Friday, September 30, 2016

Head transplant 4

Neurosurgeon to perform first head transplant: Could it actually work?
John Murphy, MDLinx, 09/22/2016

Italian neurosurgeon Sergio Canavero, MD, made headlines in June 2015 when he announced his plan to perform the first human head transplant in 2017. Now, in the September 19, 2016 issue of Surgical Neurology International, Dr. Canavero and colleagues backed up that audacious plan with a series of proof-of-principle papers that detail their extraordinary surgical procedure—which they described as “the defining event of the 21st century.”

Not surprisingly, the scientific and medical communities have reacted to Dr. Canavero’s head transplant procedure with curiosity, skepticism, and outright scorn.

“Brain transplantation is not ready for prime time,” wrote Arthur Caplan, PhD, Head of the Division of Bioethics at New York University Langone Medical Center in New York, NY, in an editorial in Forbes. “To attempt to move a brain to a new body given what is known about the medicine and science involved, one would have to be out of one’s mind.”

“My answer to Dr. Caplan,” Dr. Canavero said in an interview with, “is he doesn’t know what he’s talking about. The nutty guy is him, not me.”

Dr. Canavero, who heads the Turin Advanced Neuromodulation Group, in Turin, Italy, acknowledges that others view head transplantation as impossible; but he gives the procedure a 90% chance of success. Plus, he already has his first patient: Valery Spiridonov, 31-year-old Russian man who has Werdnig-Hoffmann disease, a rare but severe form of spinal muscular atrophy.

The procedure (dubbed cephalosomatic anastomosis) is more like a body transplant than a head transplant, literally speaking. Dr. Canavero will essentially remove Spiridonov’s deteriorating body from his head, and replace it with a brain-dead but healthy donor body. It’s expected to be a 36-hour, $15 to $20 million procedure involving at least 150 health care professionals, including doctors, nurses, technicians, psychologists, and virtual reality engineers.

Here’s how they plan to do it:

• Freeze the brain: First, both the recipient and the donor are anesthetized and intubated, and their heads are locked into place. Both patients are given immunosuppressants throughout the procedure. The recipient’s head is then cooled to 10° C (50° F) to halt electrocortical activity, rendering him temporarily brain-dead. (“As close to death as possible,” Dr. Canavero described.) The spinal cords in both patients are cooled as well.

• Sever the neck: To prevent coagulation, the recipient’s head is drained of blood and then flushed with lactated Ringer’s solution. The surgical teams then cut deep incisions around each patient’s neck (at the C5/6 level) and all of the anatomic structures are carefully separated to expose the carotid and vertebral arteries, jugular veins, and spine. Next, vascular surgeons loop silastic cannulas around the carotid arteries and jugular veins, and clamp the vessels at the tips to stop blood flow and prevent air emboli when the head is removed.

• Cut the spinal cord: Of all the steps in this lengthy procedure, this one may be the most critical. Here, the surgeons use a diamond nanoblade to “clean-cut” the spinal cords of both patients simultaneously. Unlike accidental spinal cord injury, which causes widespread damage to the spinal cord, the ultra-sharp severing used in this procedure allows the spinal cord to be reconnected with minimal damage and eventual recovery, Dr. Canavero wrote.

• Fuse the spinal cord: Immediately after decapitation, the recipient’s head is wheeled to the donor body, where the surgeons quickly join the stumps of the spinal cords. Now comes the other critical step: the severed myelinated axons are fused together with a specially-designed polyethylene glycol (PEG) polymer that reseals the cellular membranes of neurons. The “secret ingredients” in this particular PEG are graphene nanoribbons, developed by Rice University scientists, which first act as a conduit and then as a scaffold upon which the neuronal fibers can grow. Electrical stimulation is applied to the fusion point of the spinal cord to accelerate the regeneration of neural connections. In order to reinforce the link, the surgeons attach a few loose sutures around the joined spinal cord.

• Reconnect the rest: To restore circulation, the vascular surgeons remove the silastic cannulas one by one and suture the arteries and veins of the head to those of the new body. After the dura is sutured and clamped watertight, then the trachea, esophagus, vagus and phrenic nerves are reconnected and all the muscles are rejoined. Plastic surgeons suture the skin for optimum cosmetic results.

The recipient is taken to the ICU and kept in an induced coma for three to four weeks. Immunosuppression is continued and the patient is regularly screened for any sign of anti-donor antibodies. After coming out of the coma, Dr. Canavero foresees the recipient will need both physical therapy and psychological counseling; but he expects the patient will be able to walk again within 6 months of the surgery.

Could it actually work?

Dr. Canavero’s colleagues have already shown in mice and in a dog that sensorimotor function can be recovered after severing and re-attaching the spinal cord. His collaborator Xiaoping Ren, MD, of Harbin Medical University in China, performed a head transplant in a monkey in the past year. Still, “the proof of the pudding rests in human studies,” wrote Drs. Canavero and Ren. They hope to perform the first human head transplant on Spiridonov in December 2017.

But the skeptics are many, and they too have science and medicine to back up their positions.

“This is such an overwhelming project, the possibility of it happening is very unlikely,” Harry S. Goldsmith, MD, Clinical Professor of Neurosurgery at the University of California, Davis, said in a 2015 article in New Scientist. “I don’t believe it will ever work, there are too many problems with the procedure.”

Richard Borgens, PhD, Director of the Center for Paralysis Research at Purdue University in West Lafayette, Indiana, told New Scientist, “There is no evidence that the connectivity of cord and brain would lead to useful sentient or motor function following head transplantation.”

“In my opinion, this procedure has no feasibility at all,” Lorenzo Pinessi, MD, Director of the Neurology Clinic at Italy’s University of Turin, told Newsweek. “It is demented.”

For Spiridonov, who faces a mortal disease, the idea isn’t demented at all—just the opposite. “Removing all the sick parts but the head would do a great job in my case,” he told The Atlantic. “I couldn’t see any other way to treat myself.”

Dr. Canavero outlined the ideas behind head transplantation in this September 2015 TEDx talk.

Thursday, September 29, 2016

Information and treatment decisions in severe spinal muscular atrophy

Malin Lövgren, Thomas Sejersen and Ulrika Kreicbergs.  Information and treatment decisions in severe spinal muscular atrophy: A parental follow-up.  European Journal of Paediatric Neurology, in press.



The parents of children with severe spinal muscular atrophy (SMA) face difficult ethical decisions regarding their child's treatment. This study explored the experience of parents of children with severe SMA concerning information and treatment decisions.

Material and methods

This nationwide survey, conducted in 2013, is based on parents of children who were born in Sweden between 2000 and 2010 and later diagnosed with SMA type I or II where respiratory support was considered the first year of life (N = 61, participation rate: 87%). The survey involved parents' perception of the child's care and the questions used in this study covered information given and treatment decisions. Descriptive statistics were used.


None of the parents reported that the health care professionals made decisions concerning the child's treatment without informing them first, and 80% reported feeling confident about the decisions made. Of the bereaved parents, 11/48 (23%) reported that they got no information about respiratory support, compared to 2/13 (15%) of non-bereaved. Bereaved parents were more likely to report being satisfied with and understanding the information given about the illness and its treatment than non-bereaved parents.


All parents reported having been informed before treatment decisions were made and a vast majority reported feeling confident about the decisions. However, a quarter of the parents declined to have received information about respiratory support, which indicates that the parents did not sufficiently understand the available respiratory treatment options, and that their children may not receive the kind of care that is recommended in guidelines.

