Making a Difference in Clinical Research Operations
Now that risk-based monitoring (RBM) is becoming more widely accepted, the next step is to achieve the quality assurance (QA) goals as defined by the Clinical Trials Transformation Initiative (CTTI): the absence of errors that matter and are the data fit for purpose. To support these quality goals, Target Health, the industry leader in the paperless clinical trial, has developed a software toolbox and processes that are revolutionizing the clinical research enterprise.
As we are now starting our 20th study using our eSource solution fully integrated with Target e*CRF and risk-based monitoring, we would like to share some additional metrics from one of our ongoing studies. Also look at Publications on our website (www.targethealth.com) to see how Target e*CTR®(eClinical Trial Record), fully integrated with Target e*CRF® and RBM is making a profound difference in clinical trial operations and data quality.
Here are the new metrics from an ongoing study with 40 centers and hundreds of patients.
- 94% of the data were entered into Target e*CRF on the day of the office visit.
- Of the first 26,000 forms entered, source document verification (SDV) and/or source document review (SDR) was performed for 7,700 forms (30%), with only 133 (1.7%) of the queried forms modified.
- Of those 133 forms, 102 occurred at just one site, and within that site, 99 involved changes to time points that had absolutely no impact either on subject safety or trial outcomes (e.g. the absence of errors that matter and are the data are fit for purpose.
Best to Let Sleeping Crocodiles Lie
Warren Pearlson, our Director of Business Development recently returned from Costa Rica with his fantastic photo of a crocodile, basking, barely out of the river, as Pearlson’s small boat passed by.
Best to let sleeping crocodiles lie. ©Warren Pearlson Target health Inc. 2014
ON TARGET is the newsletter of Target Health Inc., a NYC-based, full-service, contract research organization (eCRO), providing strategic planning, regulatory affairs, clinical research, data management, biostatistics, medical writing and software services to the pharmaceutical and device industries, including the paperless clinical trial.
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.
Joyce Hays, Founder and Editor in Chief of On Target
Jules Mitchel, Editor
Artificial Intelligence Concerns Us All: SIRI and the Johns Hopkins Beast
Artificial intelligence (AI) is the intelligence exhibited by machines or software. It is an academic field of study which studies the goal of creating intelligence. Major AI researchers and textbooks define this field as the study and design of intelligent agents, where an intelligent agent is a system that perceives its environment and takes actions that maximize its chances of success. John McCarthy, who coined the term in 1955, defines it as the science and engineering of making 1) ___ machines. AI research is highly technical and specialized. Machine learning is the study of computer algorithms that improve automatically through experience and has been central to AI research since the field’s inception. Siri is an artificial intelligence system, on an infant level, just beginning to interact with humans, and created to be an intelligent personal assistant to 2) ___, developed by Apple Inc. No doubt everyone reading this, has experienced Siri, through use of a cell phone, and didn’t realize it. Keep in mind, Siri is learning from you, the user, the words you use, the places you go to, and in a short period of time, can anticipate your words, thus will do a spell check before you even ask for it and will complete sentences for you. Some autistic children have benefited from Siri, because the system appears to be non-threatening. Siri is an intelligent personal assistant and knowledge navigator that uses a natural language user interface to answer questions, make recommendations, and perform actions by delegating requests to a set of Web services. Siri, both in its original version and as an iOS application, adapts to the user’s individual language usage and individual searches (preferences) with continuing use, and returns results that are individualized. The name Siri is Scandinavian, a short form of the Norse name Sigrid meaning beauty and victory, and comes from the intended name for the original developer’s first child.
Siri was originally introduced as an iOS application available in the App Store by Siri, Inc., which was acquired by Apple on April 28, 2010. Siri, Inc. had announced that their software would be available for BlackBerry and for phones running Android, but all development efforts for non-Apple platforms were cancelled after the acquisition by 3) ___.
Siri has been an integral part of iOS since iOS 5 and was introduced as a feature of the iPhone 4S on October 14, 2011. Siri was added to the third generation iPad with the release of iOS 6 in September 2012, and has been included on all iOS devices released during or after October 2012. Siri was first launched as an application available on Apple’s App Store in the United States by Siri, Inc. It integrated with services such as OpenTable, Google Maps, MovieTickets and TaxiMagic. Using voice 4) ___ technology from Nuance and their service partners, users could make reservations at specific restaurants, buy movie tickets or get a cab by dictating instructions in natural language to Siri. Siri was acquired by Apple on April 28, 2010, and the original application ceased to function on October 14, 2011. A key feature both of the research and development behind the original Siri, Inc. application, and behind its function as an iOS application, is its artificial intelligence programming aimed to allow it to adapt to the user’s individual language usage and individual searches (preferences) with continuing use, with return of results that are therefore individualized.
The Siri feature shown on a white iPhone 4S.
On October 4, 2011 Apple introduced the iPhone 4S with their implementation of a beta version of Siri. The new version of Siri is integrated into iOS, and offers conversational interaction with many applications, including reminders, weather, stocks, messaging, email, calendar, contacts, notes, music, clocks, web browser, Wolfram Alpha, and maps. Currently, Siri supports English (American, Canadian, Australian, British), French, German, Japanese, Italian (Italy, Switzerland), Spanish (Mexico, Spain), Mandarin (China, Taiwan), Korean, and Cantonese. On launch, Siri had limited functionality outside the United States and Canada. However, Apple, with the release of iOS 6, added the missing functionality to other countries. Developers have now, by passed Apple’s Siri server completely by creating their own backend using APIs from services such as Google and Wolfram Alpha. On June 11, 2012, at Apple’s WWDC conference, Apple announced that Siri will be available on the iPad (third generation) beginning in late 2012 with the release of iOS 6. Also on June 11, 2012, at Apple’s WWDC conference, Apple announced updates for Siri coming in iOS 6 (which launched in fall 2012.) These new features include: opening apps, telling sports scores and other sports related information, checking movie times, finding restaurants and also ordering reservations. Siri can also tell the height of sports players in iOS 6. It also brought some previously US only features, such as Google Maps and Yelp integration, international. On June 13, 2013, Apple revealed that Siri will have a gender option, meaning that you can choose if Siri will sound like a male or a 5) ___, with the release of iOS 7.
Siri is a spin-out from the SRI International Artificial Intelligence Center, and is an offshoot of the DARPA-funded CALO project. Siri was co-founded by SRI’s Dag Kittlaus (CEO) and Adam Cheyer (VP Engineering) and by Tom Gruber (CTO). Siri’s primary technical areas focus on a Conversational Interface, Personal Context Awareness, and Service Delegation. Siri’s speech recognition engine is provided by Nuance Communications, a speech technology company, although this was not officially acknowledged by either Apple or Nuance until AllThingsD Conference (2013). The original Siri application relied upon a number of partners, including:
- OpenTable, Gayot, CitySearch, BooRah, Yelp, Yahoo Local, Yandex, ReserveTravel, and Localezefor restaurant and business questions and actions;
- Eventful, StubHub, and LiveKickfor events and concert information;
- MovieTickets, Rotten Tomatoes, and the New York Timesfor movie information and reviews;
- Bing Answers, Wolfram Alphaand Evifor factual question answering;
- Bing, Yahoo, and Googlefor web search (Bing as default since iOS 7).
