We Were All Chefs at the eClinical Forum Meeting
This past week, we had the opportunity to attend the Fall meeting of the eClinical Forum. At our meetings and during the year, we are able to share with our friends, colleagues and yes, our competitors, novel technology approaches to solve complex problems in the clinical trial space. This week we also had the opportunity to cook our dinner under supervision of a master chef. A great time was had by all.
And yes, OUR TEAM, CHICKEN TUSCANESE, won the chef’s 1st prize. Congratulations to all, for meals well done.
Our Exalted Team. Working Together ©Target Health Inc. 2016
Chicken Tuscanese. ©Target Health Inc. 2016
For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 165). 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.
Joyce Hays, Founder and Editor in Chief of On Target
Jules Mitchel, Editor
Halloween: Appealing to Your Dark Side: True Strange Deaths
Credit: Toby Ord – Own work, Wikipedia Commons
1919: The Great Molasses Flood, also known as the Boston Molasses Disaster or the Great Boston Molasses Flood, occurred in the North End neighborhood of Boston, Massachusetts when a large molasses storage tank burst, and a wave of molasses rushed through the streets at an estimated 35 mph (56 km/h), killing 21 people and injuring an additional 150. The event has entered local folklore, and for decades afterward residents claimed that on hot summer days the area still smelled of molasses.
1923: George Herbert, 5th Earl of Carnarvon, who financed Howard Carter’s search for Tutankhamun, died at age 56 from a mosquito bite on his face, which he later cut while shaving. The bite became seriously infected with erysipelas, leading to blood poisoning and eventually pneumonia. Some attributed his death to the so-called curse of the pharaohs.
1927: Isadora Duncan, world famous dancer, died of a broken neck when her long scarf caught on the wheel of a car in which she was a passenger.
1974: Basil Brown, a 48-year-old health food advocate from Croydon, England, drank himself to death by consuming 10 gallons (38 liters) of carrot juice in ten days, causing him to overdose on vitamin A and suffer severe liver damage.1978: Kurt Godel, the Austrian/American logician and mathematician, died of starvation when his wife was hospitalized. Godel suffered from extreme paranoia and refused to eat food prepared by anyone else.
1982: David Grundman was killed near Lake Pleasant, Arizona, U.S., while shooting at cacti with his shotgun. After he fired several shots at a 26 ft (8 m) tall Saguaro Cactus from extremely close range, a 4 ft. (1.2 m) limb of the cactus detached and fell on him, crushing him.
1993: Garry Hoy, a 38-year-old lawyer in Toronto, Canada, fell to his death on 9 July 1993 after he threw himself against a window on the 24th floor of the Toronto-Dominion Centre in an attempt to prove to a group of visitors that the glass was “unbreakable”, a demonstration he had done many times before. The glass did not break, but popped out of the window frame, and Hoy fell to his death.
1994: Jeremy Brenno, 16, of Gloversville, New York, was killed on a golf course when he struck a bench with a golf club, and the shaft broke, bounced back at him, and pierced his heart.
1997: Karen Wetterhahn, a professor of chemistry at Dartmouth College, died of dimethyl mercury poisoning ten months after a few drops of the substance landed on her protective gloves. Although Wetterhahn had been following the required procedures for handling the chemical, it still permeated her gloves and skin within seconds. As a result of her death, regulations were altered.
2006: Steve Irwin, the international celebrity known as the “Crocodile Hunter”, died from being pierced hundreds of times in a few seconds by the barb of an 8-foot (2.4 m) stingray in chest-deep water, just as he and his cameraman were filming the final shot of the stingray swimming away from them
2010: Mike Edwards, 62, a founding member and cellist for the band Electric Light Orchestra, died when a large round bale of hay rolled down a hill and collided with the van he was driving.
2010: Jimi Heselden was a British entrepreneur, who in 2010 bought Segway Inc., maker of the Segway personal transport system. Heselden died in 2010 from injuries apparently sustained falling from a cliff while riding his own product.
2011: Jose Luis Ochoa, 35, died after being stabbed in the leg at an illegal cockfight in Tulare County, California, U.S., by one of the birds that was holding a knife.
2012: Edward Archbold, 32, of West Palm Beach, Florida, U.S., died after winning a cockroach-eating contest. The cause of death was determined to be accidental choking due to “arthropod body parts.”
2013: Takuya Nagaya, 23, from Japan, started to slither on the floor and claim he had become a snake. His mother took this to mean that he had been possessed by a snake, and called for her husband, 53-year-old Katsumi Nagaya. Katsumi spent the next two days head-butting and biting his son “to drive [out] the snake that had possessed him” but instead causing his death.
2013 : Roger Mirro, 56, from the Chicago suburb of Palatine, Illinois, died when he was crushed by a dumpster at the condominium complex where he lived. Mirro was looking for his cellular phone, which he thought he had dropped into a bag of garbage already discarded in the trash compactor, but the dumpster was activated and Mirro died.
2013: An unnamed Belarusian fisherman, 60, was killed by a beaver while attempting to grab the animal to have his picture taken with it. The beaver bit the man, severing a large artery in his leg.
2013: 45-year-old Joao Maria de Souza was crushed by a cow falling through the roof of his home in Caratinga, Brazil (the cow having climbed onto the roof from an adjacent hillside). His wife (who was lying in bed next to him) and the cow were both unharmed. The death was labeled as “bizarre”.
2013: Kendrick Johnson, 17, American student at Lowndes High School, Georgia, was discovered trapped upside down in a rolled-up gym mat in his high school gymnasium. Police had originally ruled that the cause of Johnson’s death was accidental positional asphyxiation after he climbed in to retrieve a shoe and became trapped. The case has since been reopened and investigated as a possible homicide.
2013: Miguel Martinez, 14, from Lubbock, Texas, was impaled through the chest by the horn of a bull statue. He had been playing hide and seek at night in front of the National Ranching Heritage Center.
