Meeting – Risk-Based Approaches to Clinical Investigations

 

Target Health Inc. is pleased to announce that Dr. Jules T. Mitchel and Mr. Dean Gittleman will be presenting a Case Study on “Analyzing the Potential of Transforming Clinical Trials through Risk-Based Monitoring,” at CBI’s Meeting on Risk-Based Approaches to Clinical Investigations – Data Quality, Operational and Technological Considerations. The meeting will be held on April 10-11, 2012 at the Doubletree Hotel Center City, Philadelphia, PA. Our colleagues from Bristol-Myers Squibb, Johnson & Johnson, Vertex, Teva, Endo, Otsuka and more will be presenting.

 

As a valued reader of On Target, CBI is offering $400 off of your registration fee. Just enter priority code XPM636 when registering at www.cbinet.com/clinicalinvestigations.

 

For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website at www.targethealth.com

Profound Reorganization in Brains of Adults Who Stutter: Auditory-Motor Integration Located in Different Part of Brain

 

In adults who have stuttered since childhood the processes of auditory-motor integration are indeed located in a different part of the brain to those in adults who do not stutter, new research shows. (Credit: marksykes / Fotolia)

 

 

Hearing Beethoven while reciting Shakespeare can suppress even a King’s stutter, as recently illustrated in the movie “The King’s Speech.” This dramatic but short-lived effect of hiding the sound of one’s own 1) ___speech indicates that the integration of 1) ___hearing and motor functions plays some role in the fluency (or dysfluency) of speech. New research has shown that in adults who have stuttered since childhood, the processes of auditory-motor integration are indeed located in a different part of the 2) ___brain to those in adults who do not stutter.

 

Dr. Nicole Neef and Dr. Martin Sommer from the University of Goettingen, together with Dr. Bettina Pollok from the University of Duesseldorf, studied the performance of a group of adults who stutter, as well as a control group of adults who do not stutter, in a finger tapping exercise. They used Transcranial Magnetic Stimulation TMS 3) ___ ___ ___ to interfere temporarily with brain activity in the dorsolateral premotor cortex while the participants tapped their fingers in time with the clicks of a metronome. In control subjects, disturbing the left premotor cortex impaired the finger tapping, but disturbing the right premotor cortex had no effect. In stuttering adults, the pattern was reversed: the accuracy of finger tapping was affected by disturbing the right hemisphere, and unaffected when disturbing the 4) ___left.

 

Previous research has already linked stuttering with a right-shifted cerebral 5) ___blood flow in the motor and premotor areas during speech. In this new study, a shift of auditory-motor integration to the right side of the brain occurred even in a task not directly involving speech. Thus, in the brains of adults who stutter there appears to be a profound reorganization possibly compensating for subtle white matter disturbances in other parts of the brain — the left inferior frontal regions. These findings shed light on the extent of the 6) ___reorganization of brain functions in persistent developmental stuttering.

 

ANSWERS: 1) speech; 2) brain; 3) Transcranial Magnetic Stimulation; 4) left; 5) blood; 6) reorganization

Beethoven Unlikely to Have Died from Lead Exposure

 

 

Antique 19th-century engraving of a portrait of Ludwig van Beethoven. The German composer and pianist was born on December 17, 1770 in Bonn, Germany, he died on March 26, 1827 in Vienna, Austria. (Credit: iStockphoto)

 

 

Less than a year ago, a researcher at Mount Sinai School of Medicine measured the amount of lead in two skull fragments of Ludwig van Beethoven and found that it was unlikely for lead poisoning to have caused the renal failure that was partly responsible for Beethoven’s death, eliminating one of the many suggested causes of death for the famed composer. As much as 95% of lead in the adult body is stored in bone, where it stays for years, even after death,” said Andrew Todd, PhD, Associate Professor of Preventive Medicine, Mount Sinai School of Medicine. “Measuring the amount of lead in Beethoven’s bone fragments allows us to reach back through time to measure his lead exposure during life.”

