Friday, February 26, 2016

Disseminating clinical results

Leading academic research centers are doing a poor and variable job of disseminating clinical trial results, according to a cross-sectional analysis published online February 17 in BMJ, and that is leading to serious information gaps and ethical lapses. 
Despite there being moral and sometimes legal obligations to circulate results in the public domain, Ruijun Chen, MD, from the Department of Medicine, University of California, San Francisco, and colleagues found that just 29% of completed trials at 51 major research centers had been published 2 years after completion, and a mere 13% had submitted their results to 
"There is no excuse for the fact that researchers are using resources and conducting experiments on humans, taking up their time and maybe exposing them to risk, and then failing to report the results. Why, is beyond me," corresponding author Harlan M. Krumholz, MD, a professor of medicine at Yale University, New Haven, Connecticut, told Medscape Medical News. 
Delayed data dissemination denies healthcare providers and researchers crucial information. "If all the trial data had been made available in a timely way, then people would have realized the cardiovascular risks of Vioxx [Merck] 2 years before it was taken off the market in 2004," said Dr Krumholz, who coauthored a study of pooled trial data showing increased risk with the drug as early as 2000. 
The researchers called for timely action to correct this lapse in commitment to the investigative mission and failure to follow through on the research process. "Additional tools and mechanisms are needed to rectify this lack of timely reporting and publication, as they impair the research enterprise and threaten to undermine evidence based clinical decision making," the authors write... 
Across institutions, the proportion of trials that disseminated results within 24 months ranged from 16.2% (University of Nebraska) to 55.3% (University of Minnesota), and the proportion published within 24 months of completion extended from 10.8% (University of Nebraska) to 40.3% (Yale University). The overall range for results reported on ran from 4.1% (Memorial Sloan-Kettering Cancer Center) to 55.4% (MD Anderson Cancer Center). 
The overall rate of dissemination ran from 45.9% at the University of Nebraska to 76.7% at the universities of Minnesota and Rochester. There was also a more than twofold variation from 13.9 (University of California, Irvine) to 28.3 (Boston University) months in median time from study completion to publication or reporting. 
Previous studies found similar suboptimal dissemination rates, with 25% to 50% of trials remaining unpublished several years after completion. 
Dr Krumholz is at loss to understand the lapse in data sharing, which he considers immoral. "It's not hard to report your results. It only takes about an hour," he said. Nor does reporting to the national trial database jeopardize future publication in a peer-reviewed journal, he said. "Some studies are small, but you have to ask: If the results are not important enough to be reported, was the study important enough to be done? You should not have conducted the study if you can't provide timely results." 
He noted that those with concerns about a drug could perhaps tap into trial results circuitously by checking relevant studies registered on and asking the investigators directly to share their unreported data. 
And although researchers do need adequate time to ensure accurate data, "some, inexplicably, never share their findings," Dr Krumholz said. In his view, less effort should be put into identifying reasons and more into rectifying the unjustifiable status quo: "We can spend our time understanding the causes, or we can just fix it."
Ruijun Chen, Nihar R Desai, Joseph S Ross, Weiwei Zhang, Katherine H Chau, Brian Wayda, Karthik Murugiah, Daniel Y Lu, , Amit Mittal, Harlan M Krumholz, Harold H Hines Jr. Publication and reporting of clinical trial results: cross sectional analysis across academic medical centers.  BMJ published on line.  
Objective To determine rates of publication and reporting of results within two years for all completed clinical trials registered in across leading academic medical centers in the United States. 
Design Cross sectional analysis. 
Setting Academic medical centers in the United States. 
Participants Academic medical centers with 40 or more completed interventional trials registered on 
Methods Using the Aggregate Analysis of database and manual review, we identified all interventional clinical trials registered on with a primary completion date between October 2007 and September 2010 and with a lead investigator affiliated with an academic medical center. 
Main outcome measures The proportion of trials that disseminated results, defined as publication or reporting of results on, overall and within 24 months of study completion. 
Results We identified 4347 interventional clinical trials across 51 academic medical centers. Among the trials, 1005 (23%) enrolled more than 100 patients, 1216 (28%) were double blind, and 2169 (50%) were phase II through IV. Overall, academic medical centers disseminated results for 2892 (66%) trials, with 1560 (35.9%) achieving this within 24 months of study completion. The proportion of clinical trials with results disseminated within 24 months of study completion ranged from 16.2% (6/37) to 55.3% (57/103) across academic medical centers. The proportion of clinical trials published within 24 months of study completion ranged from 10.8% (4/37) to 40.3% (31/77) across academic medical centers, whereas results reporting on ranged from 1.6% (2/122) to 40.7% (72/177). 
Conclusions Despite the ethical mandate and expressed values and mission of academic institutions, there is poor performance and noticeable variation in the dissemination of clinical trial results across leading academic medical centers.

Thursday, February 25, 2016

BRAT1 mutations

van de Pol LA, Wolf NI, van Weissenbruch MM, Stam CJ, Weiss JM, Waisfisz Q,
Kevelam SH, Bugiani M, van de Kamp JM, van der Knaap MS. Early-Onset Severe
Encephalopathy with Epilepsy: The BRAT1 Gene Should Be Added to the List of
Causes. Neuropediatrics. 2015 Dec;46(6):392-400.

A variety of pathologies can underlie early-onset severe encephalopathy with epilepsy. To aid the diagnostic process in such patients we present an overview of causes, including the rapidly expanding list of genes involved. When no explanation is found, whole-exome sequencing (WES) can be used in an attempt to identify gene defects in patients suspected to suffer from a genetic form. We describe three siblings, born to consanguineous parents, with a lethal severe epileptic encephalopathy with early-infantile onset, including their magnetic resonance imaging, electroencephalography and, in one case, neuropathological findings. Using WES a homozygous frameshift mutation in the BRAT1 gene, c.638dup p.(Val214Glyfs*189), was identified. We present our cases in the context of all published cases with mutations in the BRAT1 gene and conclude that BRAT1 should be added to the growing list of genes related to early-onset severe encephalopathy with epilepsy.

Straussberg R, Ganelin-Cohen E, Goldberg-Stern H, Tzur S, Behar DM,
Smirin-Yosef P, Salmon-Divon M, Basel-Vanagaite L. Lethal neonatal rigidity and
multifocal seizure syndrome--report of another family with a BRAT1 mutation. Eur
J Paediatr Neurol. 2015 Mar;19(2):240-2.

We describe two siblings born to consanguineous Arab-Muslim parents who presented in early infancy with myoclonic seizures, hypertonia and contractures, arrested head growth, inability to swallow, and bouts of apnea-bradycardia, culminating in cardiac arrest and death. Whole-genome sequencing yielded a c.1173delG mutation in the BRAT1 gene. Three recent reports identified mutations in the same gene in three infants from three Amish sibships, one Mexican neonate and two Japanese siblings with similar clinical manifestations. The authors speculated that the destabilization of the encoded protein may underlie the catastrophic epilepsy and corticobasal neuronal degeneration. We suggest that BRAT1 be added to the growing list of genes that are related to severe early infantile (neonatal) epileptic encephalopathy.

Mundy SA, Krock BL, Mao R, Shen JJ. BRAT1-related disease-identification of a
patient without early lethality. Am J Med Genet A. 2016 Mar;170(3):699-702.

We present a patient with neonatal onset of hypertonia and seizures identified through whole exome sequencing to have compound heterozygous variants, c.294dupA (p.Leu99fs) and c.1925C>A (p.Ala642Glu), in the BRCA1-associated protein required for ATM activation-1 (BRAT1) gene. Variants in BRAT1 have been identified to cause lethal neonatal rigidity and multifocal seizure syndrome (OMIM# 614498), which consistently manifests a severe neurological phenotype that includes neonatal presentation of rigidity and hypertonia, microcephaly and arrested head growth, intractable seizures, absence of developmental progress, apneic episodes, and death usually by 6 months of age. Our patient initially had a similarly severe neurological picture but remains alive at 6 years of age, expanding the phenotype to include longer term survival and providing further insights into genotype-phenotype correlations and the natural history of this disease.

