported at the AAIC meeting. However, in a prespecified subgroup, patients who were not taking symptomatic treatments (e.g., cholinesterase inhibitors), the anti-tau drug therapy did show a statistically significant benefit in terms of cognition, functional ability, and brain atrophy. Patients had mild to moderate AD and the trial lasted 15 months.

We contacted neurology experts via email to ask:

How much of a disappointment are these results?

Was it a mistake not to combine this drug with an anti-amyloid drug, at least in one treatment arm?

Where does this leave the prevailing theories of Alzheimer's disease and the best ways to attack it?

The participants this week are:

Samuel Gandy, MD, PhD, professor of neurology and psychiatry at Mount Sinai Hospital in New York City

Claude Wischik, MD, PhD, study co-author and co-founder of drug sponsor TauRx, professor of psychiatric geratology at Aberdeen University

Lary C. Walker, PhD, associate professor of neurology at Emory University School of Medicine in Atlanta

Douglas Scharre, MD, professor of clinical neurology and psychiatry at The Ohio State University Wexner Medical Center in Columbus

George Grossberg, MD, Samuel W. Fordyce professor and director of geriatric psychiatry at St. Louis University School of Medicine

Disappointing?

Gandy: No surprise, no disappointment.

Wischik: The results are more a source of frustration than disappointment in that the potential of LMTX to provide an effective treatment in this devastating disease was only demonstrated in a small proportion of the trial subjects. However, the results of TauRx's second AD study confirm the findings of this first study and we look forward to the publication and presentation of these results, which is expected later in 2016.

Walker: The results are somewhat disappointing, but not necessarily surprising. Certainly the apparent positive outcome of LMTM monotherapy will need to be replicated in a larger group of subjects. As we learn more about the natural history of Alzheimer's disease, it has become clear that tau aggregation (like Abeta aggregation) is well-advanced in the brain by the time the signs of dementia set in. Hence, it may be that a therapy targeting tau must be administered much earlier in the pathogenic process to be effective.

Scharre: Very disappointing that another phase III trial for dementia treatments has failed. However, we definitely gain knowledge by every failure and that propels us closer to more efficacious treatments. The trial used mild to moderate AD subjects and so it is possible this tau aggregation inhibitor may have been applied to late in the course of the disease and that earlier use of this agent may provide benefit. Anti-amyloid agents are currently being tested in prodromal cases.

Grossberg: These results are quite disappointing, with many trying to sugarcoat the results of this negative study. The field was hoping for a new therapy with a new mode of action but this study is a clear setback for tau-based therapies.

Trial Critiques

Scharre: I think their method of not using anit-amyloid treatments was correct at this stage in their evaluation of their drug. Since anti-amyloid agents are far from proven to help AD subjects, adding another arm would have delayed the recruitment and study completion of this agent.

Gandy: I think that the ideal trial is to identity APOE4 positives in midlife 45-50 follow with annual amyloid scans and when positive, give anti-amyloid or anti-tau or both.

Wischik: It was important for a tau-targeted drug to be able to demonstrate the potential of this particular pathway as distinct from that of the amyloid pathway. Whether there is benefit from a combination of tau- and amyloid-focused treatments remains a valid question that will need to be explored in future studies when effective amyloid-focused treatments become available.

Grossberg: I am not a fan of combining two experimental drugs with different mechanisms of action and different side-effects in one vulnerable, elderly patient (with Alzheimer's disease, especially).

Walker: Eventually such combined therapy might be deemed necessary, but a single treatment would be preferable for a number of reasons. For instance, combining treatments could aggravate the side-effect profile in unexpected ways. Tau alone is a legitimate therapeutic target for AD, and it is possible that inhibition of tau aggregation could be effective later in the pathogenic cascade than are anti-amyloid-beta approaches. In my view, the design of the study was appropriate for this early stage of development of therapeutic strategies.

Future Steps

Grossberg: We still do not know which mechanism/s lead to brain cell death in Alzheimer's disease. This negative study combined with many negative amyloid-based treatment trials should encourage the field to look more aggressively at other than amyloid or tau -focused therapeutic/preventative interventions and in particular life/style and dietary modifications.

Walker: Overwhelming evidence supports the concept that the misfolding and self-assembly of amyloid-beta and tau drive the onset and evolution of Alzheimer's disease. This process begins in the brain many years before the first signs of dementia become apparent. A fundamental principal of alleviating chronic diseases is the importance of treating early; assuming that a therapeutic agent effectively engages the appropriate target in the brain, the largely negative results of AD trials to date may simply be telling us that an ounce of prevention is worth even more than a pound of cure.

Gandy: I think that we have no idea how early we need to intervene. APOE4-positive and amyloid-positive form the highest risk group. We know from autopsy some E4 have amyloid in their 40s.

Scharre: I do not feel that one negative trial regarding this tau aggregation inhibitor would at all change prevailing theories of AD. The fact that a small group of subjects not using symptomatic treatments currently available, improved with this drug, may suggest that further study of these agents or similar anti-tau agents would be worthwhile.

Wischik: I think the results of our two studies of LMTX in Alzheimer's will show that a tau-based approach to disease treatment has the potential to be effective. When we look at the number of patients suffering from the disease, and of the caregivers providing support to them, we clearly need to pursue all possible treatment avenues in parallel.

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Friday Feedback: Alzheimer Drug Flop Frustrates Field

AAP's Resuscitation App a Helpful Update

Childbirth is typically one of the most memorable and emotional moments in the lives of any parent, as well as providers who perform full-scope obstetrics. Luckily, in 90% of cases, infants tolerate the entire process of labor and delivery without issue. However, up to 10% of infants will require intervention by medical providers and approximately 1% will require extensive neonatal resuscitation (NRP).