 

Skull fragments from Beethoven were examined using a technique called x-ray fluorescence (XRF). XRF does not damage or destroy the sample and has been used by Dr. Todd in many studies of the human health effects of lead. A very small radiation dose (about the same dose as 10 minutes of natural background radiation) is used to make the lead stored in bone give off x-rays, which are recorded in a radiation detector. The larger skull fragment was found by Dr. Todd to have 12 micrograms of lead per gram of bone mineral. “For someone who was Beethoven’s age, we would expect more than that; one comparison dataset predicts 21 micrograms of lead per gram of bone mineral,” said Dr. Todd.

 

Lead exposure is known to cause irritability, for which Beethoven was renowned, as well as colic and kidney failure, from which, along with liver failure, Beethoven is thought to have died. Currently two dozen or more health issues have been suggested for Beethoven, some of them deadly. This work largely rules out one of them. Work done in 2000 at the Argonne National Laboratory examined only the surface of the small fragment of Beethoven’s bone that Dr. Todd also tested. Dr. Todd’s work also examined the complete thickness of a much larger fragment of Beethoven’s skull. According to Dr. Todd, there have been many explanations put forward about Beethoven’s death. Some have found high lead levels in Beethoven’s hair, which can show lead exposure only from the last several months of his life. According to a researcher in Vienna, that reading could have reflected the treatment used to heal a wound from surgery Beethoven underwent in an attempt to save his life. Such treatment in those days consisted of salves that might have contained lead. Dr. Todd’s bone measurements quantify lead over Beethoven’s entire lifetime. Others have theorized that Beethoven had high lead exposure from the long used practice of sweetening the cheapest wine with lead. But, those theories have been disputed based on records Beethoven kept when he became deaf which showed he had the resources to buy more expensive wines.

 

The skull fragments Dr. Todd measured are thought to have been obtained the first time Beethoven was reburied (in 1863) by a physician, Gerhard von Breuning, who as a boy had been a friend of Beethoven’s and who was a comfort to him in his last months. Dr. von Breuning is thought to have given the fragments to Romeo Seligmann (the first Professor of the History of Medicine at the University in Vienna) in whose family they have remained. The above story is reprinted from materials provided by Mount Sinai School of Medicine.

 

For your listening pleasure, below, one of the most perfect, glorious pieces of music ever written played by Daniel Barenboim – Joyce Hays, Target Health Inc.

 

Beethoven Piano Sonata “Pathetique” First Movement

 

Beethoven Piano Sonata “Pathetique” Second Movement

 

Beethoven Piano Sonata “Pathetique” Third Movement

 

HIV/AIDS

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Treatment Window for HIV-Positive Children Infected at Birth

 

The results of the Pediatric Randomized Early vs. Deferred Initiation in Cambodia and Thailand (PREDICT) study, presented at the 19th Conference on Retroviruses and Opportunistic Infections at the Washington State Convention Center in Seattle, showed that HIV-positive children older than 1 year who were treated after showing moderate HIV-related symptoms did not experience greater cognitive or behavior problems compared to peers treated when signs of their infection were still mild. However, both groups of HIV-positive children lagged behind HIV-negative children in these areas, suggesting that the first year of life may present a critical treatment window for minimizing impairments in brain development due to HIV.

 

The PREDICT trial assessed 284 HIV-positive children ages 1-12 who had mildly weakened immune systems but no severe symptoms of HIV infection. The children were randomly assigned to receive treatment immediately or to have treatment deferred until they began to show moderate signs of HIV-related illness. Results showed that at follow-up almost 3 years later, very few children in either group had progressed to AIDS. Children who received deferred treatment performed as well as those treated immediately on tests measuring intelligence, memory, and hand-eye coordination. However, both groups scored lower on these tests and had more behavior problems than HIV-negative children who took part in the PREDICT study. Though the study did not assess the children’s actual educational needs, the difference in test scores would place many HIV-positive children at a lower functional level than their HIV-negative peers, indicating they may need additional resources or special schooling.

 

According to the authors, these findings suggest that the window of opportunity for avoiding neurocognitive deficits by treating HIV infection may only occur earlier, in infancy.

ONCOLOGY

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Childhood Cancer Delays Developmental Milestones

 

In recent years, survival rates for many types of childhood cancer have increased. As a result, quality of life for young cancer survivors has become a major concern.

 

According to an article published online in the Journal of Pediatric Psychology (2 February 2012), infants and toddlers who have been treated for cancer tend to reach certain developmental milestones later than do their healthy peers. The findings show that delays may occur early in the course of treatment and suggest that young children with cancer might benefit from such early interventions as physical or language therapy.