2014: Peng Fan, a chef in Foshan, Southern China, was bitten by a cobra’s severed head, which he had cut off 20 minutes earlier. Fan had set the head aside while using the body to prepare a soup. According to investigating police, the case was “highly unusual”. The chef might have had a severe reaction to the bite.
2015: Chelsea Ake-Salvacion, 24, from Henderson, Nevada, U.S., working as a salon employee died when she used a cryotherapy machine alone without assistance. The report states that she did not have the level setting at the proper height, did not get enough oxygen, and suffocated and froze herself to death. The coroner who examined Ake-Salvacion’s body described her death as a “freak accident.”
2015: Robin Wahlgren, 28, a Swedish student at the University of New South Wales and his Swedish friend rode a shopping cart, down a steep road in Randwick, Sydney with a speed limit of 60 km/h (37 mph), reaching speeds of up to 80 km/h (50 mph) before hitting an oncoming car and getting flung out of the trolley. He died at the scene while his friend was seriously injured. It was labelled as a “freak accident”.
2015: James Shay, 58, from Browns Mills, New Jersey was found partially lodged in the donation bin outside the Country Farms Convenience Store on Pemberton Browns Mills Road. Police said their investigation revealed that he was trying to get items out of the bin when he lost his footing and got trapped in the opening. The Burlington County Medical Examiner ruled the death accidental and determined that the cause of death was compression of the neck.
2015: Ravi Subramanian, an Air India technician, died in an accident during aircraft maintenance at Mumbai airport. He was sucked into one of the aircraft’s jet engines and killed instantly.
2016: V. Kamaraj, a 40-year old Indian bus driver, died from his severe wounds after he and three others were injured by what investigators described as a meteorite which struck the grounds of Bharathidasan Engineering College, in Vellore, Tamil Nadu. Evidence collected from the 2-foot (61 cm) wide crater contained samples of carbonaceous chondrite.
2016: Caitlin Clavette, 35, a Boston-area school teacher driving near the Thomas P. O’Neill Jr. Tunnel, was struck and killed by a dislodged manhole cover, which crashed through the windshield of her car. Massachusetts Governor Charlie Baker called the incident “bizarre.”
2016: Irma Bule, 29, an Indonesian Dangdut singer known for performing with live snakes, died in the middle of a concert after being bitten by a king cobra and refusing treatment.
2016: Anton Yelchin, 27, a Los Angeles actor known for portraying Pavel Chekov in the Star Trek reboot series, and for several other prominent roles, was found pinned between his car and a brick wall. His driveway is on an incline and his car was found still running and in neutral.
2016: Robert Mwaijega, 47, a fisherman in Southern town of Kyela, Mbeya Region in Tanzania, died after one of the live fish that he had caught flip-flopped and jumped into his mouth, squeezing itself down his throat, into his chest and killing him.
2016: A seven-year-old girl died after being struck by a stone thrown by an elephant from its enclosure at Rabat Zoo in Morocco.
A traditional Irish turnip Jack-o’-lantern from the early 20th century. Photographed at the Museum of Country Life, Ireland by Rannphairti Anaithnid of English Wikipedia
Speaking of Halloween: One of History’s First Serial Killers
Poster of Fritz Lang’s 1931 film M; Credit: Wikipedia Commons
A Real Case of Macabre Mentality: Fritz Haarmann (1879-1925)
Friedrich Heinrich Karl Haarmann; Alias: Fritz The Butcher of Hanover;
The Vampire of Hanover; The Wolf Man; The Werewolf
Often, after I had killed, I pleaded to be put away in a military asylum, but not a madhouse. If [Hans] Grans had really loved me he would have been able to save me. Believe me, I’m not ill ? it’s only that I occasionally have funny turns. I want to be beheaded. It’ll only take a moment, then I’ll be at peace.
One of history’s first serial killers, Friedrich Heinrich Karl Haarmann, better known by his nickname of Fritz Haarmann and also referred to as The Butcher of Hanover or The Vampire of Hanover, was a German serial killer responsible for at least 24 murders of young males. Born in Hanover on October 25, 1879, during the German Empire, Fritz was the sixth child of a poor couple, Ollie and Johanna. He was motivated by his sickly mother to play with his sisters’ dolls instead of boys’ activities. As a result, Fritz seemed to have a bit of a feminine personality; he also had sadistic tendencies in which he would tie up his sisters and also tap windows during the nighttime to cause rumors of supernatural creatures that roam about in the middle of the night. He also harbored a dislike for his father, whom he would threaten to throw in jail as Ollie supposedly murdered a train driver. Performing terribly in school, Fritz was sent to attend a military academy at Neu Breisach. Though he did well, Fritz was eventually discharged for medical reasons after having a series of seizures. Returning to Hanover, he found employment at a local cigar factory. Sometime in 1898, he was arrested for molesting several children, but was deemed psychologically unfit to stand trial and was sentenced to a mental institution. Six months into his stay, Fritz escaped and sought shelter in Switzerland before returning to Germany at the age of 20. Around 1900, he was able to seduce and marry a woman named Erna Loewert, later impregnating her with their child. Fritz then abandoned Erna in favor of a life in the military. While becoming a soldier, Fritz, much like the serial killer William Burke, led a successful life under the occupation. However, on October of 1901, all of that abruptly ended when he collapsed during an exercise and was diagnosed as having an unspecified mental deficiency. As a result, he was discharged and sent back to live with his family. His father Ollie made at least one attempt at putting Fritz in an asylum, but the local doctors merely deemed him as morally inferior. Fritz attempted to open up a small business of his own, but it went bankrupt immediately and was closed down. Sometime after this, he started a series of petty burglaries and con jobs to easily gain money and spent about one-third of the following two decades being incarcerated for such crimes. Because of his frequent arrests, he became well-known with the Hanover police, even becoming one of their informers after his latest release in 1918, just to redirect police attention from himself. Simultaneously, World War 1 began and he was hit hard by the inflicted national poverty. Fritz also started a number of misdemeanor sexual offenses that went unnoticed by authorities mostly because his partners were too ashamed to file reports.