Hanes I, Kozenko M, Callen DJ. Lethal Neonatal Rigidity and Multifocal Seizure
Syndrome-A Misnamed Disorder? Pediatr Neurol. 2015 Dec;53(6):535-40.

Lethal neonatal rigidity and multifocal seizure syndrome is a newly recognized genetic disorder associated with early onset of rigidity, multifocal epilepsy, developmental arrest, and early death. It is an autosomal recessive condition resulting from a mutation in the BRAT1 (BRCA1 [breast cancer-1]-associated ataxia telangiectasia mutated activator 1) gene. There are few cases in the literature, and all patients have died before age 2 years, most within the first 6 months of life. The objective of this report is to expand the phenotypic spectrum of BRAT1 disorders and propose new nomenclature for this condition.
We describe a child with compound heterozygosity for mutations in BRAT1. Her neonatal course was unremarkable. Over the first year of life she was noted to have progressive global developmental delay, visual impairment, microcephaly, hypertonia, hyperreflexia, and seizures. No epileptiform discharges were seen on electroencephalogram. Serial magnetic resonance imaging of the brain showed progressive cerebellar and brainstem atrophy. Unlike previously described patients, our patient has gained a number of developmental skills and, at this time, is 3 years and 8 months old.
Despite the name of this disorder, patients with lethal neonatal rigidity and multifocal seizure syndrome may not present until after the neonatal period and may have a much longer life span than previously reported. We suggest renaming the condition "BRAT1-associated neurodegenerative disorder" to avoid the assumptions associated with the original nomenclature and to encourage clinicians to consider this condition outside the neonatal period.

Wednesday, February 24, 2016

One year ago

One year ago this blog initiated with three entries:

Now there are 555 entries.  I thank my readership for inspiring me to continue in this endeavor and I thank G-d Almighty for giving me whatever valuable insights are contained herein.

Signaling pathway and Rett syndrome

Harvard Stem Cell Institute (HSCI) researchers have identified a faulty signaling pathway that, when corrected in mice, ameliorates the symptoms of Rett syndrome, a devastating neurological condition. The findings could lead to the discovery of compounds or drugs that may benefit children affected by the disease, says neurobiologist Jeffrey Macklis, a member of the HSCI Executive Committee.
The research was published recently in Nature Communications. Noriyuki Kishi and Jessica MacDonald, both recent postdoctoral fellows in the Macklis laboratory, are co-first authors. Macklis, who directed the work, is the Max and Anne Wien Professor of Life Sciences in the Department of Stem Cell and Regenerative Biology, and Center for Brain Science at Harvard University...

“My view was that MECP2 mutation in Rett syndrome disrupts so many genes and their protein products that we weren’t going to find a single gene that we could fix to help girls with Rett,” said Macklis, former program head of HSCI’s Nervous System Diseases Program, and an Allen Distinguished Investigator of the Paul G. Allen Family Foundation. “But if we found a disrupted, improperly regulated signaling pathway that was ‘drug-able,’ that affected enough of the girls’ pathology, we might be able to make them dramatically functionally better with already available therapeutics — and that might make a real difference in their lives and their families’ lives.”

Instead of concentrating on the MECP2 gene, Macklis’ group focused on neurons he knew were “abnormal and implicated in Rett syndrome and autism spectrum disorders,” and in 2004, his lab was the first to describe abnormal development in this type of neuron. These neurons, called inter-hemispheric callosal projection neurons (CPNs), have shorter, less-developed dendrites, or “receiving antennas,” in mice with the Rett gene mutations and in individuals with Rett syndrome.

Building on their 2004 findings, the researchers were able to fluorescently label CPNs in mice with or without the Rett mutation, purify them from other types of neurons, and look at the levels at which many thousands of genes were active, and thus how much of the proteins coded for by those those genes was made.

They found that one gene for IRAK1, which Macklis’ group identified as regulated by MECP2 and which is a well-known part of the NF-kB signaling pathway, was making about three times more protein than normal. They modified IRAK1 levels both in mice with Rett mutations and in mouse neurons in culture dishes. When they reduced the activity of its gene Irak1 by roughly half, and consequently the amount of IRAK1 protein made, the neurons and their dendrites developed substantially better, indistinguishable from normal by several assays. Further, mice with reduced levels of IRAK1 had significantly fewer symptoms, better function, and much longer lifespan. They had much-improved health, well beyond only these neurons.

Now, Macklis said, the researchers have started looking into potential compounds and drugs that are already available and that might partially correct this pathway, and what dosages and timing might ultimately ameliorate the effects of Rett syndrome.
Courtesy of Neurologist Connect

Kishi N, MacDonald JL, Ye J, Molyneaux BJ, Azim E, Macklis JD. Reduction of
aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null
mice. Nat Commun. 2016 Jan 29;7:10520.


Mutations in the transcriptional regulator Mecp2 cause the severe X-linked neurodevelopmental disorder Rett syndrome (RTT). In this study, we investigate genes that function downstream of MeCP2 in cerebral cortex circuitry, and identify upregulation of Irak1, a central component of the NF-κB pathway. We show that overexpression of Irak1 mimics the reduced dendritic complexity of Mecp2-null cortical callosal projection neurons (CPN), and that NF-κB signalling is upregulated in the cortex with Mecp2 loss-of-function. Strikingly, we find that genetically reducing NF-κB signalling in Mecp2-null mice not only ameliorates CPN dendritic complexity but also substantially extends their normally shortened lifespan, indicating broader roles for NF-κB signalling in RTT pathogenesis. These results provide new insight into both the fundamental neurobiology of RTT, and potential therapeutic strategies via NF-κB pathway modulation.


Researchers at the Johns Hopkins Bloomberg School of Public Health have grown tiny, barely visible "mini-brains," balls of human neurons and other cells that mimic some of the brain's structures and functionality. The development of the mini-brains could dramatically change brain research and drug testing, replacing hundreds of thousands of animals used now in neurology labs.

Performing research using these three-dimensional mini-brains—which grow and form brain-like structures on their own over the course of eight weeks—should be superior to studying mice and rats because they are derived from human cells instead of rodents, researchers say. The findings will be presented at the American Association for the Advancement of Science conference in Washington, D.C., this weekend.

"Ninety-five percent of drugs that look promising when tested in animal models fail once they are tested in humans at great expense of time and money," says study leader Thomas Hartung, professor of environmental health sciences at the Bloomberg School. "While rodent models have been useful, we are not 150-pound rats. And even though we are not balls of cells either, you can often get much better information from these balls of cells than from rodents.

"We believe that the future of brain research will include less reliance on animals, more reliance on human cell-based models."

Hartung and his colleagues created the mini-brains using what are known as induced pluripotent stem cells, or iPSCs—adult cells genetically reprogrammed to an embryonic stem cell-like state and then stimulated to grow into brain cells. Cells from the skin of several healthy adults were used to create the mini-brains, but Hartung says that cells from people with certain genetic traits or certain diseases can be used to create mini-brains to study various types of pharmaceuticals. He says the mini-brains can be used to study Alzheimer's disease, Parkinson's disease, multiple sclerosis, and even autism. Projects to study viral infections, trauma, and stroke have been started.

Hartung's mini-brains are very small—at 350 micrometers in diameter, they are about the size of the eye of a housefly and are just visible to the human eye—and hundreds to thousands of exact copies can be produced in each batch. One hundred of them can grow easily in the same petri dish in the lab. After about two months, the mini-brains developed four types of neurons and two types of support cells. They even showed spontaneous electrophysiological activity, which could be recorded with electrodes, similar to an electroencephalogram, or EEG. To test them, researchers placed a mini-brain on an array of electrodes and listened to the spontaneous electrical communication of the neurons as test drugs were added.

