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Partnerships in Clinical Trials Meeting in Boston
Right before lunch, on Thursday April 23 at 12:30, at the Innovation Theatre Presentations at the Partnerships in Clinical Trials Meeting in Boston, Dr. Jules Mitchel will be presenting Target Health's approach to the paperless clinical trial. This will be a brief yet intense presentation and should leave you breathless. Our goal is to demonstrate clinical trials of the future, and if you're smart, you can do them right now. If you can build, test and release a clinical trial web-based application in a few days, then, using any web-based device you can do the following:
1. have eInformed Consent Forms (eICs)
2. allow patients to enter their own data
3. have sites enter source data in real time
4. verify the data in real time
And then, the data are the data
The Partnerships meeting will be held April 22-24, 2015 at the Boston Convention & Exhibition Center, Boston MA. Let us know if you will be attending so we can connect.
Sunset from Barker Dam at Joshua Tree National Park
Our friend and colleague James Farley has again shared a spectacular photo. This photo was taking during a break on some business in San Diego.
Joshua Tree National Park – Copyright JFarley Photography 2015
"As always, James Farley photography, takes my breath away! Joyce Hays, CEO, Target Health Inc.
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
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Human Microbiome Part 2
Get used to it! These are living on your face. This is one of two human face-mites, Demodex folliculorum, biota that live in the sebaceous glands and hair follicles on our faces
The human microbiome is the aggregate of microorganisms, a microbiome that resides on the surface and in deep layers of skin (including in mammary glands), in the saliva and oral mucosa, in the conjunctiva, and in the gastrointestinal tracts. They include bacteria, 1) ___, and archaea. One study indicated that microorganisms outnumber human cells 10 to 1. A total of 100 trillion seems to be an agreed upon total number. Some of these organisms perform tasks that are useful for the human host. The medical community has begun research of all aspects of the human microbiome; however, the majority of these biota have been poorly researched, up until now. We need to map them all and to understand the role they play, however communities of microflora have been shown to change their behavior in diseased individuals. This is all important for personalized 2) ___, a fast growing field and a more comprehensive knowledge of our immune system. Those microorganisms that are expected to be present, and that under normal circumstances do not cause disease, but instead participate in maintaining health, are deemed members of the normal flora. Though widely known as microflora, this is, in technical terms, a misnomer, since the word root flora pertains to plants, and biota refers to the total collection of organisms in a particular ecosystem. Recently, the more appropriate term microbiota is applied, though its use has not eclipsed the entrenched use and recognition of flora with regard to bacteria and other microorganisms. Both terms are being used in different literature.
Studies have questioned whether the decline in biota (including microfauna) as a result of human intervention might impede human health. Most of the microbes associated with 3) ___ appear to be not harmful at all, but rather assist in maintaining processes necessary for a healthy body. A surprising finding was that at specific sites on the body, a different set of microbes may perform the same function for different people. For example, on the tongues of two people, two entirely different sets of organisms will break down sugars in the same way. This suggests that medical science may be forced to abandon the one only microbe model of infectious disease, and rather pay attention to functions of groups of microbes that have somehow gone awry. Populations of microbes (such as bacteria and yeasts) inhabit the skin and mucosal surfaces in various parts of the body. Their role forms part of normal, healthy human physiology, however if microbe numbers grow beyond their typical ranges (often due to a compromised immune 4) ___) or if microbes populate (such as through poor hygiene or injury) areas of the body normally not colonized or sterile (such as the blood, or the lower respiratory tract, or the abdominal cavity), disease can result (causing, respectively, bacteremia/sepsis, pneumonia, and peritonitis).
Starting in 2012, some 200 researchers from 80 research institutions comprising the Human Microbiome Project (HMP) Consortium have used advanced DNA-sequencing to identify and catalogue the thousands of microorganisms co-existing with humans. This study examined, among other things, the carbohydrate active enzymes from microbial populations from twelve sites on and in the human body, and concluded that microbes colonize each site to utilize the available sugars. Considerable variation was found in the enzymes for carbohydrate metabolism from site to site, and the researchers suggested that the composition of local carbohydrate metabolites may be the most important factor shaping the composition of microbial sub-communities of the human microbiome. Healthy individuals have been found to host thousands of bacterial types, different body sites having their own distinctive communities. Skin and vaginal sites showed smaller diversity than the mouth and gut, these showing the greatest richness. The bacterial makeup for a given site on a body varies from person to person, not only in type, but also in abundance. Bacteria of the same species found throughout the mouth are of multiple subtypes, preferring to inhabit distinctly different locations in the mouth. Even the enterotypes in the human gut, previously thought to be well-understood, are from a broad spectrum of communities with blurred taxon boundaries.
It is estimated that 500 to 1,000 species of bacteria live in the human gut. Bacterial cells are much smaller than human cells, and there are at least ten times as many bacteria as human cells in the body (approximately 1014 versus 1013). The mass of microorganisms are estimated to account for 1-3% total body 5) ___. Though members of the flora are found on all surfaces exposed to the environment (on the skin and eyes, in the mouth, nose, small intestine), the vast majority of bacteria live in the 6) ___ intestine. Many of the bacteria in the digestive tract, collectively referred to as the gut flora, are able to break down certain nutrients such as carbohydrates that humans otherwise could not digest. The majority of these commensal bacteria are anaerobes, meaning they survive in an environment with no 7) ___. Normal flora bacteria can act as opportunistic pathogens at times of lowered immunity. Escherichia coli (a.k.a. E. coli) is a bacterium that lives in the colon; it is an extensively studied model organism and probably the best-understood bacterium of all. Certain mutated strains of these gut bacteria do cause disease; an example is E. coli O157:H7.