In 2015, the American Academy of Pediatrics (AAP), in conjunction with the American Heart Association (AHA), released the latest update to NRP. This spring, the AAP released the 7th edition of its NRP course, and last month it released a companion app.

We have reviewed several of the AAP apps here on iMedicalApps and found them decidedly mixed in quality and price. Its new NRP app combines the easy to follow NRP algorithm with a copy of the full AAP/AHA guideline and videos highlighting the critical steps of NRP. Most importantly, this version of the medical app is a true app and not a web app like the previous version.

AAP NRP incorporates the most current version of the AAP/AHA NRP guidelines. The app contains a PDF version of the guideline viewable within the app as well as an easy-to-follow algorithm and videos of critical resuscitation steps.

Likes:

• Contains the most current version of the NRP guidelines.
• Helpful videos viewable offline.
• Easy-to-follow NRP algorithm included.

Dislikes:

• Quality of images could be improved, especially for algorithm.
• Utility of Facebook posts is questionable since one cannot post from within the app.
• Doesn't contain easy-to-locate or easy-to-calculate medication doses for resuscitation.

Overall:

The new AAP/AHA NRP medical app is a nice update to the previous "web-app." This version contains the most current 2015/2016 NRP guideline with helpful videos and a copy of the entire PDF of the updated guideline document. Best of all, this is a true medical app that works online as well as offline. Anyone who is an NRP provider/instructor should have this app.

Disclaimer: The views expressed are those of the author(s) and do not reflect the official policy of the Department of the Army, the Department of Defense or the U.S. Government.

This post appeared on iMedicalApps.com.

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CDC's Frieden: Florida Zika Cases Were Expected

Local Zika transmission in Florida appears to be associated with a trendy neighborhood in North Miami but there's no immediate need to urge people to stay away, according to CDC Director Tom Frieden, MD.

The four cases reported in Florida appear to have no other risk factor for Zika than an association with the Wynwood Arts District, Frieden told reporters in a telebriefing.

What would help pin down the apparent local transmission is finding infected mosquitoes in the area, he said, but that hasn't happened yet.

In the meantime, Frieden said, it remains unlikely that Florida will see a widespread outbreak that would increase the need for a travel advisory like those the CDC has issued for many countries in Latin American and the Caribbean, including Puerto Rico.

But, he added, "we will reassess that every single day."

The four patients were probably infected in the neighborhood early in July, became sick a week later, and were diagnosed a couple of days after that, Frieden said. The Florida health department immediately began an epidemiological investigation, which suggested the association with the Wynwood area.

One of the patients lives in nearby Broward county, but works in the Wynwood area.

Florida has begun door-to-door surveys to see if other cases can be found, he said, as well as conducting mosquito abatement measures in the Wynwood district.

He noted that Zika is a "very focal disease" -- it is spread by the Aedes aegypti mosquito, which travels only a few hundred feet during its entire lifetime, so that local abatement measures can have an important effect.

Experts have been predicting that some local transmission would occur in the parts of the southern U.S. where A. aegypti lives, so the Florida cases were "not unexpected," Frieden said.

He added that the timing was also expected -- it coincides with an upsurge in mosquitoes and it is roughly the same time of year that previous outbreaks of dengue fever have been seen.

Frieden also pointed out 89% of people infected by the virus have no symptoms, so finding cases in Miami doesn't mean residents or visitors are at greater risk than they would be elsewhere. It might just mean that cases elsewhere haven't been detected, he said.

But like dengue fever and chikungunya -- two related viruses also carried by A. aegypti -- it's likely that locally acquired cases in Florida will be "dead ends" and will not result in further transmission, Frieden said.

On the other hand, he repeated the CDC's advice to pregnant women -- use a DEET-based mosquito repellent, wear long sleeves and pants, and generally avoid mosquito bites.

Frieden's comments on the Florida cases came as the agency reported that some 5,582 people in Puerto Rico have been infected with the virus, including 672 pregnant women, from Nov. 1, 2015 to July 7, 2016.

In the July 29 issue of Morbidity and Mortality Weekly Report, investigators from the CDC and the Puerto Rico health department also reported that positive tests for people with suspected Zika rose from 14% in February to 64% in June.

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CDC's Frieden: Florida Zika Cases Were Expected

Absorb Stent: Thrombosis Still a Concern Longer-Term (CME/CE)

Action Points

• Note that this observational cohort study of patients with NSTEMI who received the Absorb bioresorbable stent at a single center found a nearly 7% rate of death, MI, and revascularization at 18 months.
• Be aware that the benefits of a bioresorbable stent are not likely to be seen until several years post-procedurally.

Scaffold thrombosis remained problematic for Absorb bioresorbable vascular scaffold implantation in real-life practice mid- to long-term, a study found, although some cardiologists suggested that truly long-term data will be needed to settle the issue.

At 18 months, the combined rate of cardiac death, MI, and target lesion revascularization was 6.8% (1.8%, 5.2%, 4.0% respectively for individual endpoints). The 1-year rate of adverse events was 5.1%.

"In our study, bioresorbable vascular scaffold implantation in a complex patient and lesion subset was associated with an acceptable rate of adverse events at longer-term," Robert-Jan M. van Geuns, MD, PhD, of Erasmus Medical Center in the Netherlands, and colleagues concluded in their study appearing online in JACC: Cardiovascular Interventions.

Yet scaffold thrombosis occurred in 2.7% of patients by a year and a half, with no early cases observed.

Underexpansion was noted in 26% of the lesions studied. "Our analysis shows that underexpansion of bioresorbable vascular scaffold occurs frequently and had a nonsignificant association with an increased risk of major adverse cardiac events and probable/definite stent thrombosis," according to the authors.