Hartung is applying for a patent and is also developing a commercial entity to produce mini-brains, perhaps starting this year. He says they are easily reproducible and hopes to see them in as many labs as possible.

"We don't have the first brain model, nor are we claiming to have the best one," says Hartung, who also directs the School's Center for Alternatives to Animal Testing. "But this is the most standardized one. And when testing drugs, it is imperative that the cells being studied are as similar as possible to ensure the most comparable and accurate results."
Courtesy of Neurologist Connect
See:  Autism and brain organoids 7/19/15

Desbuquois syndrome

Turning 13 is a big deal for any child, but for one Texas teen with a rare disorder, it marks another survival milestone. To celebrate, he’s fundraising for the organization that’s supported him through the years, the Children’s Miracle Network.

Brenden Baker, of Abilene, Texas, has Desbuquois syndrome, a disorder that affects the development of the bone and cartilage. According to the National Institutes of Health (NIH), characteristics can include short stature with short extremities, distinctive facial characteristics and severe joint laxity. There have been only 50 cases described in medical literature, according to Orphanet.

“When he was first born, we weren’t sure he’d make it to the thirteenth birthday, in fact we weren’t sure he’d make it more than a couple days, but he’s been in relatively good health for the first 12 years, then about a year ago the doctors had to put him on oxygen,” Brenden’s grandfather, Bruce Bachman, told WKRC.

Since Brenden was born, the Children’s Miracle Network has supported him through Hendrick Medical Center in Abilene and for his first teenage birthday, he’s asking for donations to be made to the center in lieu of gifts.

Originally, he asked for $200, but quickly surpassed that and is now aiming higher.

“$150,000, please,” Brenden told WKRC. When asked if he could make his big goal, he responded,

“Yes, people, donate, please.”


Desbuquois syndrome (DBQD) is an osteochondrodysplasia characterized by severe micromelic dwarfism, facial dysmorphism, joint laxity with multiple dislocations, vertebral and metaphyseal abnormalities and advanced carpotarsal ossification. Two forms have been distinguished on the basis of the presence (type 1) or the absence (type 2) of characteristic hand anomalies. A variant form of DBQD, Kim variant (see these terms), has also been described and is characterized by short stature and articular, minor facial and significant hand anomalies.

To date, less than 50 cases have been described in the literature.

DBQD is characterized by severe micromelic dwarfism, facial dysmorphism (round flat face, prominent eyes, midface hypoplasia, short nose, microstomia, long upper lip with flat philtrum, microretrognathia, often resulting in isolated Pierre Robin syndrome (see this term)), thoracic hypoplasia, kyphoscoliosis, severe joint laxity with dislocation, and osteopenia. Additional features include glaucoma, cardiac septal defects, lung hypoplasia, obesity and clubbed feet with rocker bottom appearance. Two forms have been distinguished on the basis of the presence (type 1) or the absence (type 2) of characteristic hand anomalies (accessory ossification center distal to the second metacarpal, bifid distal phalanx, or thumb with delta-shaped phalanx). A variant form of DBQD, Kim variant, has been described in 7 patients originating from Korea and Japan, and is characterized by short stature, articular and minor facial anomalies, together with significant hand anomalies including short metacarpals and elongated phalanges with advanced carpal bone age.

DBQD type 1 and Kim variant are caused by mutation in the gene CANT1 (17q25.3). However, the function of CANT1 is still unknown. Mutations in the gene XYLT1 (16p12) has been reported to cause DBQD type 2. XYLT1 encodes xylosyltransferase 1 which is involved in proteoglycan synthesis. However not all DBQD type 2 have XYLT1 mutations supporting the involvement of other disease causing genes.

'Diagnosis relies upon recognition of clinical and radiological features which include an advanced carpal and tarsal bone age; broad femoral neck with a spur-like projection and prominent lesser trochanter, producing characteristic ''monkey wrench'' (Swedish key) appearance; narrow thorax; coronal or sagittal clefting of the vertebrae and typical hand changes for DBQD type 1 that consist of small delta-shaped extraphalangeal bone, distal to the second metacarpal, leading to radial deviation of the index fingers (delta phalanx or bifid thumb),and horizontal acetabular roofs with dislocation of femoral heads. Diagnosis is confirmed by the genetic screening of CANT1 in type 1 and XYLT1 in type 2DBQD.'

Differential diagnosis includes autosomal dominant or recessive Larsen syndrome, Reunion island's Larsen syndrome, Catel-Manzke syndrome, chondrodysplasia with joint dislocations, gPAPP type, CHST3-related skeletal dysplasia, spondyloepiphyseal dysplasia, Omani type, diastrophic dwarfism and humerospinal dysostosis (see these terms).

Antenatal diagnosis is achieved by ultrasound during the second trimester of pregnancy, by the detection of hydramnios, hydrops fetalis (see this term), intrauterine growth retardation, vertebral abnormalities and characteristic dysmorphic features.

Transmission is autosomal recessive and genetic counseling is recommended.

Management includes regular orthopedic survey with often a need for multiple surgeries (scoliosis, hip and knee dislocation), and eye and ear follow up.

Type 1 DBQD displays a high lethality rate of >33% due to respiratory failure. Survivors may have intellectual disability, developmental delay, generalized and progressive joint laxity with dislocated knees. Orthopedic complications often limit the ambulation in DBQD.

Tuesday, February 23, 2016

An Angelman story

A 6-year-old Canadian girl has raised about $92,000 to help save her brother’s life since she started a lemonade stand outside of her family home when she was 4. reported that Na’ama Uzan set off to sell the lemonade, and eventually baked treats, in 2014 to raise research funds for Angelman syndrome, a genetic disorder that can cause neurological and developmental disabilities, and that her brother Nadav was diagnosed with that year. According to the National Institutes of Health (NIH), Angelman syndrome affects an estimated one in 12,000 to 20,000 people.

On Monday, dubbed International Angelman Day, firefighters and paramedics participated in a charity ice hockey game in Toronto to raise funds for the research. Ru Uzan, Na'ama's mother, told that they raised more than $7,200 at the event.

"We have cupcakes and muffins," Na’ama said at the event, which also included a bake sale, according to "It's been going really, really, really, really well."

Na’ama’s fundraising has helped the Foundation for Angelman Syndrome Therapeutics (FAST) hire a post-doctoral researcher, CTV News reported.

“There’s somebody working every day knowing that a little girl is standing on the corner calling out for lemonade and that is paying her salary,” Ru Uzan, Na’ama’s mother, told CTV News
Channel.  Na’ama told CTV News Channel that she wants Nadav to be able to “skate, talk, and be able to do lots of stuff.”

Globus pallidus neuronal firing rates in dystonia

V M McClelland, A Valentin, H G Rey, D E Lumsden, M C Elze,  R Selway,  G Alarcon, J-P Lin.  Differences in globus pallidus neuronal firing rates and patterns relate to different disease biology in children with dystonia.  J Neurol Neurosurg Psychiatry.   Published Online  4 February 2016.