From the article

Life can be considerably prolonged for children with severe SMA by introducing respiratory support. However, the impact of such support on the child's wellbeing is unknown, and there is no evidence or consensus among experts on the use of respiratory support for SMA type I. In the absence of consensus, Wang and co-workers   developed care guidelines for SMA based on evidence and a Delphi consensus-building process. Their guidelines concluded that caregivers should explore treatment options together with the family in relation to the child's potential, quality-of-life issues, and family desires. This need is particularly evident and important regarding the use of respiratory support.  A key issue is to what extent respiratory support affects the quality of life of the child with severe SMA, and recommendations vary between clinics and clinicians. Some favor the use of respiratory support for SMA type I, while others strongly oppose its use, arguing that the burden for the child and family is greater than the benefit. The international care guidelines from 2007 consider such differences in treatment recommendations, and conclude that clinicians have an obligation to present treatment options to the parents in an open, fair and balanced manner…

Overall, 11/13 non-bereaved (85%) and 11/48 bereaved parents (23%) perceived that information about their child's illness had been given in an inconsiderate way, either often or occasionally. Eight of 13 non-bereaved parents (62%) and 42/48 bereaved parents (88%) reported that they were given information that helped them understand what SMA is …

When special respiratory support was discussed, the option they were most likely to be informed about was ventilation by mask. One bereaved parent was informed about tracheostomy. Fourteen bereaved parents and two non-bereaved parents (26% of the total sample) reported that they were never informed about respiratory support ( Table 2 ). Nine of these bereaved parents reported that their child received no respiratory support, two reported that their child received supplemental oxygen by nostril or mask, one that his/her child had CPAP, and two parents did not respond to this question. The two non-bereaved parents who were not informed about respiratory support reported that their child got extra respiratory support by nostril or mask…

When respiratory support was discussed, ventilation by mask was the option parents were most commonly informed about, but a quarter reported that they got no information about respiratory support at all. A vast majority of those who were given no information about respiratory support reported that their child did not receive respiratory support (all these parents were bereaved). In connection with the diagnosis, 90% of the bereaved parents were informed that their child would have a short life, but only 27% reported that a health care professional told them, in the days preceding the child's passing, that the child would pass away shortly. It is noteworthy that bereaved parents seem to have a more positive perception of the care experience than non-bereaved parents, i.e., that the information given at the time of the diagnosis was satisfactory, that the information about the child's illness had been given in a considerate way, that it has been possible for them to understand what different treatment measures could lead to for their child, and that they were given information about possible medical treatment options for their child. 

This study found that 90% of the bereaved parents were informed at the time of diagnosis that their child would have a short life, but less than a third reported that a health care professional told them, in the child's last [sic], that he or she would pass away shortly. Previous research among parents who have lost a child to cancer show that communication about the impending death is of importance for parents to make the best possible decisions about the child's care,  but also for the parents' long-term psychological health.  It has also been found that parents' awareness about a child's impending death owing to a malignancy was associated with receiving home care.  Our observation that home care was more common among those who had received information about the impending death is in harmony with that finding, since parental awareness about impending death seemed to predict home care also for children with SMA…

There were descriptive differences between bereaved and non-bereaved parents in terms of how they experienced the information given to them. Since only 13 non-bereaved parents were included in this study we have not tested these differences statistically, but still want to highlight this trend, as parents' responses to several questions differed. The children of the non-bereaved have lived longer than the deceased children and have therefore had more exposure to healthcare. This may mean that non-bereaved parents are more likely to have been exposed to unsatisfactory care at some time over the years.

Tuesday, September 27, 2016

Levetiracetam in childhood absence epilepsy

Matricardi S, Verrotti A, Chiarelli F, Cerminara C, Curatolo P. Current
advances in childhood absence epilepsy. Pediatr Neurol. 2014 Mar;50(3):205-12.

From the article:

LEV mechanisms of action may be related to modulation of a synaptic vesicle protein. A recent study assessed the efficacy, safety, and tolerability of LEV monotherapy in absence seizures and demonstrated more than a 50% reduction in seizures in newly diagnosed patients with CAE. No adverse events occurred in any patient during the treatment.  Another recent randomized controlled trial showed that, although better than placebo, LEV had moderate efficacy for absence seizure control.  Auvin et al., however, reported six children with CAE who showed an aggravation of absence seizures after starting LEV.

Verrotti A, Cerminara C, Domizio S, Mohn A, Franzoni E, Coppola G, Zamponi N,
Parisi P, Iannetti P, Curatolo P. Levetiracetam in absence epilepsy. Dev Med
Child Neurol. 2008 Nov;50(11):850-3.

The aim of the study was to assess the efficacy, tolerability, and safety of levetiracetam therapy in children and adolescents with absence epilepsy. Twenty-one participants (11 male, 10 female) with typical absence seizures were enrolled in this prospective study from seven centres in Italy. The mean age and age range at time of enrollment into the study were 8 years 9 months (SD 0.9) and 5 years 1 month to 13 years respectively. All patients were carefully evaluated at 6 months from baseline, and 12 patients were also re-evaluated at 12 months after the beginning of therapy with levetiracetam. At the 6-month evaluation, out of 21 patients studied, 11 were seizure free and one showed 'decreased' seizures (more than 50% reduction in seizures). A less than 50% reduction in seizures was observed in nine patients. At the 12-month evaluation, 10 patients were completely seizure free and two were seizure free with some anomalies in electroencephalograms. Two patients who had shown no improvement at 6 months had decreased seizures at the second follow-up. Our results suggest that monotherapy with levetiracetam could be effective and well tolerated in patients with childhood absence epilepsy and juvenile absence epilepsy. Prospective, large, long-term double-blind studies are needed to confirm these findings.

Fattore C, Boniver C, Capovilla G, Cerminara C, Citterio A, Coppola G, Costa
P, Darra F, Vecchi M, Perucca E. A multicenter, randomized, placebo-controlled
trial of levetiracetam in children and adolescents with newly diagnosed absence
epilepsy. Epilepsia. 2011 Apr;52(4):802-9.


To evaluate the potential efficacy of levetiracetam as an antiabsence agent in children and adolescents with newly diagnosed childhood or juvenile absence epilepsy.


Patients were randomized in a 2:1 ratio to receive de novo monotherapy with levetiracetam (up to 30 mg/kg/day) or placebo for 2 weeks under double-blind conditions. Responder status (primary end point) was defined as freedom from clinical seizures on days 13 and 14 and from electroencephalographic (EEG) seizures during a standard EEG recording with hyperventilation and intermittent photic stimulation on day 14. The double-blind phase was followed by an open-label follow-up.


Nine of 38 patients (23.7%) were responders in the levetiracetam group, compared with one of 21 (4.8%) in the placebo group (p = 0.08). Seven of 38 patients (18.4%) were free from clinical and EEG seizures during the last 4 days of the trial (including 24-h EEG monitoring on day 14) compared with none of the patients treated with placebo (p = 0.04). Seventeen patients remained seizure-free on levetiracetam after 1 year follow-up. Of the 41 patients who discontinued levetiracetam due to lack of efficacy (n = 39) or adverse events (n = 2), 34 became seizure-free on other treatments.


Although superiority to placebo just failed to reach statistical significance for the primary end point, the overall findings are consistent with levetiracetam having modest efficacy against absence seizures. Further controlled trials exploring larger doses and an active comparator are required to determine the role of levetiracetam in the treatment of absence epilepsy.

Auvin S, Chhun S, Berquin P, Ponchel E, Delanoë C, Chiron C. Aggravation of
absence seizure related to levetiracetam. Eur J Paediatr Neurol. 2011


Recent data have reported the effectiveness of levetiracetam (LVT) on generalized seizures. Among them, it seems that LVT can be successfully used to treat absence seizures. Many antiepileptic drugs (AEDs) have been occasionally reported to paradoxically aggravate some seizures. We retrospectively identified patients with aggravation of absence seizures using LVT from the databases of 2 pediatric neurology departments (Robert-Debré, Paris and Amiens; France). We also used the prospective data from an open-label clinical trial performed in a third pediatric neurology department (Necker, Paris; France). We included 6 patients: n = 2 childhood absence epilepsy, n = 3 juvenile absence epilepsy and n = 1 epilepsy with myoclonic absences. All of them have had an aggravation of the absences with a causal and temporal relationship between introduction of the drug and the detrimental effect. The aggravation disappeared when LVT was decreased or was withdrawn. This report highlights that LVT may aggravate epilepsy with absence seizures.

Function makes a lot more sense than pain

For instance, during the Sept. 19 hearing, the reference committee heard testimony on a resolution put forth by the Georgia and Massachusetts chapters that drew applause at its introduction. The resolution centered on eliminating the subjective measure of a patient's pain as the "fifth vital sign."