"Though the rates [of scaffold thrombosis] are similar to those observed in other bioresorbable vascular scaffold trials, it is still higher compared to second generation metallic drug-eluting stents [DES]," suggested Huay Cheem Tan, MBBS, and Rajiv Ananthakrishna, MD, DM, both of Singapore's National University Heart Centre.

"Scaffold under-expansion is a known important risk factor for scaffold thrombosis and restenosis. This can be addressed if intravascular imaging modality is more commonly adopted," the pair noted in an accompanying editorial.

"With a universal adoption of optimal implantation techniques and enhanced scaffold design, it remains to be seen whether scaffold thrombosis rates will be further reduced."

"Although it is not clear why this complication is observed in high incidence with bioresorbable vascular scaffolds, a potential explanation could be the increased thickness of the bioresorbable vascular scaffold struts, which can cause convective flow patterns, potentially triggering platelet deposition and subsequent thrombosis, especially in settings with suboptimal flow conditions," van Geuns and colleagues wrote.

"For this reason, bioresorbable vascular scaffolds with thinner struts are currently being developed and animal studies are ongoing."

The BVS Expand Registry served as the source of data for van Geuns and his team. Their prospective, single-center study included 249 patients presenting with non-ST-segment elevation MI, stable or unstable angina, or silent ischemia due to a blocked coronary artery. Notably, cases of ST-segment elevation MI were excluded.

In this study population, 38.1% had type B2 or C lesions; 21.3% had bifurcation lesions; 45.6% had multivessel disease; and 42.2% presented with moderately- or severely-calcified lesions. Men accounted for 73.5% of the group, which had a mean age of 61.3.

The mean acute lumen gain was 1.39 mm after Absorb placement.

Selection bias and the lack of direct comparison with metallic DES were two important caveats to the registry investigation, in addition to its nonrandomized design, the authors acknowledged.

Tan and Ananthakrishna, however, argued that this type of study still had its merits. Compared with what is gleaned from randomized trials, "knowledge from the registry studies do contribute to a better understanding of device-oriented patient outcomes," according to the editorialists.

The bigger issue seemed to be the availability of data on longer follow-up.

"The unique properties of bioresorbable vascular scaffolds are not expected to be obvious until 3 to 5 years after its implantation. The reported follow-up period of 18 months in this registry might be insufficient to address the potential plausible advantages of bioresorbable vascular scaffolds," they wrote.

"It is still unclear whether it should be used routinely in clinical practice, in anticipation of its potential promising long-term advantages. Perhaps, there is a need to wait a bit longer for the final verdict to be known," Tan and Ananthakrishna concluded.

The study was supported by Abbott Vascular.

Van Geuns disclosed receiving a speaker's fee from Abbott Vascular.

Tan and Ananthakrishna reported no relevant conflicts of interest.

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Absorb Stent: Thrombosis Still a Concern Longer-Term (CME/CE)

Full-Dose NOAC Safe With Single Dose-Reduction Factor (CME/CE)

Action Points

• Note that this secondary analysis of a randomized trial comparing apixaban to warfarin for stroke prevention in atrial fibrillation showed that, even among patients with one dose-reduction criteria, apixaban had similar efficacy and superior safety to warfarin.
• Dose reduction criteria include advanced age, poor renal function, and low body weight.

In patients with atrial fibrillation, the risk for major bleeding is lower with apixaban (Eliquis) than with warfarin (Coumadin), regardless of age, body weight, or serum creatinine level, a secondary analysis of the pivotal ARISTOTLE trial showed.

The 22.8% of patients assigned to receive the most common, 5-mg twice daily dose of apixaban who had one dose-reduction criterion -- advanced age, low body weight, or renal dysfunction -- were at higher risk. They had higher rates of stroke or systemic embolism (HR 1.47; 95% CI 1.20-1.81) and major bleeding (HR 1.89; 95% CI 1.62-2.20) compared with the 79.6% of participants with no dose-reduction criteria.

But the stroke or systemic embolism risk reduction was similar to warfarin in patients with one dose-reduction criterion (HR 0.94; 95% CI 0.66-1.32) and those with no dose-reduction criterion (HR 0.77; 95% CI 0.62-0.97; P=0.36 for interaction), John H. Alexander, MD, of Duke Clinical Research Institute in Durham, N.C., and colleagues reported online in JAMA Cardiology.

Likewise, the benefit on major bleeding versus warfarin was similar with one dose-reduction criterion (HR 0.68; 95% CI 0.53-0.87) and no dose-reduction criterion (HR 0.72; 95% CI 0.60-0.86; P=0.71 for interaction).

"The 5 mg twice daily dose of apixaban is safe, efficacious, and in the absence of additional data on the efficacy and safety of reduced apixaban doses compared with warfarin, should be the preferred dose of apixaban for patients with one dose- reduction criterion," the researchers wrote.

Jeffrey I. Weitz, MD, and John W. Eikelboom, MD, of McMaster University in Hamilton, Ontario, agreed in an accompanying editorial.

"Until more is known, the 2.5 mg twice daily dose should only be prescribed for patients with atrial fibrillation [AF] with at least two of the three dose-reduction criteria," they wrote, adding, "it is essential that apixaban and the other direct oral anticoagulants be given at the right dose for the right patient."

"Education is urgently needed to translate this information into practice because the inappropriate use of the lower dose of apixaban may place patients at risk for stroke," they wrote. They added that the success of educational efforts can be tracked by monitoring prescription trends.

In the study, researchers looked at a subgroup of patients with only one of three dose-reduction criteria -- an age of 80 years or older, a body weight of 60 kg or less, and a creatinine level of 1.5 mg/dL or higher -- receiving the 5-mg twice daily dose of apixaban vs warfarin in the the double-blind ARISTOTLE trial, which included 18,201 patients with AF and at least one additional risk factor for stroke or systemic embolism.