The sources in Apple’s implementation of Siri differ from the original iPhone application. It integrates with default iOS functionality, such as contacts, calendars and text messages. It also supports search from Google, Bing, Yahoo, Wolfram Alpha, Google Maps, Yelp! and Wikipedia. Siri also contains numerous pre-programmed responses to conversational and amusing questions. These are designed to provide an entertainment factor and give Siri human-like qualities. Siri was first introduced to the world through the automotive industry in April 2010 as a hands free upgrade with Ford and Honda but fell through when stocks dropped 20% due to price inflation. At WWDC 2013, Apple’s Eddy Cue announced a new system called iOS in the Car aimed at integrating Siri and other iOS functions more fully into native in-car systems, like satellite 6) ___ (Satnav) and music playback, which was later renamed CarPlay by Apple on March 3, 2014. Siri was met with critical acclaim for its ease of use and practicality, as well as its apparent personality. Writing in The Guardian, journalist Charlie Brooker considered Siri’s personality to be unpleasantly servile, but found that the software worked annoyingly well. Apple’s Siri FAQ states that, as more people use Siri and it’s exposed to more variations of a language, its overall recognition of dialects and accents will continue to improve, and Siri will work even better. Google?s executive chairman and former chief, Eric Schmidt, has conceded that Siri could pose a competitive threat to the company’s core search business. In March 2012, the American Civil Liberties Union expressed concern that Siri was sending a large amount of personal voice and user information to Apple, including the first name and nickname of the phone owner and his or her contacts, the owner’s relationship with those contacts, personal labels assigned to email accounts, and the names of songs and playlists stored on the phone. On October 30, 2012, Google released a new Google Search app for iOS, which featured an enhanced Google Voice Search function and aimed to compete with Siri. Google’s Voice Search was compared favorably to Siri, with some reviewers preferring it. The Unofficial Apple Weblog’s side-by-side comparison said that Google’s Voice Search on iOS is amazingly quick and relevant, and has more depth [than Siri]. As of iOS 6, Siri has functionality to find local businesses and other location services outside of the United States. In Siri’s original release its functionality was limited in most countries, with maps and local search with help only being available within the United States.
- The Beta Test Initiation (2012) – an episode of The Big Bang Theory TV series, in which a cast member falls in love with the Siri on his new iPhone
- Her (2013) – a film in which a man (Joaquin Phoenix) falls in love with his virtual personal assistant (Scarlett Johansson)
- Criminal Minds (2014) – episode four of season 10 briefly featured Siri at the beginning in which Siri completely misunderstood the message the driver wanted to send.
- For a detailed article in the history of the organizations and technologies preceding the development of Siri, and their influence upon that application, see Bianca Bosker, 2013, Siri Rising: The Inside Story Of Siri’s Origins (And Why She Could Overshadow The iPhone), in The Huffington Post (online), January 22, 2013 (updated January 24, 2013).
Johns Hopkins Beast
The Johns Hopkins Beast was a mobile automaton, an early pre-robot, built in the 1960s at the Johns Hopkins University Applied Physics Laboratory. The machine had a rudimentary intelligence and the ability to survive on its own. As it wandered through the white halls of the laboratory, it would seek black wall outlets. When it found one it would plug in and recharge. The robot was cybernetic. It did not use a computer. Its control circuitry consisted of dozens of transistors controlling analog voltages. It used photocell optics and sonar to navigate. The 2N404 transistors were used to create NOR logic gates that implemented the Boolean logic to tell it what to do when a specific sensor was activated. The 2N404 transistors were also used to create timing gates to tell it how long to do something. 2N1040 Power 7) ___ were used to control the power to the motion treads, the boom, and the charging mechanism.
The original sensors in Mod I were physical touch only. The wall socket was detected by physical switches on the arm that followed the wall. Once detected, two electrical prongs were extended until they entered the wall 8) ___ and made the electrical connection to charge the vehicle. The stairway, doors, and pipes on the hall wall were also detected by physical switches and recognized by appropriate logic. The sonar guidance system was developed for Mod I and improved for Mod II. It used two ultrasonic transducers to determine distance, location within the halls, and obstructions in its path. This provided The Beast with bat-like guidance. At this point, it could detect obstructions in the hallway, such as people in the hallway. Once an 9) ___ was detected, the Beast would slow down and then decide whether to stop or divert around the obstruction. It could also ultrasonically recognize the stairway and doorways to take appropriate action. An optical guidance system was added to Mod II. This provided, among other capabilities, the ability to optically identify the black wall sockets that contrasted with the white wall. The Hopkins Beast Autonomous Robot Mod II link below was written by Dr. Ronald McConnell, at that time a co-op student and one of the designers for Mod II. Siri and Beast are just the beginning of 10) ___ intelligence in its infancy. Because systems like these grow exponentially, you can expect many more of these, so-called assistants hovering around you, sooner than you may realize, or be prepared for.
ANSWERS: 1) intelligent; 2) humans; 3) Apple; 4) recognition; 5) female; 6) navigation; 7) transistors; 8) socket; 9) obstruction; 10) artificial
Alan M. Turing (1912 – 1954)
Alan M. Turing in 1951
On 22 October 2014, Alan M. Turing was inducted into the NSA Hall of Honor, in Maryland.
On June 8, 1954, Alan Turing, a forty-one-year-old research scientist at Manchester University, was found dead by his housekeeper. Before getting into bed the night before, he had taken a few bites out of an apple that was, apparently, laced with cyanide. At an inquest, a few days later, his death was ruled a suicide. Turing was, by necessity rather than by inclination, a man of secrets. One of his secrets had been exposed two years before his death, when he was convicted of gross indecency for having a homosexual affair. Another, however, had not yet come to light. It was Turing who was chiefly responsible for breaking the German Enigma code during the Second World War, an achievement that helped save Britain from defeat in the dark days of 1941. Had this been publicly known, he would have been acclaimed a national hero. But the existence of the British code-breaking effort remained closely guarded even after the end of the war; the relevant documents weren’t declassified until the 1970’s. And it wasn’t until the eighties that Turing got the credit he deserved for a second, and equally formidable, achievement: creating the blueprint for the modern computer.
Alan Mathison Turing, OBE, FRS, was a British mathematician, logician, cryptanalyst, philosopher, pioneering computer scientist, mathematical biologist, and marathon and ultra-distance runner. He was highly influential in the development of computer science, providing a formalization of the concepts of algorithm and computation with the Turing machine, which can be considered a model of the first general purpose computer. Turing is widely considered to be the father of theoretical computer science and artificial intelligence. During World War II, Turing worked for the Government Code and Cypher School (GC&CS) at Bletchley Park, Britain’s codebreaking center. For a time he led Hut 8, the section responsible for German naval cryptanalysis. He devised a number of techniques for breaking German ciphers, including improvements to the pre-war Polish bombe method, an electromechanical machine that could find settings for the Enigma machine. Winston Churchill said that Turing made the single biggest contribution to Allied victory in the war against Nazi Germany. Turing’s pivotal role in cracking intercepted coded messages enabled the Allies to defeat the Nazis in several crucial battles. It has been estimated that Turing’s work shortened the war in Europe by as many as two to four years. After the war, Turing worked at the National Physical Laboratory, where he designed the ACE, among the first designs for a stored-program computer. In 1948 Turing joined Max Newman’s Computing Laboratory at Manchester University, where he assisted development of the Manchester computers and became interested in mathematical biology. He wrote a paper on the chemical basis of morphogenesis, and predicted oscillating chemical reactions such as the Belousov-Zhabotinsky reaction, first observed in the 1960s.
