New Article on eSource Published in the DIA Journal
Lessons Learned From a Direct Data Entry Phase 2 Clinical Trial Under a US IND – DIA Journal, 2012
Target Health Inc. is very pleased to announce the publication of an article entitled “Lessons Learned From a Direct Data Entry Phase 2 Clinical Trial Under a US IND,” DIA Journal, July 2012. This article documents the results of the first Phase 2 program using eSource in lieu of paper records.
In addition to the extraordinary team at Target Health, this paper is coauthored with Dario Carrara, PhD (Ferring Pharmaceuticals), Mitchel Efros, MD, FACS and Kerri Weingard, ANP, MS, BSN, RN (AcuMed Research; both from the clinical site participating in the study) as well as our good friend and colleague Vadim Tantsyura, MS (NECDQ Consulting).
In order to assess the impact of direct data entry (DDE) on the clinical trial process, a single-site, phase 2 clinical trial, under a US IND, was performed where the clinical site entered each subject’s data into Target e*CRF® for EDC at the time of the office visit. Target e*CTR™ (electronic clinical trial record was used as the subject’s electronic source (eSource) record. The clinical data monitoring plan (CDMoP) defined the scope of source document verification, the frequency and scope of online data review, and the criteria for when to perform onsite monitoring. As a result of this novel approach to clinical research operations, (1) there were no protocol violations as screening errors were picked up prior to treatment; (2) because there were minimal transcription errors from paper source records to the EDC system, there was a major reduction in onsite monitoring compared to comparable studies that use paper source records; (3) EDC edit checks were able to be modified early in the course of the clinical trial; (4) compliance issues were identified in real time and corrected; (5) there was rapid transparency and detection of safety issues; and (6) the clinical site indicated that there were major cost savings overall and estimated that just in terms of data entry, it was able to save 70 hours of labor by not using paper as the original source records.
It is postulated that once the pharmaceutical industry adopts DDE and RBM, there will be major increases in productivity for sponsors, clinical sites, and CROs, as well as reduced time to database lock and the statistical analyses. In addition to the productivity increases, these processes and tools will improve data integrity and quality and potentially reduce overall monitoring resources and efforts by an estimated 50% to 60%.
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
Update: Medical Robots
Like the human finger, the group’s BioTac® sensor has a soft, flexible skin over a liquid filling. (Credit: USC)
Robots are being engineered to have feelings, with touch more sensitive than a 1) ___. So what exactly does a robot feel when it touches something? Little or nothing until now. But with the right sensors, actuators and software, robots can be given the sense of feel — or at least the ability to identify different materials by 2) ___. Researchers at the University of Southern California’s Viterbi School of Engineering published a study June 18 in Frontiers in Neurorobotics showing that a specially designed robot can outperform humans in identifying a wide range of natural materials according to their textures, paving the way for advancements in prostheses, personal assistive robots and consumer product testing. The robot in the photo above, was equipped with a new type of tactile sensor built to mimic the human 3) ___. It also used a newly designed algorithm to make decisions about how to explore the outside world by imitating human strategies. Capable of other human sensations, the sensor can also tell where and in which direction forces are applied to the fingertip and even the thermal properties of an object being touched.
Like the human 4) ___, the group’s BioTac® sensor has a soft, flexible skin over a liquid filling. The skin even has fingerprints on its surface, greatly enhancing its sensitivity to vibration. As the finger slides over a textured surface, the skin vibrates in characteristic ways. These vibrations are detected by a hydrophone inside the bone-like core of the finger. The human finger uses similar vibrations to identify textures, but the robot finger is even more sensitive. When humans try to identify an object by touch, they use a wide range of exploratory movements based on their prior 5) ___ with similar objects. A famous theorem by 18th century mathematician Thomas Bayes describes how decisions might be made from the information obtained during these movements. Until now, however, there was no way to decide which exploratory movement to make next. The article, authored by Professor of Biomedical Engineering Gerald Loeb and recently graduated doctoral student Jeremy Fishel, describes their new theorem for solving this general problem as “Bayesian Exploration.”