Matthew Burke, M.D., of Arlington, Va., a new physician constituency delegate, spoke in favor of the resolution. "Pain is not an objective measurement of human physiology," he said. "While we should all strive to control pain, this is an inappropriate distraction."

Alternate delegate Douglas Martin, M.D., of Sioux City, Iowa, noted his work in the area of occupational medicine and his experience with workers compensation claims. A patient will say his pain level is a nine out of 10, said Martin, even though the patient is able to carry on a normal conversation. "Function makes a lot more sense than pain" as a measure of illness or disability, he said. 

District of Columbia delegate Kandie Tate, M.D., of Laurel, Md., expressed her concerns with total elimination of the pain score, however. "I'm worried we're moving the pendulum so far that we're not treating pain adequately. What would you replace it with, and how would you address pain?" she asked.

Connecticut alternate delegate Robert Carr, M.D., of Southbury, said the pain measures "sound good and feel good" but are not evidence-based and have unintended outcomes.

The Congress agreed and adopted a substitute resolution asking the AAFP to work to eliminate the classification of pain as a determinant of quality patient care.

Courtesy of Doximity

Zika virus and microcephaly 3

Antonio Augusto Moura da SilvaComments to Author , Jucelia Sousa Santos Ganz, Patricia da Silva Sousa, Maria Juliana Carvalho Doriqui, Marizelia Rodrigues Costa Ribeiro, Maria dos Remédios Freitas Carvalho Branco, Rejane Christine de Sousa Queiroz, Maria de Jesus Torres Pacheco, Flavia Regina Vieira da Costa, Francelena de Sousa Silva, Vanda Maria Ferreira Simões, Marcos Antonio Barbosa Pacheco, Fernando Lamy-Filho, Zeni Carvalho Lamy, and Maria Teresa Seabra Soares de Britto e Alves.   Early growth and neurologic outcomes of infants with probable congenital Zika virus syndrome.  Emerging infectious diseases.  Volume 22, Number 11—November 2016.

We report the early growth and neurologic findings of 48 infants in Brazil diagnosed with probable congenital Zika virus syndrome and followed to age 1–8 months. Most of these infants had microcephaly (86.7%) and craniofacial disproportion (95.8%). The clinical pattern included poor head growth with increasingly negative z-scores, pyramidal/extrapyramidal symptoms, and epilepsy.

"These babies do not catch up as they grow," says Dr. Antonio Augusto Moura da Silva of the Federal University of Maranhao, Sao Luis, Brazil.

He's describing the findings from a study of 48 babies whose mothers were believed to have been infected with the Zika virus. Forty-two of the children were diagnosed with microcephaly. The study, on the early neurological growth pattern of the infants, will be published in the journal Emerging Infectious Diseases in November but was released early online.

The infants were studied for about four months and up to 8 months of age. Born below average on measures of weight, length and head circumference, they fell even further below average as time passed.

"As they grow, they get worse, and we would expect that they will continue to fall further behind," says da Silva, who was part of the research team. "We were expecting some degree of falling behind average, but we were astonished by the degree to which they were lagging behind."

Even when babies exposed to the Zika virus in the uterus are born with normal-size heads, they might suffer other forms of brain damage. In fact, da Silva says, six of the Zika-infected babies in the study did not have microcephaly. And yet, when examined with electroencephalographs to measure brain activity, they showed evidence of brain damage that caused problems including seizures and involuntary muscle movements.

Most of the mothers of the 48 babies were thought to be infected with Zika during the first trimester of their pregnancy. And because the babies were enrolled at a regional center that assists children with neurological disorders, their symptoms may be among the most severe. Some questions are still unanswered, da Silva says: If an infant is infected after birth, is the virus still able to damage the baby's brain? And what will be the long-term consequences for infants born with less severe cases of microcephaly? "So far, we've studied only the tip of the iceberg," da Silva says.

Courtesy of Doximity

Monday, September 26, 2016

A homecoming king with Niemann-Pick, type C

Adam Recke's classmates in the Bethlehem Area School District have never focused on his disease.

The senior from Bethlehem Township was diagnosed with a rare neurodegenerative disorder at age 6 that for many years was not obvious at first glance.

Today its toll is more evident. But that hasn't stopped Recke from making friends, cheering on Philly sports teams, going to dances, acting in plays and just being a teenager.

On Saturday night, he took it a step farther. Thanks to his classmates, the Freedom High School senior was able to add the title of homecoming king to his list of accomplishments.

He learned of his win during Freedom's homecoming dance, where he was crowned along with queen Shalyn Banas.

Recke has Type-C Niemann Pick Disease, a rare terminal disease that afflicts only 500 people around the world and has no cure. It's also known as childhood Alzheimer's.

He cannot metabolize cholesterol and other lipids in his body, which causes them to build up in his liver, spleen and brain at toxic levels that destroy the cells controlling mobility and cognition.

Recke is participating in a two-year clinical trial of a drug that's been shown to help reverse the decline of those with his disease.

His father, Sean Recke, and Lehigh Valley Health Network successfully petitioned for the network to become a study site, eliminating the twice-a-month commute to Maryland the family endured during the first phase of the trial.

Multiple sulfatase deficiency

Dylan Finglas is a happy, beautiful little 3 year old boy. Today Dylan smiles, laughs, enjoys playing, interacts, he can feed himself and he is not in any pain nor does he receive any medication. He is beginning to show minor signs of the condition. Without something to stop this devastating illness, most children don’t get to see their 10th birthday. Rapidly in the next few years he will develop breathing difficulties, he will lose his sight, his hearing, the ability to walk, to swallow and his organ functions will deteriorate and eventually fail. Children with MSD would be expected to have severe brain damage by the age of five or six. This tragic outcome is inevitable. It is a 100% certainty unless the treatment is developed for humans. Currently there is no ready cure, nor is there any treatment to slow the condition. It’s any parent’s worst nightmare to have to watch their innocent child’s health and wellbeing deteriorate.

Gene therapy at The Telethon Institute of Genetics & Medicine in Italy has successfully stopped MSD in lab tests. Unfortunately the positive research results have stopped there. Funding is critical and urgently needed to push clinical advancements to human stages as soon as possible. Every donation counts in our goal to save Dylan and all children with MSD throughout the world. Time is of the essence in order to treat these children before significant symptoms of the condition progress. Months, weeks, and days matter… Your help spreading the word and donating will help ensure the cure is produced for all affected patients. Please give these children a chance at life.


Tuesday, September 20, 2016

Brain cancer deaths in children

Brain cancer has replaced leukemia as the leading cause of cancer death among US children and adolescents aged 1 to 19 years, according to the Centers for Disease Control and Prevention (CDC).

The news comes from a report on cancer death rates in young people from 1999 to 2014 issued today by the CDC's National Center for Health Statistics (NCHS).

In 1999, the rate of cancer death by site was 29.7% for leukemia and 23.7% for brain cancer. In 2014, these death rates reversed, with 24.9% for leukemia and 29.9% for brain cancer. The difference in the percentages between the two cancer types at the beginning and end of the study period was statistically significant (P < .05).

As of 2014, other common sites of cancer-related deaths among US children and adolescents were bone and articular cartilage (10.1%), thyroid and other endocrine glands (9.0%), and mesothelial and soft tissue (7.7%).

Since the mid-1970s, cancer death rates among children and adolescents have shown "marked declines," observe the report authors, led by Sally Curtin, MA, from the Division of Vital Statistics.

The same held true for the new study period. The overall cancer death rate declined by 20% during 1999 to 2014, from 2.85 to 2.28 per 100,000 population. The decline occurred in all 5-year age groups, with the drops ranging from 14% to 26%.

The study authors speculate that "major therapeutic advances" in treating some forms of cancer, particularly leukemia, may have resulted in increased survivorship and the decreased death rate.
More than half of all cancer deaths among US children and adolescents from 1999 to 2014 were attributable to leukemia or brain cancer. That has been the case for a long time. These two cancer types combined accounted for 53.4% of all child and teen cancer deaths in 1999 and 54.8% in 2014.