Background The pathophysiology underlying different types of dystonia is not yet understood. We report microelectrode data from the globus pallidus interna (GPi) and globus pallidus externa (GPe) in children undergoing deep brain stimulation (DBS) for dystonia and investigate whether GPi and GPe firing rates differ between dystonia types. 
Methods Single pass microelectrode data were obtained to guide electrode position in 44 children (3.3–18.1 years, median 10.7) with the following dystonia types: 14 primary, 22 secondary Static and 8 progressive secondary to neuronal brain iron accumulation (NBIA). Preoperative stereotactic MRI determined coordinates for the GPi target. Digitised spike trains were analysed offline, blind to clinical data. Electrode placement was confirmed by a postoperative stereotactic CT scan. 
Findings We identified 263 GPi and 87 GPe cells. Both GPi and GPe firing frequencies differed significantly with dystonia aetiology. The median GPi firing frequency was higher in the primary group than in the secondary static group (13.5 Hz vs 9.6 Hz; p=0.002) and higher in the NBIA group than in either the primary (25 Hz vs 13.5 Hz; p=0.006) or the secondary static group (25 Hz vs 9.6 Hz; p=0.00004). The median GPe firing frequency was higher in the NBIA group than in the secondary static group (15.9 Hz vs 7 Hz; p=0.013). The NBIA group also showed a higher proportion of regularly firing GPi cells compared with the other groups (p<0.001). A higher proportion of regular GPi cells was also seen in patients with fixed/tonic dystonia compared with a phasic/dynamic dystonia phenotype (p<0.001). The GPi firing frequency showed a positive correlation with 1-year outcome from DBS measured by improvement in the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS-m) score (p=0.030). This association was stronger for the non-progressive patients (p=0.006). 
Interpretation Pallidal firing rates and patterns differ significantly with dystonia aetiology and phenotype. Identification of specific firing patterns may help determine targets and patient-specific protocols for neuromodulation therapy.
Funding National Institute of Health Research, Guy's and St. Thomas’ Charity, Dystonia Society UK, Action Medical Research, German National Academic Foundation.

Dystonia can be primary, where the only feature of the disease is muscle contractions that may cause abnormal, repetitive movements, or it can be secondary to some other disease or brain injury. There are two types of secondary dystonia, including static lesions, and progressive disorders. Static lesions usually occur after hypoxic ischemic encephalopathy (HIE), prematurity, infection, a metabolic disturbance or a vascular event, and progressive disorders include “heredodegenerative dystonias, which are characterized by neurodegeneration,” according to the researchers. Most children have secondary types of dystonia.

One of the most well-established treatments for dystonia is deep brain stimulation (DBS) of the globus pallidus interna (GPi), though it is more effective for people with primary dystonia. In this study, the researchers say they “analyzed microelectrode recordings from the GPi and globus pallidus externa (GPe) in 44 children undergoing DBS for severe generalized dystonia, aiming to test the hypothesis that pallidal firing differs between different dystonia etiologies.”

The researchers report measuring the mean firing rate, the interspike interval distribution, and the instantaneous firing rate, and they classified cells as regular, irregular or bursting based on watching the cells during the firing pattern and the interspike interval distribution, as well as the instantaneous firing rate.

“We identified 263 GPi and 87 GPe cells from 81 electrode trajectories. In three patients, no active cells were identified,” said the researchers. The three with no active cells were excluded due to the possibility of a technical problem, but they also considered the possibility of “silent cells” in those three cases.

The goal of this study was more related to GPi than to GPe, and so, the researchers said, “therefore the path through the GPe was not strongly considered in the targeting of the trajectory. Some paths may have had very little GPe involved.” ...

They suggest that it understanding the different mechanisms involved will help explain why patients with secondary dystonia have a poorer response to DBS, and that further investigations are warranted.

 - See more at:

Monday, February 22, 2016

Burzynski clinic

As a young doctor in the 1970s, Burzynski began treating patients with antineoplastons, a collection of peptides, amino acids and amino acid derivatives he originally isolated from blood and urine. Since then, by his reckoning, he’s used the drugs to treat over 2,300 cancer patients—though he isn’t trained as an oncologist. He’s been the subject of laudatory documentaries and promoted by the likes of Dr. Mehmet Oz, the famous surgeon and TV personality, and Suzanne Somers, the actress-turned-naturopathic-medicine-advocate. “No one has worked harder, and no one has been more persecuted for his maverick approach,” Somers wrote in her book Knockout: Interviews With Doctors Who Are Curing Cancer.

But there's no verifiable evidence antineoplastons work. Nor are they the gentle treatment Burzynski claims them to be. He has run Food and Drug Administration–approved clinical trials on the drugs since the 1990s, during which time at least six study participants died from hypernatremia, or high levels of sodium in the blood—likely due to the sodium-rich antineoplastons. Among the victims was a 6-year-old boy.

Over the years, Burzynski has been the subject of numerous investigations and legal proceedings, brought by grand juries, the FDA and the Texas Medical Board. As it’s become more difficult to continue registering his patients in antineoplaston trials, Burzynski has treated patients in other ways, still outside the medical mainstream. He uses chemotherapy drugs in combinations that have not been scientifically tested—and whose toxicities, according to the medical board, pose an unwarranted threat to patients.

Now the Texas Medical Board has brought yet another case against Burzynski, seeking to revoke his license. As the hearing got underway in Austin in November, some of the doctor’s former patients and admirers gathered to support him and to protest with placards...
But then Lisa heard about Burzynski. The Merritts went down to his clinic, where they learned Wayne didn’t qualify for antineoplastons but might respond to some other drugs. The couple made it very clear, Lisa said, that Wayne didn’t want chemo. They saw Burzynski for 10 minutes, then were turned over to his staff. Lisa says Wayne had a daily appointment with a woman wearing a name tag that said “Dr.,” and whom the other staff called “doctor”—but who, the Texas Medical Board says, isn’t licensed to practice medicine in Texas.

Back home in Armuchee, Georgia, they got a shock. On their next visit with their local oncologist, she looked at the clinic’s prescriptions and dropped three bombshells: One, Wayne was indeed on chemotherapy, among other drugs; two, the medications would cost about $30,000 a month—not the $3,000 to $6,000 a month they had been told; three, his medication regimen was dangerous. “It was devastating,” Lisa says. “We felt like we got dropped on our face.”...

On its website, the Burzynski Clinic says it offers “personalized cancer therapy,” using genetic analysis to customize treatment for each patient. But in expert testimony for the medical board, Dr. Cynthia Wetmore, director of the Center for Clinical and Translational Research at Emory–Children’s Pediatric Research Center in Atlanta, said, “There’s not a possible way to tell what drug is helping and what drug is not helping. The drugs are given in unstandard [ sic ] combinations that never have been tested. They’re given in unstandard doses that are not known to be effective or safe. And combining them is experimenting on humans, which cannot be done outside a clinical study. That’s unethical. ”...

The board concluded that because of Burzynski’s actions and those of his subordinates, “each of the patients in this case either suffered considerable toxicity effects or were put at significant risk of considerable toxicity effects.”

Burzynski takes a different view—he says the drug combinations are evidence of his innovative approach to medicine. In an email to his former lawyer, Richard Jaffe, in January 2015, he wrote, “It takes a single pioneer to abolish dogma and save countless lives. This is our contribution to medical science.” Burzynski argued that it’s unfeasible to restrict practitioners only to tested drug combinations, because with almost 100 cancer drugs, testing every combination of five agents would result in “hundreds of thousands of trials.” (Burzynski and his lawyers did not respond to a request for comment.)...

The most reliable scientific sources agree with the board’s assessment of antineoplastons. The National Cancer Institute (NCI), part of the National Institutes of Health (NIH), says in its summary guidance for health professionals, “No randomized controlled trials showing the effectiveness of antineoplastons have been published in the peer-reviewed scientific literature.”

Because of the lack of strong scientific evidence, there is little concrete information about the toxicity or side effects of the drugs. On the one hand, says Dr. Wayne Jonas, who reviewed antineoplastons for NCI, the drugs probably have a lower toxicity than some chemotherapies prescribed for brain cancer. But on the other, studies of antineoplastons have observed serious side effects, including severe neurological toxicity, bone marrow suppression, hypernatremia, fatigue, stupor and coma, and potassium deficiency in the blood.

