Monday, August 31, 2015

Preimplantation genetic diagnosis

Even before their daughter, Ayelet Galena, was diagnosed with a rare bone marrow disease called dyskeratosis congenita around her first birthday, parents Hindy Poupko and Seth Galena knew they wanted to have more children.

But once the diagnosis arrived, the couple had a dilemma: There was a fair chance their next child would have the life-threatening genetic disease, too.

Over the course of the next year or so, Galena and Poupko didn’t have much time to think about other kids. They were busy tending to Ayelet, whose struggle they decided to document on a blog, Eye on Ayelet. It quickly gained a following in the thousands. While her kidneys failed her, Ayelet became an Internet sensation. Galena dubbed the phenomenon Ayelet Nation.

When Ayelet died on Jan. 31, 2012, less than two months after her second birthday, thousands of people from around the world who had never met the little Orthodox Jewish girl from Manhattan’s Upper West Side seemed to share in her parents’ grief, overwhelming Poupko and Galena with condolence messages, food packages and gifts.

This month, good news finally arrived in the Galena-Poupko household: The couple had a new baby, a healthy boy born two weeks ago. On Sunday at his bris, they named him Akiva Max Galena...

When Ayelet was diagnosed, she immediately was tested for the seven known genetic mutations that cause dyskeratosis congenita. But the results showed she didn’t have any of them, which meant her illness was caused by an unknown genetic mutation that could not be identified by prenatal screening.

“From that moment we always knew that having more children and confidently healthy children would be a challenge,” Poupko said. “They couldn’t even tell us if the disease was inherited or not.”

The couple had two options: They could get pregnant again and risk having another sick child who might suffer and die young, or they could wait for the science to catch up. If the genetic mutation that caused Ayelet’s disease could be identified, they could do in-vitro fertilization and test the embryos before implanting them in the uterus to make sure they didn’t carry the disease-causing gene.
The couple decided to wait.

“A lot of people would say lightning doesn’t strike twice, but this is a science,” Poupko said. “Statistically, we knew the likelihood of us having another child with the disease was 25 percent.”

They joined a National Institutes of Health study led by Dr. Sharon Savage of the National Cancer Institute to find the genetic causes for a number of inherited bone marrow diseases. The couple was told the process could take a few years, and by the end there would be only a 50-50 chance that the genetic mutation that caused Ayelet’s illness would be found.

While they were dealing with Ayelet’s tests, hospital stays and a bone-marrow transplant at Cincinnati Children’s Hospital Medical Center — and eventually her tragic passing — researchers at the NIH were working on the genetics in consultation with scientists at the Rockefeller Institute, Mount Sinai Hospital and Johns Hopkins University School of Medicine.

With Poupko in her late 20s, the two figured they could afford to give the NIH study some time before trying for another baby...

The good news finally came on April 11, 2013. Poupko remembers where and when she was when she got the call. After the NIH nurse on the phone told her that Ayelet’s genetic mutation had been found, Poupko broke down, sobbing.

“We had been following up, calling them nonstop, but they had never called us before,” she recalled. “It was amazing. We knew at that moment that we would have that future we’d always wanted.”...

From there to getting pregnant was a relatively short road, but not an uncomplicated one. The couple went through a process called preimplantation genetic diagnosis, or PGD, in which the female’s egg and the male’s sperm are mixed in a laboratory to produce embryos. Those embryos were then tested for the mutant gene. The healthy ones were implanted via IVF. Late last year, Poupko, now 30, got pregnant.
Courtesy of my daughter.

Health care documentation is terrible. Here’s why.

Heath care documentation is done for three reasons:
  1. health care delivery (that’s the obvious one)
  2. regulatory compliance (checking all the boxes our government and payers think are important)
  3. malpractice avoidance (no one wants to get sued)
These three categories actually apply to every task we do in health care, but let’s confine this discussion to documentation.
Note in the accompanying figure, our three basic health care work requirements fit logically into a Venn diagram. Much of what we do serves only one or two of the three driving purposes. In an ideal world, we work in the center of the diagram where all three converge. Unfortunately that “sweet spot” is pretty small, especially when it comes to documentation.
If all clinicians needed to do with our documentation was practice medicine (#1 above, blue in the attached Venn diagram), our notes would be more logical and much less bloated. Laundry lists of irrelevant and inaccurate diagnoses would not populate into every note. Copy and paste would occur a lot less often, and likely could be limited to appropriate uses such as carrying over past medical history (which should always be copy and pasted after verification to reduce errors). Only relevant physical exam findings would be reported, so these would not be lost in a sea of normals. Useful information that is not valued externally, such as personal touches (i.e., a patient’s wedding anniversaries, achievements of their children) would have it’s own optimized workflow.

Regulatory compliance and malpractice protection, the #2 and #3 health care documentation purposes above, are responsible for the large majority of the drivel that shows up in our notes. Believe me, we doctors would all love to confine our work to health care delivery, but external forces box us into this uncomfortable place, and this creates junk documentation.

The result of trying to serve all of these missions results in the mess we have today. Health care IT expert Fred Trotter says that working with EHR is “like having a conversation with a habitual liar who has a speech impediment.”
unnamed (1)
As I’ve diagrammed here, EHR serves all three basic functions, but not to equal degrees. EHR is designed for and sold to hospital administrators. Their first priority is business related (i.e., making sure the system runs efficiently and within the law). They work in the peach (regulatory compliance) circle. After the federal government stepped in with EHR incentives, meaningful use requirements created a set of requirements for the EHR companies that are about 90 percent peach-colored as well.
After satisfying the needs of administrators and the government, EHR vendors allot remaining resources to serving working clinicians seeing patients, as well as the patients themselves. This results in the lesser segment of EHR devoted to care delivery represented in blue...

EHR activities fundamentally service the task of regulatory compliance (the peach circle) as their primary mission. This satisfies both the hospital administrators and the government. Because all parties have limited resources, the contribution to the health care delivery circle suffers. Both hospitals and clinicians are interested in Malpractice Protection, so the green circle is served at of mutual self-interest, although EHR workflow only tangentially addresses this need.
Clinicians need mechanisms to streamline documentation so they can spend time with patients instead of in front of computer screens. Ironically, many of the efficiencies built into EHR to give clinician more time with their patients have become targets of disapproval for our regulators and critics. I find it frustrating when I hear pundits and government officials rally against copy/paste and templates (such as normal physical exam findings). Most of these critics have no perspective on running a busy clinic or inpatient service. It would be impossible to do our jobs without some degree of automation. Do you think the legal profession would consider eliminating templates and copy/paste? Do you think contracts and wills are written freehand each time? Ridiculous.