In a finding that is rarely present in adult cancers, parity in cancer death rates was observed between both white and black children and teens, with both groups experiencing declines during the study period.

Cancer death rates continued to be higher for young males compared with their female counterparts.

Martin Gottesfeld's defense

Why I Knocked Boston Children’s Hospital Off The Internet

The answer is simpler than you might think: The defense of an innocent, learning disabled, 15-year-old girl. In the criminal complaint, she’s called “Patient A,” but to me, she has a name, Justina Pelletier. Boston Children’s Hospital disagreed with her diagnosis. They said her symptoms were psychological. They made misleading statements on an affidavit, went to court, and had Justina’s parents stripped of custody.
They stopped her painkillers, leaving her in agony. They stopped her heart medication, leaving her tachycardic. They said she was a danger to herself, and locked her in a psych ward. They said her family was part of the problem, so they limited, monitored, and censored her contact with them.
Justina resorted to sneaking notes, hidden in origami, to tell her family what she wasn’t allowed to say around eavesdroppers. Hospital staff pushed her to do things she was physically incapable of, due to the physical condition they refused to acknowledge she has. They laughed at her as she struggled futilely. They left her on a toilet for hours when she couldn’t void her bowels. They left her secluded in a bare room, or alone in the hallway, sometimes for days when she couldn’t wheel herself elsewhere.
When they did move her, they ripped her toe nails, dragging her feet on the floor. They bruised her. Her legs swelled, her gums receded, and her hair fell out. This went on for 11 months at BCH.
Her parents went to the media, and a gag order was issued specifically prohibiting them from speaking to journalists. When she finally left the hospital (in large part thanks to the negative publicity,) she still wasn’t allowed home and her ordeal wasn’t over. BCH was still in charge and her suffering continued, though the most culpable had successfully manipulated the spotlight onto others.
At her new treatment center, aptly named “Wayside,” Justina was verbally assaulted while nude in the shower. She continued to be denied her medications and treated according to the BCH plan.
Her father broke the gag order, publicly stating her life was in danger. The story made big news, but there was no indication when Justina would be returned to her family and receive the long delayed treatment she desperately needed. A former BCH nurse called what Justina was enduring its proper term: torture. According to international humanitarian law, she was right.
I had heard many, too many, such horror stories of institutionalized children who were killed or took their own lives in the so-called “troubled teen industry.” I never imagined a renowned hospital would be capable of such brutality and no amount of other good work could justify torturing Justina. She wasn’t alone either. BCH calls what it did to her a “parentectomy,” and there had been others over at least the past 20 years.
I knew that BCH’s big donation day was coming up, and that most donors give online. I felt that to have sufficient influence to save Justina from grievous bodily harm and possible death, as well as dissuade BCH from continuing its well established pattern of such harmful “parentectomies,” I’d have to hit BCH where they appear to care the most, the pocket book and reputation. All other efforts to protect Justina weren’t succeeding and time was of the essence. Almost unbelievably, they kept their donation page on the same public network as the rest of their stuff. Rookie mistake. To take it down, I’d have to knock the whole hospital off the Internet.
I also knew from my career experience as a biotech professional that no patients should be harmed if Boston Children’s was knocked offline. There’s no such thing as an outage-proof network, so hospitals have to be able to function without the Internet. It’s required by federal law, and for accreditation. The only effects would be financial and on BCH’s reputation.
The network was strong, well-funded, but especially vulnerable to a specific attack. Apparently BCH was unwilling to architect around the problem. I see such laziness often in my work, and it leaves our nation vulnerable.
I had spent my career building cyber-defenses. For the first time, I was on the offensive. I coded around the clock for two weeks to perfect the attack. Small test runs were made. BCH bragged to the media that they were withstanding the onslaught and hadn’t been taken down. They had no idea what was to come.
I finished the code just in time. It ran. BCH’s donation page went down. As they were down, I was nervous. I left it running for a few hours.
Then, with some donation time still let, I issued the command to stop the attacks—the point had been made. Justina wasn’t defenseless. Under the banner of Anonymous, she and other institutionalized children could and would be protected. There have been no such egregious parentectomies published at BCH since.
In 2016, Justina’s family announced they were suing Boston Children’s. The civil claim reads like a medical horror novel.
In the spring of 2014, the hacker collective Anonymous took credit for hitting a number of health care and treatment facilities in the Boston area in defense of a patient there named Justina Pelletier. For background on her controversial case, which became the focus of national attention, read here or here.

The attacks became somewhat less anonymous when a man named Martin Gottesfeld was arrested in connection with them in February of this year, after his sailboat ran into difficulty off the coast of Cuba. A Disney cruise ship picked up Gottesfeld and his wife, and Gottesfeld was arrested when the ship docked in Miami. He has been in detention ever since. An indictment is expected any day.

Treatment of pediatric migraine

Kacperski J, Hershey AD. Newly Approved Agents for the Treatment and
Prevention of Pediatric Migraine. CNS Drugs. 2016 Sep;30(9):837-44.

Treatment of pediatric migraine remains an unmet medical need. There continues to be a paucity of pediatric randomized controlled trials for the treatment of migraine, both in the acute and preventive settings. Pediatric studies are often complicated by high placebo-response rates and much of our current practice is based on adult trials. This lack of significant pediatric studies results in a wide variation in migraine management both amongst clinicians and between institutions, and evidence-based treatments are not always administered. In this article, we aim to briefly review newly approved abortive and preventive agents for migraine in the pediatric age group. Over-the-counter anti-inflammatory medications, including ibuprofen, naproxen sodium, aspirin, and acetaminophen are reasonable first-line options for abortive therapy. In addition, studies have shown triptans, or migraine-specific agents, to be safe and effective in children and adolescents and several formulations have been approved for the pediatric population, including rizatriptan, almotriptan, zolmitriptan nasal spray, and naproxen sodium/sumatriptan in combination.

Winner P, Farkas V, Štillová H, Woodruff B, Liss C, Lillieborg S, Raines S;
TEENZ Study Group. Efficacy and tolerability of zolmitriptan nasal spray for the
treatment of acute migraine in adolescents: Results of a randomized,
double-blind, multi-center, parallel-group study (TEENZ). Headache. 2016

The primary objective of the TEENZ Study (NCT01211145) was to assess the efficacy of zolmitriptan nasal spray in the acute treatment of adolescent migraine patients (ages 12 to 17 years), as measured by the primary outcome variable of pain-free status at 2 hours post-treatment.
This randomized, double-blind, placebo-controlled, four-arm parallel group study compared zolmitriptan nasal spray with placebo in the treatment of a single episode of adolescent migraine. Patients completed a 30-day run-in period to treat a single migraine attack with single-blind placebo nasal spray. Eligible patients, who had not responded to placebo, were randomized to one of three zolmitriptan nasal spray doses (5, 2.5, or 0.5 mg) or placebo in a ratio of 5:3:3:5 according to a computer-generated randomization scheme. Patients completed diaries for 24 hours after treatment, recording headache pain scores, adverse events (AEs), and medications taken.
In an interim futility analysis, zolmitriptan nasal spray doses of 0.5 and 2.5 mg were declared futile relative to placebo and further randomization to these treatment arms was discontinued. Of 1653 patients enrolled into the study, 855 patients failed to meet study eligibility criteria and were considered screen failures. The most common reason for screen failure was response to placebo challenge (325 patients [38.0%]). Of the 798 patients who were randomized to treatment, 721 (90.4%) completed the study period. Of these, 657 (82.3%) treated a migraine within the study period and contributed data for analysis. Zolmitriptan nasal spray 5 mg was significantly more effective than placebo in achieving pain-free status at 2 hours after treatment (P < .001), with 30% of patients achieving pain-free status at 2 hours vs 17% of placebo-treated patients (OR 2.18; 95% CI 1.40, 3.39). Zolmitriptan nasal spray 5 mg was also more effective than placebo in achieving pain-free status at 3 and 4 hours post-treatment (45 vs 24%, and 56 vs 39%; both P < .001). Zolmitriptan nasal spray 5 mg was also more effective than placebo in achieving headache response at 2, 3, and 4 hours after treatment (51 vs 39%, 61 vs 48%, and 69 vs 57%, respectively; all P ≤ .011). Zolmitriptan nasal spray was well-tolerated at all doses. Dysgeusia was the most frequently reported AE, with greater frequencies reported in active treatment groups versus placebo. No serious AEs or AEs leading to discontinuation were reported. Most AEs were mild or moderate in severity, and consistent with the known profile of zolmitriptan in adult and adolescent populations.
Zolmitriptan nasal spray was well-tolerated in the acute treatment of adolescent (ages 12 to 17 years) migraine. Zolmitriptan 5 mg nasal spray demonstrated superior efficacy compared with placebo for the primary efficacy endpoint of pain-free status 2 hours after treatment and the efficacy of the 5 mg dose was supported by the majority of secondary efficacy endpoints.