I never intended to hurt those youngsters, but I knew that if I got going something would happen and that made me cry. I would throw myself on top of those boys and bite through the Adam’s apple, throttling them at the same time.
Some of the many bones of Haarmann’s victims that were recovered from the Leine River. Credit: Wikipedia Commons
Finally, Fritz suddenly snapped and murdered a 17-year-old youth named Friedel Rothe on September 25, 1918. Following from eyewitness accounts provided by Rothe’s friends and the pressure from Rothe’s family, authorities raided Fritz’s residence and found him with a teenage boy in bed, having been seduced by him for about nine months. Fritz was arrested for sexual assault, but the police, for some unknown reason, never searched his house and, as a result, he was cleared of any suspicion of Rothe’s murder. Eventually released, Fritz later met Hans Grans at the Hanover central station, and the two became fast friends and, eventually, lovers. In early 1922, they moved to an apartment, number 27 Cellerstrasse, which was located in the haunted area of Hanover. Fritz then started murdering young men again, this time by luring them in by pretending to be a police officer. Hans became his accomplice after unexpectedly returning home to witness Fritz murder his second victim, 17-year-old Fritz Franke. In the following nine months, twelve men were murdered this way, with their dismembered remains being dumped in the Leine River and their valuables used to provide Fritz and Hans with money. The killings went unnoticed, until in May 1924, when over 500 human bones belonging to Fritz’s victims started washing up downstream in the Leine River. Sheer terror gripped Hanover and citizens dubbed the killer as The Butcher of Hanover.
Haarmann’s Apartment. Credit: Wikipedia Commons
Fritz’s last murdered victim was 17-year-old Erich de Vries; at this time, police had begun an enormous manhunt for the serial killer. Suspicion quickly fell on him due to knowledge of his 1898 molestation crimes and the disappearance of Friedel Rothe years ago. Police silently observed Fritz, and on June 22, they apprehended him after he attempted to lure in a would-be victim, Karl Fromm, from Hanover’s central station; Fromm had spent several days in Fritz’s apartment before, during which he was assaulted by him. Fritz would later confess to his intention of killing Fromm, marking the first time that he was guided by moral principles, although it ironically proved to be his downfall. Police searched Fritz’s home and found the walls sporting bloodstains, with Fritz alleging it to be an unhandy result of the illegal meat-trade business he ran there. However, officers found clothing and belongings of his victims and arrested him on suspicion of the Hanover murders. Fritz quickly confessed to being the perpetrator and claimed that the amount of lives he took ranged from somewhere between 50 and 70, though police made it official that the true body count was measured to 24-27 victims. He then aided officers in finding undiscovered parts of his victims and the dump sites at the Leine River. He proved overall to become extremely cooperative in the investigation, save for instances in which he was confronted by families of his victims or conversing about decapitation, to which he would become withdrawn.
Haarmann (middle) with police detectives.
Credit: By Bundesarchiv, Bild; Wikipedia Commons
Fritz’s trial began on December 4, 1924, and was conducted at the Hannover Assizes. As the term serial killer had not been coined yet, there were no words to describe Fritz other than werewolf or vampire. Hoping to take Hans with him to execution, he resorted to accusing him of some of the murders, which the court actually came to believe. A notable aspect of the case was the shock that came to the public after the discovery that Fritz was a police informant, and therefore, the police never came to suspect him of the murders even though witnesses pointed him out as being with his last victims. Fritz’s trial lasted for two weeks and required 200 witnesses to explain their accounts. He was found guilty of murdering all but three of the victims tied to him and sentenced to death by guillotine. On April 15, 1925, he was beheaded by guillotine, but not before he said as his last words, I repent, but I do not fear death. The remains of his victims were buried together in a grave at Stockener Cemetery months before his execution, with a large, granite, triptych-style memorial inscribed with the victims’ names and ages being erected on April 1928. Fritz’s head was preserved in a jar by scientists, who used it in their studies to examine the structure of his brain. It was being kept at the Gottingen medical school until 2014, when it was cremated.
Haarmann (seated in front of chalkboard sketch of his apartment), during his trial in 1924.
Credit: Bundesarchiv_Bild; Wikipedia Commons
Hans Grans spent his early years as a petty thief before running away from his home, making his living by selling old clothes. He soon met Fritz Haarmann at Hanover’s central station after offering to prostitute himself in exchange for money. The two soon became friends, and then lovers. From March 1920 to December of the same year, Hans traveled through Germany, committing petty robberies before returning to Hanover and reuniting with Fritz on Christmas, later moving into a new apartment, number 27 Cellerstrasse, with him. On February 12, 1923, he returned home unexpectedly to find Fritz murdering his second victim, 17-year-old Fritz Franke. Condoning the act, he soon became Fritz’s accomplice and live-in partner. Hans even chose two of Fritz’s victims for him, one of them 17-year-old Adolf Hannappel, who was murdered on November 11, 1923. Hans was arrested on July 8, 1924, and initially found guilty to enticement to the murder of Hannappel. Fritz and eyewitnesses verified that Hans picked Hannappel out for the former and as a result, Hans was sentenced to death. However, he was cleared and the sentence was reduced after a letter written by Fritz that declared Hans’s innocence was discovered. Instead, Hans served twelve years in prison and was eventually released. He continued to live in Hanover until his death in 1975, from natural causes.
I’d make two cuts in the abdomen and put the intestines in a bucket, then soak up the blood and crush the bones until the shoulders broke. Now I could get the heart, lungs and kidneys and chop them up and put them in my bucket. I’d take the flesh off the bones and put it in my waxcloth bag. It would take me five or six trips to take everything and throw it down the toilet or into the river. I always hated doing this, but I couldn’t help it – my passion was so much stronger than the horror of the cutting and chopping.