Turing was prosecuted in 1952 for homosexual acts, when such behavior was still criminalized in the UK. He accepted treatment with estrogen injections (chemical castration) as an alternative to prison. Turing died in 1954, 16 days before his 42nd birthday, from cyanide poisoning. An inquest determined his death a suicide; his mother and some others believed it was accidental. In 2009, following an Internet campaign, British Prime Minister Gordon Brown made an official public apology on behalf of the British government for the appalling way he was treated. The Queen granted him a posthumous pardon in 2013.
Turing was born in Paddington, London, while his father was on leave from his position with the Indian Civil Service (ICS) at Chhatrapur, Bihar and Orissa Province, in British India. Turing’s father, Julius Mathison Turing (1873-1947), was the son of a clergyman from a Scottish family of merchants which had been based in the Netherlands and included a baronet. Julius’s wife, Alan’s mother, was Ethel Sara 1881-1976), daughter of Edward Waller Stoney, chief engineer of the Madras Railways. The Stoneys were a Protestant Anglo-Irish gentry family from both County Tipperary and County Longford, while Ethel herself had spent much of her childhood in County Clare. Julius’ work with the ICS brought the family to British India, where his grandfather had been a general in the Bengal Army. However, both Julius and Ethel wanted their children to be brought up in England, so they moved to Maida Vale, London, where Turing was born on 23 June 1912, as recorded by a blue plaque on the outside of the house of his birth, later the Colonnade Hotel. He had an elder brother, John (the father of Sir John Dermot Turing, 12th Baronet of the Turing baronets). His father’s civil service commission was still active, and during Turing’s childhood years his parents travelled between Hastings in England and India, leaving their two sons to stay with a retired Army couple. At Hastings, Turing stayed at Baston Lodge, Upper Maze Hill, St Leonards-on-Sea, now marked with a blue plaque. Very early in life, Turing showed signs of the genius he was later to display prominently. His parents purchased a house in Guildford in 1927, and Turing lived there during school holidays. The location is also marked with a blue plaque. His parents enrolled him at St Michael’s, a day school at 20 Charles Road, St Leonards-on-Sea, at the age of six. The headmistress recognized his talent early on, as did many of his subsequent educators. In 1926, at the age of 13, he went on to Sherborne School, a well-known independent school in the market town of Sherborne in Dorset. The first day of term coincided with the 1926 General Strike in Britain, but so determined was he to attend that he rode his bicycle unaccompanied more than 60 miles (97 km) from Southampton to Sherborne, stopping overnight at an inn.
Turing’s natural inclination toward mathematics and science did not earn him respect from some of the teachers at Sherborne, whose definition of education placed more emphasis on the classics. His headmaster wrote to his parents: I hope he will not fall between two stools. If he is to stay at public school, he must aim at becoming educated. If he is to be solely a Scientific Specialist, he is wasting his time at a public school. Despite this, Turing continued to show remarkable ability in the studies he loved, solving advanced problems in 1927 without having studied even elementary calculus. In 1928, aged 16, Turing encountered Albert Einstein’s work; not only did he grasp it, but he extrapolated Einstein’s questioning of Newton’s laws of motion from a text in which this was never made explicit. At Sherborne, Turing formed an important friendship with fellow pupil Christopher Morcom, which provided inspiration in Turing’s future endeavors. However, the friendship was cut short by Morcom’s death in February 1930 from complications of bovine tuberculosis contracted after drinking infected cow’s milk some years previously. This event shattered Turing’s religious faith. He became an atheist. He believed that all phenomena, including the workings of the human brain, must be materialistic, while maintaining a belief that the spirit survives after death. After Sherborne, Turing studied as an undergraduate from 1931 to 1934 at King’s College, Cambridge, from where he gained first-class honors in mathematics. In 1935, at the young age of 22, he was elected a fellow at King’s on the strength of a dissertation in which he proved the central limit theorem, despite the fact that he had failed to find out that it had already been proved in 1922 by Jarl Waldemar Lindeberg.
Alan Turing memorial statue in Sackville Park, Manchester
In 1928, German mathematician David Hilbert had called attention to the Entscheidungs problem (decision problem). In his momentous paper On Computable Numbers, with an Application to the Entscheidungs problem, Turing reformulated Kurt Godel’s 1931 results on the limits of proof and computation, replacing Godel’s universal arithmetic-based formal language with the formal and simple hypothetical devices that became known as Turing machines. He proved that some such machine would be capable of performing any conceivable mathematical computation if it were representable as an algorithm. He went on to prove that there was no solution to the Entscheidungs problem by first showing that the halting problem for Turing machines is undecidable: in general, it is not possible to decide algorithmically whether a given Turing machine will ever halt. Although Turing’s proof was published shortly after Alonzo Church’s equivalent proof using his lambda calculus, Turing had been unaware of Church’s work. Turing’s approach is considerably more accessible and intuitive than Church’s. It was also novel in its notion of a ?Universal Machine’ (now known as a Universal Turing machine), with the idea that such a machine could perform the tasks of any other computation machine, or in other words, it is provably capable of computing anything that is computable. Von Neumann acknowledged that the central concept of the modern computer was due to this paper. Turing machines are to this day a central object of study in theory of computation.
From September 1936 to July 1938, he spent most of his time studying under Church at Princeton University. In addition to his purely mathematical work, he studied cryptology and also built three of four stages of an electro-mechanical binary multiplier. In June 1938, he obtained his PhD from Princeton; his dissertation, Systems of Logic Based on Ordinals, introduced the concept of ordinal logic and the notion of relative computing, where Turing machines are augmented with so-called oracles, allowing a study of problems that cannot be solved by a Turing machine. When Turing returned to Cambridge, he attended lectures given by Ludwig Wittgenstein about the foundations of mathematics. The two argued and disagreed, with Turing defending formalism and Wittgenstein propounding his view that mathematics does not discover any absolute truths but rather invents them. He also started to work part-time with the Government Code and Cypher School (GC&CS)
Two cottages in the stable yard at Bletchley Park. Turing worked here in 1939 and 1940, before moving to Hut 8.