A number of types of bacteria, such as Actinomyces viscosus and A. naeslundii, live in the mouth, where they are part of a sticky substance called plaque. If this is not removed by brushing, it hardens into calculus (also called tartar). The same bacteria also secrete acids that dissolve tooth enamel, causing tooth decay. Archaea are present in the human gut, but, in contrast to the enormous variety of bacteria in this organ, the numbers of archaeal species are much more limited. The dominant group are the methanogens, particularly Methanobrevibacter smithii and Methanosphaera stadtmanae. However, colonization by methanogens is variable, and only about 50% of humans have easily detectable populations of these organisms. A relationship has been proposed between the presence of some methanogens and human periodontal disease.
Fungi, in particular yeasts, are present in the human gut. The best-studied of these are Candida species. This is because of their ability to become pathogenic in immuno-compromised hosts. Yeasts are also present on the skin, particularly Malassezia species, where they consume oils secreted from the sebaceous glands. Among the biota living on human skin are two face mites, namely Demodex folliculorum and Demodex brevis, which reside in the sebaceous glands and hair follicles. These two Demodex face-mite species are obligate human saprophytic ecto-parasites which feed on skin cells, hormones and oils. Presence of mites is usually asymptomatic and does not imply human Demodicosis, a disease caused by the face-mites and which is considered as a multi-factorial disease, influenced by external and/or internal factors. Presence of mites in different groups of people have been found to range from 23% to 100%.
Microbial colonization in the human body begins shortly after 8) ___. The skin acts as a barrier to deter the invasion of pathogenic bacteria. The human skin contains microbes that reside either in or on the skin and can be residential or transient. Glands such as oil or sweat glands provide the bacteria with water, amino acids, and fatty acids that provide nutrients for the microbes. A small number of bacteria are normally present in the conjunctiva. The lachrymal glands continuously secrete, keeping the conjunctiva moist, while intermittent blinking lubricates the conjunctiva and washes away foreign material. Tears contain bactericides such as lysozyme, so that microorganisms have difficulty in surviving the lysozyme and settling on the epithelial surfaces. Some pathogens able to infect the conjunctiva. Newborn infants are particularly prone to bacterial attachment. Chlamydia and Neisseria may be present in an infected mother and show up on the cervical and vaginal epithelium – in such cases the newborn's eyes may be treated with silver nitrate or antibiotics.
The gut flora is the human flora of microorganisms that normally live in the digestive tract and can perform a number of useful functions for their hosts. The bacterial flora of the human gut encompasses a wide variety of microorganisms that aid in digestion, the synthesis of vitamins, and creating enzymes not produced by the human body. According to scientific research, the human gut consists of different enterotypes that have an inconspicuous impact on human health. It is suggested that the intestines of infants are colonized by bacteria that alter the gut to support those specific bacteria. The average human body, consisting of about ten trillion cells, has about ten times that number of microorganisms in the gut. The metabolic activity performed by these bacteria is equal to that of a virtual organ, leading to gut bacteria being termed a forgotten organ. Due to the high acidity of the stomach, most microorganisms cannot survive. The main bacterial inhabitants of the stomach include: Streptococcus, Staphylococcus, Lactobacillus, Peptostreptococcus, and types of yeast. Helicobacter pylori is a Gram-negative spiral organism that establishes on gastric mucosa causing chronic gastritis and peptic ulcer disease. H. pylori has also been classified as a carcinogen for gastric cancer. The small intestine contains a trace amount of microorganisms due to the proximity and influence of the stomach. The bacterial flora of the small intestine aid in a wide range of intestinal functions. The bacterial flora provide regulatory signals that enable the development and utility of the gut. The large intestine contains the largest bacterial ecosystem in the human 9) ___. Factors that disrupt the microorganism population of the large intestine include antibiotics, stress, and parasites. Bacteria make up most of the flora in the colon and 60% of the dry mass of feces. This fact makes feces an ideal source to test for gut flora for any tests and experiments by extracting the nucleic acid from fecal specimens. This form of testing is also often preferable to more invasive techniques, such as biopsies.
Research suggests that the relationship between gut flora and humans is not merely commensal (a non-harmful coexistence), but rather is a mutualistic, symbiotic relationship. Though people can survive with no gut flora, these microorganisms perform a host of useful functions, such as fermenting unused energy substrates, training the immune system, preventing growth of harmful species, regulating the development of the gut, producing vitamins for the host (such as biotin and vitamin K), and producing hormones to direct the host to store fats. Extensive modification and imbalances of the gut microbiota and its microbiome or gene collection are associated with obesity. However, in certain conditions, some species are thought to be capable of causing disease by causing infection or increasing cancer risk for the host. The human mouth is an ideal environment of the existence and growth of microorganisms. It provides a source of water and nutrients, as well as a moderate temperature. Resident bacteria of the mouth adhere to the teeth and gums to resist mechanical flushing from the mouth to stomach where they are destroyed by hydrochloric acid. Like the oral cavity, the upper and lower respiratory system possess mechanical deterrents to remove bacteria. Goblet cells produce mucous which traps bacteria and moves them out of the respiratory system via continuously moving ciliated epithelial cells. In addition, a bactericidal effect is generated by nasal mucus which contains the enzyme lysozyme. The upper and lower respiratory tract appears to have a normal bacterial flora. Some bacteria considered normal biota in the respiratory tract can cause serious disease especially in immuno-compromised individuals. Unusual bacterial flora in the respiratory system can be detrimental and have been seen in patients with cystic 10) ___. The bacterial flora found in the lungs of patients with cystic fibrosis often contains antibiotic-resistant and slow-growing bacteria, and the frequency of these pathogens changes in relation to age.