Although most of the patients randomized to apixaban in the trial received the 5 mg twice daily dose, patients with two or three dose-reduction criteria at baseline were assigned the reduced 2.5 mg twice daily dose. Those patients were excluded from the secondary analysis. Warfarin was dose adjusted to achieve a target international normalized ratio (INR) of 2.0 to 3.0.

Even for the oldest, slimmest patients with the most compromised renal function, the 5-mg twice daily dose of apixaban was associated with substantially less bleeding than warfarin, Alexander and colleagues noted.

Patterns for each dose-reduction criterion were similar across the spectrum of age, body weight, creatinine level, and creatinine clearance, the researchers said.

They pointed out that while anticoagulation alternatives to warfarin hold the promise of more effective and safer stroke prevention, quality improvement programs must ensure that patients with AF receive "the correct dose on the basis of available evidence from clinical trials."

The researchers acknowledged that data from the ARISTOTLE trial population may not be generalizable to other populations of patients with AF and that no study has been conducted comparing the efficacy of the 5 versus 2.5 mg twice daily doses of apixaban in any population of patients with AF.

"The effect of the 2.5 mg twice daily dose of apixaban on stroke or bleeding in patients without two or more dose-reduction criteria is unknown," they said.

The study was supported by Bristol-Myers Squibb and Pfizer.

Alexander reported relationships with Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Pfizer, Tenax Therapeutics, Regado Biosciences, Bayer, Bristol-Myers Squibb, CSL Behring, Daiichi Sankyo, GlaxoSmithKline, Janssen, Pfizer, Inc., Portola, and Somahlution. The other study authors also reported relationships with industry.

Weitz reported relationships with Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Daiichi-Sankyo, Ionis Pharmaceuticals, Janssen Pharmaceuticals, Merck, and Portola.

Eikelboom reported relationships with AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Janssen Pharmaceuticals, and Sanofi Aventis.

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Full-Dose NOAC Safe With Single Dose-Reduction Factor (CME/CE)

Flu Shot Cuts CVD in T2D; TAVR Leak Blood Test; HFpEF Survival Up

Fatigue in Sjogren's: A Paradoxical Response (CME/CE)

Action Points

• Factors that were associated with high levels of fatigue among patients with Sjogren's syndrome included pain and depression, as well as low levels of two proinflammatory cytokines, inerferon (IFN)-γ and IFN-γ-induced protein-10.
• Note that clinical disease activity did not appear to correlate with fatigue.

Factors that were associated with high levels of fatigue among patients with Sjogren's syndrome included pain, depression, and -- unexpectedly -- low levels of two proinflammatory cytokines, a U.K. study found.

In a logistic regression model, pain, depression, and low levels of interferon (IFN)-γ and IFN-γ-induced protein-10 (IP-10) predicted fatigue in 67% of cases, according to Wan-Fai Ng, PhD, of the Institute of Cellular Medicine at Newcastle University in Newcastle-upon-Tyne in England, and colleagues.

However, clinical disease activity did not appear to correlate with fatigue, the researchers reported online in RMD Open: Rheumatic & Musculoskeletal Diseases.

Inflammation has been postulated to have a central role in fatigue associated with chronic autoimmune disease as part of a phenomenon termed sickness behavior.

"Sickness behavior is considered an evolutionarily adaptive behavioral response to infection facilitating speedy recovery, minimizing energy expenditure, and reducing environmental risks when an organism is in a weakened state during and following an infection," Ng and colleagues explained.

Because this response is mediated by proinflammatory cytokines, it has been assumed that inflammation would be responsible for fatigue in chronic disease.

However, the finding that proinflammatory cytokine levels were lower among patients with high levels of fatigue "does not ... support a simple concept of higher levels of inflammation leading to worse fatigue,"

Previous research has found that inflammatory burden does not necessarily correlate with fatigue scores in diseases such as Sjogren's syndrome, rheumatoid arthritis, and lupus, "suggesting that there may be a complex range of positive and negative feedback loops contributing to fatigue in autoimmune conditions," they wrote.

Sjogren's syndrome is a suitable disease model for investigating fatigue because of its straightforward diagnostic criteria and the fact that patients generally are not receiving potent immunosuppressive drugs that could influence fatigue, according to the authors. There also is a wide variability in the degree of fatigue that patients with this condition report.

Therefore, to explore the potential relationship between inflammation, fatigue, and other disease characteristics, the researchers selected 159 women and 28 healthy controls from the U.K. Primary Sjogren's Syndrome Registry.

Physical fatigue was rated as minimal, mild, moderate, and severe on a 0-7 scale, while depression and anxiety were assessed with the Hospital Anxiety and Depression Score. Clinical assessments included the European League Against Rheumatism Sjogren's Syndrome Disease Activity Index and Patient Reported Index, along with measures of salivary gland function and sicca scores.

Immunoassays for 24 pro- and anti-inflammatory cytokines were performed using specimens from the registry's biobank, and other inflammatory markers such as C-reactive protein and erythrocyte sedimentation rate also were measured.

At baseline, 43% of patients were receiving immunomodulating agents, most often hydroxychloroquine.

Increased fatigue was associated with higher lymphocyte counts and lower IgG levels and also with depression, pain, anxiety, salivary dryness, and overall symptoms.

"As expected," multiple proinflammatory cytokines were present in higher levels among patients with Sjogren's syndrome than among controls, including tumor necrosis factor (TNF)-α, IP-10, interleukin (IL)-6, IL-10, IL-17, and lymphotoxin (LT)-α.

But when levels of those cytokines were analyzed according to levels of fatigue, inverse correlations were seen for IP-10, TNF-α, LT-α, and IFN-γ.