Good clinicians need to fight external forces to protect their ability to care for their patients. That means we need to devote the large bulk of our time and thoughts to working in the blue circle of health care delivery. That’s where our mission is served. The other two circles? We should click/copy/paste/dictate/template only what is necessary to prevent us from being sued, sanctioned, denied payment, or accused of poor quality. If we can do that efficiently, we can get back to taking care of our patients. One casualty of this appropriate triage is ugly documentation.

Folks need to stop confusing health care documentation with health care delivery. Those who grade and pay us give far too much weight to the former. Those actually taking care of patients know where to set their priorities.
Edward J. Schloss is a cardiac electrophysiologist who blogs at Left to my own devices. He can be reached on Twitter @EJSMD.
Image credit:

Sunday, August 30, 2015

Brain tumors: innovative genetic information

Gajjar A, Bowers DC, Karajannis MA, Leary S, Witt H, Gottardo NG. Pediatric
Brain Tumors: Innovative Genomic Information Is Transforming the Diagnostic and
Clinical Landscape. J Clin Oncol. 2015 Aug 24. pii: JCO.2014.59.9217. [Epub ahead
of print] Review.


Pediatric neuro-oncology has undergone an exciting and dramatic transformation during the past 5 years. This article summarizes data from collaborative group and institutional trials that have advanced the science of pediatric brain tumors and survival of patients with these tumors. Advanced genomic analysis of the entire spectrum of pediatric brain tumors has heralded an era in which stakeholders in the pediatric neuro-oncology community are being challenged to reconsider their current research and diagnostic and treatment strategies. The incorporation of this new information into the next-generation treatment protocols will unleash new challenges. This review succinctly summarizes the key advances in our understanding of the common pediatric brain tumors (ie, medulloblastoma, low- and high-grade gliomas, diffuse intrinsic pontine glioma, and ependymoma) and some selected rare tumors (ie, atypical teratoid/rhabdoid tumor and CNS primitive neuroectodermal tumor). The potential impact of this new information on future clinical protocols also is discussed. Cutting-edge genomics technologies and the information gained from such studies are facilitating the identification of molecularly defined subgroups within patients with particular pediatric brain tumors. The number of evaluable patients in each subgroup is small, particularly in the subgroups of rare diseases. Therefore, international collaboration will be crucial to draw meaningful conclusions about novel approaches to treating pediatric brain tumors.

Courtesy of

Friday, August 28, 2015

Seizure action plans (surprise)

Roundy LM, Filloux FM, Kerr L, Rimer A, Bonkowsky JL. Seizure Action Plans Do
Not Reduce Health Care Utilization in Pediatric Epilepsy Patients. J Child
Neurol. 2015 Aug 5. pii: 0883073815597755. [Epub ahead of print]


Management of pediatric epilepsy requires complex coordination of care. We hypothesized that an improved seizure management care plan would reduce health care utilization and improve outcomes. The authors conducted a cohort study with historical controls of 120 epilepsy patients before and after implementation of a "Seizure Action Plan." The authors evaluated for differences in health care utilization including emergency department visits, hospitalizations, clinic visits, telephone calls, and the percentage of emergency department visits that resulted in hospitalization in patients who did or did not have a Seizure Action Plan. The authors found that there was no decrease in these measures of health care utilization, and in fact the number of follow-up clinic visits was increased in the group with Seizure Action Plans (4.2 vs 3.3, P = .006). However, the study was underpowered to detect smaller differences. This study suggests that pediatric epilepsy quality improvement measures may require alternative approaches to reduce health care utilization and improve outcomes.

Courtesy of

Thursday, August 27, 2015

Research reproducibility

The past several years have been bruising ones for the credibility of the social sciences. A star social psychologist was caught fabricating data, leading to more than 50 retracted papers. A top journal published a study supporting the existence of ESP that was widely criticized. The journal Science pulled a political science paper on the effect of gay canvassers on voters’ behavior because of concerns about faked data.
Now, a painstaking yearslong effort to reproduce 100 studies published in three leading psychology journals has found that more than half of the findings did not hold up when retested. The analysis was done by research psychologists, many of whom volunteered their time to double-check what they considered important work. Their conclusions, reported Thursday in the journal Science, have confirmed the worst fears of scientists who have long worried that the field needed a strong correction.
The vetted studies were considered part of the core knowledge by which scientists understand the dynamics of personality, relationships, learning and memory. Therapists and educators rely on such findings to help guide decisions, and the fact that so many of the studies were called into question could sow doubt in the scientific underpinnings of their work.
“I think we knew or suspected that the literature had problems, but to see it so clearly, on such a large scale — it’s unprecedented,” said Jelte Wicherts, an associate professor in the department of methodology and statistics at Tilburg University in the Netherlands...
The new analysis, called the Reproducibility Project, found no evidence of fraud or that any original study was definitively false. Rather, it concluded that the evidence for most published findings was not nearly as strong as originally claimed.
Dr. John Ioannidis, a director of Stanford University’s Meta-Research Innovation Center, who once estimated that about half of published results across medicine were inflated or wrong, noted the proportion in psychology was even larger than he had thought. He said the problem could be even worse in other fields, including cell biology, economics, neuroscience, clinical medicine, and animal research.
The report appears at a time when the number of retractions of published papers is rising sharply in wide variety of disciplines. Scientists have pointed to a hypercompetitive culture across science that favors novel, sexy results and provides little incentive for researchers to replicate the findings of others, or for journals to publish studies that fail to find a splashy result.
“We see this is a call to action, both to the research community to do more replication, and to funders and journals to address the dysfunctional incentives,” said Brian Nosek, a psychology professor at the University of Virginia and executive director of the Center for Open Science, the nonprofit data-sharing service that coordinated the project published Thursday, in part with $250,000 from the Laura and John Arnold Foundation
Open Science Collaboration.  Estimating the reproducibility of psychological science. Science
Reproducibility is a defining feature of science, but the extent to which it characterizes current research is unknown. We conducted replications of 100 experimental and correlational studies published in three psychology journals using high-powered designs and original materials when available. Replication effects were half the magnitude of original effects, representing a substantial decline. Ninety-seven percent of original studies had statistically significant results. Thirty-six percent of replications had statistically significant results; 47% of original effect sizes were in the 95% confidence interval of the replication effect size; 39% of effects were subjectively rated to have replicated the original result; and if no bias in original results is assumed, combining original and replication results left 68% with statistically significant effects. Correlational tests suggest that replication success was better predicted by the strength of original evidence than by characteristics of the original and replication teams.
Courtesy of a colleague

Asymptomatic patients and unstable cervical spine injury

Hale DF, Fitzpatrick CM, Doski JJ, Stewart RM, Mueller DL. Absence of clinical
findings reliably excludes unstable cervical spine injuries in children 5 years
or younger. J Trauma Acute Care Surg. 2015 May;78(5):943-8.