Built by Fishel, the specialized robot was trained on 117 common materials gathered from fabric, stationery and hardware stores. When confronted with one material at random, the robot could correctly identify the material 95% of the time, after intelligently selecting and making an average of five exploratory movements. It was only rarely confused by pairs of similar textures that human subjects making their own exploratory movements could not distinguish at all. So, is touch another task that humans will outsource to robots? Fishel and Loeb point out that while their robot is very good at identifying which textures are similar to each other, it has no way to tell what textures people will prefer. Instead, they say this robot touch technology could be used in human prostheses or to assist companies who employ experts to assess the feel of consumer products and even human 6) ___.
Loeb and Fishel are partners in SynTouch LLC, which develops and manufactures tactile sensors for mechatronic systems that mimic the human hand. Founded in 2008 by researchers from USC’s Medical Device Development Facility, the start-up is now selling their BioTac sensors to other researchers and manufacturers of industrial robots and prosthetic hands.
How will humans respond to being touched by a robotic nurse?
In the study, researchers looked at how people responded when a robotic nurse, known as Cody, touched and wiped a person’s forearm. Although Cody touched the subjects in exactly the same way, they reacted more positively when they believed Cody intended to clean their arm versus when they believed Cody intended to comfort them. (Credit: Georgia Tech)
For people, being touched can initiate many different reactions from comfort to discomfort, from intimacy to aggression. But how might people react if they were touched by a 7) ___? Would they recoil, or would they take it in stride? In an initial study, researchers at the Georgia Institute of Technology found people generally had a positive response toward being touched by a robotic nurse, but that their perception of the robot’s intent made a significant difference. The research was presented at the Human-Robot Interaction conference in Lausanne, Switzerland. “What was found was that, how 8) ___ perceived the intent of the robot was really important to how they responded. So, even though the robot touched people in the same way, if people thought the robot was doing that to clean them, versus doing that to comfort them, it made a significant difference in the way they responded and whether they found that contact favorable or not,” said Charlie Kemp, assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University.
In the study, researchers looked at how people responded when a robotic nurse, known as Cody, touched and wiped a person’s forearm. Although Cody touched the subjects in exactly the same way, they reacted more positively when they believed Cody intended to clean their arm versus when they believed Cody intended to comfort them. These results echo similar studies done with regular human 9) ___. “There have been studies of nurses and they’ve looked at how people respond to physical contact with nurses,” said Kemp, who is also an adjunct professor in Georgia Tech’s College of Computing. “And they found that, in general, if people interpreted the touch of the nurse as being instrumental, as being important to the task, then people were OK with it. But if people interpreted the touch as being to provide comfort – people were not so comfortable with that.” In addition, Kemp and his research team tested whether people responded more favorably when the robot verbally indicated that it was about to touch them versus touching them without saying anything.
“The results suggest that people preferred when the robot did not actually give them the warning,” said Tiffany Chen, doctoral student at Georgia Tech. “We think this might be because they were startled when the robot started speaking, but the results are generally inconclusive.” Since many useful tasks require that a robot touch a person, the team believes that future research should investigate ways to make robot touch more acceptable to people, especially in healthcare. Many important healthcare tasks, such as wound dressing and assisting with hygiene, would require a robotic nurse to touch the patient’s body. “If we want robots to be successful in healthcare, we’re going to need to think about how do we make those robots communicate their intention and how do people interpret the intentions of the robot,” added Kemp. “And I think people haven’t been as focused on that until now. Primarily people have been focused on how can we make the robot safe, how can we make it do its task effectively. But that’s not going to be enough if we actually want these robots out there helping people in the real world.”
Robots Redefine Cancer Surgery
UC Irvine Healthcare performs robotic thyroidectomies.
Drs. Thomas E. Ahlering (left) and Michael K. Louie, who head UC Irvine Medical Center’s Robotic Oncology Center, battle cancer with such state-of-the-art technology as the da Vinci Surgical System. Photo by Steve Zylius .