In the wake of his killings, Fritz has inspired three films to date. The first, a 1931 German drama-thriller named M, is well-known and has also been inspired by two other serial killers, Peter Kurten and Carl Grossmann. The second, The Tenderness of the Wolves (Die Zartlichkeit der Wolfe), was released on July 1973 and is directly based upon Fritz’s murders. And finally, the most recent is Der Totmacher (The Deathmaker), which was released on 1995 and, like the previous film, is based on Fritz’s murders. Fritz has also been mentioned in several novels, a subject of focus in a song called Fritz Haarmann [sic] der Metzger (Fritz Haarmann the butcher) by the band Macabre, and has even been used as a company logo for Beton Kopf Media, a record label.
Though Fritz wasn’t mentioned or referenced in Lucky, Floyd Feylinn Ferell’s habit of dismembering his victims post-mortem and selling them as meat to unsuspecting customers appears to be an allusion to a rumor that Fritz did the exact same thing. Fritz was mentioned in Magnum Opus, when the BAU compared his sloppy method of drawing blood from his victims (by biting) with that of the prominent unsub, who was more organized, using a tube instead. A scene where Wallace Hines feeds the pieces of a victim’s head to unsuspecting restaurant customers in The Inspiration is also a possible allusion to the aforementioned rumor.
The New York Times clebrated Halloween with an article entitled: Victorian Cocktails and Medical Curiosities in (Where Else?) Brooklyn
Gene Therapy for Niemann-Pick Disease, Type C1 (NPC1)
Niemann-Pick disease is a rare and fatal disorder of the central nervous system (the brain and spinal cord) that has no cure. The disease occurs when a faulty housekeeping gene fails to remove cell waste, like lipids and cholesterol. The accumulation of waste in the spleen, liver and brain causes progressive deterioration in intellectual and motor functions. It also shortens patient’s lives, as people with Niemann-Pick disease typically die in their teens. There are several types of Niemann-Pick disease; this study focused on mice that had been bred with a faulty NPC1 gene to model Niemann-Pick disease, type C1.
According to an article published online in the journal Human Molecular Genetics (26 October 2016), for the first time, it has been demonstrated in mice that gene therapy may be the best method for correcting the single faulty gene that causes Niemann-Pick disease, type C1 (NPC1). The gene therapy involved inserting a functional copy of the NPC1 gene into mice with the disease; the treated animals were then found to have less severe NPC1 symptoms. The study was led by researchers at NIH’s National Human Genome Research Institute (NHGRI) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
The researchers’ goal was to correct the faulty NPC1 gene in as many cells and organs as possible, with a strong focus on the brain. To do this, they used a non-disease-causing virus called the adeno-associated virus serotype 9 (AAV9) to transfer functioning NPC1 to the cells. The AAV9 containing a functioning NPC1 gene successfully crossed the blood-brain barrier, reaching cells in the brain and elsewhere. Once inside cells, the normal NPC1 gene was then able to make the functional NPC1 protein to correct the cell defects. With a single injection, mice showed improvements in motor coordination, weight gain and longevity compared to those without this gene therapy. The effect of gene therapy equaled that of a drug called VTS-270, which has been evaluated in preclinical and clinical studies at numerous academic labs. However, to be effective, the VTS-270 compound has to be given three times a week for the life of the mouse and does not provide a true cure. The team is now investigating if a combination of the two therapies will improve results.
According to the authors, their work in NPC1 mice may help lead to human clinical trials and eventually FDA approval for gene therapy as a treatment for NPC1 disease, and that for NPC1 patients, gene therapy could halt progression of the disease, improve the quality of their lives and, hopefully, increase the patient’s life span. The authors added that their work on gene therapy for NPC1 also has the potential to treat genetic disorders with some similar features, including mucolipidosis IV, Batten disease and Danon disease.
Skin Patch to Treat Peanut Allergy Shows Benefit in Children
According to an article published online in the Journal of Allergy and Clinical Immunology (26 October 2016), a wearable patch that delivers small amounts of peanut protein through the skin showed promise for treating children and young adults with peanut allergy, with greater benefits for younger children. According to the article, the treatment, called epicutaneous immunotherapy or EPIT, was found safe and well-tolerated, and nearly all participants used the skin patch daily as directed.
According to the NIH, to avoid potentially life-threatening allergic reactions, people with peanut allergy must be vigilant about the foods they eat and the environments they enter, which can be very stressful. Therefore, one goal of experimental approaches such as epicutaneous immunotherapy is to reduce this burden by training the immune system to tolerate enough peanut to protect against accidental ingestion or exposure.
The study, which was performed at 5 clinical research sites, randomly assigned 74 peanut-allergic volunteers aged 4 to 25 years to treatment with either a high-dose (250 micrograms peanut protein), low-dose (100 micrograms peanut protein), or placebo patch. The investigators assessed peanut allergy at the beginning of the study with a supervised, oral food challenge with peanut-containing food. The patches were developed and provided by the biopharmaceutical company DBV Technologies under the trade name Viaskin. Each day, study participants applied a new patch to their arm or between their shoulder blades.
After one year, the team assessed each participant’s ability to consume at least 10 times more peanut protein than he or she was able to consume before starting EPIT. The low-dose and high-dose regimens offered similar benefits, with 46% of the low-dose group and 48%of the high-dose group achieving treatment success, compared with 12% of the placebo group. In addition, the peanut patches induced immune responses similar to those seen with other investigational forms of immunotherapy for food allergy. Investigators observed greater treatment effects among children aged 4 to 11 years, with significantly less effect in participants aged 12 years and older.
Nearly all of the study participants followed the EPIT regimen as directed. None reported serious reactions to the patch, although most experienced mild skin reactions, such as itching or rash, at the site of patch application. Additional studies in larger groups of children are needed before the therapy could be approved for wider use. The study continues to assess the long-term safety and effectiveness of peanut EPIT. After the first year, all participants began receiving high-dose daily patches, and they will continue in the study for a total of two and a half years of EPIT.