Increased accessibility and rapidity of computed tomography (CT) have led to increased use and radiation exposure to pediatric trauma patients. The thyroid is radiosensitive and therefore at risk for developing malignancy from radiation exposure during cervical spine CT. This analysis aimed to determine which preelementary trauma patients warrant cervical spine CT by defining incidence and clinical characteristics of preelementary cervical spine injury.


This was a retrospective review of pre-elementary trauma patients from 1998 to 2010 with cervical spine injury admitted to a Level I trauma center. Patients were identified from the trauma registry using DRG International Classification of Diseases-9th Rev. codes and reviewed for demographics, mechanism of injury, clinical presentation, injury location, injury type, treatment, and outcome.


A total of 2,972 preelementary trauma patients were identified. Twenty-two (0.74%) had confirmed cervical spine injuries. Eleven (50%) were boys, and the mean (SD) age was 3 (1.7) years. The most common mechanism of injury was motor vehicle collision (n = 16, 73%). The majority (59%) were in extremis, and 12 (55%) arrived intubated. The median Glasgow Coma Scale (GCS) score was 3 (interquartile range, 3-10); the median Injury Severity Score (ISS) was 33 (interquartile range, 17-56). Nineteen injuries (76%) were at the level of C4 level and higher. The mortality rate was 50%. All patients had clinical findings suggestive of or diagnostic for cervical spine injury; 18 (82%) had abnormal neurologic examination result, 2 (9%) had torticollis, and 2 (9%) had neck pain.


The incidence of cervical spine injury in preelementary patients was consistent with previous reports. Missing a cervical spine injury in asymptomatic preelementary patients is extremely low. Reserving cervical spine CT to symptomatic preelementary patients would decrease unnecessary radiation exposure to the thyroid.


Therapeutic study, level IV.

From :
In this well done retrospective review of ~3,000 patients aged 5 years and younger who have imaging of their cervical spine, the authors give us some data and a common sense approach for the pre-elementary aged trauma patient’s c-spine evaluation. Essentially, in the words of the authors:“In those who were clinically evaluable (not in a coma), there were no asymptomatic patients who later were found to have unstable cervical spine injury”.So, if there is no neurologic deficit, and no pain or tenderness, there is no need to go crazy looking for an extremely rare, unlikely injury.

Courtesy of:

Lions and tigers and bears! Oh my!

H. Prüss, J. Leubner, N. K. Wenke, G. Á. Czirják, C. A. Szentik,  A. D. Greenwood.  Anti-NMDA Receptor Encephalitis in the Polar Bear (Ursus maritimus) Knut.  Scientific Reports Published online:
Knut the polar bear of the Berlin Zoological Garden drowned in 2011 following seizures and was diagnosed as having suffered encephalitis of unknown etiology after exhaustive pathogen screening. Using the diagnostic criteria applied to human patients, we demonstrate that Knut’s encephalitis is almost identical to anti-NMDA receptor encephalitis which is a severe autoimmune disease representing the most common non-infectious encephalitis in humans. High concentrations of antibodies specific against the NR1 subunit of the NMDA receptor were detected in Knut’s cerebrospinal fluid. Histological examination demonstrated very similar patterns of plasma cell infiltration and minimal neuronal loss in affected brain areas. We conclude that Knut suffered anti-NMDA receptor encephalitis making his the first reported non-human case of this treatable disease. The results suggest that anti-NMDA receptor encephalitis may be a disease of broad relevance to mammals that until now has remained undiagnosed.
Courtesy of a colleague

Wednesday, August 26, 2015

I'm taking back medicine

I’m taking back medicine.

If you didn’t know it left or that someone stole it, I’ll give you a pass. Medicine has been disguised for a long time now. And, when you leave the scene in camouflage, you often go unnoticed.

Medicine is supposed to be the science or practice of diagnosing, treating, and preventing disease. I love medicine. There’s so much to learn. Lots of complexities and so many people to help. Medicine gives me an avenue to serve, because if we don’t have our health, what do we have? Illness. And, none of us want that.

I’ve trained to be a physician. I’ve learned lots of things that can help you with sickness. But, in order to do this, they have to let me practice. And, yes, they are the people who have taken medicine.
When did medicine become more about meeting than doing? When I first became interested in medicine, physicians worked. We worked days and nights, hours on end. We learned by working. We worked by doing. And, things weren’t perfect then. But, we took care of patients by actually doing something that literally moved the needle. 

Now, it’s different. We just meet about it.

Toward the end of my medical training, administrative meetings were already running rampant. We’d meet because some group said we should be doing a quality improvement project. Just some new regulatory thing. Gotta come up with a project. Every year.

News flash for the folks scheduling meetings: that’s not how innovation works.

Bureaucracies don’t drive innovation. Never have. Never will. I’ll tell you how we did those practice improvement projects that someone else told us we should be doing. We usually would type up some protocol that we were already doing and then add it as another formal policy. Box checked. That’s what humans do when they are given futile tasks with poor incentives.

Meetings in health care have really just become smokescreens for government-driven busywork. Sure, they can be functional, and in fact, they always add more functions for all of us to be doing. But, most of the time these meetings aren’t productive for patient care because they’ve lost sight of the one thing medicine was built upon: the patient-physician relationship.

Take a look at the graph included here (below). It outlines the growth of administrators in health care compared to physicians over the last forty years. And, it includes an overlay of America’s health care spending over that same time. Take a look at the yellow color. A picture is worth a thousand words, isn’t it?

You see, when you have that much administration, what you really have is a bunch of meetings. Lots of folks carrying their coffee from place to place. They are meeting about more policies, more protocols to satisfy government-created nonsense. But, this type of thing in health care isn’t fixing things. It’s not moving the needle.