 

Results of the study showed that compared to children who had not had cancer, children treated for cancer before age 4 progressed more slowly in vocabulary, cognitive functions such as attention and memory, and motor skills. However, having cancer did not appear to affect children’s social and emotional development. Their ability to respond to their parents was comparable to that of their peers who did not have cancer. Also unaffected by cancer was the ability to engage in make-believe play, such as pretending to pour and serve tea, which typically develops between 12 and 18 months of age.

 

The current study is the first to document, prospectively, the potential effects of having cancer on young children’s development, enrolling the children after their diagnosis and testing them after they had received treatment. Previous studies have attempted to discern the influence of childhood cancer many years after the cancer had gone into remission – in adolescence or beyond.

 

The study evaluated 61 children between 6 months and 3.5 years old. All were being treated for tumors or cancers of the blood when they entered the study. The children averaged 19 months old at diagnosis, and had received an average of three months of treatment at the time the researchers evaluated their cognitive and emotional development. Pediatricians evaluated all of the children to ensure they were well enough to participate in the testing. Experts familiar to the children and their families then conducted a series of assessments to evaluate the children in several areas of development:

 

1. Their ability to understand language and to express themselves, for example, by identifying a toy by name

 

2. Their cognitive abilities on an age-appropriate battery of tests, including attention, memory, problem-solving and the ability to classify objects

 

3. Gross motor skills (their ability to sit up, crawl or walk) and fine-motor skills (the ability to control precise movements, like using a spoon)

 

The study also videotaped the children and their mothers while they engaged in play in order to gauge the children’s social and emotional development by rating their responsiveness to and involvement with their mothers, exploration of new toys, and ability to engage in make-believe play. Mothers also responded to questions about their child’s language ability and behavior at three points in time: one month before, one week before and on the day of the cognitive, motor and social/emotional testing.

 

The cancer survivors did not score as well on tests of language, cognition and motor milestones as did children who did not have cancer. In terms of developmental averages, children with cancer were about 7 points below average on tests of mental development, and 14 points below average on motor tests.

Early Surgical Therapy for Drug-Resistant Temporal Lobe Epilepsy

 

Despite reported success, surgery for drug treatment resistant seizures is often seen as a last resort. Patients are typically referred for surgery after 20 years of seizures, often too late to avoid significant disability and premature death. As a result, a study published in the Journal of the American Medical Association (2012;307:922-930), was performed to determine whether surgery soon after failure of 2 antiepileptic drug (AED) trials is superior to continued medical management in controlling seizures and improving quality of life (QOL).

 

The Early Randomized Surgical Epilepsy Trial (ERSET) is a multicenter, controlled, parallel-group clinical trial performed at 16 US epilepsy surgery centers. The 38 participants (18 men and 20 women; aged >12 years) had mesial temporal lobe epilepsy (MTLE) and disabling seizures for no more than 2 consecutive years following adequate trials of 2 brand-name AEDs. Eligibility for anteromesial temporal resection (AMTR) was based on a standardized presurgical evaluation protocol. Participants were randomized to continued AED treatment or AMTR 2003-2007, and observed for 2 years. Planned enrollment was 200, but the trial was halted prematurely due to slow accrual.

 

Treatments included receipt of continued AED treatment (n = 23) or a standardized AMTR plus AED treatment (n = 15). In the medical group, 7 participants underwent AMTR prior to the end of follow-up and 1 participant in the surgical group never received surgery.

The primary outcome variable was freedom from disabling seizures during year 2 of follow-up. Secondary outcome variables were health-related QOL (measured primarily by the 2-year change in the Quality of Life in Epilepsy 89 [QOLIE-89]]overall T-score), cognitive function, and social adaptation.