In the logistic regression analysis including all potentially predictive clinical and laboratory parameters plus the 24 cytokines, fatigue was predicted accurately in 67% of cases. Narrowing the analysis to include only the cytokines IFN-γ and IP-10 along with pain and depression, but eliminating clinical measures, resulted in the same "reasonably accurate" predictive value.

"This suggests that measures of disease activity in primary Sjogren's syndrome appear to be less important than cytokines, depression, and pain in accurately predicting fatigue levels," the researchers observed.

As to why lower levels of inflammatory markers would be associated with worse fatigue, the authors suggested that there might be a negative feedback loop where inflammatory markers are reduced but fatigue persists.

"Thus, although fatigue is induced by proinflammatory cytokines as part of an 'adaptive behavior response,' which has evolved as a protective motivational state during and following an infection, a potentially maladaptive immune response may contribute to the maintenance of persistent fatigue after clearance of a pathogen or in a chronic inflammatory state," Ng and colleagues wrote.

In a healthy patient, they explained, exposure to an infectious agent leads to an immune response triggering inflammatory pathways resulting in sickness behavior, followed by restoration of immune homeostasis and normalization of the behavioral response. But in a patient whose immune response is dysregulated, the anti-inflammatory response becomes excessive and continues to upregulate the immune system "in a pathological feedback loop," and the sickness behavior persists.

Limitations of the study included its cross-sectional design and the possibility of additional unmeasured factors contributing to fatigue.

The study was funded by the Medical Research Council, th eNewcastle NIHR Biomedical Research Center for Aging and Chronic Diseases, and the North East and North Cumbria Local Comprehensive Research Network.

Ng and co-authors disclosed financial relationships with Celgene, Eli Lilly, Glenmark, GlaxoSmithKline, Medimmune, Novartis, Ono, Pfizer, Takeda, and UCB.

• Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco

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Fatigue in Sjogren's: A Paradoxical Response (CME/CE)

Improved T2DM Survival Fuels Higher Prevalence (CME/CE)

Action Points

• Note that this registry-based study found an increasing prevalence of diabetes in Scotland from 2004 to 2013, driven largely by decreases in mortality.
• Be aware that the excess risk of death among those with diabetes compared to the general population remain quite high.

The prevalence of type 2 diabetes has increased in Scotland during the last decade, as it has in other Western countries, but that's not necessarily a bad thing, U.K. researchers said.

Mortality rates among people with type 2 diabetes have declined, while the incidence of new cases has levelled off. It's those twin trends that have led to a net increase in the number of people living with the disease, explained Stephanie Read, PhD, of the University of Edinburgh, Scotland, and colleagues.

In Scotland, the mortality rate among people with type 2 diabetes declined from 19.8 per 1,000 in 2004 to 16.7 per 1,000 in 2013. During the same time period, the incidence of new cases remained at about 4 per 1,000 and the prevalence of the disease increased from 3.2% to 5.1%, Read and colleagues reported in Diabetologia, the journal of the European Association for the Study of Diabetes.

In raw numbers, there were 77,953 deaths among people with type 2 diabetes in Scotland from 2004-2013, and 180,290 new cases were diagnosed during that time, leading to an increase of 102,337 in the number of people living with the disease.

"Our findings suggest that improved survival is the leading contributor to increasing diabetes prevalence, and these trends are likely to have important implications for health services, partly through the possible increased incidence of complications resulting from longer diabetes durations," Read and colleagues said.

Despite the declining mortality rates, the excess risk of death among people with type 2 diabetes, compared with those without, remained high. The excess risk of death was approximately 40% among men and 80% among women, Read and colleagues said.

"Despite improvements in absolute mortality rates, type 2 diabetes confers an excess risk of death compared with the non-diabetic population, and this excess risk is higher in Scotland than in other countries. There is still scope to address the increased mortality associated with type 2 diabetes," the study authors said.

The researchers analyzed data from the Scottish national diabetes register, Scottish Care Information-Diabetes (SCI-Diabetes). They determined overall type 2 diabetes incidence and mortality rates, as well as age- and sex-specific rates, stratified by year from 2004 to 2013. Their findings mirrored those from other Western countries, including the United States, Denmark, Sweden, Canada, and Australia, they said.

Highlights of the study included the following:

• Standardized mortality rates declined by 11.5% for men and 15.7% for women with type 2 diabetes during the study period
• The proportion of men among incident cases increased from 53% to 57%
• For both men and women, incidence rates were highest at 75 years of age and lowest at 45 years of age
• Incidence rates increased slightly over the study period in 45-year-old women but declined in older women
• From 2004 to 2009, incidence rates increased in men ages 45 and 55 years, but declined after 2009. In older men, incidence rates declined during the study period
• Incidence rates were higher among the poor, and actually increased among the poorest individuals from 2010 onward

One reason for the stabilized type 2 diabetes incidence rates may be a dwindling pool of undiagnosed cases, Read and colleagues suggested. They noted that when the World Health Organization lowered the threshold for diagnosing diabetes in 1998, it led to a marked increase in diabetes incidence rates. But recent studies have suggested the number of undiagnosed cases is dropping in Scotland, Germany, and the U.S., the researchers said.

Another reason may be the prevalence of adult obesity, an established risk factor for type 2 diabetes, has also stabilized. "Estimates from the Scottish Health Surveys indicate that the proportion of adults who were obese increased from 24.2% in 2003 to 27.1% in 2009 but remained constant thereafter," Read and colleagues said.

The higher incidence rates observed in men may be due to the higher risk associated with male body fat distribution and greater insulin resistance among men relative to women, Read and colleagues suggested. "Findings from a study conducted using the SCI-Diabetes dataset support this notion, with men developing type 2 diabetes at lower BMIs [body-mass indexes] than women of a similar age, with particularly marked differences at younger ages," they said.