What moves things is innovation. And, innovation isn’t some concept that responds to being forced. It develops when the right chemicals exist in the right moment for an exciting explosion. It happens when someone in a free-market recognizes a problem and creates a business idea to solve it. But, we’ve completely lost this environment for innovation in health care. Medicine has been kidnapped by a bunch of government-driven regulations that cost billions of unnecessary taxpayer dollars for oversight...

But, the point I’m making is that the bureaucracy has exploded out of control. When you have so many excessive regulations that you need that many people overseeing checkboxes instead of delivering medical care, you aren’t just stifling innovation, you are having untoward effects on cost control. Medicine used to be about you and me. In fact, where in the world did the patient-physician relationship go? I guess that it left when Medicine did.

I don’t care what you do. You can take me out, join me, or get out of my way. But, I’m on a mission to take medicine back.
Courtesy of:

Medical mayhem

Long before he faced lawsuits and criminal charges, a North Texas neurosurgeon emailed one of his employees.

“I am ready to leave the love and kindness and goodness and patience that I mix with everything else that I am and become a cold blooded killer,” Christopher Duntsch wrote.

To authorities, the chilling Dec. 11, 2011, email points to Duntsch’s mind-set in the months before he “intentionally, knowingly and recklessly” botched spinal surgeries, severely injuring four people and killing one woman, Floella Brown, who died in July 2012.

The email was among new evidence Dallas County prosecutors presented against Duntsch at a hearing Friday in which Criminal District Judge Carter Thompson refused to reduce Duntsch’s $600,000 bail.

“I am very well-pleased that he will remain in jail and that justice will eventually be served for the crimes that he has committed,” said Philip Mayfield, 45, who awoke paralyzed from the neck down in April 2013 after Duntsch performed surgery on his spine...

Dallas police said in a search warrant affidavit that he is also under investigation in the botching of at least 10 other patients’ surgeries in Plano and Dallas that occurred from November 2011 through June 2013. Duntsch “knowingly takes actions that place the patients’ lives at risk,” police said, such as causing extreme blood loss by cutting a major vein and then not taking proper steps to correct it. In one case, Duntsch left a surgical sponge inside a man's body. During that same surgery, another doctor forced him to stop operating because of his “unacceptable surgical technique,” the affidavit said....

Shughart asked Duntsch’s father if his son was trying to get his medical license reinstated.
“I guess that’s probably true,” Donald Duntsch said. “I knew that was an intention of his at some point, in light of what happened, that he would be able to practice again as a doctor.”...

Duntsch has claimed to be a victim of misunderstandings, rival surgeons and personal injury lawyers. He told The Dallas Morning News in a 2014 story about the accusations that “99 percent of everything that has been said about me is completely false.”

But in that startling 2011 email to his employee, Duntsch wrote: “how can I do anything I want and cross every disclipline boundary like it’s a playground and never ever lose.”...

Shughart, the prosecutor, sought to show Duntsch has ongoing substance abuse issues. She said Duntsch’s friend called his hospital and reported Duntsch had been up all night doing drugs the night before an operation. The hospital then sent him to rehab, she said.
Donald Duntsch testified that while his son was a college student in Tennessee, the school ordered him to go into rehab. In addition, the elder Duntsch said, his son was arrested last year in Colorado for impaired driving, and he testified that he had been concerned that his son was abusing Ritalin and alcohol.

“I know that he uses alcohol, particularly, which was an issue for us in the home, and we talked about it,” Donald Duntsch said. “The reality was, as he’s been going through this incredibly traumatic time, I think he’s probably used it some to self-medicate.”...

“He needs to be where he is right now until he gets to trial,” said Lee Passmore, 40, a former patient who reportedly suffered extreme pain and other complications as a result of a Duntsch surgery.
Courtesy of:

Tuesday, August 25, 2015

Focal seizure symptoms in idiopathic generalized epilepsies

Seneviratne U, Woo JJ, Boston RC, Cook M, D'Souza W. Focal seizure symptoms in
idiopathic generalized epilepsies. Neurology. 2015 Aug 18;85(7):589-95.



We sought to study the frequency and prognostic value of focal seizure symptoms (FSS) in idiopathic generalized epilepsies (IGE) using a validated tool: Epilepsy Diagnostic Interview Questionnaire and Partial Seizure Symptom Definitions.


Participants with IGE were recruited from epilepsy clinics at 2 tertiary hospitals. The diagnosis was validated and classified into syndromes according to the International League Against Epilepsy criteria by 2 epileptologists independently with discordance resolved by consensus. The Epilepsy Diagnostic Interview Questionnaire utilizes both open- and closed-ended questions to elicit FSS in association with generalized tonic-clonic seizures, myoclonus, and absences. The elicited FSS were classified according to the Partial Seizure Symptom Definitions. Regression analysis was conducted to examine the relationship between the duration of seizure freedom and FSS.


A total of 135 patients were studied, of whom 70 (51.9%) reported FSS. Those symptoms occurred in association with generalized tonic-clonic seizures (53.1%) as well as myoclonus and absences (58%). FSS were reported with similar frequency in juvenile absence epilepsy (62.5%) and juvenile myoclonic epilepsy (60%), and with a lesser frequency in generalized epilepsy with tonic-clonic seizures only (39.5%) and childhood absence epilepsy (33.3%). A strong relationship between FSS and duration of seizure freedom was found (regression coefficient -0.665, p = 0.037).


FSS are frequently reported by patients with IGE. A shorter duration of seizure freedom is associated with FSS. Recognition of the presence of FSS in IGE is important to avoid misdiagnosis and delayed diagnosis as well as to choose appropriate antiepileptic drug therapy.

From the paper:

The most interesting and novel finding in our study is the association between FSS and duration of seizure freedom. A shorter duration of seizure freedom was significantly associated with FSS. This relationship was unaffected by confounders such as number of AEDs, age of seizure onset, age at interview, duration of epilepsy, presence of GTCS, and presence of focal discharges in the EEG. We acknowledge that 95% confidence interval includes zero when adjusted for some confounders such as number of AEDs. However, we believe it is attributable to the relatively small sample size, and the association between the duration of seizure freedom and FSS is still clinically relevant. Overall, our study raises the possibility that the presence of FSS may be an important prognostic factor associated with the duration of seizure freedom. Previous studies have reported conflicting results on the presence of focal EEG abnormalities as a predictor of prognosis. To our knowledge, the prognostic significance of FSS in IGE has not been previously published. However, an alternative explanation is recall bias, whereby those with a shorter duration of seizure freedom and more frequent seizures may be more likely to remember their FSS. Patients with shorter durations of seizure freedom have had more recent seizures, hence, are more likely to be able to reinforce their perceptions and recall subtle FSS...