FDA is Working with Hospitals to Modernize Data Collection About Medical Devices
Extracted from FDA Voice by Jeffrey Shuren, M.D., J.D., Director of FDA’s Center for Devices and Radiological Health
Throughout their work day, hospital staff use a variety of medical devices: imaging machines, EKGs and in vitro tests to make diagnoses; infusion pumps, ventilators and robotics to provide treatment, and an array of implants to replace diseased joints and organs. And, as the nation’s hubs for real-time health care data, hospitals are uniquely positioned to help identify new safety problems with devices as well as changes in the frequency of already known safety problems. The reason is that hospitals use these technologies in the real-world setting of clinical practice, outside of the more controlled setting of a clinical trial. FDA is looking to improve the way we work with hospitals to modernize and streamline data collection about medical devices.
FDA’s evaluation of medical device safety presents unique challenges not seen with drugs and biologics, given: 1) the greater diversity and complexity of medical devices today; 2) the rapid technological advances and iterative nature of medical device product development; 3) the interface between the technology and the user; and, 4) in some cases, a relatively short product life cycle that can be measured in months, not years. Therefore, assuring the safety of medical devices depends on many factors and should a problem arise, it could be due to a variety of causes.
At the time of premarket evaluation, however, it is not feasible to identify all possible risks or to have absolute certainty regarding a technology’s benefit-risk profile. The reaon is that studies required to do so would likely be prohibitively large in order to capture less frequent and more unpredictable effects or consequences. In addition, such larger studies still may not reflect the true benefit-risk profile of the device. Once a device is on the market, for example, doctors may use it beyond the FDA cleared intended use. In addition, subsequent modifications to the device or changes in how the device is used in practice can result in new safety risks or greater frequency of known risks.
FDA has several tools for watching devices once they are on the market, all of which have inherent limitations. For one thing, FDA can require that a manufacturer conduct a post-approval or postmarket surveillance study that focuses on identifying potential longer-term issues noted at the time of clearance or approval or specific safety concerns that may arise after clearance or approval. However, conducting studies on a product after it’s already on the market can be challenging because patients often have little incentive to enroll in a study when the device is already available to them. Likely the most well-known of FDA’s postmarket surveillance tools is medical device reporting, which FDA requires from certain entities, including device manufacturers and device user facilities, such as hospitals.
Federal law requires hospitals and other user facilities to report when they become aware of information reasonably suggesting that a medical device has or may have caused or contributed to a death or serious injury to a patient. These facilities must report these medical device-related deaths to both FDA and the manufacturer, if known; and device-related serious injuries to the manufacturer, or to FDA, if the manufacturer is not known. Such passive surveillance has important limitations because it relies on people to identify that a harm occurred or a risk is present, recognize that the harm or risk is associated with the use of a particular device, and take the time to report it.
Congress mandated this reporting by user facilities in 1990 to complement similar adverse event reporting by manufacturers. But then, in 1997, Congress required that FDA establish a reporting program that could limit user facility reporting to a subset of representative user facilities. As part of our efforts to develop this reporting program, FDA set up a large-scale network of about 300 hospitals, called MedSun (the Medical Product Safety Network), with whom FDA works interactively to better understand and report on device use in the real-world environment. Even with MedSun, all hospitals were required to continue reporting until FDA implements by regulation a program limiting user facility reporting to a subset of facilities. Although FDA has recognized that requiring all hospitals and other user facilities to report may provide limited added value and could entail unnecessary costs that take away from patient care, FDA has not yet established the program limiting reporting to a subset of user facilities. In the past, FDA has also not enforced universal reporting requirements for hospitals and other user facilities. In light of several high-profile device safety issues occurring in hospitals, FDA, in December 2015, initiated inspections at 17 hospitals, chosen because there were reports of events at these facilities related to the spread of uterine cancer from the use of morcellators or the spread of infections associated with contaminated duodenoscopes. While these events appeared to be the kind that would have fallen under our current medical device reporting requirements, FDA did not see corresponding adverse event reports in its adverse event (MAUDE) database. From those inspections, FDA learned three important lessons:
First, some hospitals didn’t submit required reports for deaths or serious injuries related to devices used at their facilities, and in some cases, they did not have adequate procedures in place for reporting device-related death or serious injury events to FDA or to the manufacturers. Based on the number of user facilities in the United States and the number of reports FDA receives, FDA believes that these hospitals are not unique in that there is limited to no reporting to FDA or to the manufacturers at some hospitals. FDA wants to work with all hospitals to address these issues.
Second, hospital staff often were not aware of nor trained to comply with all of FDA’s medical device reporting requirements.
Third, FDA feelsthat there is a better way to work with hospitals to get the real-world information it needs.
Fourth, FDA should work with the hospital community to find that right path, especially in light of developments in the creation and evaluation of electronic health information.
In order to effectively address these issues, FDA will work with the hospital community on what role they should play in assuring the safe use of medical devices. This work will include how they can effectively participate in the National Evaluation System for health Technology (NEST), and whether or not current reporting requirements should remain, be modified, or eliminated in light of more effective modern tools, such as software tools to conduct active surveillance of electronic health information that contain unique device identifiers. In many cases, FDA inspections of these 17 hospitals turned up violations of FDA’s medical device reporting regulation. For some hospitals with significant violations of the regulation, FDA received a response that FDA determined was not adequate to address those violations, and FDA engaged with these facilities to facilitate an effective path to compliance. These hospitals indicated their willingness to work with FDA and address the violations, and at this time, FDA does not believe any additional action with regard to these hospitals is necessary. Some hospitals also expressed willingness to work with FDA on more efficient and effective ways to collect the information FDA needs.
On December 5, FDA will hold a public workshop to solicit input and advice on improving hospital-based surveillance systems, and the broader role of using hospitals to evaluate how well devices work in the clinical setting. FDA is encouraging all hospital stakeholders – from clinicians to IT system managers – to attend and discuss current hospital-based surveillance efforts, the role of hospitals in evidence generation and future opportunities for hospital-based surveillance. FDA would also like input on the incorporation of unique device identifiers (UDIs) into electronic health records to aid in the future development of evidence generation efforts, including the support of better device development, surveillance and health care delivery. FDA is already working directly with the Association of American Medical Colleges and the American Hospital Association to prepare for this workshop and help develop improvements to FDA systems.