ANSWERS: 1) fungi; 2) medicine; 3) humans; 4) system; 5) mass; 6) large; 7) oxygen; 8) birth; 9) body; 10) fibrosis
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Robert Hooke (1635-1703) FRS (Fellow of the Royal Society)
Modern portrait of Robert Hooke (Rita Greer 2004), based on descriptions by Aubrey and Waller; no contemporary depictions of Hooke are known to survive. Either they were destroyed by the great London fire in 1666, or never existed Because Hooke believed he was very ugly and didn't want to leave his likeness behind. Those who wrote about his appearance, were not complementary.
Robert Hooke was an English natural philosopher, scientist, architect and polymath. Because he was erudite in so many fields, as well as fascinating to read about, we are giving him more space than usual. Hooke's life is also interesting in that it shows how in England then and now, a person from a relatively modest background, could rise to the positions that he eventually occupied. Robert Hooke's adult life was comprised of three distinct periods: first, as a scientific inquirer lacking money; next, achieving great wealth and standing through his reputation for hard work and scrupulous honesty following the great fire of 1666, and finally, in addition to aging and more susceptible to illness, he became involved in jealous intellectual disputes, which we now settle with patent and copyright laws. These issues may have contributed to his relative historical obscurity.
Hooke was at one time, simultaneously the curator of experiments of the Royal Society and a member of its council, a situation that today, we might call a conflict of interest. Hooke was also Gresham Professor of Geometry and a Surveyor to the City of London after the Great Fire of London, in which capacity he appears to have performed more than half of all the surveys after the fire. He was also an important architect of his time – though few of his buildings now survive and some of those are generally misattributed – and was instrumental in devising a set of planning controls for London whose influence remains today. Allan Chapman has characterized him as England's Leonardo. Robert Gunther's Early Science in Oxford, a history of science in Oxford during the Protectorate, Restoration and Age of Enlightenment, devotes five of its fourteen volumes to Hooke.
Hooke studied at Wadham College during the Protectorate where he became one of a tightly knit group of ardent Royalists led by John Wilkins. Here he was employed as an assistant to Thomas Willis and to Robert Boyle, for whom he built the vacuum pumps used in Boyle's gas law experiments. He built some of the earliest Gregorian telescopes and observed the rotations of Mars and Jupiter. In 1665 he inspired the use of microscopes for scientific exploration with his book, Micrographia. Based on his microscopic observations of fossils, Hooke was an early proponent of biological evolution. He investigated the phenomenon of refraction, deducing the wave theory of light, and was the first to suggest that matter expands when heated and that air is made of small particles separated by relatively large distances. He performed pioneering work in the field of surveying and map-making and was involved in the work that led to the first modern plan-form map, though his plan for London on a grid system was rejected in favor of rebuilding along the existing routes. He also came near to an experimental proof that gravity follows an inverse square law, and hypothesized that such a relation governs the motions of the planets, an idea which was subsequently developed by Isaac Newton. Much of Hooke's scientific work was conducted in his capacity as curator of experiments of the Royal Society, a post he held from 1662, or as part of the household of Robert Boyle.
Hooke's microscope, from an engraving in Micrographia.
Much of what is known of Hooke's early life comes from an autobiography that he commenced in 1696 but never completed. Richard Waller mentions it in his introduction to The Posthumous Works of Robert Hooke, M.D. S.R.S., printed in 1705. The work of Waller, along with John Ward's Lives of the Gresham Professors and John Aubrey's Brief Lives, form the major near-contemporaneous biographical accounts of Hooke. Robert Hooke was born in 1635 in Freshwater on the Isle of Wight to John Hooke and Cecily Gyles. Robert was the last of four children, two boys and two girls, and there was an age difference of seven years between him and the next youngest. Their father John was a Church of England priest, the curate of Freshwater's Church of All Saints, and his two brothers (Robert's uncles) were also ministers. Robert Hooke was expected to succeed in his education and join the Church. John Hooke also was in charge of a local school, and so was able to teach Robert, at least partly at home perhaps due to the boy's frail health. He was a Royalist and almost certainly a member of a group who went to pay their respects to Charles I when he escaped to the Isle of Wight. Robert, too, grew up to be a staunch monarchist. As a youth, Robert Hooke was fascinated by observation, mechanical works, and drawing, interests that he would pursue in various ways throughout his life. He dismantled a brass clock and built a wooden replica that, by all accounts, worked well enough, and he learned to draw, making his own materials from coal, chalk and ruddle (iron ore). On his father's death in 1648, Robert was left a sum of forty pounds that enabled him to buy an apprenticeship. With poor health throughout his life but evident mechanical facility, his father had in mind that he might become a watchmaker or limner (a decorator of illuminated manuscripts), though Hooke was also interested in painting. Hooke was an apt student, so although he went to London to take up an apprenticeship, and studied briefly with Samuel Cowper and Peter Lely, he was soon able to enter Westminster School in London, under Dr. Richard Busby. Hooke quickly mastered Latin and Greek, made some study of Hebrew, and mastered Euclid's Elements. Here, too, he embarked on his lifelong study of mechanics. It appears that Hooke was one of a group of students whom Busby educated in parallel to the main work of the school. Contemporary accounts say he was not much seen in the school, and this appears to be true of others in a similar position. Busby, an ardent and outspoken Royalist (he had the school observe a fast-day on the anniversary of the King's beheading), was by all accounts trying to preserve the nascent spirit of scientific inquiry that had begun to flourish in Carolean (Restoration) England but which was at odds with the literal Biblical teachings of the Protectorate. To Busby and his select students, the Anglican Church was a framework to support the spirit of inquiry into God's work, those who were able were destined by God to explore and study His creation, and the priesthood functioned as teachers to explain it to those who were less able. This was exemplified in the person of George Hooper, the Bishop of Bath and Wells, whom Busby described as the best scholar, the finest gentleman and will make the completest bishop that ever was educated at Westminster School.