Courtesy of:

Gutman D, Hellriegel E, Aycardi E, Bigal ME, Kunta J, Chitra R, Kansagra S,
Kidron OS, Knebel H, Linder S, Ma Y, Pierce M, Winner PK, Spiegelstein O. A Phase
I, Open-Label, Single-Dose Safety, Pharmacokinetic, and Tolerability Study of the
Sumatriptan Iontophoretic Transdermal System in Adolescent Migraine Patients.
Headache. 2016 Sep;56(8):1300-9.

To evaluate the safety, tolerability, and pharmacokinetics of sumatriptan delivered by the iontophoretic transdermal system (TDS) in adolescent patients.
Since nausea can be a prominent and early symptom of migraine, nonoral treatment options are often required. Sumatriptan iontophoretic TDS is approved for the acute treatment of migraine in adults. The present study evaluates the pharmacokinetics of sumatriptan administered via the iontophoretic TDS in adolescents, contrasting the findings with historical data from adults.
Patients aged 12-17 years (inclusive) with acute migraine were treated with sumatriptan iontophoretic TDS for 4 hours. Blood samples for pharmacokinetic profiling of sumatriptan were obtained prior to dosing and at predetermined time points covering the 12 hours postonset of treatment. Key pharmacokinetic endpoints included Cmax (peak plasma drug concentration), tmax (time to Cmax ), AUC0-∞ (area under the plasma concentration-time curve from time 0 to infinity), and t½ (terminal elimination half-life). Safety was evaluated by monitoring of adverse events in addition to laboratory and clinical assessments.
The sample consisted of 37 patients, and 36 were included in the PK evaluable population. Cmax , tmax , AUC0-∞ , and t½ values were all similar between male and female patients and between younger (12-14 years) and older (15-17 years) adolescents. When compared with historical adult data, adolescent patients demonstrated similar systemic exposures to those observed in adults (mean Cmax 20.20 (±6.43) ng/mL in adolescents vs 21.89 (±6.15) ng/mL in adults; mean AUC0-∞ 98.1 (±28.1) ng·h/mL in adolescents vs 109.7 (±26.1) ng·h/mL in adults). All adverse events were mild or moderate, with application-site paresthesia being the most common (32%). No clinically relevant changes in laboratory values, vital signs, or electrocardiogram findings were observed.

The iontophoretic TDS produced mean systemic exposures to sumatriptan in younger and older adolescents, in line with what was seen in adult subjects. It was generally well tolerated.

Monday, September 19, 2016

Eteplirsen revisited

The US Food and Drug Administration (FDA) has granted accelerated approval to eteplirsen injection (Exondys 51, Sarepta Therapeutics), the first drug approved to treat patients with Duchenne muscular dystrophy (DMD).

Eteplirsen is specifically indicated for patients with a confirmed mutation of the dystrophin gene amenable to exon 51 skipping, which affects about 13% of the roughly 9000 to 12,000 people with DMD in the United States.

"Accelerated approval makes this drug available to patients based on initial data, but we eagerly await learning more about the efficacy of this drug through a confirmatory clinical trial that the company must conduct after approval," Janet Woodcock, MD, director of the FDA's Center for Drug Evaluation and Research, said in the statement.

The road to approval for eteplirsen has been rocky. In late April, as reported by Medscape Medical News, the FDA's Peripheral and Central Nervous System Drugs Advisory Committee concluded that studies of eteplirsen failed to provide persuasive evidence that the drug is effective in DMD.

But the vote was close. Three panel members felt that substantial evidence was provided to support eteplirsen as effective for treating DMD, compared with 7 who didn't and 3 who abstained. Some panel members acknowledged that the public speakers — 52 of them during the day-long proceedings — were compelling and that there is a profound unmet need for boys with DMD. In late May, the FDA deferred a decision on eteplirsen.

DMD is a progressive, debilitating, and ultimately fatal inherited X-linked neuromuscular disease caused by mutations of the dystrophin gene that disrupts the mRNA reading frame, resulting in a lack of dystrophin. Eteplirsen was developed to cause "skipping" of exon 51 in mRNA, which could increase production of a truncated but partially functional dystrophin protein. 

The accelerated approval of eteplirsen is based on the surrogate endpoint of dystrophin increase in skeletal muscle observed in some patients treated with the drug.

"The FDA has concluded that the data submitted by the applicant demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit in some patients with DMD who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping," the agency said.

A clinical benefit of eteplirsen, including improved motor function, has not been established, and Sarepta Therapeutics is required to do a clinical trial to confirm the drug's clinical benefit.

Specifically, the trial will assess whether eteplirsen improves motor function of patients with DMD who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping. If the trial fails to verify clinical benefit, the FDA may initiate proceedings to withdraw approval of the drug, the agency said. 
The most common side effects reported by patients taking eteplirsen in clinical trials to date were balance disorder and vomiting.


Child euthanasia

On February 14, 2014, under the title of "advances in pediatrics" in another forum I wrote:

Belgium's parliament votes through child euthanasia.

An update:

The first case of a minor who was helped to die since a change in Belgian law has been reported, according to local media.

Professor Wim Distelmans, head of Belgium's federal euthanasia commission said he was informed about the death by a local doctor and that the child was in an "exceptional and hopeless" position.

Belgium is the only country in the world so far that permits minors of any age to choose to end their life, since the law was changed in 2014. They are required to have rational decision-making capacity and be in the last stages of a terminal illness.

If the minor is under 18, parents also need to give their consent.

Belgian law states that children must be "in a hopeless medical situation of constant and unbearable suffering that cannot be eased and which will cause death in the short-term.

"Only in very exceptional and hopeless cases (is) euthanasia of a minor really an option," Distelmans told Het Nieuwsblad.
"Fortunately there are very few children who are considered (for euthanasia) but that does not mean we should refuse them the right to a dignified death."

Distelmans revealed no other information about the minor, although Reuters reported that the deceased was 17 years old.
"It is difficult to give an age limit, however, as there is this condition that a child must understand his actions, euthanasia could only apply to a child who had a full understanding of what death means, and what their death would mean.

"We have however realised that children who suffer from incurable or terminal illnesses can have an impressive level of maturity."

A total of of 8,752 people were euthanised in Belgium between 2003-2013, according to the national euthanasia control committee.

Saturday, September 17, 2016

The nine most terrifying words

Ronald Reagan once said that “the nine most terrifying words in the English language are ‘I’m from the government and I’m here to help.’” But even Reagan couldn’t have imagined how the government would come to intervene in our child-rearing decisions. Stories like this are becoming commonplace: A mother named Susan Terrillion leaves her children, six and eight years of age, for less than an hour at their vacation rental to get takeout food and finds herself inside a police station by the end of the night, booked and charged with child endangerment, with the future of her custody arrangement in doubt.

The Meitivs of Silver Spring Maryland had their kids, 10 and six, picked up by local police not once, but twice, because they were allowed to walk home by themselves from the park. And the parents of Justina Pelletier lost custody of their 14-year-old daughter for over a year because the doctors and staff of Boston Children’s Hospital objected to their decision to transfer her medical care to Tuft’s University Medical Center. Decisions once entirely within the realm of normal for any parent have now been criminalized.