As far back as 1994, an FDA inspection found that Burzynski was misrepresenting side effects as minimal. Eighteen years later, a 6-year-old boy in one of Burzynski’s trials died with hypernatremia. When the FDA found out, they put a partial hold on his trials, forbidding him from enrolling children. Later, the agency expanded the hold to include adults. As part of his effort to lift the hold, Burzynski sent the FDA an analysis of 2,185 trial subjects. Nearly half had suffered hypernatremia; the FDA argued that Burzynski had underestimated the number of cases caused by antineoplastons in this analysis and especially in his trial brochure, which claimed, “Most cases were not related to antineoplaston therapy.”...

When you cut through all the grandiose claims, Burzynski’s drug trials appear to be a smokescreen. His goal, it seems, isn’t to prove his invention through the scientific process but only to treat as many patients with antineoplastons as he can. That claim doesn’t come from his critics—it comes from his former lawyer, Richard Jaffe. “As far as clinical trials go, it was a joke,” he wrote of one trial’s design in his book, Galileo’s Lawyer . “It was all an artifice, a vehicle we and the FDA created to legally give the patients Burzynski’s treatment.”

Given this startlingly frank admission, many critics ask why Burzynski is still allowed to run his clinic and to enroll patients in trials. “The FDA has inspected him quite a few times, and they always find stuff, but they never can quite seem to shut down his clinical trials,” says David Gorski, a surgical oncologist at the Barbara Ann Karmanos Cancer Institute, and a blogger who’s written extensively about Burzynski. Gorski says he’s asked the FDA why it hasn’t shut down Burzynski, and they’ve never explained. When Newsweek asked the agency the same question, it responded with a general statement, making no reference to Burzynski, saying simply that it takes action based on its most recent inspections, using all available information.

Sandra Cohen is a Burzynski success story—sort of. She went to him seeking antineoplastons, and when she didn’t qualify, she reluctantly started on chemotherapy and later agreed to surgery. Five years later, she is cancer-free. “Dr. Burzynski saved my life,” Cohen says.
Courtesy of a colleague

Failure to communicate

"What we've got here is failure to communicate," the Captain, a prison warden, famously said to
his stubborn prisoner in the 1967 film classic Cool Hand Luke. It's far from a friendly pronouncement, of course. But too often, communication channels really do break down, and the results in the medical arena can be especially dire, even catastrophic. That's the underlying message of a new report by CRICO Strategies, a Harvard-affiliated group of evidenced-based risk-management companies. "When information falls through the cracks, diagnoses are confounded, procedures are complicated, and subsequent care is compromised," says Heather Riah, CRICO's assistant vice president.

To probe the problem of communication failure, researchers looked at 23,658 medical malpractice cases filed between 2009 and 2013. (The CRICO database, which reflects the medical liability experience of more than 400 US hospitals and 165,000 physicians, contains 350,000 cases overall.)

Of the cases examined, communication failures of one kind or another contributed to patient harm in about 30%, or 7149, of the cases. Most failures occurred in surgery (27%), followed by general medicine (13%), nursing (9%), and obstetrics (5%). The inpatient setting—including the emergency department—accounted for 52% of the communication breakdowns, while ambulatory and other settings accounted for the remaining 48%. Researchers also found that 37% of all high-severity injury cases—including wrongful death cases—involved a communication failure.

Communication breakdowns were almost evenly split between clinician to clinician and clinician to patient, with some overlap between the two categories. On the clinician-to-clinician side, the most common breakdown involved a miscommunication regarding a patient's condition (26%), followed by poor documentation (12%) and failure to read the medical record (7%). On the clinician-to-patient side, breakdowns included inadequate informed consent (13%), unsympathetic responses to patient complaints (11%), and inadequate medication instructions (5%).

The report found that cases triggered by clinician-to-clinician communication failures were more likely to result in a payout than those centered on clinician-to-patient communications (49% versus 35%). The average payouts in cases involving communication lapses between clinicians were also higher: $484,000 versus $381,000.

What can be done to address these breakdowns? Researchers propose a greater emphasis on empathy—thereby increasing the odds that information is not only conveyed but received and well understood—and a more effective consent process, which is especially critical prior to surgery.

Sunday, February 21, 2016

Engaging with the anti-vaxers

Among scientists and in the media, anti-vaxers have earned a certain reputation. “They just don’t know something, or they’re anti-science, or there’s just something pathological about them,” as Mark Largent, a professor at Michigan State University and the author of Vaccine: The Debate in Modern America, characterized it. There is near-consensus among researchers that widespread immunization is crucial for children and American public health. Yet, according to Largent, 40 percent of American parents have either refused or delayed a recommended vaccine for one of their kids.

The question is: Why?
In Largent’s view, the answer has to do with imbalances of power. Many parents feel helpless and overwhelmed within a dysfunctional health-care system, he argued; on an average vaccine schedule, kids may get up to 25 inoculations in their first 18 months, and up to six in a single doctor’s visit. In interviews with people who seek out waivers in Michigan, he and his colleagues found that vaccine-skeptical parents show “tremendously high trust in medical communities,” he said. “Who don’t they trust? The feds, and pharma.” This research, along with rhetoric from recent political fights, suggests some parents may feel uncertain about vaccines partly because they’re skeptical of pharmaceutical companies, whose profit motives mix with their vaccine-promotion campaigns. And while state governments can mandate immunization, this may end up pushing parents away from the public-school system if they feel that regulations are forcing them to make certain decisions about their children’s health…
But as Largent said to a room full of scientists during the annual meeting of the American Association for the Advancement of Science this weekend, “You need to understand your own position. You think you do, but unless you’ve done a tremendous amount of psychotherapy, you really don’t.”
“You are an intensely privileged group of people. You receive tremendous amounts of funding from the economic system, from the political system. You are revered. You have more cultural, social, and economic authority than probably any other group as a group, besides some very, very, very wealthy people. You guys are it. You possess the wheel of the largest and most powerful institution that’s ever existed—that’s modern science.
You’re the hegemon. When you forget that and think, ‘Oh, I’m just this embattled scientist, constantly under fire,’ it’s like, yeah, I understand that you’re being harassed, but it’s because you have so much power and authority.”
To put it another way, doctors and medical researchers have a lot of control over what happens to people’s kids. These scientists have training and expertise that’s inaccessible to the general public, and the way they use their knowledge can define a child’s health and life. Faced with this imbalance of power and information, who can blame parents for being nervous and striking out on the Internet for a second opinion?...
On average, immunization opponents are relatively well-educated, upper middle class, Protestant, and married. Protests and public opposition tend to be led by mothers, rather than fathers. And they’re often relatively older parents—those over 40 tend to be particularly concerned about the possible effects of vaccines, according to Largent.
All of this matters for shaping public policy. State governments, health departments, and researchers have tried various approaches, including all-out bans on non-medical waivers, as in California, or alternative modes of counseling—showing parents gnarly pictures of kids with the measles, making conversations on vaccines more consultative, that sort of thing. All of these approaches have their downsides, but Largent pointed to one glimmer of success. In Michigan, the number of non-medical vaccination waivers reportedly fell by 39 percent in 2015, following a new mandate requiring parents to go through one-on-one counseling sessions with a county official before they can get an exemption. Most parents who go through the counseling don’t change their minds, he said; the difference comes from those parents who don’t bother attending the sessions. Largent believes this success is a result of compromise: Passionately anti-vaccine parents feel like they have a way out of immunizing their kids, but the state has an effective way of discouraging less dogged parents from opting out. And knowing who parents trust matters. That’s why, he said, public-health organizations “have to decouple vaccine efforts from pharmaceutical companies. I don’t want Merck talking about the value of vaccines. Just be quiet. Stop putting Pfizer on your board when you’re doing a local vaccine effort.”
Empathizing with vaccine-skeptical parents is not the same as equivocation. From a public-health standpoint, parents should get their kids immunized against diseases. But Largent’s argument is that public-health efforts are more humane, and likely more effective, when they’re undertaken with an eye toward the feelings of powerlessness that can come along with these kinds of medical decisions.
“Vaccinology has nothing to learn from anti-vaxers,” Largent said to me after the session. “But medicine is an art, not a science. Engaging with anti-vaxers may help you understand how to do medicine better.”