Robert Boyle
In 1653, Hooke (who had also undertaken a course of twenty lessons on the organ) secured a chorister's place at Christ Church, Oxford. He was employed as a chemical assistant to Dr Thomas Willis, for whom Hooke developed a great admiration. There he met the natural philosopher Robert Boyle, and gained employment as his assistant from about 1655 to 1662, constructing, operating, and demonstrating Boyle's machina Boyleana or air pump. He did not take his Master of Arts until 1662 or 1663. In 1659 Hooke described some elements of a method of heavier-than-air flight to Wilkins, but concluded that human muscles were insufficient to the task. Hooke himself characterized his Oxford days as the foundation of his lifelong passion for science, and the friends he made there were of paramount importance to him throughout his career, particularly Christopher Wren. Wadham was then under the guidance of John Wilkins, who had a profound impact on Hooke and those around him. Wilkins was also a Royalist, and acutely conscious of the turmoil and uncertainty of the times. There was a sense of urgency in preserving the scientific work which they perceived as being threatened by the Protectorate. Wilkins' philosophical meetings in his study were clearly important, though few records survive except for the experiments Boyle conducted in 1658 and published in 1660. This group went on to form the nucleus of the Royal Society. Hooke developed an air pump for Boyle's experiments based on the pump of Ralph Greatorex, which was considered, in Hooke's words, too gross to perform any great matter.
It is known that Hooke had a particularly keen eye, and was an adept mathematician, neither of which applied to Boyle. Gunther suggests that Hooke probably made the observations and may well have developed the mathematics of Boyle's law. Regardless, it is clear that Hooke was a valued assistant to Boyle and the two retained a mutual high regard. A chance surviving copy of Willis' pioneering De anima brutorum, a gift from the author, was chosen by Hooke from Wilkins' library on his death as a memento at John Tillotson's invitation. This book is now in the Wellcome Library. The book and its inscription in Hooke's hand are a testament to the lasting influence of Wilkins and his circle on the young Hooke. The Royal Society was founded in 1660, and in April 1661 the society debated a short tract on the rising of water in slender glass pipes, in which Hooke reported that the height water rose was related to the bore of the pipe (due to what is now termed capillary action). His explanation of this phenomenon was subsequently published in Micrography Observ. issue 6, in which he also explored the nature of the fluidity of gravity. On 5 November 1661, Sir Robert Moray proposed that a Curator be appointed to furnish the society with Experiments, and this was unanimously passed with Hooke being named. His appointment was made on 12 November, with thanks recorded to Dr. Boyle for releasing him to the Society's employment. In 1664, Sir John Cutler settled an annual gratuity of fifty pounds on the Society for the founding of a Mechanick Lecture, and the Fellows appointed Hooke to this task. On 27 June 1664 he was confirmed to the office, and on 11 January 1665 was named Curator by Office for life with an additional salary of 30 pounds to Cutler's annuity. Hooke's role at the Royal Society was to demonstrate experiments from his own methods or at the suggestion of members. Among his earliest demonstrations were discussions of the nature of air, the implosion of glass bubbles which had been sealed with hot air, and demonstrating that the Pabulum vitae and flammae were one and the same. He also demonstrated that a dog could be kept alive with its thorax opened, provided air was pumped in and out of its lungs, and noting the difference between venous and arterial blood. There were also experiments on the subject of gravity, the falling of objects, the weighing of bodies and measuring of barometric pressure at different heights, and pendulums up to 200 feet long (61 meters). Instruments were devised to measure a second of arc in the movement of the sun or other stars, to measure the strength of gunpowder, and in particular an engine to cut teeth for watches, much finer than could be managed by hand, an invention which was, by Hooke's death, in constant use. In 1663 and 1664, Hooke produced his microscopy observations, subsequently collated in Micrographia in 1665. On 20 March 1664, Hooke succeeded Arthur Dacres as Gresham Professor of Geometry. Hooke received the degree of Doctor of Physic in December 1691.
Antonie von Leeuwenhoek's work fully captured the attention of the Royal Society, and he began regularly corresponding with the Society (Robert Hooke) regarding his observations. He had at first been reluctant to publicize his findings. Despite the initial success of Leeuwenhoek's relationship with the Royal Society, this relationship was soon severely strained. In 1676, his credibility was questioned when he sent the Royal Society a copy of his first observations of microscopic single-celled organisms. Previously, the existence of single-celled organisms was entirely unknown. Thus, even with his established reputation with the Royal Society as a reliable observer, his observations of microscopic life were initially met with both skepticism and open ridicule. Eventually, in the face of Leeuwenhoek's insistence, the Royal Society arranged for Alexander Petrie, minister to the English Reformed Church in Delft, Benedict Haan, at that time Lutheran minister at Delft, and Henrik Cordes, then Lutheran minister at the Hague, accompanied by Sir Robert Gordon and four others to determine whether it was in fact Leeuwenhoek's ability to observe and reason clearly, or perhaps the Royal Society's theories of life itself that might require reform. Finally in 1677 Leeuwenhoek's observations were fully vindicated by the Society. He was elected to the Royal Society in February 1680. By the end of the 17th century, Leeuwenhoek had a virtual monopoly on microscopic study and discovery. Robert Hooke, also an early microscope pioneer, bemoaned that the field had come to rest entirely on one man's shoulders.