Our study demonstrates that FSS are often reported by patients with IGE in association with both major and minor seizures. The duration of seizure freedom is associated with FSS. Our findings have implications for clinical practice. First, we emphasize that clinicians need to be aware of FSS in IGE to avoid misdiagnosis and delayed diagnosis as well as to choose appropriate AED treatment. Second, FSS may lead to inappropriate investigations for focal epilepsy including evaluation for epilepsy surgery. Third, the presence of FSS should alert the clinician as a potential marker of reduced likelihood of prolonged seizure freedom. Further studies are needed to confirm these findings, preferably in incident cases with prospective follow-up, and to examine the underlying pathophysiologic and network mechanisms of focal abnormalities in IGE. A greater understanding of these network mechanisms may assist in long-term management of IGE.


Doctor doesn't always know best

In her 2013 essay in the Atlantic, Thinking About Pregnancy Like an Economist, Emily Oster, then an associate professor at the University of Chicago, objects to the state of pregnancy care. I am not an expert in obstetrics, but her point, and mine, applies to most medical decisions. Be sure, obstetrics is not the only area of healthcare mired in anachronism.

Prof Oster is an economist who read a lot about pregnancy. That information, taken together with her expertise in statistics, transformed her into a (very) informed patient. She is not a medical doctor, but she acquired much of the same information medical doctors had. That became a problem. And that it was a problem is the issue we should discuss.

The pregnant professor thought a medical decision would work like any economic decision. First, there would be an actual choice—not a decree. Then, accurate data would frame the decision and multiple paths would be presented, each with their pluses and minuses. In the end, her preferences would guide her choice.

Was she wrong.

Read the following quote. Don't get stuck on the word amniocentesis. Substitute mammogram, cardiac cath, ablation, or stent, for instance. (The italics are mine.)
Take something like amniocentesis. I thought my doctor would start by outlining a framework for making this decision—pluses and minuses. She'd tell me the plus of this test is you can get a lot of information about the baby; the minus is that there is a risk of miscarriage. She'd give me the data I needed. She'd tell me how much extra information I'd get, and she'd tell me the exact risk of miscarriage. She'd then sit back, Jesse [Oster's husband] and I would discuss it, and we'd come to a decision that worked for us. This is not what it was like at all.
In the paragraphs that followed, the expert in decision making went on to describe the state of healthcare decisions as they exist today. Four themes stood out:

Misinformation: Medicine overflows with arbitrary rules. Rules become dogma without any basis in evidence. (Think low-fat diets.) Oster writes that, in the worst case, the advice of doctors runs counter to the evidence. In other cases, advice is born from shoddy evidence.

Misthink about risk: Oster laments the failure to consider risk on a continuum. It's easier to make risk a yes-or-no deal (dichotomize). The risk of sudden cardiac death, for instance, does not disappear when the heart's ejection fraction goes from 35% (the cutoff for an ICD) to 36%. Continuous risk is harder to explain, but failing to do so tilts the discussion toward certainty—which is an illusion.

Failure to consider patient preferences: Oster discusses how equally educated people feel differently about risk. Consider the decision to take a clot-preventing drug in a patient with atrial fibrillation. For some, a small decrease in stroke risk is not worth taking a drug that increases the risk of bleeding. They fear bleeding more than stroke; they see themselves in the majority of those who will get no benefit from the preventive drug. Others fear stroke; for them, it's worth taking the drug. The point is that when a doctor says, "You need to take this pill or you will have a stroke," it's the doctor's preference that stands out.

Imbalance of power: Power tilts the doctor's way because we are the presumed experts. Oster raises an issue I have gradually come to know: When you educate yourself about the methodology of science and look at medical studies with an eye for critical appraisal, it's less clear we doctors know as much as we think we know. It's sobering to think how little of what I decreed to patients early in my career would have stood up to critical appraisal...

I see four basic concepts that if doctors embraced would increase the odds of getting to a good medical decision. None were emphasized in my medical training. I learned them through practical experience.

Know the evidence: Doctors should know the evidence—not the translation of the evidence from key opinion leaders or pharma reps, the actual evidence. If we did this, it would be less likely that we would conflate the benefits of acute-care medicine (the easy kind) to those with chronic disease. Think cardiac stents. We would also be less apt to waste resources on low-value care. Medical literature and its media coverage is expanding; critical appraisal has never been more important.

Embrace uncertainty: Doctors train a long time. This brings knowledge, specific skills, and experience. Yet we cannot know the future. We have the history of medical reversals to keep us clear-minded. The best doctors I know say they don't know when they don't know—which is often. They treat the medical decision as the gamble that it is.

See the person: The third concept is the notion of seeing our patients—not their diseases. In training, we were taught to put diseases in silos—cardiac, pulmonary, orthopedic, etc. The problem with that view is it leads to framing errors. A man who can't remember what he had for lunch or how he got to your office has bigger problems than his aortic valve or ejection fraction. A person without a ride to the doctor's office will have trouble taking warfarin.

Control is an illusion: A seminal moment in my career occurred when a wise old doctor sat me down in the doctor's lounge and explained how little we controlled. "John," he said, "in the ICU, I treat two patients with the same problem in the same way. One dies and one lives. We do our best with what we know at the moment, but outcomes are mostly out of our control."


It's easy to assume that a patient with a poor social situation who repeatedly shows up to the emergency room with an exacerbation of chronic medical conditions is having trouble adhering to home medications, or that a patient known to have a history of opioid abuse presenting with a frequent complaint of pain may just be seeking narcotics instead of having an actual organic process causing the pain.

Most of the time, making that quick assumption saves an unnecessary admission and helps to reduce the strain on the health care system. However, there are times that making that assumption could potentially put certain patients at risk, and it is important to make sure to take a step back and look at everything prior to making a medical decision.

I was reminded of this one day during residency with regards to a particular patient who had a history of opioid dependence. She came to the hospital complaining mainly of abdominal pain that she said was unrelenting; nothing could make it better except for pain medications, she told us. Initial labs looked relatively unremarkable, but since she still was having abdominal pain, we made the decision to admit mainly for pain control.