In her powerful and angry new book, No Child Left Alone, the Pittsburgh-based writer Abby Schachter explains that “daycare rules are what turned me into a Captain Mommy.” She uses the term to describe a mother who is “on guard against overprotective, overbearing, nannying authorities trying to take my choices away.” What were some of the regulations with which the Schachter family was forced to comply to send their children to day care? Only certain foods could be sent, and had to be sent with strict instructions (grapes had to be peeled and quartered). There could be no plastic bags. All uneaten food—even a second half of a sandwich (without nuts, of course!)—had to be disposed of at the end of the day. A different sippy cup had to be sent for every single meal and snack time. New babies could not be swaddled without a note from the child’s pediatrician. Is swaddling a medical decision or simply a choice that each parent makes? The state of Pennsylvania believes it to be the former…

She cites numerous examples of parents told individually that the lunches they packed for their own children were inappropriate. One school in Chicago, Little Village Academy, banned such lunches because the principal “didn’t like the choices parents were making.” The policy was retracted after public shaming, though the story is just one of many instances of government employees—teachers—dictating to and micromanaging parents about how they should be raising their own children…

Just as schools don’t trust parents to feed their own children, they apparently also don’t trust them to guard their health. Despite the fact that most schools require proof of well-visits and vaccinations in order for students to start the school year, Schachter reveals: “The federal government and some 21 states have instituted rules that public-school kids get health screenings during school hours.” During school visits to the nurse for additional health checks, students are weighed (even by their own peers if the nurses are short-staffed) and have their body mass index (BMI) recorded. If that number is outside a certain range, a letter is sent home to parents. Not unsurprisingly, these letters aren’t exactly optimal for students’ self-esteem and self-image. Schachter cites real-life examples of young people—mostly girls—whose “Fitnessgrams” sent their self-worth into a tailspin.

The ironic part about the obsession with weight is the contributing role the school day now plays in the American “obesity epidemic.” Recesses and free play have been eliminated in favor of more time spent on academics, despite the fact that additional classroom hours have not been shown to improve test scores. Schachter and many other parents bemoan the loss of recess for most kids, which is, as she says, the simplest and cheapest remedy to obesity and a sedentary culture. Who spends more time outside, maximum-security prisoners or children? A new study shockingly indicated the former; children spend on average 30 minutes per day outside…

Across the country, parents and guardians are targeted by law-enforcement and child-protective agencies for the crimes our parents committed daily: making reasonable and nuanced decisions about how, when, where, and for how long children can be left alone. If we now expect children to be supervised at every moment until their teens, they won’t get nearly as much time outside as previous generations enjoyed. While it’s never been safer (according to crime statistics) to raise a child, we are more protective than ever, stifling our kids and keeping them indoors, addicted to screens.

Friday, September 16, 2016

Psychiatric comorbidity in pediatric demyelinating disease

Children and teens with demyelinating diseases of the central nervous system (CNS), including multiple sclerosis (MS), are at increased risk for comorbid psychiatric disorders, new research suggests.

The population-based cohort study compared almost 1100 pediatric patients with demyelinating diseases and under age 18 years to more than 1 million healthy children. It showed that the first group had a significantly higher risk for being hospitalized for psychotic disorders (such as bipolar and schizophrenia), anxiety, intellectual disability, stress-related and somatoform disorders, and behavioral disorders than did the reference group.

Those who had MS only were also at an increased risk for psychotic disorders, intellectual disability, and mood disorders.

Interestingly, the associations appeared to go both ways. Reverse analysis showed that children who first had psychiatric disorders had high rates of developing demyelinating diseases.

The findings were presented here at the Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2016.

Lead author Julia Pakpoor, academic clinical trainee at Oxford University, United Kingdom, told attendees that the results highlight the importance of involving mental health professionals early on in the treatment of these children…

"We know that in large epidemiology studies in adults these comorbidities have been found in individuals with MS, leading to a decrease in medication adherence and a worsening in quality of life. So we thought exploring all of this in younger patients was important for investigators, neurologists, pediatricians, and parents as it may help to guide their care," she said.

The researchers assessed records for 1097 children under age 18 years with CNS demyelinating disease, including a subgroup of 201 who specifically had MS, from mortality data and linked English Hospital Episode Statistics from 1999 to 2011.

In the full group of children with a demyelinating disease, the standardized rate ratio (RR) was 5.8 for psychotic disorders compared with the reference group of children (95% confidence interval [CI], 2.5 - 11.4; P < .001) and 2.4 for risk for anxiety and stress-related/somatoform disorders combined (95% CI, 1.4 - 3.8; P < .001).

The risk for other psychiatric comorbidities ranged from nearly 2-fold to 9-fold higher for the CNS disease group than for the healthy group.

"These remained significant with a 1-year minimum interval between first demyelinating disease episode and first psychiatric disorder episode, and remained significant for psychotic disorders, intellectual disability, and other behavioral disorders with a minimum 5-year interval," report the investigators.

When researchers examined just the group with pediatric-onset MS, the RRs were 10.8 for psychotic disorders, 6.1 for intellectual disability, and 2.6 for mood disorders (P= .001, .004, and .02, respectively).

Further analysis showed significantly increased rates of demyelinating disease development after a hospitalization for many psychiatric disorders (P < .001, all comparisons)…
Overall, "I think our most intriguing finding was the association with these diseases and psychotic disorders. To our knowledge that has not been previously reported in a pediatric population," said Pakpoor.

She added that the study raises many questions. "But in the meantime, there is a need for early holistic multidisciplinary care. There needs to be monitoring right at disease onset."

When a meeting delegate asked after the presentation why the role of the parent wasn't addressed, as that could be an important variable in a child's development, Pakpoor admitted that that information would have been helpful.

"Parents need to be incorporated into the mental health process. It's also important that parents are careful in how they handle a child's MS diagnosis," she said, adding that this includes not burdening children with the parents' own stress and fears.

After the session, cochair Dr Sastre-Garriga told Medscape Medical News that a limitation of the study was that it included only admitted patients and "that was an important bias for the interpretation of the results."

"Although the results were very interesting, we need to confirm with other studies using outpatient samples or using both inpatient and outpatient groups."

Pakpoor agreed. "We could only look at a first recorded episode in a hospital record, which is not the same as first diagnosis." She added that the number of those affected could be much higher with the inclusion of nonhospitalized patients.

On the other hand, a hospitalization for intellectual disability or some of the other disorders is not that common, she said. "So we were dealing with the most severe cases — and it could be that the association is strongest in those with increased disorder severity."

Even with the limitations, Dr Sastre-Garriga noted that monitoring kids with MS early is "definitely" a good idea.

"Not only does it not hurt anything, I think it's necessary to use a more multidisciplinary approach. We do that at our center: including all of the specialties," he said.

Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2016. Young Scientific Investigators' session 2, oral presentation 72. Presented September 14, 2016.

Thursday, September 15, 2016

Chocolate milk and concussions 2

The sugar industry paid scientists in the 1960s to play down the link between sugar and heart disease and promote saturated fat as the culprit instead, newly released historical documents show.

The internal sugar industry documents, recently discovered by a researcher at the University of California, San Francisco, and published Monday in JAMA Internal Medicine, suggest that five decades of research into the role of nutrition and heart disease, including many of today’s dietary recommendations, may have been largely shaped by the sugar industry.

“They were able to derail the discussion about sugar for decades,” said Stanton Glantz, a professor of medicine at U.C.S.F. and an author of the JAMA Internal Medicine paper.

The documents show that a trade group called the Sugar Research Foundation, known today as the Sugar Association, paid three Harvard scientists the equivalent of about $50,000 in today’s dollars to publish a 1967 review of research on sugar, fat and heart disease. The studies used in the review were handpicked by the sugar group, and the article, which was published in the prestigious New England Journal of Medicine, minimized the link between sugar and heart health and cast aspersions on the role of saturated fat.

Even though the influence-peddling revealed in the documents dates back nearly 50 years, more recent reports show that the food industry has continued to influence nutrition science.