UC Irvine’s innovative Robotic Oncology Center offers minimally invasive treatment in multiple disciplines. In the ever-evolving battle against 10) ___, the surgical robot is gaining ground. UC Irvine Healthcare announced that it’s the first medical center on the West Coast to perform robotic thyroidectomies, which remove the diseased gland without leaving a visible scar on the neck. The da Vinci Surgical System is facilitating an increasing number of such procedures, and to further advance use of this new technology, UC Irvine Healthcare in July established a Robotic Oncology Center. Dr. Jason H. Kim, associate clinical professor of otolaryngology and a head & neck cancer specialist, has employed the da Vinci system on three patients with thyroid tumors. “We’re excited to be able to offer this kind of surgery to the Orange County community,” Kim says. “Traditional ‘open’ surgery to remove the thyroid gland requires a 3- to 5-inch incision across the front of the 11) ___, and other minimally invasive surgical techniques can reduce the scar to about 1 inch. But with the robot, we avoid the neck incision altogether by making a small, easily hidden cut in the patient’s armpit. That opening provides access for the robot’s arms, which then are maneuvered by the surgeon to the thyroid.”
At UC Irvine Medical Center, prostate, kidney, ureteral and gynecologic cancers also are being addressed via robotic surgery.
Miniature Medical Robots
Several medical robots are used in a wide range of surgical applications, from neurosurgery to radiosurgery, even in pediatrics and orthopedics. But medical robots are not confined only to a surgical role. In Israel, a miniature robot called ViRob was developed in order to crawl through the human body, locate a 12) ___, and treat it with drugs. Measuring only one millimeter long and four millimeters from end to end, the bot uses tiny arms controlled by an electromagnetic field to propel its way through different cavities of the human body, looking for deadly tumors to treat.
Another robotic device is the IntelliFill i.v. a robot that can fill up to 60 drug-filled, patient-specific syringes per hour, also designed to ensure that the right medicine in the right dose gets to the right 13) ___. A study by the Institute of Medicine in 1999 has estimated that as many as 98,000 Americans die each year because of medical errors – 7,000 of them from medication errors. This has therefore prompted hospitals to computerize systems for prescription orders and use devices that automate the prescription-filling process. According to the following manufacturer website FHT Inc, http://www.fhtinc.com/ it has delivered over 30 Million IV doses.
A Syringe robot called RIVA, developed by Intelligent Hospital Systems, has likewise automated the preparation of IV solutions in hospital 14) ___, making the process safer, cheaper and more efficient.
ANSWERS: 1) human’s; 2) touch; 3) fingertip; 4) finger; 5) experience; 6) skin; 7) robot; 8) people; 9) nurses; 10) cancer; 11) neck; 12) tumor; 13) patient; 14) pharmacies
Part One, Brief History of Robots (Next week, Part Two, Robots in Medicine)
19th Century tea-serving Japanese robot, “karakuri ningyo”, with mechanism (right)
Since the beginning of philosophical thinking and mind-musings into the meaning of existence and the defining of “human”, our curiosity and ingenuity extended into creating human-like objects. A robot or automaton is a self-operating machine. The word automaton is the latinization of the Greek automaton, (neuter) “acting of one’s own will”. It was, more often used to describe non-electronic moving machines, especially those that have been made to resemble human or animal actions, such as the jacks on old public striking clocks, or the cuckoo and any other animated figures on a cuckoo clock.
Robots or automata in the Hellenistic world were intended as toys, religious idols, or tools for demonstrating basic scientific principles, including those built by Greek mathematician Hero of Alexandria (sometimes known as Heron). When his writings on hydraulics, pneumatics, and mechanics were translated into Latin in the sixteenth century, Hero’s readers initiated reconstruction of his machines, which included siphons, a fire engine, a water organ, the aeolipile, and a programmable cart.
The Antikythera mechanism from 150-100 BC was designed to calculate the positions of astronomical objects.
Complex mechanical devices are known to have existed in ancient Greece, though the only surviving example is the Antikythera mechanism. It is thought to have come originally from Rhodes, where there was apparently a tradition of mechanical engineering; the island was renowned for its automata; to quote Pindar’s seventh Olympic Ode:
The animated figures stand
Adorning every public street
And seem to breathe in stone, or
move their marble feet.
However, the information gleaned from recent scans of the fragments indicates that it may have come from the colonies of Corinth in Sicily and implies a connection with Archimedes. There are also examples from myth: Daedalus used quicksilver to install a voice in his statues. Hephaestus created automata for his workshop: Talos, an artificial man of bronze, and, according to Hesiod, the woman Pandora.