There is a widely reported story that Dr. Hooke corresponded with Thomas Newcomen in connection with Newcomen's invention of the steam engine. This story was discussed by Rhys Jenkins, a past President of the Newcomen Society, in 1936. Jenkins traced the origin of the story to an article Steam Engines by Dr. John Robison (1739-1805) in the third edition of the Encyclopaedia Britannica, which says There are to be found among Hooke's papers, in the possession of the Royal Society, some notes of observations, for the use of Newcomen, his countryman, on Papin's boasted method of transmitting to a great distance the action of a mill by means of pipes and that Hooke had dissuaded Newcomen from erecting a machine on this principle. Jenkins points out a number of errors in Robison's article, and questions whether the correspondent might in fact have been Newton, who Hooke is known to have corresponded with, the name being misread as Newcomen. A search by Mr. H W Dickinson of Hooke's papers held by the Royal Society, which had been bound together in the middle of the 18th century, i.e. before Robison's time, and carefully preserved since, revealed no trace of any correspondence between Hooke and Newcomen. Jenkins concluded that this story must be omitted from the history of the steam engine, at any rate until documentary evidence is forthcoming. In the intervening years since 1936 no such evidence has been found, but the story persists. For instance, in a book published in 2011 it is said that in a letter dated 1703 Hooke did suggest that Newcomen use condensing steam to drive the piston. Hooke was irascible, at least in later life, proud, and prone to take umbrage with intellectual competitors, though he was by all accounts also a staunch friend and ally and was loyal always to the circle of ardent Royalists with whom he had his early training at Wadham College, particularly Christopher Wren. His reputation suffered after his death and this is popularly attributed to a dispute with Isaac Newton over credit for his work on gravitation, the planets and to a lesser degree light. His dispute with Oldenburg about whether Oldenburg had leaked or passed on details of Hooke's watch escapement to others is another well-known example. Newton, as President of the Royal Society, did much to obscure Hooke, including, it is said, destroying (or failing to preserve) the only known portrait of the man. It did not help that the first life of Wren, Parentalis, was written by Wren's son, and tended to exaggerate Wren's work over all others. Hooke's reputation was revived during the twentieth century through studies of Robert Gunther and Margaret ?Espinasse. After a long period of relative obscurity he has now been recognized as one of the most important scientists of his age.
Hooke was apt to use ciphers and anagrams to guard (encrypt) his ideas; and by the way, he wasn't the only one. As curator of Experiments to the Royal Society he was responsible for demonstrating many ideas sent in to the Society, and there is evidence that he would subsequently assume some credit for these ideas. Hooke also was immensely busy and thus unable — or in some cases unwilling, pending a way of profiting from the enterprise via letters patent — to develop all of his own ideas. This was a time of immense scientific progress, and numerous ideas were developed in several places simultaneously. None of this should distract from Hooke's inventiveness, his remarkable experimental facility, and his capacity for hard work. His ideas about gravitation, and his claim of priority for the inverse square law, are outlined below. He was granted a large number of patents for inventions and refinements in the fields of elasticity, optics, and barometry. The Royal Society's Hooke papers (recently discovered after disappearing when Newton took over) will open up a modern reassessment.
Diagram of a louse from Hooke's Micrographia
Much has been written about the unpleasant side of Hooke's personality, starting with comments by his first biographer, Richard Waller, that Hooke was in person, but despicable and melancholy, mistrustful, and jealous. Waller's comments influenced other writers for well over two centuries, so that a picture of Hooke as a disgruntled, selfish, anti-social curmudgeon dominates many older books and articles. For example, Arthur Berry said that Hooke claimed credit for most of the scientific discoveries of the time. Sullivan wrote that Hooke was positively unscrupulous and possessing an uneasy apprehensive vanity in dealings with Newton. Manuel used the phrase cantankerous, envious, vengeful in his description. More described Hooke having both a cynical temperament and a caustic tongue. Andrade was more sympathetic, but still used the adjectives difficult, suspicious, and irritable in describing Hooke. The publication of Hooke's diary in 1935 revealed other sides of the man that ?Espinasse, in particular, has detailed carefully. She writes that the picture which is usually painted of Hooke as a morose and envious recluse is completely false. Hooke interacted with noted craftsmen such as Thomas Tompion, the clockmaker, and Christopher Cocks (Cox), an instrument maker. Hooke often met Christopher Wren, with whom he shared many interests, and had a lasting friendship with John Aubrey. Hooke's diaries also make frequent reference to meetings at coffeehouses and taverns, and to dinners with Robert Boyle. He took tea on many occasions with his lab assistant, Harry Hunt. Within his family, Hooke took both a niece and a cousin into his home, teaching them mathematics. Robert Hooke spent his life largely on the Isle of Wight, at Oxford, and in London. He never married, but his diary shows that he was not without affections for others. On March 3, 1703, Hooke died in London, having amassed a sizable sum of money, which was found in his room at Gresham College. He was buried at St Helen's Bishopsgate, but the precise location of his grave is unknown.
Hooke's drawing of a flea
In 1660, Hooke discovered the law of elasticity which bears his name and which describes the linear variation of tension with extension in an elastic spring. He first described this discovery in the anagram ceiiinosssttuv, whose solution he published in 1678 as Ut tensio, sic vis meaning As the extension, so the force. Hooke's work on elasticity culminated, for practical purposes, in his development of the balance spring or hairspring, which for the first time enabled a portable timepiece – a watch – to keep time with reasonable accuracy. A bitter dispute between Hooke and Christiaan Huygens on the priority of this invention was to continue for centuries after the death of both; but a note dated June 23, 1670 in the Hooke Folio, describing a demonstration of a balance-controlled watch before the Royal Society, has been held to favor Hooke's claim.