Last year, an article in The New York Times revealed that Coca-Cola, the world’s largest producer of sugary beverages, had provided millions of dollars in funding to researchers who sought to play down the link between sugary drinks and obesity. In June, The Associated Press reported that candy makers were funding studies that claimed that children who eat candy tend to weigh less than those who do not.

The Harvard scientists and the sugar executives with whom they collaborated are no longer alive. One of the scientists who was paid by the sugar industry was D. Mark Hegsted, who went on to become the head of nutrition at the United States Department of Agriculture, where in 1977 he helped draft the forerunner to the federal government’s dietary guidelines. Another was Dr. Fredrick J. Stare, the chairman of Harvard’s nutrition department.

In a statement responding to the JAMA journal report, the Sugar Association said that the 1967 review was published at a time when medical journals did not typically require researchers to disclose funding sources. The New England Journal of Medicine did not begin to require financial disclosures until 1984.

The industry “should have exercised greater transparency in all of its research activities,” the Sugar Association statement said. Even so, it defended industry-funded research as playing an important and informative role in scientific debate. It said that several decades of research had concluded that sugar “does not have a unique role in heart disease.”…

The documents show that in 1964, John Hickson, a top sugar industry executive, discussed a plan with others in the industry to shift public opinion “through our research and information and legislative programs.”

At the time, studies had begun pointing to a relationship between high-sugar diets and the country’s high rates of heart disease. At the same time, other scientists, including the prominent Minnesota physiologist Ancel Keys, were investigating a competing theory that it was saturated fat and dietary cholesterol that posed the biggest risk for heart disease.

Mr. Hickson proposed countering the alarming findings on sugar with industry-funded research. “Then we can publish the data and refute our detractors,” he wrote.

In 1965, Mr. Hickson enlisted the Harvard researchers to write a review that would debunk the anti-sugar studies. He paid them a total of $6,500, the equivalent of $49,000 today. Mr. Hickson selected the papers for them to review and made it clear he wanted the result to favor sugar.

Harvard’s Dr. Hegsted reassured the sugar executives. “We are well aware of your particular interest,” he wrote, “and will cover this as well as we can.”

As they worked on their review, the Harvard researchers shared and discussed early drafts with Mr. Hickson, who responded that he was pleased with what they were writing. The Harvard scientists had dismissed the data on sugar as weak and given far more credence to the data implicating saturated fat.

“Let me assure you this is quite what we had in mind, and we look forward to its appearance in print,” Mr. Hickson wrote.

After the review was published, the debate about sugar and heart disease died down, while low-fat diets gained the endorsement of many health authorities, Dr. Glantz said.

“By today’s standards, they behaved very badly,” he said.

Courtesy of a colleague.

Kearns CE, Schmidt LA, Glantz SA. Sugar Industry and Coronary Heart Disease
Research: A Historical Analysis of Internal Industry Documents. JAMA Intern Med.
2016 Sep 12. doi: 10.1001/jamainternmed.2016.5394. [Epub ahead of print]

Early warning signals of the coronary heart disease (CHD) risk of sugar (sucrose) emerged in the 1950s. We examined Sugar Research Foundation (SRF) internal documents, historical reports, and statements relevant to early debates about the dietary causes of CHD and assembled findings chronologically into a narrative case study. The SRF sponsored its first CHD research project in 1965, a literature review published in the New England Journal of Medicine, which singled out fat and cholesterol as the dietary causes of CHD and downplayed evidence that sucrose consumption was also a risk factor. The SRF set the review's objective, contributed articles for inclusion, and received drafts. The SRF's funding and role was not disclosed. Together with other recent analyses of sugar industry documents, our findings suggest the industry sponsored a research program in the 1960s and 1970s that successfully cast doubt about the hazards of sucrose while promoting fat as the dietary culprit in CHD. Policymaking committees should consider giving less weight to food industry-funded studies and include mechanistic and animal studies as well as studies appraising the effect of added sugars on multiple CHD biomarkers and disease development.

Wednesday, September 14, 2016

Higher prepregnancy BMI increases risk of CP in offspring

Forthun I, Wilcox AJ, Strandberg-Larsen K, Moster D, Nohr EA, Lie RT, Surén P, Tollånes MC. Maternal Prepregnancy BMI and Risk of Cerebral Palsy in Offspring. Pediatrics. 2016 Sep 8. [Epub ahead of print]

To investigate the association between maternal pre-pregnancy BMI and risk of cerebral palsy (CP) in offspring.
The study population consisted of 188 788 children in the Mothers and Babies in Norway and Denmark CP study, using data from 2 population-based, prospective birth cohorts: the Norwegian Mother and Child Cohort Study and the Danish National Birth Cohort. Prepregnancy BMI was classified as underweight (BMI <18.5), lower normal weight (BMI 18.5-22.9), upper normal weight (BMI 23.0-24.9), overweight (BMI 25.0-29.9), and obese (BMI ≥30). CP diagnoses were obtained from the national CP registries. Associations between maternal prepregnancy BMI and CP in offspring were investigated by using log-binomial regression models.
The 2 cohorts had 390 eligible cases of CP (2.1 per 1000 live-born children). Compared with mothers in the lower normal weight group, mothers in the upper normal group had a 40% excess risk of having a child with CP (relative risk [RR], 1.35; 95% confidence interval [CI], 1.03-1.78). Excess risk was 60% (RR, 1.56; 95% CI, 1.21-2.01) for overweight mothers and 60% (RR, 1.55; 95% CI 1.11-2.18) for obese mothers. The risk of CP increased 4% for each unit increase in BMI (RR, 1.04; 95% CI, 1.02-1.06). Estimates changed little with adjustment for mother's occupational status, age, and smoking habits.

Higher prepregnancy maternal BMI was associated with increased risk of CP in offspring.

Courtesy of  Doximity

Tuesday, September 13, 2016

The wish to die in ALS

Rabkin J, Goetz R, Murphy JM, Factor-Litvak P, Mitsumoto H; ALS COSMOS Study
Group. Cognitive impairment, behavioral impairment, depression, and wish to die
in an ALS cohort. Neurology. 2016 Aug 5. pii: 10.1212/WNL.0000000000003035. [Epub
ahead of print]

To evaluate relationships among cognitive, behavioral, and psychiatric/psychosocial measures assessed in a multicenter cohort of patients with amyotrophic lateral sclerosis (ALS).
Recently diagnosed patients with definite or probable ALS diagnosis were administered 7 standardized psychiatric/psychosocial measures, including the Patient Health Questionnaire for diagnosis of depression and elicitation of wish to die. The Cognitive Behavioral Screen was used to classify both cognitive and behavioral impairment (emotional-interpersonal function). An ALS version of the Frontal Behavioral Inventory and Mini-Mental State Examination were also administered.
Of 247 patients included, 79 patients (32%) had neither cognitive nor behavioral impairment, 100 (40%) had cognitive impairment, 23 (9%) had behavioral impairment, and 45 (18%) had comorbid cognitive and behavioral decline. Cognitive impairment, when present, was in the mild range for 90% and severe for 10%. Thirty-one patients (12%) had a major or minor depressive disorder (DSM-IV criteria). Cognitive impairment was unrelated to all psychiatric/psychosocial measures. In contrast, patients with behavioral impairment reported more depressive symptoms, greater hopelessness, negative mood, and more negative feedback from spouse or caregiver. A wish to die was unrelated to either cognitive or behavioral impairment.
While we found no association between cognitive impairment and depression or any measure of distress, behavioral impairment was strongly associated with depressive symptoms and diagnoses although seldom addressed by clinicians. Thoughts about ending life were unrelated to either cognitive or behavioral changes, a finding useful to consider in the context of policy debate about physician-assisted death.