During her hospitalization, she was getting pain medications, and every time we saw her in the morning, she was complaining about the pain not being well controlled with the current medications. The thing that complicated matters was that every time I would walk by her room, she would be sleeping comfortably in bed, or sitting up eating food without any issues. When I went in to ask her what was going on, she would start talking about her pain again and asking me for an adjustment to the pain medications she was receiving.

At this point, it was easy for me to start assuming that she was just taking up a hospital bed in order to receive pain medications. After all, she did have a history of opioid dependence, so what else could it be?

My team was at a loss; we could not send her out with her pain being uncontrolled, but nothing on physical exam or labs stuck out as a potential cause for her pain. Finally, as a last resort, we decided to get an ultrasound of her abdomen and pelvis to evaluate what was going on since we had no other explanations. Our thought was that if the imaging came back negative, we would have enough evidence to say to her that there was no organic cause for the pain, and that she could ultimately be discharged home with outpatient follow-up.

To our surprise, the ultrasound came back positive for a large ovarian cyst that was beginning to cause ovarian torsion. It was an unexpected finding given the intermittent pain that she had. We thought there would be an elevated white count or another lab finding that would indicate something was going on in the abdomen or pelvis, but nothing helpful came back on her labs.
The next thing I knew, she was being transferred over to the obstetrics and gynecology service, and she ultimately needed a surgical procedure later on during the admission. All I could think to myself was that if we had waited longer to do imaging, just because we assumed all this was in line with her opioid use, a more serious situation would have come up.

I and the rest of my team fell into the trap of treating our idea of the patient, instead of the patient herself. We treated her in a way assuming that all this was based on opioid dependence, and it was only near the end that we started to think that maybe this was something else. And to be honest, after having prior experiences where people with chronic opioid dependence have fooled me and other physicians in the past and have ended up receiving free narcotics for no known cause of their pain, it is not surprising for us to make this assumption in the setting of seeing numerous patients in a day and trying to efficiently make a diagnosis.

Most of the time, this is a reasonable assumption to make, but sometimes we have to remind ourselves to keep an open mind in terms of what else could be going on with the patients we come across.

We have a tendency to put people in a box, to immediately form assumptions of people based on what they look like or what we know of them from previous interactions. This extends into medicine, where we go through numerous medical charts to figure out what may be going on with the patients that come across our paths. Integrating past history with the current presentation, we come up with an idea.

We think we know what is going on with a patient, and based on that, we figure out a treatment plan that we may become more connected to depending on how well the data correlate with each other. It is easier to have an idea match up with the reality of the patient in front of us when it comes to a purely medical history, based on prior labs, vital signs and imaging.

It is a lot harder when what we are going on is a social history. Perhaps the patient is a homeless person who has not seen a doctor in many years. Perhaps the patient has a known history of substance abuse with prior admissions for substance withdrawal or dependence. Most of the time, the assumptions we make based on a particular social aspect of a patient match up with what is actually going on, whether it be medication non-compliance or seeking of narcotics.

However, this prior event taught me, and should continue to teach all of us as physicians, that an idea that is easy to become married to in the setting of medical care may not be the reality. That time, the idea we had about the patient was wrong, even though numerous things about her presentation pointed to that idea. An organic event leading to her presentation was actually happening, despite the lack of significant prior medical history we had.

Thankfully, we changed our assumptions before anything got worse, but there are probably examples out there of the clinical situation getting worse prior to physicians changing their assumptions. Any doctor, no matter where they are in their training or practice, is vulnerable to ultimately treating ideas of patients rather than the  than the patients themselves.

We should always take a step back and look at the whole picture to make sure we have the right idea of patients so that we end up correctly treating them. At the end of the day, it is the patients, and not our ideas of them, that depend on the medical decisions we make.
Courtesy of:

Monday, August 24, 2015


Haven Fowler was born a healthy baby. She remained so until the age of two and a half when she began to gain weight very rapidly, gaining 40 pounds over eight months. She also started having unusual neurological symptoms, including hallucinations, sleep-eating and sleepwalking, irritability and profuse sweating.

Month after month, Haven’s parents took her from doctor to doctor, each one increasingly bewildered by her mysterious symptoms and unable to find an answer. Finally, the Fowlers — then living in California — were told that if they wanted answers, they needed to go to Johns Hopkins. And so they did. About three weeks after her cross-country trip to Baltimore, Haven suffered a serious seizure, which landed her at Hopkins Children’s, where the mystery of her condition eventually would be solved.

Haven arrived at Hopkins Children’s in the middle of the night with elevated blood pressure and heart rate and what one resident described as a “striking presentation.” The girl’s weight suddenly shot up – 25 pounds in one month – and she had been sleep walking and experiencing night terrors and a seizure....

When blood tests showed elevated levels of the hormone metanephrine, Cooke started thinking neuroblastoma, an early childhood cancer that typically forms in the adrenal gland. Indeed, a CT scan and an MRI test indicated there was a tumor near the spine. Haven underwent surgery to remove the tumor, which marked the beginning of a very long treatment.

Despite expectations to the contrary, Haven’s symptoms did not improve after the surgery...

Then serendipity played a hand when senior pediatric resident Hema Dave reviewed the literature and found an association between neuroblastomas and paraneoplastic syndrome – a rare degenerative disorder of unknown origins, though one hypothesis is that it may be an autoimmune reaction to a tumor. The syndrome’s symptoms include loss of muscle tone, sleep disturbances, and seizures, all of which the child had experienced.

This was the Eureka moment for the clinical team: Haven had ROHHAD, or Rapid-Onset Obesity, Hypothalamic Dysfunction, Hypoventilation and Autonomic Dysregulation. Haven’s tumor was just one of many problems requiring treatment. Thus, Cooke and his colleagues from oncology devised a special immune-suppressive cocktail to “reboot” Haven’s overactive immune system. Doing so, they believed, would also reduce or completely eliminate her seizures, sleep problems and the weight gain. So far, it’s been working, so much so that the novel treatment was described in the medical Journal of Pediatrics in 2010 (editor's note: actually 2011).
From Paz-Priel I, Cooke DW, Chen AR. Cyclophosphamide for rapid-onset obesity,
hypothalamic dysfunction, hypoventilation, and autonomic dysregulation syndrome.
J Pediatr. 2011 Feb;158(2):337-9:

A syndrome characterized by rapid onset of obesity, hypothalamic dysfunction, hypoventilation, autonomic dysregulation (ROHHAD), and neural crest tumors has been recently identified.  Although the spectrum of this syndrome's manifestations has been described, the underlying pathogenesis is not clear, and an extensive effort to sequence candidate genes, including PHOX2B, was unrevealing.  The association with neural crest tumors suggests a paraneoplastic, autoimmune etiology; this has not yet been confirmed, however.  Many patients with ROHHAD succumb to respiratory failure or sudden death, and survivors experience debilitating sociocognitive deficits.  Better therapeutic approaches are needed...