During the Second World War, Turing was a leading participant in the breaking of German ciphers at Bletchley Park. The historian and wartime code breaker Asa Briggs has said, You needed exceptional talent, you needed genius at Bletchley and Turing’s was that genius. From September 1938, Turing had been working part-time with the GC&CS, the British code breaking organization. He concentrated on cryptanalysis of the Enigma, with Dilly Knox, a senior GC&CS code breaker. Soon after the July 1939 Warsaw meeting at which the Polish Cipher Bureau had provided the British and French with the details of the wiring of Enigma rotors and their method of decrypting Enigma messages, Turing and Knox started to work on a less fragile approach to the problem. The Polish method relied on an insecure indicator procedure that the Germans were likely to change, which they did in May 1940. Turing’s approach was more general, using crib-based decryption for which he produced the functional specification of the bombe (an improvement of the Polish Bomba). On 4 September 1939, the day after the UK declared war on Germany, Turing reported to Bletchley Park, the wartime station of GC&CS. Specifying the bombe was the first of five major crypt analytical advances that Turing made during the war. The others were: deducing the indicator procedure used by the German navy; developing a statistical procedure for making much more efficient use of the bombes dubbed Banburismus; developing a procedure for working out the cam settings of the wheels of the Lorenz SZ 40/42 (Tunny) dubbed Turingery and, towards the end of the war, the development of a portable secure voice scrambler at Hanslope Park that was code named Delilah. By using statistical techniques to optimize the trial of different possibilities in the code breaking process, Turing made an innovative contribution to the subject. He wrote two papers discussing mathematical approaches which were entitled Report on the applications of probability to cryptography and Paper on statistics of repetitions, which were of such value to GC&CS and its successor GCHQ, that they were not released to the UK National Archives until April 2012, shortly before the centenary of his birth. A GCHQ mathematician said at the time that the fact that the contents had been restricted for some 70 years demonstrated their importance.
Turing had something of a reputation for eccentricity at Bletchley Park. He was known to his colleagues as ?Prof’ and his treatise on Enigma was known as ?The Prof’s Book’. Jack Good, a cryptanalyst who worked with him, is quoted by Ronald Lewin as having said of Turing:
In the first week of June each year he would get a bad attack of hay fever, and he would cycle to the office wearing a service gas mask to keep the pollen off. His bicycle had a fault: the chain would come off at regular intervals. Instead of having it mended he would count the number of times the pedals went round and would get off the bicycle in time to adjust the chain by hand. Another of his eccentricities is that he chained his mug to the radiator pipes to prevent it being stolen.
While working at Bletchley, Turing occasionally ran the 40 miles (64 km) to London when he was needed for high-level meetings, and he was capable of world-class marathon standards. Turing tried out for the 1948 British Olympic team, hampered by an injury. His tryout time for the marathon was only 11 minutes slower than British silver medalist Thomas Richards’ Olympic race time of 2 hours 35 minutes. He was Walton Athletic Club’s best runner, a fact discovered when he passed the group while running alone.
Within weeks of arriving at Bletchley Park, Turing had specified an electromechanical machine that could help break Enigma more effectively than the Polish bomba kryptologiczna, from which its name was derived. The bombe, with an enhancement suggested by mathematician Gordon Welchman, became one of the primary tools, and the major automated one, used to attack Enigma-enciphered messages.
Jack Good opined:
Turing’s most important contribution, I think, was of part of the design of the bombe, the cryptanalytic machine. He had the idea that you could use, in effect, a theorem in logic which sounds to the untrained ear rather absurd; namely that from a contradiction, you can deduce everything.
A complete and working replica of a bombe at the National Codes Centre at Bletchley Park
The bombe searched for possible correct settings used for an Enigma message (i.e. rotor order, rotor settings and plug board settings), using a suitable crib: a fragment of probable plain text. For each possible setting of the rotors (which had of the order of 1019 states, or 1022 for the four-rotor U-boat variant), the bombe performed a chain of logical deductions based on the crib, implemented electrically. The bombe detected when a contradiction had occurred, and ruled out that setting, moving on to the next. Most of the possible settings would cause contradictions and be discarded, leaving only a few to be investigated in detail. The first bombe was installed on 18 March 1940. By late 1941, Turing and his fellow cryptanalysts Gordon Welchman, Hugh Alexander, and Stuart Milner-Barry were frustrated. Building on the brilliant work of the Poles, they had set up a good working system for decrypting Enigma signals but they only had a few people and a few bombes so they did not have time to translate all the signals. In the summer they had had considerable success; shipping losses had fallen to under 100,000 tons a month but they were still on a razor-edge. They badly needed more resources to keep abreast of German adjustments. They had tried to get more people and fund more bombes through the proper channels but they were getting nowhere. Finally, breaking all the rules, on 28 October they wrote directly to Churchill spelling out their difficulties. They emphasized how small their need was compared with the vast expenditure of men and money by the forces and compared with the level of assistance they could offer to the forces. The effect was electric. Churchill wrote a memo to General Ismay which read: ACTION THIS DAY. Make sure they have all they want on extreme priority and report to me that this has been done. On 18 November the chief of the secret service reported that every possible measure was being taken. More than two hundred bombes were in operation by the end of the war.
Turing decided to tackle the particularly difficult problem of German naval Enigma because no one else was doing anything about it and I could have it to myself. In December 1939, Turing solved the essential part of the naval indicator system, which was more complex than the indicator systems used by the other services. That same night he also conceived of the idea of Banburismus, a sequential statistical technique (what Abraham Wald later called sequential analysis) to assist in breaking naval Enigma, though I was not sure that it would work in practice, and was not in fact sure until some days had actually broken. For this he invented a measure of weight of evidence that he called the ban. Banburismus could rule out certain sequences of the Enigma rotors, substantially reducing the time needed to test settings on the bombes. In 1941, Turing proposed marriage to Hut 8 co-worker Joan Clarke, a fellow mathematician and cryptanalyst, but their engagement was short-lived. After admitting his homosexuality to his fiancee, who was reportedly unfazed by the revelation, Turing decided that he could not go through with the marriage. Turing travelled to the United States in November 1942 and worked with US Navy cryptanalysts on Naval Enigma and bombe construction in Washington. He visited their Computing Machine Laboratory at Dayton, Ohio. His reaction to the American Bombe design was far from enthusiastic:
It seems a pity for them to go out of their way to build a machine to do all this stopping if it is not necessary. I am now converted to the extent of thinking that starting from scratch on the design of a Bombe, this method is about as good as our own. The American Bombe program was to produce 336 Bombes, one for each wheel order. I used to smile inwardly at the conception of test (of commutators) can hardly be considered conclusive as they were not testing for the bounce with electronic stop finding devices.
During this trip, he also assisted at Bell Labs with the development of secure speech devices. He returned to Bletchley Park in March 1943. During his absence, Hugh Alexander had officially assumed the position of head of Hut 8, although Alexander had been de facto head for some time – Turing having little interest in the day-to-day running of the section. Turing became a general consultant for cryptanalysis at Bletchley Park. Alexander wrote as follows about his contribution:
There should be no question in anyone’s mind that Turing’s work was the biggest factor in Hut 8’s success. In the early days he was the only cryptographer who thought the problem worth tackling and not only was he primarily responsible for the main theoretical work within the Hut but he also shared with Welchman and Keen the chief credit for the invention of the Bombe. It is always difficult to say that anyone is absolutely indispensable but if anyone was indispensable to Hut 8 it was Turing. The pioneer’s work always tends to be forgotten when experience and routine later make everything seem easy and many of us in Hut 8 felt that the magnitude of Turing’s contribution was never fully realized by the outside world.