According to Jewish legend, Solomon used his wisdom to design a throne with mechanical animals which hailed him as king when he ascended it; upon sitting down an eagle would place a crown upon his head, and a dove would bring him a Torah scroll. It’s also said that when King Solomon stepped upon the throne, a mechanism was set in motion. As soon as he stepped upon the first step, a golden ox and a golden lion each stretched out one foot to support him and help him rise to the next step. On each side, the animals helped the King up until he was comfortably seated upon the throne.
In ancient China, a curious account of automata is found in the Lie Zi text, written in the 3rd century BCE. Within it there is a description of a much earlier encounter between King Mu of Zhou (1023-957 BCE) and a mechanical engineer known as Yan Shi, an ‘artificer’. The latter proudly presented the king with a life-size, human-shaped figure of his mechanical handiwork (Wade-Giles spelling):
The king stared at the figure in astonishment. It walked with rapid strides, moving its head up and down, so that anyone would have taken it for a live human being. The artificer touched its chin, and it began singing, perfectly in tune. He touched its hand, and it began posturing, keeping perfect time…As the performance was drawing to an end, the robot winked its eye and made advances to the ladies in attendance, whereupon the king became incensed and would have had Yen Shih [Yan Shi] executed on the spot had not the latter, in mortal fear, instantly taken the robot to pieces to let him see what it really was. And, indeed, it turned out to be only a construction of leather, wood, glue and lacquer, variously colored white, black, red and blue. Examining it closely, the king found all the internal organs complete – liver, gall, heart, lungs, spleen, kidneys, stomach and intestines; and over these again, muscles, bones and limbs with their joints, skin, teeth and hair, all of them artificial. The king tried the effect of taking away the heart, and found that the mouth could no longer speak; he took away the liver and the eyes could no longer see; he took away the kidneys and the legs lost their power of locomotion. The king was delighted.
Other notable examples of automata include Archytas’s dove, mentioned by Aulus Gellius. Similar Chinese accounts of flying automata are written of the 5th century BCE Mohist philosopher Mozi and his contemporary Lu Ban, who made artificial wooden birds (ma yuan) that could successfully fly according to the Han Fei Zi and other texts.
Medieval Robots or Automata
In the mid-8th century, the first wind powered automata were built: “statues that turned with the wind over the domes of the four gates and the palace complex of the Round City of Baghdad”. The “public spectacle of wind-powered statues had its private counterpart in the ‘Abbasid palaces where automata of various types were predominantly displayed.” Also in the 8th century, the Muslim alchemist, Jabir ibn Hayyan (Geber), included recipes for constructing artificial snakes, scorpions, and humans which would be subject to their creator’s control in his coded Book of Stones. In 827, Caliph Al-Ma’mun had a silver and golden tree in his palace in Baghdad, which had the features of an automatic machine. There were metal birds that sang automatically on the swinging branches of this tree built by Muslim inventors and engineers at the time. The Abbasid Caliph Al-Muqtadir also had a golden tree in his palace in Baghdad in 915, with birds on it flapping their wings and singing. In the 9th century, the Banu Musa brothers invented a programmable automatic flute player and which they described in their Book of Ingenious Devices.
Automaton in the Swiss Museum CIMA
An Automaton writing a letter in Swiss Museum CIMA
Al-Jazari described complex programmable humanoid automata amongst other machines he designed and constructed in the “Book of Knowledge of Ingenious Mechanical Devices” in 1206. His automaton was a boat with four automatic musicians that floated on a lake to entertain guests at royal drinking parties. His mechanism had a programmable drum machine with pegs (cams) that bump into little levers that operate the percussion. The drummer could be made to play different rhythms and different drum patterns if the pegs were moved around.According to Charles B. Fowler, the automata were a “robot band” which performed “more than 50 facial and body actions during each musical selection.” Al-Jazari also constructed a hand washing automaton first employing the flush mechanism now used in modern flush toilets. It features a female automaton standing by a basin filled with water. When the user pulls the lever, the water drains and the female automaton refills the basin.His “peacock fountain” was another more sophisticated hand washing device featuring humanoid automata as servants which offer soap and towels. Mark E. Rosheim describes it as follows: “Pulling a plug on the peacock’s tail releases water out of the beak; as the dirty water from the basin fills the hollow base a float rises and actuates a linkage which makes a servant figure appear from behind a door under the peacock and offer soap. When more water is used, a second float at a higher level trips and causes the appearance of a second servant figure – with a towel!” Al-Jazari thus appears to have been the first inventor to display an interest in creating human-like machines for practical purposes such as manipulating the environment for human comfort.