A 3-year, 10-month-old girl presented with hyperphagia and rapid weight gain. After growth at the 50th percentile up to age 2 years, her body mass index increased from 16.8 kg/m2 (standard deviation [SD], 0.0) to 20.7 kg/m2 (SD, 2.45) at age 30 months, and then to 25.4 kg/m2 (SD, 6.18) at age 36 months. This was associated with aggressive food-seeking behavior, abnormal sleep patterns, hypertension, decreased pain sensitivity, irritability, aggressive behavior, loss of toilet training, diffuse sweating without temperature instability, and left eye exotropia. Her serum prolactin level was 76.5 ng/mL, and her thyroid and adrenal gland function were normal. Computed tomography revealed a retroperitoneal tumor, which was resected and identified as a ganglioneuroblastoma with favorable biological features. No further therapy for this neoplasm was indicated.

Because of the associated ganglioneuroblastoma, an immune-mediated process, akin to opsoclonus myoclonus ataxia (OMA) syndrome, was presumed. The patient was treated with cyclophosphamide, 750 mg/m2/dose every 28 days for 6 doses; intravenous immunoglobulin, 1g/kg/dose every 28 days for 8 doses and then every 56 days for 2 additional doses; and prednisone, 2 mg/kg/day for 28 days, followed by a 20-week-long taper. Five weekly doses of rituximab, 375 mg/m2/dose, were added based on previous reports of failure of conventional dose immunosuppression and the utility of this agent in OMA...

Our patient failed conventional-dose immunosupression, as previously reported, and experienced only short-lived relief from rituximab. High-dose cyclophosphamide “reboots” the immune system by ablating the mature immune elements and has been found to be efficacious in patients who fail conventional immunosuppression.  The acute toxicity of this regimen is well tolerated, and quality-of-life measures compare favorably with those associated with conventional-dose cyclophosphamide. However, potential risks, including infection, infertility, and secondary neoplasm, must be considered. Our patient markedly improved after high-dose cyclophosphamide, albeit with limited follow-up. Given the progressive deterioration of most patients with ROHHAD, our experience is encouraging, and in carefully selected patients, this therapy may balance the potential risks of intensive immunosuppression.

Inspired by a patient here with ROHHAD.

Autism and creativity

A new study showing that people with autism display higher levels of creativity has been welcomed by campaigners, who say it helps debunk a myth about people with learning disabilities.

Scientists found that people with the developmental condition were far more likely to come up with unique answers to creative problems despite having traits that can be socially crippling and make it difficult to find jobs. The co-author of the study, Dr Catherine Best from the University of Stirling, said that while the results, from a study of 312 people, were a measure of just one aspect of the creative process, it revealed a link between autistic traits and unusual and original ideas.

“We speculate that it may be because they are approaching things very differently. It goes a way towards explaining how some people with what is often characterised as a disability exhibit superior creative talents in some domains.”

Autism is a lifelong disorder which affects 1 in 100 in the UK, changing the way they communicate and experience the world, and varying greatly from person to person. Jolanta Lasota, chief executive of the charity Ambitious about Autism, said lack of creativity is one of many autism myths. She welcomed the study for suggesting that seeing the world in a different way can be a positive trait
She said: “There are many misconceptions and myths about autism, the biggest one including being antisocial and having a lack of empathy. However, what people with autism struggle with is fitting their feelings of sympathy and caring into everyday interactions.

“While it is true that some people with autism can have very specific interests and may struggle with abstract concepts, this research helps to highlight the fact that seeing the world in a different way can be a positive trait too. We find time and again that many of our pupils in our TreeHouse School and Ambitious College are very creative, whether that be through art, music, film or photography. It is great to see research continued in this area to help dispel more autism myths.”

Lasota has been campaigning for employers to consider people with learning disabilities when they’re hiring, and hopes that studies like this will help. “With the right support, planning and opportunities from parents and employers, many people with autism have the ability to work. Despite this, recent figures show that only 15% of people with autism are in full-time paid employment – 79% of those polled who are not in employment would like to be.”
Courtesy of:

Best C, Arora S, Porter F, Doherty M. The Relationship Between Subthreshold
Autistic Traits, Ambiguous Figure Perception and Divergent Thinking. J Autism Dev
Disord. 2015 Aug 14. [Epub ahead of print]

This research investigates the paradox of creativity in autism. That is, whether people with subclinical autistic traits have cognitive styles conducive to creativity or whether they are disadvantaged by the implied cognitive and behavioural rigidity of the autism phenotype. The relationship between divergent thinking (a cognitive component of creativity), perception of ambiguous figures, and self-reported autistic traits was evaluated in 312 individuals in a non-clinical sample. High levels of autistic traits were significantly associated with lower fluency scores on the divergent thinking tasks. However autistic traits were associated with high numbers of unusual responses on the divergent thinking tasks. Generation of novel ideas is a prerequisite for creative problem solving and may be an adaptive advantage associated with autistic traits.

Trisomy 21 and abortion

Opening a new front in the abortion wars, abortion opponents are pushing Ohio to make it illegal for a doctor to perform an abortion if a woman is terminating her pregnancy to avoid having a baby with Down syndrome.