In July 1942, Turing devised a technique termed Turingery (or jokingly Turingismus) for use against the Lorenz cipher, messages produced by the Germans’ new Geheimschreiber (secret writer) machine. This was a teleprinter rotor cipher attachment code named Tunny at Bletchley Park. Turingery was a method of wheel-breaking, i.e. a procedure for working out the cam settings of Tunny’s wheels. He also introduced the Tunny team to Tommy Flowers who, under the guidance of Max Newman, went on to build the Colossus computer, the world’s first programmable digital electronic computer, which replaced a simpler prior machine (the Heath Robinson), and whose superior speed allowed the statistical decryption techniques to be applied usefully to the messages. Some have mistakenly said that Turing was a key figure in the design of the Colossus computer. Turingery and the statistical approach of Banburismus undoubtedly fed into the thinking about cryptanalysis of the Lorenz cipher, but he was not directly involved in the Colossus development.
Following his work at Bell Labs in the US, Turing pursued the idea of electronic enciphering of speech in the telephone system, and in the latter part of the war, he moved to work for the Secret Service’s Radio Security Service (later HMGCC) at Hanslope Park. There he further developed his knowledge of electronics with the assistance of engineer Donald Bayley. Together they undertook the design and construction of a portable secure voice communications machine code named, Delilah. It was intended for different applications, lacking capability for use with long-distance radio transmissions, and in any case, Delilah was completed too late to be used during the war. Though the system worked fully, with Turing demonstrating it to officials by encrypting and decrypting a recording of a Winston Churchill speech, Delilah was not adopted for use. Turing also consulted with Bell Labs on the development of SIGSALY, a secure voice system that was used in the later years of the war. From 1945 to 1947, Turing lived in Hampton, London while he worked on the design of the ACE (Automatic Computing Engine) at the National Physical Laboratory (NPL). He presented a paper on 19 February 1946, which was the first detailed design of a stored-program computer. Von Neumann’s incomplete First Draft of a Report on the EDVAC had predated Turing’s paper, but it was much less detailed and, according to John R. Womersley, Superintendent of the NPL Mathematics Division, it contains a number of ideas which are Dr. Turing’s own. Although ACE was a feasible design, the secrecy surrounding the wartime work at Bletchley Park led to delays in starting the project and he became disillusioned. In late 1947 he returned to Cambridge for a sabbatical year during which he produced a seminal work on Intelligent Machinery that was not published in his lifetime. While he was at Cambridge, the Pilot ACE was being built in his absence. It executed its first program on 10 May 1950. Although the full version of Turing’s ACE was never built, a number of computers around the world owe much to it, for example, the English Electric DEUCE and the American Bendix G-15.
According to the memoirs of the German computer pioneer Heinz Billing from the Max Planck Institute for Physics, published by Genscher, D?sseldorf (1997), there was a meeting between Alan Turing and Konrad Zuse. It took place in Gottingen in 1947. The interrogation had the form of a colloquium. Participants were Womersley, Turing, Porter from England and a few German researchers like Zuse, Walther, and Billing. (For more details see Herbert Bruderer, Konrad Zuse und die Schweiz). In 1948, Turing was appointed Reader in the Mathematics Department at the University of Manchester. In 1949, he became Deputy Director of the Computing Laboratory there, working on software for one of the earliest stored-program computers – the Manchester Mark 1. During this time he continued to do more abstract work in mathematics, and in Computing machinery and intelligence (Mind, October 1950), Turing addressed the problem of artificial intelligence, and proposed an experiment which became known as the Turing test, an attempt to define a standard for a machine to be called intelligent. The idea was that a computer could be said to think if a human interrogator could not tell it apart, through conversation, from a human being. In the paper, Turing suggested that rather than building a program to simulate the adult mind, it would be better rather to produce a simpler one to simulate a child’s mind and then to subject it to a course of education. A reversed form of the Turing test is widely used on the Internet; the CAPTCHA test is intended to determine whether the user is a human or a computer. In 1948, Turing, working with his former undergraduate colleague, D. G. Champernowne, began writing a chess program for a computer that did not yet exist. By 1950, the program was completed and dubbed the Turbochamp. In 1952, he tried to implement it on a Ferranti Mark 1, but lacking enough power, the computer was unable to execute the program. Instead, Turing played a game in which he simulated the computer, taking about half an hour per move. The game was recorded. The program lost to Turing’s colleague Alick Glennie, although it is said that it won a game against Champernowne’s wife. His Turing test was a significant, characteristically provocative and lasting contribution to the debate regarding artificial intelligence, which continues after more than half a century. He also invented the LU decomposition method in 1948, used today for solving matrix equations.
Turing worked from 1952 until his death in 1954 on mathematical biology, specifically morphogenesis. He published one paper on the subject called The Chemical Basis of Morphogenesis in 1952, putting forth the Turing hypothesis of pattern formation (the theory was experimentally confirmed 60 years after his death). His central interest in the field was understanding Fibonacci phyllotaxis, the existence of Fibonacci numbers in plant structures. He used reaction-diffusion equations which are central to the field of pattern formation. Later papers went unpublished until 1992 when Collected Works of A.M. Turing was published. His contribution is considered a seminal piece of work in this field. Removal of Hox genes causes an increased number of digits (up to 14) in mice, demonstrating a Turing-type mechanism in the development of the hand. In January 1952, Turing, then 39, started a relationship with Arnold Murray, a 19-year-old unemployed man. Turing met Murray just before Christmas outside the Regal Cinema when walking down Manchester’s Oxford Road and had invited him to lunch. On 23 January Turing’s house was burgled. Murray told Turing that the burglar was an acquaintance of his, and Turing reported the crime to the police. During the investigation he acknowledged a sexual relationship with Murray. Homosexual acts were criminal offences in the United Kingdom at that time, and both men were charged with gross indecency under Section 11 of the Criminal Law Amendment Act 1885. Initial committal proceedings for the trial occurred on 27 February, where Turing’s solicitor reserved his defense. Later, convinced by the advice of his brother and other lawyers, Turing entered a plea of guilty, in spite of the fact that he felt no remorse or guilt for having committed acts of homosexuality. The case, Regina v. Turing and Murray, was brought to trial on 31 March 1952, when Turing was convicted and given a choice between imprisonment and probation, which would be conditional on his agreement to undergo hormonal treatment designed to reduce libido. He accepted the option of treatment via injections of stilboestrol, a synthetic estrogen; this treatment was continued for the course of one year. The treatment rendered Turing impotent and caused gynaecomastia, fulfilling in the literal sense, Turing’s prediction that no doubt I shall emerge from it all a different man, but quite who I’ve not found out. Murray was given a conditional discharge. Turing’s conviction led to the removal of his security clearance and barred him from continuing with his cryptographic consultancy for the Government Communications Headquarters (GCHQ), the British signals intelligence agency that had evolved from GC&CS in 1946 (though he kept his academic job). He was denied entry into the United States after his conviction in 1952, but was free to visit other European countries, even though this was viewed by some as a security risk. At the time, there was acute public anxiety about homosexual entrapment of spies by Soviet agents, because of the recent exposure of the first two members of the Cambridge Five, Guy Burgess and Donald Maclean, as KGB double agents. Turing was never accused of espionage, but in common with all who had worked at Bletchley Park, he was prevented by the Official Secrets Act from discussing his war work.