Villard de Honnecourt, in his 1230s sketchbook, show plans for animal automata and an angel that perpetually turns to face the sun.
The Chinese author Xiao Xun wrote that when the Ming Dynasty founder Hongwu (1368-1398) was destroying the palaces of Khanbaliq belonging to the previous Yuan Dynasty, there were – amongst many other mechanical devices -automatons found that were in the shape of tigers.
A Cuckoo clock with a built in automaton of a Cuckoo that flaps its wings and opens its beak in time to the sounds of the cuckoo call to mark the number of hours on the analogue dial. The Renaissance witnessed a considerable revival of interest in automata. Hero’s treatises were edited and translated into Latin and Italian. Giovanni Fontana created mechanical devils and rocket-propelled animal automata. Numerous clockwork automata were manufactured in the 16th century, principally by the goldsmiths of the Free Imperial Cities of central Europe. These wondrous devices found a home in the cabinet of curiosities or Wunderkammern of the princely courts of Europe. Hydraulic and pneumatic automata, similar to those described by Hero, were created for garden grottoes.
Leonardo da Vinci sketched a more complex automaton around the year 1495. The design of Leonardo’s robot was not rediscovered until the 1950s. The robot could, if built successfully, move its arms, twist its head, and sit up.
The Smithsonian Institution has in its collection a clockwork monk, about 15 inch (380mm) high, possibly dating as early as 1560. The monk is driven by a key-wound spring and walks the path of a square, striking his chest with his right arm, while raising and lowering a small wooden cross and rosary in his left hand, turning and nodding his head, rolling his eyes, and mouthing silent obsequies. From time to time, he brings the cross to his lips and kisses it. It is believed that the monk was manufactured by Juanelo Turriano, mechanician to the Holy Roman Emperor Charles V.
A new attitude towards automata is to be found in Descartes when he suggested that the bodies of animals are nothing more than complex machines – the bones, muscles and organs could be replaced with cogs, pistons and cams. Thus mechanism became the standard to which Nature and the organism was compared. France in the 17th century was the birthplace of those ingenious mechanical toys that were to become prototypes for the engines of the Industrial Revolution. Thus, in 1649, when Louis XIV was still a child, an artisan named Camus designed for him a miniature coach, and horses complete with footmen, page and a lady within the coach; all these figures exhibited a perfect movement. According to P. Labat, General de Gennes constructed, in 1688, in addition to machines for gunnery and navigation, a peacock that walked and ate. Athanasiu Kircher produced many automatons to create Jesuit shows, including a statue which spoke and listened via a speaking tube.
The Digesting Duck by Jacques de Vaucanson, hailed in 1739 as the first automaton capable of digestion
The world’s first successfully-built biomechanical automaton is considered to be The Flute Player, invented by the French engineer Jacques de Vaucanson in 1737. He also constructed the Digesting Duck, a mechanical duck that gave the false illusion of eating and defecating, seeming to endorse Cartesian ideas that animals are no more than machines of flesh. In 1769, a chess-playing machine called the Turk, created by Wolfgang von Kempelen, made the rounds of the courts of Europe purporting to be an automaton. The Turk was operated from inside by a hidden human director, and was not a true automaton.
Other 18th century automaton makers include the prolific Frenchman Pierre Jaquet-Droz (see Jaquet-Droz automata) and his contemporary Henri Maillardet. Maillardet, a Swiss mechanic, created an automaton capable of drawing four pictures and writing three poems. Maillardet’s Automaton is now part of the collections at the Franklin Institute Science Museum in Philadelphia. Belgian-born John Joseph Merlin created the mechanism of the Silver Swan automaton, now at Bowes Museum.Tipu’s Tiger is a late-18th century example of automata, made for Tipu Sultan, featuring a European soldier being mauled by a tiger.