The legislature is expected to approve the measure this fall because lawmakers endorsed by the National Right to Life Committee, which supports the bill, make up more than two-thirds of both houses.
Gov. John R. Kasich, a Republican who is running for president, opposes abortion but has not yet taken a position on this bill. Since his election in 2010, he has signed a variety of abortion restrictions, including a law requiring women to have an ultrasound and be offered a chance to see an image of the fetus before undergoing the procedure.
Mike Gonidakis, the president of Ohio Right to Life, said his group had made the bill here a legislative priority because Down syndrome is so recognizable, so easily diagnosed in pregnancy — and so likely to lead to abortion.
“We all want to be born perfect, but none of us are, and everyone has a right to live, perfect or not,” he said. “You go to any supermarket or mall and see these families who just happen to have a child with Down syndrome, and they will tell you how fortunate they are to have those children. Pretty soon, we’re going to find the gene for autism. Are we going to abort for that, too?”...
Between 60 and 90 percent of fetal Down syndrome diagnoses lead to abortion, according to an academic article reviewing research studies from 1995 to 2011 on the percentage of women who choose to terminate their pregnancies....
In 2013, North Dakota made it illegal for a doctor to perform an abortion because of fetal genetic anomalies, including Down syndrome. Indiana, Missouri and South Dakota considered similar laws this year. Seven states — Arizona, Kansas, North Carolina, North Dakota, Oklahoma, Pennsylvania and South Dakota — have laws banning abortions if the reason is gender selection. In 2012, the United States House of Representatives rejected such a measure...
If abortion on demand is legal,” said Dr. Marjorie Greenfield, a professor of obstetrics and gynecology at Case Western Reserve University School of Medicine, “and you can have an abortion just because you want to, what does it mean to say you can’t abort for Down syndrome? It seems bizarre.”
Indeed, there is currently no requirement for a woman to disclose her motivation for terminating a pregnancy.
Courtesy of:
See:  Tell me why 5/27/15

Sunday, August 23, 2015

Our family secrets

In an anonymous essay published in the Annals of Internal Medicine this week, one physician describes -- in graphic detail -- what happened to two women when they were asleep in operating rooms. The stories are horrifying.

"I bet she's enjoying this," one doctor reportedly said while prepping a woman for a vaginal hysterectomy. In another case, a obstetrician performed an obscene dance after saving the life of a woman who was bleeding out after having a baby.

The article is an unusual one for the the journal, which was established in 1927 by the American College of Physicians and typically publishes technical articles about disease management and medical research.

In a letter accompanying the essay, the editorial team agonized over whether to publish the piece. They said everyone agreed that the piece was "disgusting and scandalous" and could damage the profession's reputation. But some argued that this was why they shouldn't publish it while others felt that was why they should publish it.

"The discussion was so impassioned and opinions so disparate that we needed a 'time-out,'" editor-in-chief Christine Laine and her deputies wrote in a letter accompanying the essay.

In the end they said they decided to do so in order to "expose medicine's dark underbelly." They said the first incident "reeked of misogyny and disrespect--the second reeked of all that plus heavy overtones of sexual assault and racism."

"It is our hope that the essay will gnaw on the consciences of readers who may recall any instance of their own repugnant behavior. The story is an opportunity to see what this behavior looks like to others and starkly shows that it is anything but funny," they wrote...

The author said he learned of the first incident when teaching a medical humanities course and asking, "Do any of you have someone to forgive from your clinical experiences?" "Did anything ever happen that you need to forgive or perhaps still can't forgive?"

A student he called David said he was observing the surgery when an attending physician made the lewd comments while cleansing and scrubbing the patient...

The author says the student turned the discussion around by asking him the same question. He said he "felt my face flush" and before he knew it, he told the class about the second incident, which occurred in his third year of medical school while he was on an ob/gyn rotation. He said that he ended up laughing and joining in on the doctor's disrespectful dance until the anesthesiologist in the room yelled "Knock it off" and swore at them...

The journal's editors said that they hope that medical educators and others will use the essay as a "jumping-off point for discussions that explore the reasons why physicians sometimes behave badly."

"If the essay squelches such behavior even once, then it was well worth publishing," they wrote.

Deborah Hall, president of the American Medical Student Association, told U.S. News and World Report that medical students might be reluctant to express their objection even though they know they should because they are at the bottom of the pecking order in an operating theater filled with doctors, nurses and technicians

"Students feel incredibly vulnerable," Hall told the publication. "It's incredibly difficult to speak up."

Anonymous.  Our family secrets. Ann Intern Med. 2015;163(4):321

Courtesy of Doximity

Friday, August 21, 2015

Genetics of epilepsy in clinical practice

Berkovic SF.  Genetics of epilepsy in clinical practice. Epilepsy Currents, Vol. 15, No. 4 (July/August) 2015 pp. 192–196

Genetics should now be part of everyday clinical epilepsy practice. Good data exist to provide empiric risks based on epilepsy syndrome diagnosis. Investigation of the molecular basis of some epilepsies is now a practical clinical task and is of clear value to the patient and family. In some cases, specific therapeutic decisions can now be made based on genetic findings, and this scenario of precision therapy is likely to increase in the coming years,

From the article
Nihilistic views are sometimes expressed that finding a genetic cause does not alter management, and therefore genetic testing is unnecessary. If such views were ever defensible, they are certainly not now, for a number of reasons.

First, even if a condition is untreatable, patients and families nearly always want to know why the affliction has occurred. “Closure” of diagnosis is very important; it brings an end to the diagnostic odyssey, and families can stop searching for “answers” from multiple physicians or alternative medicine practitioners. This situation is particularly true when a previously healthy child develops an epileptic encephalopathy with refractory seizures and developmental regression. The parents may carry guilt, with a false belief that minor head knocks or vaccination caused the disorder—identifying the true cause can provide considerable consolation and assuage unfounded blame. Even in milder familial epilepsies, subjects generally wish to know.

Second, a specific genetic diagnosis avoids unnecessary testing with repeated blood tests, MRIs, invasive biopsies, pre-surgical workup, and even intracranial electrodes in the vain hope that a focal lesion or some other cause might be found in an unsolved case of epileptic encephalopathy. In turn, this allows families to focus on the problem and not be distracted by searching for the cause. A genetic diagnosis may provide useful prognostic information regarding the natural history of the disorder as large case series accumulate—this has already happened with Dravet syndrome and PCDH19-related epilepsy and will occur in time for rarer epilepsies. Families often derive benefit by meeting similarly affected families, either in person or online. Family-driven groups focused on a specific disorder have become a powerful force for aggregation of accessible information, for effective public advocacy, and for encouraging and driving research…

In addition to the general benefits of testing outlined above, there is a small but growing number of genetic diagnoses in which specific alterations in management are indicated. This may include the choice of conventional antiepileptic agents or the use of an alternative treatment…

Genetics is transforming clinical practice in epilepsy, especially in children. Useful clinical information can be provided to families, and a specific molecular diagnosis, where possible, adds greatly to the accuracy of the information. The promise of precision therapies is becoming a reality and may eventually become widely applicable.