On 8 June 1954, Turing’s housekeeper found him dead. He had died the previous day. A post-mortem examination established that the cause of death was cyanide poisoning. When his body was discovered, an apple lay half-eaten beside his bed, and although the apple was not tested for cyanide, it was speculated that this was the means by which a fatal dose was consumed. An inquest determined that he had committed suicide, and he was cremated at Woking Crematorium on 12 June 1954. Turing’s ashes were scattered there, just as his father’s had been. Philosophy professor Jack Copeland has questioned various aspects of the coroner’s historical verdict, suggesting the alternative explanation of the accidental inhalation of cyanide fumes from an apparatus for gold electroplating spoons, using potassium cyanide to dissolve the gold, which Turing had set up in his tiny spare room. Copeland notes that the autopsy findings were more consistent with inhalation than with ingestion of the poison. Turing also habitually ate an apple before bed, and it was not unusual for it to be discarded half-eaten. In addition, Turing had reportedly born his legal setbacks and hormone treatment (which had been discontinued a year previously) with good humor and had shown no sign of despondency prior to his death, in fact, setting down a list of tasks he intended to complete upon return to his office after the holiday weekend. At the time, Turing’s mother believed that the ingestion was accidental, caused by her son’s careless storage of laboratory chemicals. Biographer Andrew Hodges suggests that Turing may have arranged the cyanide experiment deliberately, to give his mother some plausible deniability. Turing’s biographers Andrew Hodges and David Leavitt have suggested that Turing was re-enacting a scene from the 1937 Walt Disney film Snow White, his favorite fairy tale, both noting that (in Leavitt’s words) he took an especially keen pleasure in the scene where the Wicked Queen immerses her apple in the poisonous brew.
Three remarkable papers written just before the war, on three diverse mathematical subjects, show the quality of the work that might have been produced if he had settled down to work on some big problem at that critical time. For his work at the Foreign Office he was awarded the OBE. Since 1966, the Turing Award has been given annually by the Association for Computing Machinery (ACM) for technical or theoretical contributions to the computing community. It is widely considered to be the computing world’s highest honor, equivalent to the Nobel Prize. Breaking the Code is a 1986 play by Hugh Whitemore about Alan Turing. The play ran in London’s West End beginning in November 1986 and on Broadway from 15 November 1987 to 10 April 1988. There was also a 1996 BBC television production (broadcast in the United States by PBS). In all three performances Turing was played by Derek Jacobi. The Broadway production was nominated for three Tony Awards including Best Actor in a Play, Best Featured Actor in a Play, and Best Direction of a Play, and for two Drama Desk Awards, for Best Actor and Best Featured Actor. On 23 June 1998, on what would have been Turing’s 86th birthday, his biographer, Andrew Hodges, unveiled an official English Heritage blue plaque at his birthplace and childhood home in Warrington Crescent, London, later the Colonnade Hotel. To mark the 50th anniversary of his death, a memorial plaque was unveiled on 7 June 2004 at his former residence, Hollymeade, in Wilmslow, Cheshire. On 13 March 2000, Saint Vincent and the Grenadines issued a set of postage stamps to celebrate the greatest achievements of the 20th century, one of which carries a portrait of Turing against a background of repeated 0s and 1s, and is captioned: 1937: Alan Turing’s theory of digital computing. On 1 April 2003, Turing’s work at Bletchley Park was named an IEEE Milestone. On 28 October 2004, a bronze statue of Alan Turing sculpted by John W. Mills was unveiled at the University of Surrey in Guildford, marking the 50th anniversary of Turing’s death; it portrays him carrying his books across the campus. In 2006, Boston Pride named Turing their Honorary Grand Marshal.
Turing was one of four mathematicians examined in the 2008 BBC documentary entitled Dangerous Knowledge. The Princeton Alumni Weekly named Turing the second most significant alumnus in the history of Princeton University, second only to President James Madison. A 1.5-ton, life-size statue of Turing was unveiled on 19 June 2007 at Bletchley Park. Built from approximately half a million pieces of Welsh slate, it was sculpted by Stephen Kettle, having been commissioned by the late American billionaire Sidney Frank. Turing has been honored in various ways in Manchester, the city where he worked towards the end of his life. In 1994, a stretch of the A6010 road (the Manchester city intermediate ring road) was named Alan Turing Way. A bridge carrying this road was widened, and carries the name Alan Turing Bridge. A statue of Turing was unveiled in Manchester on 23 June 2001 in Sackville Park, between the University of Manchester building on Whitworth Street and the Canal Street gay village. The memorial statue, depicts the father of Computer Science sitting on a bench at a central position in the park.
Turing memorial statue plaque in Sackville Park, Manchester
Turing is shown holding an apple. The cast bronze bench carries in relief the text ‘Alan Mathison Turing 1912-1954’, and the motto ‘Founder of Computer Science’ as it could appear if encoded by an Enigma machine: ?IEKYF ROMSI ADXUO KVKZC GUBJ’. A plinth at the statue’s feet says ‘Father of computer science, mathematician, logician, wartime codebreaker, victim of prejudice’. There is also a Bertrand Russell quotation saying ‘Mathematics, rightly viewed, possesses not only truth, but supreme beauty – a beauty cold and austere, like that of sculpture.’ The sculptor buried his old Amstrad computer, which was an early popular home computer, under the plinth, as a tribute to the godfather of all modern computers. In 1999, Time Magazine named Turing as one of the 100 Most Important People of the 20th century and stated: The fact remains that everyone who taps at a keyboard, opening a spreadsheet or a word-processing program, is working on an incarnation of a Turing machine. Turing is featured in the 1999 Neal Stephenson novel Cryptonomicon. In 2002, a new building named after Alan Turing was constructed on the Malvern site of QinetiQ. It houses about 200 scientists and engineers, some of whom work on big data computing. In 2002, Turing was ranked twenty-first on the BBC nationwide poll of the 100 Greatest Britons. In 2006 British writer and mathematician Ioan James chose Turing as one of twenty people to feature in his book about famous historical figures who may have had some of the traits of Asperger syndrome. In 2010, actor/playwright Jade Esteban Estrada portrayed Turing in the solo musical, ICONS: The Lesbian and Gay History of the World, Vol. 4. In 2011, in The Guardian’s My hero series, writer Alan Garner chose Turing as his hero and described how they had met whilst out jogging in the early 1950s. Garner remembered Turing as funny and witty and said that he talked endlessly. In 2006, Alan Turing was named with online resources as an LGBT History Month Icon. In February 2011, Turing’s papers from the Second World War were bought for the nation with an 11th-hour bid by the National Heritage Memorial Fund, allowing them to stay at Bletchley Park. In November 2011, Channel 4 aired the docudrama Britain’s Greatest Codebreaker about the life of Turing. The logo of Apple Computer is often erroneously referred to as a tribute to Alan Turing, with the bite mark a reference to his death. Both the designer of the logo and the company deny that there is any homage to Turing in the design of the logo. Stephen Fry has recounted asking Steve Jobs whether the design was intentional, saying that Jobs’ response was, God, we wish it were. The Turing Rainbow Festival, held in Madurai, India in 2012 for celebrating the LGBT and Gender queer cause, was named in honor of Alan Turing by Gopi Shankar of Srishti Madurai. Also in 2012 Turing was inducted into the Legacy Walk, an outdoor public display which celebrates LGBT history and people. The francophone singer-songwriter Salvatore Adamo makes a tribute to Turing with his song Alan et la Pomme. Turing’s life and work featured in a BBC children’s program about famous scientists – Absolute Genius with Dick and Dom – the episode was first broadcast on 12 March 2014. On 26 April 2014, a choral work written by James McCarthy depicting the life of Alan Turing is premiered in the Barbican hall, London, by the Hertfordshire Chorus. On 17 May 2014, the world’s first work of public art to recognize Alan Turing as gay was commissioned in Bletchley, close by to Bletchley Park where his famous work was carried out. The commission was announced by the owners of Milton Keynes-based LGBT venue and nightclub, Pink Punters to mark International Day Against Homophobia and Transphobia. The work was unveiled at a ceremony on Turing’s birthday, June 23 2014, and is placed outside Pink Punter’s alongside the busy Watling Street, the old main road to London where Turing himself would have passed by on many occasions.