According to philosopher Michel Foucault, Frederick the Great, king of Prussia from 1740 to 1786, was “obsessed” with automata.According to Manuel de Landa, “he put together his armies as a well-oiled clockwork mechanism whose components were robot-like warriors”. Japan adopted automata during the Edo period (1603-1867); they were known as karakuri ningyōo. Automata, particularly watches and clocks, were popular in China during the 18th and 19th centuries, and items were produced for the Chinese market. Strong interest by Chinese collectors in the 21st century brought many interesting items to market where they have had dramatic realizations.
Modern robots or automata
The famous magician Jean Eugene Robert-Houdin (1805-1871) was known for creating automata for his stage shows. The period 1860 to 1910 is known as “The Golden Age of Automata”. During this period many small family based companies of Automata makers thrived in Paris. From their workshops they exported thousands of clockwork automata and mechanical singing birds around the world. It is these French automata that are collected today, although now rare and expensive they attract collectors worldwide. The main French makers were Vichy, Roullet & Decamps, Lambert, Phalibois, Renou and Bontems.
Contemporary automata continue this tradition with an emphasis on art, rather than technological sophistication. Contemporary automata are represented by the works of Cabaret Mechanical Theatre in the United Kingdom, Dug North and Chomick+Meder,Thomas Kuntz,Arthur Ganson, Joe Jones in the United States, and Le Defenseur du Temps by French artist Jacques Monestier. Some mechanized toys developed during the 18th and 19th centuries were automata made with paper. Despite the relative simplicity of the material, paper automata require a high degree of technical ingenuity.
The potential educational value of mechanical toys in teaching transversal skills has been recognized by the European Union education project Clockwork objects, enhanced learning: Automata Toys Construction (CLOHE).
Fixing the “mechanical man” automaton, created by the character of George Melies is the life’s mission for the central character Hugo in the 2011 film “Hugo.”
In Theater and Dance
Last August 2012, here in Manhattan, your ON TARGET editors, attended a program of the dance company, PILOBOLUS. One of the presentations was a choreography collaboration between PILOBOLUS and MIT Media Labs of a human doing a dance number with three robots. We loved it. Music by Shubert
Patient-Derived Stem Cells Could Improve Drug Research for Parkinson’s Disease
Parkinson’s disease (PD) affects a number of brain regions, including a motor control area of the brain called the substantia nigra. There, it destroys neurons that produce the chemical dopamine. Loss of these neurons leads to involuntary shaking, slowed movements, muscle stiffness and other symptoms. Medications can help manage the symptoms, but there is no treatment to slow or stop the disease. Most cases of PD are sporadic, meaning that the cause is unknown. However, genetics plays a strong role. There are 17 regions of the genome with common variations that affect the risk of developing PD. Researchers have also identified nine genes that, when mutated, can cause the disease.
According to an article published online in Science Translational Medicine (4 July 2012), steps have been taken toward personalized medicine for Parkinson’s disease, by investigating signs of the disease in patient-derived cells and testing how the cells respond to drug treatments. The study collected skin cells from patients with genetically inherited forms of PD and reprogrammed those cells into neurons. Results showed that neurons derived from individuals with distinct types of PD showed common signs of distress and vulnerability — in particular, abnormalities in the cellular energy factories known as mitochondria. At the same time, the cells’ responses to different treatments depended on the type of PD each patient had.
A consortium of researchers conducted the study with primary funding from National Institute of Neurological Disorders and Stroke (NINDS). The consortium’s first goal was to transform the patients’ skin cells into induced pluripotent stem (iPS) cells, which are adult cells that have been reprogrammed to behave like embryonic stem cells. The study then used a combination of growth conditions and growth-stimulating molecules to coax these iPS cells into becoming neurons, including the type that die in PD.
iPS cells were derived from five people with genetic forms of PD. By focusing on genetic cases, rather than sporadic cases, it was hoped that there would be a better chance of seeing patterns in the disease process and in treatment responses. Three of the individuals had mutations in a gene called LRRK2, and two others were siblings who had mutations in the gene PINK1. The study also derived iPS cells from two of the siblings’ family members who did not have PD or any known mutations linked to it.