FDA has made it very clear that hospitals are our partners in building the infrastructure for NEST. Together all stakeholders can build a state-of-the-art system that not only quickly identifies life-threatening problems caused by medical devices but also expedites patient access to crucial life-saving devices. Armed with such information, health care providers can help patients make more informed medical decisions that improve their health.
The October Julz
When the weather outside is cold, and you start to shiver, come inside and create liquid fire, down your throat; feel it spread to your neck and beyond. This is effect of The October Julz, an original birthday gift to my beloved husband, Jules Mitchel. This is fire, you won’t ever want to put out. ©Joyce Hays, Target Health Inc.
This is NOT a summer cocktail. ©Joyce Hays, Target Health Inc.
Ingredients (for 2 people)
2 jiggers of your best Bourbon
2 jiggers Apricot Brandy
2 jiggers Orange Curacao or Cointreau
1/2-1 jigger Amaretto liqueur
2 Cinnamon sticks (1 per glass)
1 Orange, for the peels
1 Lime, for the peels
Candied orange peels, for garnish
Luxardo cherries, for garnish
All the liquor and liqueur were purchased from Sherry-Lehmann, a reliable and amazing resource, for decades. ©Joyce Hays, Target Health Inc.
Sturdy glasses for this substantial cocktail. Good for some spiked cider, as well as this recipe. ©Joyce Hays, Target Health Inc.
Besides glasses, you need a jigger and a container to pour the ingredients into. You don’t need the strainer, shown, above. ©Joyce Hays, Target Health Inc.
You’ll need a small cutting board, a Y peeler, a paring knife if you prefer. Cut long orange peels and thick lime peels, one each, for each drink you make. ©Joyce Hays, Target Health Inc.
Cut a long slit in each lime peel. Fold the long orange peel, and slip it through the slit in the lime peel. ©Joyce Hays, Target Health Inc.
Into each glass, put the orange/lime peels, a cherry, a cinnamon stick and a candied orange peel (if you can find it), stuck onto the rim of each glass. ©Joyce Hays, Target Health Inc.
Next step is to stir, not shake, all the ingredients, in a cocktail shaker or tall glass cocktail pitcher. Use a long cocktail stirrer, then pour the cocktail into each glass. You can serve this cocktail over ice cubes or straight up, neat. Our recommendation is not to use ice, as it will soon dilute a drink that needs no diluting.
Cinnamon stick adds to the flavor. ©Joyce Hays, Target Health Inc.
Using cinnamon sticks with this cocktail adds an autumn touch. ©Joyce Hays, Target Health Inc.
This is a very smooth bourbon. ©Joyce Hays, Target Health Inc.
A delicious but powerful addition. Use only 1/2 jigger for each drink or its flavor will take over. ©Joyce Hays, Target Health Inc.
Apricot brandy was the first ingredient to come to mind for creating this cocktail from scratch. ©Joyce Hays, Target Health Inc.
A favorite everywhere! ©Joyce Hays, Target Health Inc.
Added just the right touch. ©Joyce Hays, Target Health Inc.
The fruit adds nuance to this warm mellow October Julz cocktail. ©Joyce Hays, Target Health Inc.
I knew I wanted to create a brand new cocktail, that I would name after Jules, as a birthday present; however, together, over a period of about two or three weeks, I put together dozens of combinations of ingredients, trying to get the exact flavor and color that I had in mind. We tried, orange juice, mango puree, champagne, Proseco, Campari, Aperol, seltzer water, Sprite, and many other liquors and liqueurs. It turned out to be a fun filled, drawn out experiment, that ended up with what we think is a new great cocktail, the October Julz
We hope you’ll try it and let us know how you liked it, and if it warmed you.
This was a Halloween birthday weekend to remember! Below are two birthday desserts for two separate birthday dinners.
Boo! ©Joyce Hays, Target Health Inc.
Moist chocolate layer cake with pumpkin ice cream. ©Joyce Hays, Target Health Inc.
From Our Table to Yours !
October 27, 2016
University of Cambridge
Researchers have identified the cause of chronic, and currently untreatable, pain in those with amputations and severe nerve damage, as well as a potential treatment which relies on engineering instead of drugs.
Researchers have identified the cause of chronic, and currently untreatable, pain in those with amputations and severe nerve damage, as well as a potential treatment which relies on engineering instead of drugs.
Researchers have discovered that a ‘reorganisation’ of the wiring of the brain is the underlying cause of phantom limb pain, which occurs in the vast majority of individuals who have had limbs amputated, and a potential method of treating it which uses artificial intelligence techniques.
The researchers, led by a group from Osaka University in Japan in collaboration with the University of Cambridge, used a brain-machine interface to train a group of ten individuals to control a robotic arm with their brains. They found that if a patient tried to control the prosthetic by associating the movement with their missing arm, it increased their pain, but training them to associate the movement of the prosthetic with the unaffected hand decreased their pain.
Their results, reported in the journal Nature Communications, demonstrate that in patients with chronic pain associated with amputation or nerve injury, there are ‘crossed wires’ in the part of the brain associated with sensation and movement, and that by mending that disruption, the pain can be treated. The findings could also be applied to those with other forms of chronic pain, including pain due to arthritis.
Approximately 5,000 amputations are carried out in the UK every year, and those with type 1 or type 2 diabetes are at particular risk of needing an amputation. In most cases, individuals who have had a hand or arm amputated, or who have had severe nerve injuries which result in a loss of sensation in their hand, continue to feel the existence of the affected hand as if it were still there. Between 50 and 80 percent of these patients suffer with chronic pain in the ‘phantom’ hand, known as phantom limb pain.
“Even though the hand is gone, people with phantom limb pain still feel like there’s a hand there — it basically feels painful, like a burning or hypersensitive type of pain, and conventional painkillers are ineffective in treating it,” said study co-author Dr Ben Seymour, a neuroscientist based in Cambridge’s Department of Engineering. “We wanted to see if we could come up with an engineering-based treatment as opposed to a drug-based treatment.”