The finding of higher incidence rates among the poor "underline the importance of targeting efforts to improve levels of modifiable risk factors in more deprived groups to achieve reductions in type 2 diabetes incidence and health inequalities," Read and colleagues said.

As far as the reduced mortality rates, better management of risk factors such as hypertension, cholesterol, blood sugar, and smoking have likely contributed, the investigators said. They noted that in Scotland, the proportion of type 2 diabetics with glycated hemoglobin levels below 7.5%, indicating good diabetes control, increased from 63% in 2004 to 79% in 2013.

"Our findings support the notion that stabilizing obesity prevalence and the potentially smaller numbers of people with undiagnosed diabetes through intensified diagnostic activities in earlier years have resulted in stable or declining type 2 diabetes incidence in Scotland," Read and colleagues concluded.

They added, "Major inequalities by age, sex and socioeconomic status in type 2 diabetes incidence and mortality highlight the need to implement effective approaches to the prevention and treatment of type 2 diabetes that also attempt to address existing inequalities."

The study was funded by the Scottish Government and NHS Research Scotland.

Read reported no financial relationships with industry.

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Improved T2DM Survival Fuels Higher Prevalence (CME/CE)

Locked Psych Wards Found No Safer

Locked inpatient wards do not reduce suicide attempts or unauthorized absence among patients with mental illness, researchers said.

A 15-year observational study of approximately 145,000 cases led researchers to that conclusion, published online in Lancet Psychiatry.

"These findings suggest that locked-door policies may not help to improve the safety of patients in psychiatric hospitals, and are not generally successful in preventing people from absconding," said lead study author Christian Huber, MD, of the Universitäre Psychiatrische Kliniken Basel in Switzerland, in a statement. "In fact, a locked-door policy probably imposes a more oppressive atmosphere, which could reduce the effectiveness of treatments, resulting in longer stays in hospital. The practice may even lend motivation for patients to abscond."

Many hospitals that care for the mentally ill use locked-door policies that restrict freedom of movement in the name of safety.

The study examined 145,738 admissions to 21 German inpatient psychiatric hospitals from 1998 to 2012. The most common diagnoses included dementia, substance use disorders, schizophrenia, affective disorders, stress related disorders, and personality disorders. The four measured outcomes were suicide, suicide attempts, absconding with return, and absconding without return.

Huber and colleagues found, in comparing overall outcomes in hospitals that used locked wards with those that had none, that suicide (OR 1.326, 95% CI 0.803-2.113; P=0.24), suicide attempts (OR 1.057, CI 0.787-1.412; P=0.71), absconding with return (OR 1.288, CI 0.874-1.929; P=0.21), and absconding without return (OR 1.090, CI 0.722-1.659; P=0.69) all were not significantly greater under open-door policies.

In a separate analysis comparing patients in locked wards to those in unlocked units, the latter had lower probabilities of suicide attempts (OR 0.658, 95% CI 0.504-0.864; P=0.003), absconding with return (OR 0.629, 0.524-0.764; P<0·0001), and absconding without return (OR 0.707, CI 0.546-0.925; P=0.01).

Completed suicides were neither more nor less common in unlocked versus locked wards (OR 0.823, CI 0.376-1.766; P=0.63).

"It could be supposed that in completely open hospitals, patients at higher risk of suicide might be more able to leave and die by suicide," the authors wrote. "However, locked wards might not adequately address this issue: about 13%-38% of patients leave a locked unit without the permission of staff. Indeed, patients seem to wait until they have their first chance to leave as soon as coercive measures are ceased. Thus, the safety of locked wards for the prevention of suicide might be overestimated, and patients at high-risk might be lost from treatment."

Huber and colleagues called for more studies to determine whether their findings are applicable in different countries and circumstances, but noted that "the large sample size and naturalistic study design, the inclusion of a large number of hospitals, and the availability of data over an extended observation period all enhance the generalisability of our findings."

In an accompanying commentary, Tom Burns, from the University of Oxford's psychiatry department, questioned some of the study authors' interpretations but agreed that "the authors are surely justified in concluding that locked doors do not seem to provide the anticipated protection."

Burns commented that, in developed countries, "compulsion and control" in psychiatric care is becoming more common, without any basis in actual patient behavior but instead derives from "local customs and traditions." This trend, he suggest, reflects "a neglect of attention to establishing trusting relationships" with psychiatric patients that needs to be reemphasized.

None of the authors or commenters disclosed any relationships with industry.

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Locked Psych Wards Found No Safer

DNC: Georgia Doctor/Delegate Wants Docs to Join the Fray

PHILADELPHIA -- In addition to voting, physicians should consider becoming more involved in their communities through civic engagement, according to Camara Phyllis Jones, MD, MPH, PhD.

Doctors -- especially those in primary care -- used to be a bigger part of the community when they were doing home visits, but now they are often sitting behind a computer during an office visit and are less engaged in the world outside of the office, said Jones, a Clinton delegate from Georgia and senior fellow at the Satcher Health Leadership Institute at Morehouse School of Medicine, in Atlanta. In a video interview Thursday at the Democratic National Convention, she also discussed her hopes for the presidential race and healthcare reform.

Wondering why MedPage Today covers politics see this explanation from Editor-in-Chief Peggy Peck, editor-in-chief.

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DNC: Georgia Doctor/Delegate Wants Docs to Join the Fray

EndoBreak: Obesity Drug Spiked; Fossil Clues to Vit D

A once-promising obesity drug -- beloranib, from drugmaker Zafgen -- is being scrapped after two patient deaths. (STAT News)

Exercise didn't affect gestational weight gain among pregnant women, but it did have a slight effect on type 2 diabetes risk in a randomized trial. (PLOS Medicine)

Sernova and JDRF announced that they are collaborating to fund research testing an implantable device that delivers therapeutic cells for type 1 diabetes patients.