On 22 October 2014, Alan M. Turing was inducted into the NSA Hall of Honor, in Maryland.
Sources: The New Yorker magazine; Wikipedia
Brain Abnormality Found in Group of SIDS Cases
Sudden infant death syndrome (SIDS) is the sudden death of an infant younger than 1 year of age that is still unexplained after a complete post mortem investigation by a coroner or medical examiner. This investigation includes an autopsy, a review of the death scene, and review of family and medical histories. In the United States, SIDS is the leading cause of death between one month and one year of age. The deaths are associated with an infant’s sleep period.
According to a study published online in Acta Neuropathologica (24 November 2014), it was reported that more than 40% of infants in a group who died of SIDS were found to have an abnormality in the hippocampus, a key part of the brain. The hippocampus is involved in memory, learning, spatial orientation, and, through its connections to the brainstem, controls some aspects of breathing, cardiac function, heart rate, and body temperature. Specifically, the authors traced the abnormality to a structure within the hippocampus known as the dentate gyrus. According to the authors, the abnormality was present more often in infants who died of SIDS than in infants whose deaths could be attributed to known causes, and that the abnormality may destabilize the brain’s control of breathing and heart rate patterns during sleep, or during the periodic brief arousals from sleep that occur throughout the night.
In the SIDS cases, the authors found that the dentate gyrus, at certain intervals along its length, contained a double layer of nerve cells instead of the usual single layer. This abnormality is called focal granule cell bilamination. According to the authors, the pattern of abnormal changes in the dentate gyrus suggests that there was a problem in its development at some point in late fetal life or in the months right after birth. In contrast, signs of injury to the brain by low oxygen levels was not observed, such as scarring and loss of nerve cells.
The authors undertook their study after finding abnormalities in the hippocampal region of brain tissue from SIDS cases that were sent to them for diagnostic consultation. Another clue to the possibility of an abnormality in the hippocampus came from earlier findings by members of the research team that a group of children who died suddenly and unexpectedly after 1 year of age also had an abnormality in this brain structure. These children died of sudden unexplained death in childhood which occurs from 1 year of age through adolescence. It is far less common than SIDS, but, like SIDS, it is also defined by inability to identify a cause of death after a complete autopsy or death scene investigation.
To conduct the study, the authors examined sections of hippocampus from 153 infants autopsied at the San Diego, medical examiner’s office. The infants had died suddenly and unexpectedly between 1991 and 2012. The deaths were classified as unexplained (which included SIDS and other cases in which the cause of death was unknown,) or explained, with death, due to such known causes of death as infection, accident, homicide, or asphyxia (oxygen deprivation). After examining the hippocampal samples, abnormality in the dentate gyrus was found in 41.2% of the unexplained group and in 7.7% of the explained (control) group. When the authors considered the 86 cases within the unexplained group that were classified as SIDS, about 43% (37) had the abnormality.
The authors believe that the dentate gyrus abnormality in the SIDS cases may lead to instability in the brain areas directly responsible for breathing and heart function. Importantly, the authors found the abnormality in SIDS cases that were discovered in unsafe sleep environments such as face down, as well as in safe sleep environments such as with infants found on their backs.
The authors also noted that the hippocampal abnormality they found in the SIDS cases is similar to a hippocampal abnormality found at autopsy in some cases of temporal lobe epilepsy, a brain disorder in which a person has repeated seizures over time. Seizures are episodes of disturbed brain activity that cause changes in attention, behavior, breathing, and heart function. The epilepsies are a spectrum of brain disorders ranging from severe, life-threatening and disabling, to others that are less severe. Previous research groups have theorized that SIDS could be due to an unwitnessed seizure that stops the heart and breathing. The authors stressed, however, that more research is needed to prove that seizure is the cause of death in many SIDS cases. The authors also do not know why they didn’t find the hippocampal abnormality in all of the SIDS cases they examined, but only in about 43%. In earlier work, it was found that many infants who died of SIDS had abnormalities in serotonin metabolism. The SIDS infants had low levels of the neurotransmitter serotonin, and of the different types of serotonin receptors in the parts of the brainstem involved in breathing, heart rate patterns, blood pressure, temperature regulation, and arousal during sleep. It has been theorized that an abnormality in serotonin-producing parts of the brainstem could result in abnormal development of the dentate gyrus. This potential relationship of the hippocampal abnormality to brainstem serotonin abnormalities in SIDS babies is currently under investigation.
The NICHD led Safe to Sleep Campaign advises that infants should be placed on their backs for sleep, in their own sleep area, on a firm sleep surface, such as a mattress in a safety-approved crib. These practices reduce the risk of SIDS and SIDS rates have declined by half since more babies have been placed to sleep on their backs.
How the Environment May Contribute to Human Diseases
According to an article published online in the journal Nature (17 November 2014), using a new imaging technique, it was discovered that the biological machinery that builds DNA can insert molecules into the DNA strand that are damaged as a result of environmental exposures. These damaged molecules trigger cell death that produces some human diseases, and provides a possible explanation for how one type of DNA damage may lead to cancer, diabetes, hypertension, cardiovascular and lung disease, and Alzheimer’s disease. The authors used time-lapse crystallography to determine that DNA polymerase, the enzyme responsible for assembling the nucleotides or building blocks of DNA, incorporates nucleotides with a specific kind of damage into the DNA strand. Time-lapse crystallography is a technique that takes snapshots of biochemical reactions occurring in cells.
The authors explained that the damage is caused by oxidative stress, or the generation of free oxygen molecules, in response to environmental factors, such as ultraviolet exposure, diet, and chemical compounds in paints, plastics, and other consumer products, and that it has been suspected for some time that the DNA polymerase was inserting nucleotides that were damaged by carrying an additional oxygen atom. When one of these oxidized nucleotides is placed into the DNA strand, it can’t pair with the opposing nucleotide as usual, which leaves a gap in the DNA.
The authors saw the process in real time, by forming crystal complexes made of DNA, polymerase, and oxidized nucleotides, and capturing snapshots at different time points through time-lapse crystallography. The procedure not only uncovered the stages of nucleotide insertion, but indicated that the new DNA stopped the DNA repair machinery from sealing the gap. This fissure in the DNA prevented further DNA repair and replication, or caused an immediate double-strand break. Large numbers of these pileups and double-strand breaks are lethal to the cell, serving as a jumping off point for the development of disease.