A popular theory of the cause of phantom limb pain is faulty ‘wiring’ of the sensorimotor cortex, the part of the brain that is responsible for processing sensory inputs and executing movements. In other words, there is a mismatch between a movement and the perception of that movement.
In the study, Seymour and his colleagues, led by Takufumi Yanagisawa from Osaka University, used a brain-machine interface to decode the neural activity of the mental action needed for a patient to move their ‘phantom’ hand, and then converted the decoded phantom hand movement into that of a robotic neuroprosthetic using artificial intelligence techniques.
“We found that the better their affected side of the brain got at using the robotic arm, the worse their pain got,” said Yanagisawa. “The movement part of the brain is working fine, but they are not getting sensory feedback — there’s a discrepancy there.”
The researchers then altered their technique to train the ‘wrong’ side of the brain: for example, a patient who was missing their left arm was trained to move the prosthetic arm by decoding movements associated with their right arm, or vice versa. When they were trained in this counter-intuitive technique, the patients found that their pain significantly decreased. As they learned to control the arm in this way, it takes advantage of the plasticity — the ability of the brain to restructure and learn new things — of the sensorimotor cortex, showing a clear link between plasticity and pain.
Although the results are promising, Seymour warns that the effects are temporary, and require a large, expensive piece of medical equipment to be effective. However, he believes that a treatment based on their technique could be available within five to ten years. “Ideally, we’d like to see something that people could have at home, or that they could incorporate with physio treatments,” he said. “But the results demonstrate that combining AI techniques with new technologies is a promising avenue for treating pain, and an important area for future UK-Japan research collaboration.”
- Takufumi Yanagisawa, Ryohei Fukuma, Ben Seymour, Koichi Hosomi, Haruhiko Kishima, Takeshi Shimizu, Hiroshi Yokoi, Masayuki Hirata, Toshiki Yoshimine, Yukiyasu Kamitani, Youichi Saitoh. Induced sensorimotor brain plasticity controls pain in phantom limb patients. Nature Communications, 2016; 13209 DOI: 10.1038/ncomms13209
Source: University of Cambridge. “Cause of phantom limb pain in amputees, and potential treatment, identified.” ScienceDaily. ScienceDaily, 27 October 2016. <www.sciencedaily.com/releases/2016/10/161027123325.htm>.
October 26, 2016
University of Saskatchewan
A new immunotherapy technique has been developed that nearly eliminates the allergic response to peanut and egg white proteins in food-allergic mice, reducing the anaphylactic response by up to 90 per cent with only one treatment.
“This discovery reverses food allergies in mice, and we have many people with allergies volunteering their own cells for us to use in lab testing to move this research forward,” said professor John Gordon, lead scientist behind the discovery just published in the current issue of the Journal of Allergy and Clinical Immunology.
The findings open the door to test this new allergy treatment in “humanized mice” — mice with non-existent immune systems implanted with cells from a human immune system, for example, from a peanut-allergic person. With Health Canada approval, the first human trial could begin in about one year, Gordon said.
“If we can reliably ‘cure’ food allergies, or related conditions such as asthma or autoimmune diseases such as multiple sclerosis with this new therapy, it would be life-changing for affected individuals.”
Roughly 2.5 million Canadians self-report having at least one food allergy. Anaphylaxis, defined as a severe rapid-onset allergic reaction, can be life-threatening and treatment options are limited.
The discovery involves generating a type of naturally occurring immune cell that sends a signal to reverse the hyper-immune response present in allergic reactions. That signal triggers another “off switch” that turns off reactive cells further along the allergic pathway.
“We predict the treatment could be on the market within the next five to 10 years,” said Gordon, who is also a research leader in the Allergy, Genes and Environment (AllerGen) Network. AllerGen — part of the federally funded Networks of Centres of Excellence program — aims to help Canadians address the challenges of living with asthma, allergies, anaphylaxis and related immune diseases.
Gordon’s team will collaborate with other AllerGen investigators located at the U of S, McGill University, Queen’s University, McMaster University, and University of Alberta to pilot the new technique.
“This discovery portends a major breakthrough towards a therapeutic reversal of food allergen sensitivity,” said Dr. Judah Denburg, scientific director and CEO of AllerGen. “The treatment prevents anaphylactic responses in what were previously fully sensitive mice, opening the door for translating this therapy into the clinic.”
There is compelling evidence this technique could be effective in humans. In 2010, Gordon’s team demonstrated they could reverse an asthmatic response in human cells in a test tube. Using three applications of a similar therapy in a 2012 study, the researchers effectively eliminated asthma in afflicted mice, within only eight weeks.
“Even if we only cure 25 per cent of subjects, we will dramatically improve the health of those individuals, and also reduce healthcare system expenses,” said Gordon, who worked with Wojciech Dawicki, a research associate and the primary author and lead researcher in this study. Master’s student Chunyan Li and lab technicians Xiaobei Zhang and Jennifer Town also worked on the project.
Here’s how the technique works:
•The key component of this research is dendritic cells, which serve as the gate-keepers of the immune system and are present in tissues in contact with the external environment, such as the skin and the inner lining of the nose, lungs, stomach and intestines.
•Gordon’s pioneering treatment involves producing dendritic cells in a test tube and then exposing them to a unique mix of proteins, a vitamin A-related acid naturally occurring in the human gut, and to the allergen, in this case, peanut or ovalbumin (egg white protein). The modified dendritic cells are then reintroduced into the mouse.
•Using this technique, the researchers were able to nearly eliminate the allergic reaction by converting allergen-sensitive immune cells into cells that mimic the response seen in healthy, non-allergic individuals.
The treatment reduced the observed symptoms of anaphylaxis, and lowered other key protein markers in the allergic response by up to 90 per cent.
Food allergy is a growing public health issue in Canada. Currently, there is no known cure. According to the Canadian Institute for Health Information, an estimated 171,000 Canadians visited emergency rooms for allergic reactions from 2013 to 2014, the rate of anaphylaxis visits increased by 95 per cent from 2006 to 2014, and the severity of reactions is increasing.