What can the study of fossil teeth tell us about vitamin D deficiency? (New York Times)

Why don't many of your patients take diabetes medications? Bill Polonsky, MD, discusses his latest research. (diaTribe)

Bariatric surgery for teens was associated with less walking pain and improved mobility in a new study. (JAMA Pediatrics)

Philly recently passed a soda tax, but the tax also acts as an "innovative anti-poverty policy," according to an editorial in Annals of Internal Medicine.

One beer can range anywhere from 100 to 300 calories. Vox breaks down your drink.

"The food industry spends a cancer moonshot on advertising every three weeks," writes Yoni Freedhoff, MD.

Here's a fact check on a recent (and controversial) National Obesity Forum report called "Eat Fat, Cut The Carbs and Avoid Snacking to Reverse Obesity and Type 2 Diabetes."

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EndoBreak: Obesity Drug Spiked; Fossil Clues to Vit D

Morning Break: Drug in the Nose?; Schmacon and Eggs; Genetic Deadend

A protein fragment found in nasal bacteria showed potential as a treatment for multiple types of antibiotic-resistant bacteria, such as methicillin-resistant Staphylococcus aureus. (CNN)

Medicare payments for inpatient psychiatric services will increase by 2.2% ($100 million) in fiscal year 2017, according to an announcement from the Centers for Medicare and Medicaid Services.

Love the taste of bacon but not the fat and calories -- or the various turkey-based alternatives? How about Schmacon? (Fox News)

More than a half-century after the "Texas Tower" shootings, the debate continues over laws about gun violence and mental health. (NPR)

Light-intensity exercise and stretching for 10 minutes a day may help relieve menopausal symptoms and depression in middle-age women, according to a small Japanese study. (Reuters)

The earliest known evidence of human cancer emerged from an analysis of hominid fossils 1.7 to 2.0 million years old. (CNN)

Fans of gluten-free diets are saying "I told you so": Non-celiac sensitivity is real. (USA Today)

The data-gathering potential of Fitbit wristbands has attracted the interest of a growing number of health and medical researchers. (Buzzfeed)

Second-hand marijuana smoke caused blood vessel dysfunction in rats that lasted three times as long as effects observed after exposure to tobacco smoke. (New York Daily News)

English Bulldogs have reached a genetic deadend, lacking the diversity to improve the breed and its notorious multitude of health problems. (Gizmodo)

Morning Break is a daily guide to what's new and interesting on the Web for healthcare professionals, powered by the MedPage Today community. Got a tip? Send it to us: MPT_editorial@everydayhealthinc.com.

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DNC: Clinton Accepts Nomination, Promises to Work for All

PHILADELPHIA -- The 2016 Democratic National Convention ended late Thursday with former Secretary of State Hillary Clinton accepting the party's nomination for president, promising that "I will be a President for Democrats, Republicans, and Independents. For the struggling, the striving and the successful. For those who vote for me and those who don't. For all Americans."

In her acceptance speech, Clinton shared her image of her mother, her role model and the seed of her concern for children. Clinton's mother was abandoned by her parents and had to raise herself working as a housemaid. Clinton said that when she fought to help disabled children gain equal access to education, while working for the Children's Defense Fund, it was her mother's difficult childhood she pictured.

Clinton credited her mother for her own pluck and courage.

"When I tried to hide from the neighborhood bully, she literally blocked the door," Clinton said. "And she was right. You have to stand up to bullies," she said, an apparent reference to the GOP nominee, Donald Trump.

She took other, more direct swipes at Trump, portraying him as someone easily provoked and ill-suited to be commander-in-chief -- "A man you can bait with a tweet is not a man we can trust with nuclear weapons" -- and highlighting his privileged upbringing while recounting her own working class roots.

She also attacked Trump for his broad-brush approach to policy while painting her own wonkishness as a virtue.

"It's true... I sweat the details of policy – whether we're talking about the exact level of lead in the drinking water in Flint, Michigan, the number of mental health facilities in Iowa, or the cost of your prescription drugs."

She continued, "Because it's not just a detail if it's your kid -- if it's your family it's a big deal. And it should be a big deal to your president."

And she thanked Sen. Bernie Sanders (I-Vt.) for bringing economic and social issues to the front of the Democratic agenda.

"And to all of your supporters here and around the country. I want you to know. I've heard you. Your cause is our cause. Our country needs your ideas, energy and passion. "

Clinton gave a litany of the Democratic party's platform: creating more clean energy jobs; developing comprehensive immigration reform; establishing a "living wage" and universal healthcare; appointing Supreme Court justices "to get money out of politics."

She hinted that she would reject "unfair trade deals," a subtle nod to the controversial Trans-Pacific Partnership, which many Sanders fans have opposed arguing that it will raise drug prices and cost American jobs -- a treaty she initially backed.

She pledge to protect Social Security as well as a woman's right to terminate pregnancies.

Earlier in the evening, members of Congress, 9/11 survivors, and celebrities presented their candidate as a woman of courage, compassion and heart, whose resilience has seen her overcome countless challenges.

The women of the Senate spoke of Clinton as a compassionate doer, while military generals praised her toughness and calm temperament and professed their faith in her ability to make life and death decisions.

But no one did a better job of characterizing Clinton than her only child, Chelsea.

Chelsea described a mother who left individual notes for each day she was away on business, and a grandmother who delighted Chelsea's own daughter Charlotte with countless readings of "Chugga Chugga Choo Choo" over Facetime.

But Chelsea also spoke of the times her mother was tested. In the summer of 1994, Clinton lost her fight for universal healthcare. "She fought her heart out and she lost.... And then she got right back to work, because she thought she could still make a difference for kids," Chelsea said.