Extended-release antiepileptic drugs

Seizures may result in physical, psychological, and social repercussions. One might assume that people with epilepsy would adhere rigorously to their medication regimens in order to prevent these deleterious outcomes. However, epilepsy patients, like patients with other illnesses, do not always take their medications as prescribed.

Furthermore, an inverse relationship exists between the number of doses prescribed per day and adherence: The more frequently medication must be taken, the less likely it is the patient will consume all doses. Many patients fail to achieve 100% adherence even with once-a-day dosing. Although 100% medication adherence does not guarantee seizure control, lack of adherence, not surprisingly, may result in increased seizure frequency.
More than 25 years ago, Cramer and colleagues  used a medication event monitoring system to measure adherence in several groups of people with epilepsy. The system records the time that the medication bottle is opened on a computer chip contained within the cap. The results can then be printed and analyzed when the patient returns for follow-up.
Even though patients had consented to the study and knew they were being monitored, only 76% of doses were taken as prescribed. Adherence was 87% for once-a-day medications, 81% for twice-daily medications, 77% for medications taken three times daily, and only 39% for those taken four times daily.
Other adherence studies have revealed similar results.  These findings provide a clear rationale for clinicians to limit the number of daily medication doses for each patient in order to optimize adherence.
Extended-release (ER) preparations offer a means to decrease dosing frequency compared with immediate-release (IR) medications. In addition, ER preparations offer more consistent serum drug levels with higher troughs, which may protect against breakthrough seizures, and lower peaks, which may mitigate dose-related side effects…
Although compliance may be enhanced by a once-a-day ER product, clinicians may hesitate to prescribe such preparations because the consequences of a missed dose may be more severe owing to the extended interval before the next dose.  Pellock and Brittain  recently addressed this issue in an industry-sponsored computer-modeling pharmacokinetics study. Defining "forgiveness" (F) as the "margin of therapeutic effect following a missed dose," the authors calculated F as the difference between duration of action (D) and dosing interval (I), or F = D – I.
Concentration/time curves were calculated for IR and ER formulations (called "XR" in their study). For both formulations, duration of action increased with larger doses. The duration of action was longer post-dose for ER than IR products, which tended to mitigate the drop in level from a missed dose.
The authors observed, "Compared with TID [three times daily] dosing of the IR formulation, the forgiveness interval was the same (XRBID) or even longer (XRqd) with the XR AEDs." They attributed this effect to the slower release rate and prolonged time of absorption of the ER product.
The choice of an AED must be individualized for each patient, taking into account such factors as patient age, comorbidities, seizure type, epilepsy syndrome, adverse events, genetic profile, formulation (liquid, tablet, capsule, sprinkle), insurance coverage, and medication cost.
A choice must also be made between IR and ER preparations, and sometimes between different ER preparations. Pharmacokinetic modeling by Pellock and Brittain suggests that patients may benefit from ER products without necessarily suffering a larger drop in serum level compared with an IR product after a missed dose. More detailed in vivo comparative studies between ER and IR products that include seizure counts, adverse effects, and serum levels would fortify their argument.
Nonetheless, ER preparations offer the possibility of improved tolerability, more stable serum levels, and enhanced adherence and should be considered for appropriate patients. In addition, all patients with epilepsy should be educated regarding the importance of not missing a dose, whether they are taking an IR or ER product.

Ictal coprolalia

Cerin Daniel,  M. Scott Perry.   Ictal Coprolalia: A Case Report and Review of Ictal Speech as a Localizing Feature in Epilepsy.  Pediatric Neurology.  Article in press.



Recognizing ictal semiology is an essential component to localization of seizure onset, especially in intractable epilepsy where surgical therapies may be beneficial. Ictal speech can be a common component of seizure semiology, but the various forms of ictal speech may have different lateralizing and localizing value. Coprolalia is a very rare form of ictal speech.


We present the case of a 15 year old with seizures characterized by agitation and coprolalia which was medically intractable.


The patient underwent surgical evaluation including video EEG, MRI, and functional neuroimaging. Data indicated onset within the dominant frontal lobe which was further localized using stereo-electroencephalography prior to focal cortical resection.


Ictal coprolalia is a rare presentation of ictal speech. We review the various forms of ictal speech and their value in localizing seizure onset.


From the article:

Coprolalia is a form of involuntary swearing that is used out of social and emotional context. Although it occurs most commonly in individuals with Tourette syndrome, it may be present in other neurological disorders such as traumatic brain injuries, stroke, encephalitis, and, very rarely, epilepsy...

He returned to our clinic at age 12 years for evaluation of possible Tourette syndrome after being treated by mental health providers for coprolalia in the setting of oppositional defiant disorder. Careful history revealed no motor or vocal tics; however, his events were characterized by a sudden onset of downturned pursed lips (chapeau de gendarme), followed by prominent agitation with coprolalia and bilateral manual automatisms. After his coprolalia was recognized to be related to frontal lobe epilepsy, he was treated with maximum doses of oxcarbazepine, zonisamide, lacosomide, and clobazam without remission, prompting an epilepsy surgery evaluation. Presurgical testing revealed a nonlesional magnetic resonance imaging with video EEG demonstrating bifrontal interictal spikes with typical ictal events characterized by bifrontal attenuation with maximum evolution of repetitive spike discharges within the left frontal lobe. Positron emission tomography (PET) demonstrated a focal region of hypometabolism within the left mesial frontal lobe extending to the anterior cingulate gyrus, which was also a region of interictal dipole localization by magnetoencephalography. Language was localized to the left hemisphere.                         .
Given the likelihood of deep mesial frontal localization based on presurgical evaluation and the need to investigate the presence or absence of primary speech (i.e., Broca area) involvement in the epileptogenic zone, we pursued stereo-electroencephalography (SEEG) with depth electrodes over a subdural grid placement. The SEEG approach allows monitoring of deep, difficult-to-access cortical regions and can aid in delineating the epileptogenic network when more diffuse cortical regions may be involved. Depth electrodes were placed within the left anterior insula, left anterior cingulate, body of the left cingulate gyrus, Broca region, left frontal pole, and orbitofrontal surface. SEEG data of typical seizures localized onset within the mesial left frontal lobe at the appearance of typical chapeau facies, followed by involvement of the left anterior cingulate gyrus when coprolalia begins corresponding to the hypometabolic cortex demonstrated by PET. The Broca area was not involved in the ictal EEG pattern. Surgical resection of the region of PET hypometabolism including the left frontal pole and anterior cingulate gyrus was completed without complication and he has remained seizure free since surgery...

 Coprolalia, a unique form of nonpropositional ictal speech, may be a unique localizing and lateralizing feature of frontal lobe epilepsy. Nonpropositional swearing presents as overlearned and automatic expressions, whereas propositional forms of cursing present in a controlled manner, and involve both intact Broca and Wernicke areas.  Although the definitive pathophysiologic mechanism remains unknown, dysfunction in the cortical-striatal-limbic pathways has been implicated to play a role in coprolalia.

There is a very interesting video with the article.

Thursday, February 18, 2016

Doogie Howser

A teenager in South Florida who was advertising his health care services had certifications in holistic healthcare. He had lab coats and a stethoscope. He even had a medical office.What the 18-year-old Malachi A. Love-Robinson didn’t have, officials say, is a medical degree.