Because prior studies have suggested that PD involves a breakdown of mitochondrial function, the authors looked for signs of impaired mitochondria in patient-derived neurons. Mitochondria turn oxygen and glucose into cellular energy. Results showed that oxygen consumption rates were lower in patient cells with LRRK2 mutations, and higher in cells with the PINK1 mutation. In PINK1 mutant cells, it was also found increased vulnerability to oxidative stress, a damaging process that in theory can be counteracted with antioxidants.
Next, the authors tested if neurons derived from patients and healthy volunteers were vulnerable to a variety of toxins, including some that target mitochondria. Compared to neurons from healthy individuals, patient-derived neurons were more likely to become damaged or die after exposure to mitochondrial toxins. Patient-derived neurons also suffered more damage from the toxins than did patient-derived skin cells. Next, the authors attempted to rescue the toxin-exposed cells with various drug treatments that have shown promise in animal models of PD, including the antioxidant coenzyme Q10 and the immunosuppressant rapamycin. All patient-derived neurons — whether they carried LRRK2 or PINK1 mutations — had beneficial responses to coenzyme Q10. However, the patient-derived neurons differed in their response to rapamycin; the drug helped prevent damage to neurons with LRRK2 mutations, but it did not protect the neurons with PINK1 mutations.
These results hint that iPS cell technology could be used to help define subgroups of patients for clinical trials. To date, interventional trials for PD have not focused on specific groups of patients or forms of the disease, because there have been few clues to point investigators toward individualized treatments. Although the current study focused on genetic forms of PD, iPS cell technology could be used to define disease mechanisms and the most promising treatments for sporadic PD as well.
Skin cell and iPS cell lines developed by the consortia are available to both academic and industry researchers through the NINDS human cell line repository at the Coriell Institute. To date the NINDS repository has distributed more than 200 cell lines worldwide.
Association Between Vaccination for Herpes Zoster and Risk of Herpes Zoster Infection Among Older Patients With Selected Immune-Mediated Diseases
Based on limited data, the live attenuated herpes zoster (HZ) vaccine is contraindicated in patients taking anti-tumor necrosis factor (anti-TNF) therapies or other biologics commonly used to treat immune-mediated diseases. The safety and effectiveness of the vaccine are unclear for these patients. As a result, a study published in the Journal of the American Medical Association (2012;308:43-49), was performed to examine the association between HZ vaccination and HZ incidence within and beyond 42 days after vaccination in patients with selected immune-mediated diseases and in relation to biologics and other therapies used to treat these conditions.
The investigation was a retrospective cohort study of 463,541 Medicare beneficiaries 60 years and older with rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, or inflammatory bowel disease using Medicare claims data from January 1, 2006, through December 31, 2009. The main outcome measure was HZ incidence rate within 42 days after vaccination (a safety concern) and beyond 42 days.
A total of 4.0% of patients received the HZ vaccine with a median duration of follow-up of 2.0 years (interquartile range, 0.8-3.0). The overall crude HZ incidence rate was 7.8 cases per 1,000 person-years within 42 days after vaccination. The rate among the unvaccinated was 11.6 cases per 1,000 person-years. Among 633 patients exposed to biologics at the time of vaccination or within the subsequent 42 days, no case of HZ or varicella occurred. After multivariable adjustment, HZ vaccination was associated with a hazard ratio of 0.61 for HZ risk after 42 days.
According to the authors, receipt of HZ vaccine was not associated with a short-term increase in HZ incidence among Medicare beneficiaries with selected immune-mediated diseases, including those exposed to biologics and that the vaccine was associated with a lower HZ incidence over a median of 2 years of follow-up.
Dementia Incidence and Mortality in Middle-Income Countries, and Associations with Indicators of Cognitive Reserve
Results of the few cohort studies from countries with low incomes or middle incomes have suggested a lower incidence of dementia than in high-income countries. As a result, a study published online in The Lancet (23 May 2012), was performed to assess 1) the incidence of dementia according to criteria from the 10/66 Dementia Research Group and Diagnostic and Statistical Manual of Mental Disorders (DSM) IV, 2) the effect of dementia at baseline on mortality, and 3) the independent effects of age, gender, socioeconomic position, and indicators of cognitive reserve.