When others ask her about her mother's ability to never give up on a cause, Chelsea told them her secret: "She never forgets who she's fighting for."

Dozens of other speeches lauded Clinton's character, aiming to capture her authenticity and her concern for others. From the 9/11 survivor and amputee who shared in a video how Clinton promised she would dance at her wedding and followed through on that oath, to the parents of Humayan S.M. Khan, a Muslim American who served in the U.S. Army and was killed in Iraq.

"Donald Trump, you are asking Americans to trust you with our future," said Khizr Kahn of Virginia, Humayan's father. "Let me ask you: Have you even read the U.S. Constitution? I will gladly lend you my copy," he said, holding up a pocket-sized edition.

"Vote for the healer. Vote for the strongest, most qualified candidate."

Organizers even recruited some Republicans to endorse Clinton, including Doug Elmets, a former Reagan Administration official, who throughout last week's convention in Cleveland drew comparisons to Ronald Reagan.

"I knew Ronald Reagan, I worked for Ronald Reagan – Donald Trump, you are no Ronald Reagan! ... Trump is a petulant, dangerous unbalanced reality star who will ... alienate allies."

And the women of Congress also stood up for Clinton.

Sen. Amy Klobuchar (D-Minn.) described how, as Secretary of State, Clinton helped her connect couples in Minnesota with orphan children following the 2010 earthquake in Haiti. She expected that someone at Clinton's level would pass the task off on an underling, but she didn't.

"That's Hillary the friend who takes the call, the mom who gets it done right," said Klobuchar.

Sen. Patty Murray (D-Wash.) praised Clinton's work in fighting conservatives who tried to block access to Plan B emergency contraception.

"We refused to back down until the FDA did their job and put science and women first," she said.

Another star of the evening was Sarah McBride, the first transgender person to speak at the convention of a major party.

"But despite our progress so much work remains... Tomorrow we can be respected and protected especially if Hillary Clinton is elected president."

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DNC: Pro-Life Dems Want More Inclusion

PHILADELPHIA -- Democrats for Life of America spoke about growing the Democratic party by electing more pro-life legislators at a luncheon downtown on Wednesday.

The group also spoke favorably of Hillary Clinton's vice presidential pick, but stopped short of an endorsement.

"Being anti-abortion does not make you pro-life," said Louisiana governor John Bel Edwards (D), the luncheon's keynote speaker who received the Gov. Casey Whole Life Leadership Award. Being truly pro-life means giving women the support they need to raise their children, he said.

When his wife was pregnant with their daughter they learned she would have spina bifida. Edwards said their doctor recommended abortion and took his wife to visit children with the disease at different levels of severity.

His daughter is now 24 years old and training to become a public school counselor.

Edwards said conservatives have difficulty squaring how a person can be both pro-life and a Democrat. The same Catholic beliefs that inspire his pro-life views also inform his support for Medicaid expansion and equal pay for women, he said.

"We don't just toss people aside," Kristen Day, the executive director of Democrats for Life, told MedPage Today, in explaining the difference between Democrats for Life and pro-life Republicans. Many women have abortions are poor and lack social support. They are often pressured by boyfriends into getting abortions.

"We want to look at all those reasons [for having abortions] and try to pick away at the reasons," she said.

To that end, her organization helped draft a bill and ultimately got the Pregnancy Assistance Fund, a $25 million grant program, included in the Affordable Care Act. The group also supported raising the minimum wage, giving parental leave, and expanding perinatal hospice.

Day said one in three Democrats is pro-life but in Congress many Democrats remain silent on their views.

"Right now our party is in trouble," said Day pointing to a colored-coded red and blue map of the United States.

"Since 2008, we've lost 912 legislative seats, 30 state legislative chambers... 11 governorships have been lost, 69 U.S. House Seats ... and 13 U.S. Senate seats," she said during the luncheon.

One way for Democrats to win back Republican seats is to embrace pro-life candidates.

"We [Democrats] claim to be the big tent party but the platform says that only this group of people [pro-abortion rights] can be allowed in. Around the country Democratic party chairmen are telling people that they can't run if they're pro-life and this platform endorses that kind of philosophy," she told MedPage Today.

When asked about the recently chosen Democratic vice presidential nominee, Sen. Tim Kaine (D-Va.), "I think he'll be a friend and maybe help moderate and open up the party." However, she noted, "We only endorse candidates who are both pro-life and Democrat. Those are the criteria." This means it would not endorse Clinton nor Kaine. However, the group also will not back a pro-life Republican.

Edwards said, "I see in him a lot of the things that I aspire to be." Kaine continues to personally oppose abortion, but on his Senate website, he says that "I support the right of women to make their own health and reproductive decisions .... The right way to [reduce abortions] is through education and access to health care and contraception rather than by restricting and criminalizing women's reproductive decisions. For that reason, I oppose efforts to weaken Roe v. Wade."

On the other hand, some group members didn't trust the pro-life credentials of the Republican candidates. "I'm convinced that Mike [Pence, the Republican vice-presidential candidate] is pro-life window dressing. He's a prop for a Trump administration, which will likely not deliver on their promises to pro-life people in the party," said Rev. Rob Schenck, president and lead missionary of Faith and Action in the Nation's Capital, a Christian outreach group that lobbies Congress, who attended the luncheon. Schenck said he's not convinced Trump is pro-life "no matter what he says."

Schenck has not voted for a Democrat since Pres. Jimmy Carter.

"Now it's time for me to look again at the party of my youth."

Wondering why MedPage Today covers politics see this explanation from Editor-in-Chief Peggy Peck, editor-in-chief.

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DNC: Pro-Life Dems Want More Inclusion