Cell structure of Cork by Hooke
It is interesting from a 20th century vantage point that Hooke first announced his law of elasticity as anagram. This was a method sometimes used by scientists, such as Hooke, Huygens, Galileo, and others, to establish priority for a discovery without revealing details. Hooke became Curator of Experiments in 1662 to the newly founded Royal Society, and took responsibility for experiments performed at its weekly meetings. This was a position he held for over 40 years. While this position kept him in the thick of science in Britain and beyond, it also led to some heated arguments with other scientists, such as Huygens (see above) and particularly with Isaac Newton and the Royal Society's Henry Oldenburg. In 1664 Hooke also was appointed Professor of Geometryat Gresham College in London and Cutlerian Lecturer in Mechanics. On 8 July 1680, Hooke observed the nodal patterns associated with the modes of vibration of glass plates. He ran a bow along the edge of a glass plate covered with flour, and saw the nodal patterns emerge. In acoustics, in 1681 he showed the Royal Society that musical tones could be generated from spinning brass cogs cut with teeth in particular proportions. While many of his contemporaries believed in the aether as a medium for transmitting attraction or repulsion between separated celestial bodies, Hooke argued for an attracting principle of gravitation in Micrographia of 1665. Hooke's 1666 Royal Society lecture On gravity added two further principles – that all bodies move in straight lines till deflected by some force and that the attractive force is stronger for closer bodies. Dugald Stewart, in his Elements of the Philosophy of the Human Mind, quoted Hooke's own words on his system of the world. I will explain, says Hooke, in a communication to the Royal Society in 1666, a system of the world very different from any yet received. It is founded on the following positions. 1. That all the heavenly bodies have not only a gravitation of their parts to their own proper centre, but that they also mutually attract each other within their spheres of action. 2. That all bodies having a simple motion, will continue to move in a straight line, unless continually deflected from it by some extraneous force, causing them to describe a circle, an ellipse, or some other curve. 3. That this attraction is so much the greater as the bodies are nearer. As to the proportion in which those forces diminish by an increase of distance, I own I have not discovered it. Hooke's 1670 Gresham lecture explained that gravitation applied to all celestial bodies and added the principles that the gravitating power decreases with distance and that in the absence of any such power bodies move in straight lines. Hooke published his ideas about the System of the World again in somewhat developed form in 1674, as an addition to An Attempt to Prove the Motion of the Earth from Observations. Hooke clearly postulated mutual attractions between the Sun and planets, in a way that increased with nearness to the attracting body. Hooke's statements up to 1674 made no mention, however, that an inverse square law applies or might apply to these attractions. Hooke's gravitation was also not yet universal, though it approached universality more closely than previous hypotheses.[32] Hooke also did not provide accompanying evidence or mathematical demonstration. On these two aspects, Hooke stated in 1674: Now what these several degrees [of gravitational attraction] are I have not yet experimentally verified (indicating that he did not yet know what law the gravitation might follow); and as to his whole proposal: This I only hint at present, having my self many other things in hand which I would first compleat, and therefore cannot so well attend it (i.e. prosecuting this Inquiry).
In November 1679, Hooke initiated a remarkable exchange of letters with Newton (of which the full text is now published). Hooke's ostensible purpose was to tell Newton that Hooke had been appointed to manage the Royal Society's correspondence. Hooke therefore wanted to hear from members about their researches, or their views about the researches of others; and as if to whet Newton's interest, he asked what Newton thought about various matters, giving a whole list, mentioning compounding the celestial motions of the planets of a direct motion by the tangent and an attractive motion towards the central body, and my hypothesis of the lawes or causes of springinesse, and then a new hypothesis from Paris about planetary motions (which Hooke described at length), and then efforts to carry out or improve national surveys, the difference of latitude between London and Cambridge, and other items. Newton's reply offered a fansy of my own about a terrestrial experiment (not a proposal about celestial motions) which might detect the Earth's motion, by the use of a body first suspended in air and then dropped to let it fall. The main point was to indicate how Newton thought the falling body could experimentally reveal the Earth's motion by its direction of deviation from the vertical, but he went on hypothetically to consider how its motion could continue if the solid Earth had not been in the way (on a spiral path to the centre). Hooke disagreed with Newton's idea of how the body would continue to move. A short further correspondence developed, and towards the end of it Hooke, writing on January 6, 1679 to Newton, communicated his supposition that the Attraction always is in a duplicate proportion to the Distance from the Center Reciprocall, and Consequently that the Velocity will be in a subduplicate proportion to the Attraction and Consequently as Kepler Supposes Reciprocall to the Distance. (Hooke's inference about the velocity was actually incorrect). In 1686, when the first book of Newton's ?Principia? was presented to the Royal Society, Hooke claimed that Newton had had from him the notion of the rule of the decrease of Gravity, being reciprocally as the squares of the distances from the Center. At the same time (according to Edmond Halley?s contemporary report) Hooke agreed that the Demonstration of the Curves generated therby was wholly Newton's.