On Tuesday, Mr. Love-Robinson was accused of practicing medicine without a license after officials said he was caught performing a physical exam and offering medical advice to an undercover agent. The episode is the latest in a series of encounters with law enforcement dating back to early 2015 as Mr. Love-Robinson tried time and again to portray himself as a doctor, officials said.
The Palm Beach County Sheriff’s Office said in a statement that Mr. Love-Robinson managed to open and operate his own office, called New Birth New Life Medical Center & Urgent Care, in a building populated by medical and dentistry offices in West Palm Beach, complete with a grand-opening celebration held in January.
In Florida, practicing medicine without a license is a third-degree felony. Mr. Love-Robinson was scheduled to appear in court on Wednesday...
Reached by phone, Mr. Love-Robinson said Wednesday that he had been forced to close his office and called the charges against him “gut wrenching.”
“I’m not trying to hurt people,” he said. “I’m just a young black guy who opened up a practice who is trying to do some good in the community. If that is a negative thing, we have a lot more work to do in the community than to single out me.”
He said that the undercover agent who posed as a patient came in complaining of an itchy throat. Mr. Love-Robinson took her weight, checked her breathing and checked her temperature, then recommended she visit a local pharmacy for allergy medication.
“There were no scripts given,” he said, “no medical advice given.”
Mr. Love-Robinson said that he had received a Ph.D. in another field from a “private Christian university,” but he refused to name the institution or the field in which he received the degree.
He also said that he was certified to provide alternative health care...
That certificate was provided by the American Association of Drugless Practitioners, a group for holistic health professionals including herbalists and other so-called drug-free practitioners. The organization approved Mr. Love-Robinson’s application after reviewing copies of degrees and diplomas sent by mail, according to the group’s director, Donald Rosenthal.
Mr. Rosenthal said that the credential, which has been issued to some 21,000 people, does not allow for people to diagnose or treat medical conditions.
But this week’s episode was not the first time he was accused of portraying himself as a medical doctor. Last October, he was arrested after he was accused of spending about three weeks practicing medicine without a license at New Directions, a treatment office specializing in addiction recovery, in Boynton Beach, Fla., Mr. Dalton, the spokesman for the Florida Department of Health, said.
Mr. Dalton added that the teenager was also taken into custody as a minor in January 2015 after he spent several weeks walking the halls of St. Mary’s Medical Center in West Palm Beach wearing a lab coat and a stethoscope, an episode reported at the time by The Palm Beach Post.
The newspaper reported that Mr. Love-Robinson’s mother said the teenager was suffering from an illness and refused to take medication. Mr. Love-Robinson’s illness was not disclosed...
As he moved throughout the area attempting to practice medicine, according to the authorities, Mr. Love-Robinson appeared to maintain profiles on several websites allowing for consumer reviews to build up his reputation. On, his specializations were listed as naturopathy and psychology.
On his profile on the National Provider Identifier Database his offered treatments included minor and orificial surgery. He was listed as a student in a health care training program, but his profile on the database didn’t contain any information about which schools he attended.
“I value my practice skills which include great communication skills as well as timely and prompt care,” his biography on Healthgrades said. “I am a strong believer that patients in general are the strongest medical tools there is.”

Tuesday, February 16, 2016

Autism screening

Albert L. Siu, and the US Preventive Services Task Force (USPSTF).  Screening for Autism Spectrum Disorder in Young Children: US Preventive Services Task Force Recommendation Statement.  JAMA. 2016;315(7):691-696.

Description New US Preventive Services Task Force (USPSTF) recommendation on screening for autism spectrum disorder (ASD) in young children.
Methods The USPSTF reviewed the evidence on the accuracy, benefits, and potential harms of brief, formal screening instruments for ASD administered during routine primary care visits and the benefits and potential harms of early behavioral treatment for young children identified with ASD through screening.
Population This recommendation applies to children aged 18 to 30 months who have not been diagnosed with ASD or developmental delay and for whom no concerns of ASD have been raised by parents, other caregivers, or health care professionals.
Recommendation The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for ASD in young children for whom no concerns of ASD have been raised by their parents or a clinician. (I statement)

In a decision on pediatric care that has dismayed autism advocates and some experts, a federal task force has ruled there is not enough evidence to show that screening all US toddlers for autism is good idea.

That decision contradicts recommendations from the American Academy of Pediatrics (AAP) which say children should be screened for ASD at ages 18 and 24 months, along with regular developmental surveillance.

But in a statement published in JAMA on Feb. 16, the US Preventive Services Task Force (USPSTF) left the decision on whether to screen up to parents and clinicians. The USPSTF also called for more research on whether screening is reliable and if early intervention is effective.

“The current evidence is insufficient to balance the benefits and harms of screening for autism spectrum disorder (ASD) in young children for whom no concerns of ASD have been raised by parents or a clinician,” the USPSTF concluded.

The USPSTF decision applies to children 18 months to 30 months old.

Screenings involve simply asking parents standardized questions about their child’s behaviors, scoring the responses, and then making referrals to other specialists if warranted.

While leaving the choice on whether or not to screen up to parents and clinicians, the task force explained that it is not saying screening is necessarily a bad idea—just that it's not clear that everyone needs it, at least based on available studies...

The task force’s final decision remains controversial. It comes at a time when the prevalence of American children diagnosed with autism has risen has increased by 23% since 2008. According to the US Centers for Disease Control and Prevention, that prevalence was 1 on 150 in 2000.

In four accompanying editorials in JAMA reaction to the decision was split.

“There is ample evidence that justifies the current practice of universal autism screening,” Geraldine Dawson PhD argued in her JAMA editorial. Dawson is director of the Duke Center for Autism and Brain Development at the Duke University School of Medicine “Studies indicate that available screening tools do identify children with ASD who would have been otherwise missed and children who begin intervention at an earlier age have improved outcomes,” she added.

Two psychiatrists suggested in their editorial that the task force’s recommendation could have negative impacts on Medicaid funding for pediatricians who screen toddlers and pre-schoolers for developmental symptoms.

Jeremy Veenstra-VanderWeele MD of the Center for Autism and the Developing Brain at New York Presbyterian Hospital and Kelly McGuire MD of Maine Behavioral Healthcare’s Center for Autism and Developmental Disorders in Portland said the assessments are necessary.

Screening for ASD is needed now “to establish appropriate special education services mandated by the Individuals with Disabilities Education and Improvement Act," they wrote. The task force recommendation may reinforce the current disparity of children from affluent, well-educated families being diagnosed at an earlier age than those from lower income groups, they added.

Taking the opposite position in their JAMA editorial, two pediatricians endorsed the task force’s findings. “Although this recommendation may be disappointing to many people, the USPSTF has appropriately applied its methodology to the question of ASD screening and has fulfilled its charge of applying rigorous analysis to the best available evidence,” they said.  Instead, the focus should be on the task force's “call for more research,” Michael Silverstein MD, MPH of Boston University Medical School’s division of general pediatrics, and Jenny Radesky MD, of University of Michigan School of Medicine.

The task force called for large randomized clinical trials of treatment of children whose screenings identified ASD, compared with controls.

In another JAMA editorial, Craig M. Powell MD, PhD. of the University of Texas Southwestern Medical Center in Dallas, TX said the USPSTF’s recommendation is not the “death knell” for autism screening. He sees it as but a “call to arms’’ for funding more neurological research to find ways to help patients and their families.

The task force also found potential harm should there be false-positive screening results. Those could include the time and expense of the up to 40 hours a week of interventions these children may require.

Nevertheless, neither the task force recommendation nor the editorials questioned whether autism represents a huge public health problem. The lifetime cost of supporting an individual with autism ranges from $1.4 million to $2.4 million, Dawson reported in her editorial.