Gordon said the new technique also shows promise for treating autoimmune disorders such as multiple sclerosis. “It would take very little to adapt the therapy for autoimmune diseases,” he said.
- Wojciech Dawicki, Chunyan Li, Jennifer Town, Xiaobei Zhang, John R. Gordon. Therapeutic reversal of food allergen sensitivity by mature retinoic acid–differentiated dendritic cell induction of LAG3 CD49b−Foxp3− regulatory T cells. Journal of Allergy and Clinical Immunology, 2016; DOI: 10.1016/j.jaci.2016.07.042
Source: University of Saskatchewan. “New immunotherapy technique holds promise for curing food allergies.” ScienceDaily. ScienceDaily, 26 October 2016. <www.sciencedaily.com/releases/2016/10/161026133229.htm>.
October 25, 2016
European Society of Cardiology (ESC)
Long-term exposure to air pollution is linked to a greater incidence of high blood pressure, according to the largest study to investigate the effects of both air pollution and traffic noise by following over 41,000 people in five different countries for five to nine years.
Long-term exposure to air pollution is linked to a greater incidence of high blood pressure, according to the largest study to investigate the effects of both air pollution and traffic noise by following over 41,000 people in five different countries for five to nine years.
The study, which is published October 25 in the European Heart Journal, found that among adults, up to one extra person per 100 people of the same age group living in the most polluted areas of cities would develop high blood pressure (hypertension) compared to those living in the less polluted areas. This risk is similar to the effect of being overweight with a body mass index (BMI) between 25-30 compared to people with normal weight (BMI 18.5-25). High blood pressure is the most important risk factor for premature illness and death.
This study is one of the first to investigate both air pollution and traffic noise simultaneously and it found that traffic noise is associated with an increase in cases of hypertension as well. The way the study was conducted enabled the researchers to estimate the risk that was linked to air pollution and the risk linked to noise separately. The association of air pollution with hypertension remained even when exposure to traffic noise was considered in the analysis. The researchers say this is an important finding because there are differing ways of reducing air pollution and noise.
A total of 41,072 people living in Norway, Sweden, Denmark, Germany and Spain participated in the study, which was part of the “European Study of Cohorts for Air Pollution Effects” (ESCAPE) project that is investigating long-term effects of exposure to air pollution on human health in Europe. Information on blood pressure was gathered when the participants joined the study and during a follow-up examination in later years. None had hypertension when they joined the study, but during the follow-up period 6,207 people (15%) reported that they developed hypertension or started to take blood pressure-lowering medications.
Between 2008 and 2011, the researchers measured air pollution during three separate two-week periods (to allow for seasonal effects). They used filters to capture information on concentrations of polluting particles known as “particulate matter” (PM) of different sizes: PM10 (particles less than or equal to 10 microns  in diameter), PM2.5 (less than or equal to 2.5 microns), PMcoarse (PM10 minus PM2.5) and PM2.5 absorbance (a measurement of soot particles). These measurements were taken at 20 sites in each of the areas being studied, and measurements of nitrogen oxides were measured at 40 different sites in each area. Traffic density was assessed outside the homes of the participants and traffic noise was modelled according to the EU Directive on environmental noise.
The researchers found that for every five micrograms  per cubic metre (5 µg/m3) of PM2.5, the risk of hypertension increased by a fifth (22%) in people living in the most polluted areas compared to those in the least polluted areas. Higher soot concentrations also increased the risk.
For exposure to chronic traffic noise, the researchers found that people living in noisy streets, where there were average night time noise levels of 50 decibels, had a six percent increased risk of developing hypertension compared to those living on quieter streets where average noise levels were 40 decibels during the night.
Professor Barbara Hoffmann, Professor of Environmental Epidemiology at the Centre for Health and Society at Heinrich-Heine-University of Düsseldorf, Germany, who led the analysis, said: “Our findings show that long-term exposure to particulate air pollution is associated with a higher incidence of self-reported hypertension and with intake of anti-hypertensive medication. As virtually everybody is exposed to air pollution for all of their lives, this leads to a high number of hypertension cases, posing a great burden on the individual and on society.
“Exposure to traffic noise shares many of the same sources with air pollution and so has the potential to confound the estimates of the adverse effects of pollution on human health. However, this study controlled for traffic noise exposure and found that the associations of air pollution with hypertension did not vanish. This is important because preventive measures for air pollution and noise differ.
“One very important aspect is that these associations can be seen in people living well below current European air pollution standards. This means, the current legislation does not protect the European population adequately from adverse effects of air pollution. Given the ubiquitous presence of air pollution and the importance of hypertension as the most important risk factor for cardiovascular disease, these results have important public health consequences and call for more stringent air quality regulations.”
The study found there were higher average levels of pollution in the central and southern European study areas — Germany and Spain — than in the Scandinavian areas — Norway, Sweden and Denmark. Exposure to traffic noise and traffic load was highest in the study areas of Sweden and Spain.
The researchers say that it is possible that air pollution and noise affect different, or not completely overlapping, pathways involved in disturbances in the way the body normally functions. Possible biological mechanisms for the adverse effect of air pollution on the functioning of the heart and blood vessels include local and systemic inflammation, oxidative stress (a build-up of damaging molecules in the body), and an imbalance in correct functioning of the nervous system. Noise is thought to affect the functioning of both the nervous and hormonal systems.
 A micron is one millionth of a metre.
 A microgram is one millionth of a gram.
- Kateryna B. Fuks et al. Long-term exposure to ambient air pollution and traffic noise and incident hypertension in seven cohorts of the European study of cohorts for air pollution effects (ESCAPE). European Heart Journal, 2016 DOI: 10.1093/eurheartj/ehw413
Source: European Society of Cardiology (ESC). “World’s largest study shows effects of long-term exposure to air pollution and traffic noise on blood pressure.” ScienceDaily. ScienceDaily, 25 October 2016. <www.sciencedaily.com/releases/2016/10/161025084744.htm>.