A recent assessment about the early history of the inverse square law is that by the late 1660s, the assumption of an inverse proportion between gravity and the square of distance was rather common and had been advanced by a number of different people for different reasons Newton himself had shown in the 1660s that for planetary motion under a circular assumption, force in the radial direction had an inverse-square relation with distance from the center. Newton, faced in May 1686 with Hooke's claim on the inverse square law, denied that Hooke was to be credited as author of the idea, giving reasons including the citation of prior work by others before Hooke. Newton also firmly claimed that even if he had first heard of the inverse square proportion from Hooke, which he had not, he would still have some rights to it in view of his mathematical developments and demonstrations, which enabled observations to be relied on as evidence of its accuracy, while Hooke, without mathematical demonstrations and evidence in favor of the supposition, could only guess (according to Newton) that it was approximately valid at great distances from the center. On the other hand, Newton did accept and acknowledge, in all editions of the ?Principia', that Hooke (but not exclusively Hooke) had separately appreciated the inverse square law in the solar system. Newton acknowledged Wren, Hooke and Halley in this connection in the Scholium to Proposition 4 in Book 1. Newton also acknowledged to Halley that his correspondence with Hooke in 1679-80 had reawakened his dormant interest in astronomical matters, but that did not mean, according to Newton, that Hooke had told Newton anything new or original: yet am I not beholden to him for any light into that business but only for the diversion he gave me from my other studies to think on these things & for his dogmaticalness in writing as if he had found the motion in the Ellipsis, which inclined me to try it. One of the contrasts between the two men was that Newton was primarily a pioneer in mathematical analysis and its applications as well as optical experimentation, while Hooke was a creative experimenter of such great range, that it is not surprising to find that he left some of his ideas, such as those about gravitation, undeveloped. This in turn makes it understandable how in 1759, decades after the deaths of both Newton and Hooke, Alexis Clairaut, mathematical astronomer eminent in his own right in the field of gravitational studies, made his assessment after reviewing what Hooke had published on gravitation. One must not think that this idea ..of Hooke diminishes Newton's glory, Clairaut wrote; The example of Hooke serves to show what a distance there is between a truth that is glimpsed and a truth that is demonstrated
Hooke made tremendously important contributions to the science of timekeeping, being intimately involved in the advances of his time; the introduction of the pendulum as a better regulator for clocks, the balance spring to improve the timekeeping of watches, and the proposal that a precise timekeeper could be used to find the longitude at sea.
Anchor escapement
Henry Sully, writing in Paris in 1717, described the anchor escapement as an admirable invention of which Dr. Hooke, formerly professor of geometry inGresham College at London, was the inventor. William Derham another contemporary writer, also attributes it to Hooke.
Watch Balance Spring
Christiaan Huygens
Hooke recorded that he conceived of a way to determine longitude (then a critical problem for navigation), and with the help of Boyle and others he attempted to patent it. In the process, Hooke demonstrated a pocket-watch of his own devising, fitted with a coil spring attached to the arbour of the balance. Hooke's ultimate failure to secure sufficiently lucrative terms for the exploitation of this idea resulted in its being shelved, and evidently caused him to become more possessive of his inventions. There is substantial evidence to state with reasonable confidence, as Ward, Aubrey, Waller and others all do, that Hooke developed the balance spring independently of and some fifteen years before Christiaan Huygens, who published his own work in Journal de Scavans in February 1675.
Hooke's microscope
In 1665 Hooke published Micrographia, a book describing observations made with microscopes and telescopes, as well as some original work in biology. Hooke coined the term cell for describing biological organisms, the term being suggested by the resemblance of plant cells to cells of a honeycomb. The hand-crafted, leather and gold-tooled microscope he used to make the observations for Micrographia, originally constructed by Christopher White in London, is on display at the National Museum of Health and Medicine in Washington, DC. Micrographia also contains Hooke's, or perhaps Boyle and Hooke's, ideas on combustion. Hooke's experiments led him to conclude that combustion involves a substance that is mixed with air, a statement with which modern scientists would agree, but that was not widely understood, if at all, in the seventeenth century. Hooke went on to conclude that respiration also involves a specific component of the air. Partington even goes so far as to claim that if Hooke had continued his experiments on combustion it is probable that he would have discovered oxygen.
Drawings of the Moon and the Pleiades from Hooke's Micrographia
One of the observations in Micrographia was of fossil wood, the microscopic structure of which he compared to ordinary wood. This led him to conclude that fossilized objects like petrified wood and fossil shells, such as Ammonites, were the remains of living things that had been soaked in petrifying water laden with minerals. Hooke believed that such fossils provided reliable clues to the past history of life on earth, and, despite the objections of contemporary naturalists like John Ray who found the concept of extinction theologically unacceptable, that in some cases they might represent species that had become extinct through some geological disaster. Charles Lyell wrote the following in his Principles of Geology (1832). The Posthumous Works of Robert Hooke M.D.,'… appeared in 1705, containing ?A Discourse of Earthquakes' His treatise?is the most philosophical production of that age, in regard to the causes of former changes in the organic and inorganic kingdoms of nature. ?However trivial a thing,' he says, ?a rotten shell may appear to some, yet these monuments of nature are more certain tokens of antiquity than coins or medals, since the best of those may be counterfeited or made by art and design, as may also books, manuscripts, and inscriptions, as all the learned are now sufficiently satisfied has often been actually practised,' &c.; ?and though it must be granted that it is very difficult to read them and to raise a chronology out of them, and to state the intervals of the time wherein such or such catastrophes and mutations have happened, yet it is not impossible.
Hooke noted the shadows (a and b) cast by both the globe and the rings on each other in this drawing of Saturn
One of the more-challenging problems tackled by Hooke was the measurement of the distance to a star (other than the Sun). The star chosen was Gamma Draconis and the method to be used was parallax determination. After several months of observing, in 1669, Hooke believed that the desired result had been achieved. It is now known that Hooke's equipment was far too imprecise to allow the measurement to succeed. Gamma Draconis was the same star James Bradley used in 1725 in discovering the aberration of light. Hooke's activities in astronomy extended beyond the study of stellar distance. His Micrographia contains illustrations of the Pleiades star cluster as well as of lunar craters. He performed experiments to study how such craters might have formed. Hooke also was an early observer of the rings of Saturn, and discovered one of the first observed double-star systems, Gamma Arietis, in 1664.