The authors stressed that the quantities of oxidized nucleotides in the nucleotide pool are usually under tight control, but if they accumulate and start to outnumber undamaged nucleotides, the DNA polymerase adds more of them to the strand. Molecules that inhibit oxidation, known as antioxidants, reduce the level of oxidized nucleotides, and may help prevent some diseases.
Drug Approved to Treat Polycythemia Vera
Polycythemia vera occurs when too many red blood cells are made in the bone marrow. Patients may also experience an increase in white blood cells and platelets. An overabundance of blood cells can cause the spleen to swell, bleeding problems and blood clots in the veins near the skin surface (phlebitis). In addition, it puts patients at increased risk of stroke or heart attack.
The FDA has approved a new use for Jakafi (ruxolitinib) the first drug approved by the FDA to treat patients with polycythemia vera.
Jakafi’s new use is intended to treat polycythemia vera patients who have an inadequate response to or cannot tolerate hydroxyurea, another medicine often prescribed to reduce the number of red blood cells and platelets in the blood. Jakafi works by inhibiting enzymes called Janus Associated Kinase (JAK) 1 and 2 that are involved in regulating blood and immunological functioning. The drug’s approval to treat polycythemia vera will help decrease the occurrence of an enlarged spleen (splenomegaly) and the need for phlebotomy, a procedure to remove excess blood from the body.
Jakafi’s safety and effectiveness to treat polycythemia vera were evaluated in a clinical study involving 222 participants who had the disease for at least 24 weeks, had an inadequate response to or could not tolerate hydroxyurea, had undergone a phlebotomy procedure and exhibited an enlarged spleen. Participants were randomly assigned to receive Jakafi or the best available therapy, as determined by the investigator on a participant-by-participant basis. The study was designed to measure the reduced need for phlebotomy beginning at Week 8 and continuing through Week 32, in addition to at least 35% reduction in spleen volume at Week 32. Results showed 21% of Jakafi-treated participants experienced a reduction in the need for a phlebotomy and a reduction in spleen volume, compared to 1% of participants who received best available therapy.
The most common side effects associated with use of Jakafi were low red blood cell counts (anemia) and low blood platelet counts (thrombocytopenia). The most common non-blood related side effects were dizziness, constipation and shingles.
The FDA reviewed Jakafi’s use for polycythemia vera under the agency’s priority review program because, at the time the application was submitted, the drug demonstrated the potential to be a significant improvement in safety or effectiveness over available therapy in the treatment of a serious condition. Priority review provides an expedited review of a drug’s application. Jakafi also received orphan product designation because it is intended to treat a rare disease.
In 2011, the FDA approved Jakafi for treatment of patients with another bone marrow disorder, intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis.
Jakafi is marketed by Wilmington, Delaware-based Incyte Corp.
Persimmon Custard Cake
Persimmon Custard Cake with two slices fresh persimmon and a piece of caramelized sugar that oozed from the bottom of the cake, when I took it out of the oven. Cool Whip (fat free) on top. This is a delicious dessert! ©Joyce Hays, Target Health Inc.
Assistant Pastry Chef, Mimi Yao (left) Junior Trainee, BillyBob Aroo (right) – ©Joyce Hays, Target Health Inc.
Gather ingredients, so you know you have everything. It’s a real pain to realize, in the middle of cooking, that one ingredient is missing and you have to go out again to buy it. ©Joyce Hays, Target Health Inc.
4 Tablespoons butter, melted, plus more for the dish
5 Fuyu persimmons, trimmed and chopped
2 eggs, beaten
1 cup sugar
1 cup Splenda
1 teaspoon baking soda
1 cup buttermilk
1 1/2 cups almond flour
2 1/2 teaspoons baking powder
1 cup heavy cream
1/4 teaspoon salt
1/2 teaspoon vanilla extract
Dash of cinnamon
- Heat oven to 325 degrees and butter a 2-quart baking dish.
Out of the food processor and into the strainer for a perfect custard. ©Joyce Hays, Target Health Inc.
- Puree persimmons in a food processor or blender until smooth. Then strain the pulp through a fine mesh strainer into a bowl, using the back of a spoon or a spatula to push pur?e through. Measure out 2 cups of pulp (discard remaining pulp).
Combining eggs, sugar and strained persimmon ©Joyce Hays, Target Health Inc.
- Combine eggs, sugar and persimmon pulp in a large bowl and beat with an electric mixer on medium speed until well mixed.
- Stir baking soda into buttermilk, then add to persimmon mixture and beat to combine.
In a separate bowl, sift together flour and baking powder.
- Now, beat the flour mixture into persimmon mixture in 3 separate additions, alternating with the 1/2 of the heavy cream. Begin and end with the flour. So, to be clear: add 1/3 of the flour, then 1/2 cup cream, then 1/3 flour, then second half cream and finally the last 1/3 of the flour.
Melting the butter ©Joyce Hays, Target Health Inc.
- Stir in melted butter, salt, vanilla and cinnamon. Transfer batter to prepared dish and bake until cake is set, 1 hour to 1 hour 15 minutes.
About to go into the oven ©Joyce Hays, Target Health Inc.
Out of the oven and cooling ©Joyce Hays, Target Health Inc.
Spectacular to the last bite ©Joyce Hays, Target Health Inc.
Fuyu persimmons are my favorite. Wash them, pull the leaves and stem off, eat them plain, cut up bite size, with skins on. Only eat them when they are soft and ripe. If they’re still firm or hard, they’ll taste bitter. When ripe they become very sweet and delicious. The persimmon is a fruit of Chinese origin. Originally cultivated in both Japan and China for centuries, this fruit is now grown in Italy and other Mediterranean countries, the Middle East and theUSA.
Paul Hobbs, pinot noir, a delicious CA wine – over 90 pts ©Joyce Hays, Target Health Inc.
Some people learn from mistakes (like me). Here is one attempt at a custard-y cake with persimmons, pears and cognac. A complete flop! Too much fruit, too little cake, juice dripping all over the oven, smoke alarms screeching – such a mess! Eventually, I recovered and came up with the recipe for this week.©Joyce Hays, Target Health Inc.
So, Jules had been in Boston for a conference and Steering Committee Meeting of the Multi-Regional Clinical Trials (MRCT) Center at Harvard and arrived back home tired and starving. He said the hotel food had been miserable and couldn’t wait for a home cooked meal. We started with a salad, simple with wonderfully fresh: sweet tomatoes, mini tender cucumbers, green olives, crisp endive, perfect ripe avocados cut in bite-size cubes and a fresh lemon/olive oil dressing. Paul Hobbs pinot noir was the wine (photo above). Next a casserole (new recipe) using left-over turkey, golden raisins and spices from the Middle East and a new recipe for baked, kale and cheese, stuffed potatoes. Last the dessert described above, Persimmon Custard Cake, which was scrumptious, if I do say so myself.
Holiday time has arrived in Manhattan and we hardly experienced fall colors, Alas, tempus fugit.
From Our Table to Yours!