 

Results showed that none (0) of 23 participants in the medical group and 11 of 15 in the surgical group were seizure free during year 2 of follow-up (P < 0.001). In an intention-to-treat analysis, the mean improvement in QOLIE-89 overall T-score was higher in the surgical group than in the medical group but this difference was not statistically significant (12.6 vs. 4.0 points; P = 0.08). When data obtained after surgery from participants in the medical group were excluded, the effect of surgery on QOL was significant (12.8 vs. 2.8 points; P =0.01). Memory decline (assessed using the Rey Auditory Verbal Learning Test) occurred in 4 participants (36%) after surgery, consistent with rates seen in the literature; but the sample was too small to permit definitive conclusions about treatment group differences in cognitive outcomes. Adverse events included a transient neurologic deficit attributed to a magnetic resonance imaging-identified postoperative stroke in a participant who had surgery and 3 cases of status epilepticus in the medical group.

 

According to the authors, among patients with newly intractable disabling MTLE, resective surgery plus AED treatment resulted in a lower probability of seizures during year 2 of follow-up than continued AED treatment alone. However, given the premature termination of the trial, the results should be interpreted with appropriate caution.

TARGET HEALTH excels in Regulatory Affairs. Each week we highlight new information in this challenging area.

 

Feeding Tube Misconnections

 

 

The most serious mistake occurs when nutrients intended for the gastrointestinal tract are inadvertently delivered elsewhere, such as the vasculature. This mistake can cause death, usually by embolus or sepsis.

 

The FDA has urged making connectors and adaptors uniform, so that built-in incompatibility will prevent misconnections. Color-coding was also recommended. Making such changes is voluntary, however, and feeding tube misconnections continue.

 

Whenever possible, hospitals should use enteral pumps for enteral feeding and trace lines from end to end when making an initial connection or reconnection. Users should not modify or adapt intravenous or feeding devices, which could compromise their safety features. It would be very useful to label or color-code feeding tubes and connectors and to purchase only feeding sets that meet ANSI/AAMI ID54 standards. Image Courtesy of Getty/Thinkstock

The Pre-Existing Condition Insurance Plan – Success or Boondoggle?

 

 

By Mark L. Horn, MD, MPH, Chief Medical Officer, Target Health Inc.

 

 

A progress report from the Center for Consumer Information and Insurance Oversight (CCIIO) on an element of the Affordable Care Act (ACA) was issued this week and seemed to attract less attention than typically accrues to ACA matters. Perhaps some have forgotten, but the ACA created a temporary mechanism for uninsured patients with pre-existing conditions to secure health coverage prior to 2014 when the ACA established Insurance Exchanges, mandating that all insurers cover pre-existing conditions, become operational. The idea is straightforward, there are many Americans who, due to job loss, disability, financial distress or simple bad luck find themselves uninsured, and among this group there is a doubly unfortunate segment that has a pre-existing significant health problem. This combination of events creates a potentially unsolvable and financially ruinous problem, uninsurable health costs.

 

Since this dilemma, widely known and lamented, was intensively discussed during the health reform debates, it’s surprising that this report has not received more attention. The program, labeled the Pre-Existing Condition Insurance Plan (PCIP) is operational, and will have enrolled nearly 50,000 people in either federally or state run (it is structured on a ‘Federalist’ model) PCIPs through December, 2011.

 

The demographics of the enrollees suggest that the program has attracted, as presumably was anticipated, individuals who for a variety of reasons are unable to secure employer coverage and are too young for Medicare, a population long recognized as especially vulnerable to the coverage ‘cracks’ in our health system. Among medical needs covered, and specifically cited in the report, are cancer, circulatory disorders, and rehabilitative care including “certain forms of radiation and chemotherapy”. Among criticisms: the current anticipated cost of coverage, nearly $29,000 per member/per year, is significantly higher than the $13,000 estimated in November 2010. The report notes that this reflects the significant and severe medical needs of this especially vulnerable population.

 

What are we to make of this?

 

To this observer, it is hard to call this anything but a success. A highly vulnerable population without viable insurance options has been defined, and a mechanism of insuring them at rational premiums (e.g. prices they can manage) has been devised. There is no suggestion in the report that the cost overruns emanate from anything other than legitimate medical expenses; finally, coverage, while ‘actuarially’ subsidized is not free, e.g. premiums are charged and paid.

 

This seems a particularly American solution, effective, pragmatic, (and imperfect), to a serious social problem affecting a clearly vulnerable group of people. Its imperfections are non-trivial, among these its expense; nevertheless for many it apparently successfully addresses a critical problem. As citizens, we should be proud of, and grateful for, this success.