The investigation was a population-based cohort study of all people aged 65 years and older living in urban sites in Cuba, the Dominican Republic, and Venezuela, and rural and urban sites in Peru, Mexico, and China, with ascertainment of incident 10/66 and DSM-IV dementia 3-5 years after cohort inception. The study used questionnaires to obtain information about age in years, gender, educational level, literacy, occupational attainment, and number of household assets. Information was obtained about mortality from all sites. For participants who had died, a friend or relative was interviewed to ascertain the likelihood that they had dementia before death.
A total of 12,887 participants were interviewed at baseline, of whom11,718 were free of dementia. Of the 11,718, participants, 8,137 (69%) were reinterviewed, contributing 34,718 person-years of follow-up. Results showed that incidence for 10/66 dementia varied between 18.2 and 30.4 per 1,000 person-years, and were 1.4-2.7 times higher than were those for DSM-IV dementia (9.9-15.7 per 1,000 person-years). Mortality hazards were 1.56-5.69 times higher in individuals with dementia at baseline than in those who were dementia-free.
Informant reports suggested a high incidence of dementia before death and that overall incidence might be 4-19% higher if these data were included. 1Older age was independently associated with 10/66 dementia incidence in all sites. After meta-analysis, the incidence of 10/66 dementia tended to be lower in men than in women, and education tended to be inversely associated with the incidence of 10/66 dementia. Occupational attainment was not associated with 10/66 dementia incidence,
According to the authors, the results provide supportive evidence for the cognitive reserve hypothesis, showing that in middle-income countries as in high-income countries, education, literacy, verbal fluency, and motor sequencing confer substantial protection against the onset of dementia.
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FDA Approves Genetic Test to Help Some Colon Cancer Patients Physicians Considering Erbitux Therapy
Colorectal cancer (CRC) is the third leading cause of cancer death in the United States. According to the American Cancer Society, there were more than 141,000 new CRC cases in 2011, and nearly 50,000 deaths resulted from CRC.
The FDA has approved the first genetic test that can help some CRC patients and their doctors determine if the drug Erbitux (cetuximab) would be an effective treatment based on the absence of a gene mutation. The therascreen KRAS RGQ PCR Kit can provide information about the KRAS gene mutation in patients whose CRC has spread to other parts of their body (metastasized). Studies have found that Eribitux is not effective in those who have the mutation.
Erbitux targets the epidermal growth factor receptor (EGFR) on the surface of CRC cells. When certain chemicals in the body bind to EGFR, the receptor starts a complex chain of biochemical reactions inside the cell that signals the cancer cell to reproduce. Erbitux blocks EGFR, interrupting a signal to reproduce which can stop the growth of CRC cells. However, when CRC cells have a mutation in the KRAS gene, they continue to reproduce even when Erbitux blocks EGFR.
The FDA first approved Erbitux in 2004 to treat EGFR-expressing late-stage colorectal cancer after patients stopped responding to chemotherapy. In 2009, the FDA approved updated recommendations for Erbitux, based on studies that found the drug is not effective in patients whose tumors have a mutated KRAS gene.
To support the approval of the test, tumor samples from patients in clinical trials used to support the approval of Erbitux were evaluated. The benefits of Erbitux were limited to patients whose tumors did not have one of the seven KRAS mutations detected by the test. Among those whose tumors did not have a KRAS mutation, median survival was 8.6 months for those receiving Erbitux compared with 5 months for those who did not. Among patients whose tumors had a KRAS mutation, median survival was similar between those who received Erbitux compared with those who did not (4.8 months and 4.6 months, respectively).
The FDA simultaneously approved a new indication for Erbitux for use in combination with FOLFIRI, chemotherapy drugs consisting of irinotecan, 5-fluorouracil, and leucovorin, as a first-line treatment in patients with metastatic CRC who have EGFR-expressing, and KRAS wild-type (no mutations) tumors. Among patients with tumors that did not have one of the seven KRAS mutations, median survival was 23.5 months for those who received Erbitux plus FOLFIRI compared with 19.5 months for those who received FOLFIRI. Among patients whose tumors had a KRAS mutation, median survival was similar between those who received Erbitux compared with those who did not.
The therascreen KRAS RGQ PCR Kit was developed by QIAGEN Manchester Ltd., of Manchester, England.
Erbitux is co-marketed by New York City-based Bristol-Myers Squibb and Eli Lilly and Company of Indianapolis.