Monday, February 15, 2016

When doctors strike, deaths decline, but when nurses strike,,,

Junior doctors across the United Kingdom traded their stethoscopes for picket signs last month in a 24-hour strike against changes to the National Health Service, the first labor disruption of its kind in nearly 40 years. And unless the British government makes concessions, the 37,000 doctors say they will strike again on Feb. 10 — this time withholding even emergency services.

The thought of physicians shutting down operating theaters and emergency rooms has understandably provoked concern among some Britons. NHS managers, seeking to win public sympathy for their side, have stoked this alarm, stating they “fear patient deaths” resulting from the strikes.
But politics and histrionics can be set aside — it turns out medical researchers have applied the cold, hard tools of science to explore the consequences of striking physicians. And what they have found is an apparent paradox: Not only is there no harm to patients when doctors strike, there nearly always seems to be a decrease in patient deaths.

Investigating physicians strikes is not an easy thing to do because among high-income countries, they are exceedingly rare. Physicians are less frequently unionized than other workers, many countries have imposed barriers on the abilities of physicians to strike, and physicians have tended to regard this organizing tool as unavailable to them.

Yet a 2008 analysis led by Solveig Cunningham of Emory University attempted to bring together existing research on physician strikes to see whether patterns existed on patient impact. Five strikes — lasting from nine days to five weeks in places as varied as Los Angeles, Jerusalem (twice), Spain, and Croatia — yielded sufficient data to study. Researchers found that mortality in all cases either stayed the same or substantially declined when physicians walked out. In the case of the first Israeli strike of 1973, patient deaths dropped by 50 percent.

The authors acknowledge a number of potential flaws in the review. The first is that in none of these strikes did medical care cease completely — emergency services were always made available. What’s more, some high-risk patients may have sought care elsewhere during the work stoppages, relieving the system of cases more likely to end up dying.

Nonetheless, the results seem to describe a pattern that repeats itself consistently from California to Croatia, and from 1973 to 2003: Fewer doctors on the job results in better health outcomes.

Cunningham has been chewing on this phenomenon ever since writing the 2008 paper. She believes there is something important in the findings for policy makers to consider. “Elective procedures are really what are driving this,” Cunningham explained. “There are a lot of procedures that are not actually life saving that have small risks associated with them. These small risks — including infections from hospitalization — are potentially leading to the results we see.”

When physicians who provide non-urgent care are away, elective procedures are canceled. These elective procedures may actually have greater risks than benefits; when they are nixed, the death rate declines. It is a counterintuitive idea, but it is a reasonable conclusion to draw — that what the strike data actually illustrate is that, at least for certain procedures, less is more in health care.

A 2015 study led by Harvard’s Dr. Anupam Jena echoes this observation. It is a large investigation looking at deaths in hospitals across the United States when the American Heart Association and the American College of Cardiologists are in session — measuring patient health when most of America’s cardiologists are away from their home institutions. In the outcomes it considers, the study finds that patient death rates either stayed the same or significantly improved when doctors were away at the conferences.

One finding in particular from Jena’s study sticks out: Angioplasty — where a catheter is floated through the vascular system to open up blocked arteries of the heart — occurred less often when the heart doctors were away. But levels of patient deaths remained unchanged, i.e. the absence of physicians doing modern procedures did not harm patient outcomes. Disagreement exists among doctors as to when the benefits outweigh the risks of angioplasty. This research may be more direct evidence that some physicians tend to pursue the more invasive of treatment options, and that this behavior may worsen patient outcomes.

These studies do not definitively confirm a less-is-more approach is always better — there are plenty of confounding variables that would require more research to clarify relationships between absent doctors and better outcomes. But perhaps too many angioplasties, as well as bypass surgeries, cesarean sections, and tonsillectomies, are being performed when they are not really indicated.

Interestingly, studies of nurses going on strike show a negative effect on patient health. A 2012 study by MIT’s Jonathan Gruber examined nursing walkouts in New York State from 1984 to 2004. He found that patients admitted on days of labor actions had death rates 18.3 percent above the normal. It’s a reassuring indicator that nurses — more involved in bedside care and less involved in treatment plans — actually improve patient outcomes when staffed appropriately.

A refrain sometimes heard by senior physicians to doctors in training is “don’t just do something, stand there.” Rather than reflexively order a diagnostic test or recommend a surgery to alleviate a patient woe, it is often better to watch and wait.


For most people, the pager represents a sad, humorous relic of the past—a reminder of the primitive time before cellphones, Google, and the Twitterverse. But for doctors like me, pagers are still an important part of everyday life. It’s estimated that about 85 percent of hospitals still rely on pagers for communication, and during a recent episode of post-call delirium, I wondered why...

By 1994, there were more than 61 million pagers in service worldwide. But the advent of cellular phones led to a rapid decline in beeper use, and there are now a mere few million pagers still out there, many in hospitals, and all of them slowly and annoyingly beeping their way to obsolescence. If doctors were among the first adopters of paging technology, they will almost certainly be the last to abandon it...

During medical residency shifts that span a day and a night and then some, I have grown to despise my pager with a burning rage previously reserved for Boston drivers. The device’s rude, sudden blare, with a knack for jolting me awake on call just as I drift into a shallow, anxiety-ridden sleep, now triggers a visceral reaction. My heart leaps into overdrive and my palms transform into a sweaty wetland that occasionally facilitates “accidentally” dropping the bleeping thing....

Surely there’s a better way for doctors to communicate, yet pagers remain the maddening norm. Why? For one thing, they’re low-maintenance. The batteries in pagers don’t need to be changed more than once every few weeks, even with heavy use...

 Another major benefit struck me recently as I chatted on my phone while strolling through the bowels of the hospital... Paging networks have more broadcast power than those for cellphones, which makes the signals better at penetrating buildings...

The way pager systems work also makes it easy to send group messages that are received nearly instantaneously...

Of course, pagers have lots of disadvantages, too. The most annoying part of pager-based messaging is the fact that it only works in one direction. The sender types a brief message into a web page, or has a phone operator do the same, and then, a few seconds later, the text arrives on the tiny screen of the recipient’s pager with a loud beep. This can be a real hassle. When I’m on call, for example, someone might page me to find out whether or not I want to give a blood transfusion to someone with a low cell count or whether a patient should refrain from eating after midnight in preparation for the next day’s procedure. But even answering these simple yes-or-no questions turns into a labor-intensive task. To respond, I have to leave my patient’s bedside, find a landline phone, dial the right extension, and wait for someone to pick up. And sometimes the callback number I received sends me to the front desk on the hospital floor, at which point I have to wait to be transferred. All of this so I can give a one-word answer to a question.

This inconvenience really adds up. A colleague once tallied the number of pages he received during a single 12-hour overnight shift. He arrived at nearly 90 messages, or an average of one every eight minutes, beeping at him as he admitted new patients and tried to take care of old ones. The time we lose in this constant back and forth between returning pages and doing other work can be a real drain. (A 2010 survey of 60 junior doctors in Ireland confirmed that 59 of them preferred using mobile phones for work communications.).

For one thing, nothing beats that infernal bleeping when it comes to getting a doctor’s attention. On a Voalte phone, as on a regular cellphone, text messages blend together in your inbox—and since they all have the same alert tone, important messages get lost among the myriad other correspondence practitioners receive daily. If a pager goes off, the beeping indicates the message may be important enough to be sent via page...

For all its inconveniences, a pager still offers benefits that have yet to be replicated by more modern forms of communication. It provides an alert that can’t be ignored and a reliability that is crucial in the health care setting. And carrying a pager has symbolic value, too: It connects today’s doctors with those from the past and represents the notion that we’ll always be available to take care of our patients. In the end, perhaps my excitement over my first beeper wasn’t so misplaced after all. Now if you’ll excuse me, I need to go return a few pages.