In August, a 41-year-old artist with amyotrophic lateral sclerosis (ALS) generated headlines in the mainstream press when she held a two-day gathering of friends and family before taking a fatal combination of medications. She became one of California's first residents to use the state's new law allowing physicians to help terminally ill people end their lives…

In the latest study, known as the the Cohort Study of Oxidative Stress (COSMOS), researchers at multiple institutions sought to determine if there were possible associations between cognitive, behavioral, and psychiatric/psychosocial impairments in ALS patients, and the wish to die…

“Being depressed was not related to having a wish to die,” said the principal study author Hiroshi Mitsumoto, MD, FAAN, the Wesley J. Howe professor of neurology at Columbia University at the Neurological Institute of New York and New York-Presbyterian Hospital/Columbia University Medical Center. Of the 62 patients who expressed a wish to die, only 23 were determined to be clinically depressed…

Still, he noted, the study did find that patients with behavioral impairment showed “considerable and consistent” associations between disease characteristics, and were more likely to have depressive symptoms, lower quality of life and higher stress levels. Patients with behavioral impairment were more likely to to have depressive symptoms, lower levels of positive affect and higher levels of negative affect, and higher mean scores of hopelessness, lower quality of life, and higher stress levels…

In the study, the researchers looked at 247 recently diagnosed ALS patients, 32 percent of whom had neither cognitive nor behavioral impairment. Of those who had cognitive impairment, 90 percent were in the mild to moderate range, and 10 percent had severe cognitive impairment. Twelve percent had a major or minor depressive disorder…

“That way if there are cognitive, behavioral, and psychological issues noted, the patient can be properly treated and appropriate counseling should be given,” he said. “The goal is to take care of the patient and the family, and be aware of these issues, because the wish to die and physician-assisted death issue will come up more and more in the future, so we simply cannot ignore them.”…

Linda Ganzini, MD, MPH, professor of psychiatry and medicine at Oregon Health and Science University in Portland, agreed that loss of autonomy is a primary concern. ALS patients are 30 times more likely to die with physician-assisted death in Oregon, compared to all other deaths, and about 3 percent of ALS patients choose that option…

“For me and people in the field working with ALS patients, this study is reassuring that depression isn't much of a worry as part of their decision-making capacity as much as we have feared,” said Dr. Ganzini.“It's still very important to test patients for their understanding of their options, whether it's about the disease or treatment, and whether they understand the options of palliative measures that might improve their quality of life and make them want to live longer.”

Dr. Katz did not feel that the study findings would necessarily help neurologists respond to requests for physician-assisted death. Patients who were demented and who had severe depression would not be allowed to be part of physician-assisted suicide, he said, because they don't have decision-making capacity, adding that the laws specifically address the role of depression.

“Those who feel strongly that physician-assisted death is a bad idea will find reasons to either refute what the data provide in this article or will say it's irrelevant because physician participation in death is never justifiable within the purview of professional responsibility,” said Dr. Russell, chairman of the Ethics, Law and Humanities, a joint committee of the AAN, American Neurological Association and the Child Neurology Society. “For the physicians who endorse participation in hastened death when lawful and when terminally ill patients request it, it will perhaps make them feel slightly better about their participation because there has been an unanswered question about whether depression interferes with a person's decision-making capacity.”,_the_Wish_to_Die_Is_Not.8.aspx

Antibiotic resistance

Antibiotic resistance could have a drastic impact on all of our lives, but is invisible to the naked eye and impossible for most to comprehend. So researchers at Harvard Medical School and the Technion-Israel Institute of Technology decided to make it obvious: They designed a model to show bacteria mutating to overcome drugs meant to stop and destroy them.

Along the way, their experiments, which have been described and videotaped for the journal Science, revealed something even more profound. Not only does the model vividly illustrate how antibiotic resistance happens, it also demonstrates "survival of the fittest" and other Darwinian concepts that have been often discussed but never once seen.

"When I saw those videos it kinda hit me viscerally -- I'm watching evolution, I don't have to think about it, there it is, I can see it," said Sam P. Brown, an evolutionary biologist at Georgia Institute of Technology, who was not involved in the experiments. He and Luke McNally of the University of Edinburgh, co-wrote a commentary published with the research.

To observe the do-or-die encounter between bacteria and an antibiotic drug, the research team constructed a two-foot by four-foot petri dish -- dubbed the Microbial Evolution and Growth Arena or MEGA plate -- and filled it with agar, a jellylike nourishment used in labs to feed growing organisms. Next, they searched among bacteria for the right one to work with and landed on E. coli.
"In order to grow bacteria on a petri dish of that size, it needs to be able to swim, which is something E. coli can do but many other model organisms cannot," said Dr. Michael Baym, first author of the study and a postdoctoral fellow in microbial evolution at Harvard Medical School. E. coli also possesses fundamental mechanisms in common with infection-causing bacteria, explained Baym, and quite simply, "we knew how to work with it."

Next, the researchers divided the MEGA plate into sections and added increasing doses of an antibiotic, trimethoprim. This antibiotic was chosen because it is well-known, explained Baym. "We have a lot of experience understanding how resistance of trimethoprim evolves," said Baym. "We were developing a new system to study evolution and so we wanted to work with as many parts that we sort of understood as possible."

Preparing the MEGA plate for their experiments, the research team left the outermost area clean of trimethoprim. In the area nearest this outermost section, they added a single dose of the drug and then, as the sections progressed to the center, the dosage kept increasing until it reached 1,000 times the initial dose.

Over two weeks, a ceiling-mounted camera snapped periodic shots of what transpired in the MEGA plate below. Later, the researchers spliced these shots into a time-lapsed videotape that showed how most of the bacteria spread until they reached the antibiotic dose that was too strong for them to continue growing or living.

However, at each dosage level, a small group of bacteria were able to survive. Bacteria, like other living beings, evolve to adapt to changes in their environment and one way they do this is through genetics. New genes can arise through mutations and these then get passed down to subsequent generations.

The MEGA plate revealed all this and more: Descendants of the drug-resistant mutants instinctively migrated to new territories, the areas of fresh agar nourishment and also higher antibiotic concentration. Once there, multiple lineages of mutants competed for dominance within the same space. And so, over a span of just days, the wily E. coli strains made their way from the good life of easy nourishment in a drug-free outer layer through sections of the MEGA plate containing increasingly higher doses of antibiotic.

The early low-resistance mutants soon gave rise to moderately resistant mutants and ultimately these intermediate bacteria spawned highly resistant strains able to overcome a dose of trimethoprim 1,000 times more intense than the one that killed their ancestors.

"You can just see mutations and selections and trade-offs happening right in front of you," said Baym.
Along with the usual package of genes inherited from their forebears, bacteria also contain plasmids, small rings of additional DNA. Scientists have known that plasmids enable wider and faster spread of resistance among bacteria. Within the MEGA plate, the bacteria strains traded plasmids containing genes essential to survival…

In this second experiment, the E. coli mutated to develop 100,000-fold resistance to an initial dose of cipro and, as the researchers anticipated, the evolutionary process "looked quite different" from that of trimethoprim, according to Baym. Still, the branches of a tree could be traced along the ever-more-resistant bacteria.

In both cases, though, location of a particular bacterial strain determined its success --- or failure --- in developing resistance. When the researchers moved mutants trapped behind their parents to the so-called "frontlines" of the culture, they were able to grow into new regions where the parents could not. Survival may not be driven by the fittest mutants, suggest Baym and his colleagues; what matters most for survival is a combination of sufficient fitness and sufficient closeness to the advancing front.

Courtesy of a colleague

Baym M, Lieberman TD, Kelsic ED, Chait R, Gross R, Yelin I, Kishony R.
Spatiotemporal microbial evolution on antibiotic landscapes. Science. 2016 Sep

A key aspect of bacterial survival is the ability to evolve while migrating across spatially varying environmental challenges. Laboratory experiments, however, often study evolution in well-mixed systems. Here, we introduce an experimental device, the microbial evolution and growth arena (MEGA)-plate, in which bacteria spread and evolved on a large antibiotic landscape (120 × 60 centimeters) that allowed visual observation of mutation and selection in a migrating bacterial front. While resistance increased consistently, multiple coexisting lineages diversified both phenotypically and genotypically. Analyzing mutants at and behind the propagating front, we found that evolution is not always led by the most resistant mutants; highly resistant mutants may be trapped behind more sensitive lineages. The MEGA-plate provides a versatile platform for studying microbial adaption and directly visualizing evolutionary dynamics.

For those who can access the article on line, there are videos of this process.