A lesser-known contribution, however one of the first of its kind, was Hooke's scientific model of human memory. Hooke in a 1682 lecture to the Royal Society proposed a mechanistic model of human memory, which would bear little resemblance to the mainly philosophical models before it. This model addressed the components of encoding, memory capacity, repetition, retrieval, and forgetting – some with surprising modern accuracy. This work, overlooked for nearly 200 years, shared a variety of similarities with Richard Semon?s work of 1919, both assuming memories were physical and located in the brain. The model's more interesting points are that it (1) allows for attention and other top-down influences on encoding; (2) it uses resonance to implement parallel, cue-dependent retrieval; (3) it explains memory for short term; (4) it offers a single-system account of repetition and priming, and (5) the power law of forgetting can be derived from the model's assumption in a straightforward way. This lecture would be published posthumously in 1705 as the memory model was unusually placed in a series of works on the nature of light. It has been speculated that this work saw little review as the printing was done in small batches in a post-Newtonian age of science and was most likely deemed out of date by the time it was published. Further interfering with its success was contemporary memory psychologists' rejection of immaterial souls, which Hooke invoked to some degree in regards to the processes of attention, encoding and retrieval.
Church of St Mary Magdalene at Willen, Milton Keynes, designed by Hooke
Hooke was Surveyor to the City of London and chief assistant to Christopher Wren, in which capacity he helped Wren rebuild London after the Great Fire in 1666, and also worked on the design of London's Monument to the fire, the Royal Greenwich Observatory, Montagu House in Bloomsbury, and the infamous Bethlem Royal Hospital (which became known as ?Bedlam'). Other buildings designed by Hooke include The Royal College of Physicians(1679), Ragley Hall in Warwickshire, Ramsbury Manor in Wiltshire and the parish church of St Mary Magdalene at Willen in Milton Keynes, Buckinghamshire. Hooke's collaboration with Christopher Wren also included St Paul's Cathedral, whose dome uses a method of construction conceived by Hooke. Hooke also participated in the design of the Pepys Library, which held the manuscripts of Samuel Pepys? diaries, the most frequently cited eyewitness account of the Great Fire of London.
Hooke and Wren both being keen astronomers, the Monument was designed to serve a scientific function as a telescope for observing transits, though Hooke's characteristically precise measurements after completion showed that the movement of the column in the wind made it unusable for this purpose. The legacy of this can be observed in the construction of the spiral staircase, which has no central column, and in the observation chamber which remains in place below ground level. In the reconstruction after the Great Fire, Hooke proposed redesigning London's streets on a grid pattern with wide boulevards and arteries, a pattern subsequently used in the renovation of Paris, Liverpool, and many American cities, especially New York City. This proposal was thwarted by arguments over property rights, as property owners were surreptitiously shifting their boundaries. Hooke was in demand to settle many of these disputes, due to his competence as a surveyor and his tact as an arbitrator.
Strange but true, no authenticated portrait of Robert Hooke exists. This situation has sometimes been attributed to the heated conflicts between Hooke and Newton, although Hooke's biographer Allan Chapman rejects as a myth the claims that Newton or his acolytes deliberately destroyed Hooke's portrait. German antiquarian and scholar Zacharias Conrad von Uffenbach visited the Royal Society in 1710 and his account of his visit specifically mentions him being shown the portraits of ?Boyle and Hoock' (which were said to be good likenesses), but while Boyle's portrait survives, Hooke's has evidently been lost. In Hooke's time, the Royal Society met at Gresham College, but within a few months of Hooke's death Newton became the Society's president and plans were laid for a new meeting place. When the move to new quarters finally was made a few years later, in 1710, Hooke's Royal Society portrait went missing, and has yet to be found. Two contemporary written descriptions of Hooke's appearance have survived. The first was recorded by his close friend John Aubrey, who described Hooke in middle age and at the height of his creative powers: He is but of midling stature, something crooked, pale faced, and his face but little below, but his head is lardge, his eie full and popping, and not quick; a grey eie. He haz a delicate head of haire, browne, and of an excellent moist curle. He is and ever was temperate and modera.te in dyet, etc. The second is a rather unflattering description of Hooke as an old man, written by Richard Waller: As to his Person he was but despicable, being very crooked, tho' I have heard from himself, and others, that he was strait till about 16 Years of Age when he first grew awry, by frequent practising, with a Turn-Lath ? He was always very pale and lean, and laterly nothing but Skin and Bone, with a Meagre Aspect, his Eyes grey and full, with a sharp ingenious Look whilst younger; his nose but thin, of a moderate height and length; his Mouth meanly wide, and upper lip thin; his Chin sharp, and Forehead large; his Head of a middle size. He wore his own Hair of a dark Brown colour, very long and hanging neglected over his Face uncut and lank? Time magazine published a portrait, supposedly of Hooke, on July 3, 1939. However, when the source was traced by Ashley Montagu, it was found to lack a verifiable connection to Hooke. Moreover, Montagu found that two contemporary written descriptions of Hooke's appearance agreed with one another, but that neither matched the Time's portrait.
PS: Early scientists and astronomers used anagrams as a form of commitment scheme (encryption) to lay claim to new discoveries before their results were ready for publication. Galileo Galilei used the following anagram: smaismrmilmepoetaleumibunenugttauiras for Altissimum planetam tergeminum observavi (I have observed the most distant planet to have a triple form) for discovering the rings of Saturn.
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Promoting Maternal Interaction Improves Growth, Weight Gain in Preemies
During their first year, infants born preterm are at high risk for life-threatening infections, blindness, breathing problems, feeding problems, learning and developmental disabilities, and cerebral palsy. According to the U.S. Centers for Disease Control and Prevention, nearly 500,000 U.S. infants were born preterm in 2013, the most recent year for which statistics are available. Roughly 11% of births to Hispanics were preterm. It is common for preterm infants to grow more slowly than normal and it is well-known that infants who grow at an appropriate rate have the best chances for avoiding problems in their neurological development. A key element to growth inhibition is that infants born preterm often are not developed enough to feed on their own. Typically, the muscle control needed for infants to feed unassisted does not completely develop until the 34th week of pregnancy. Infants born before this time usually are fed through a nasogastric tube — a line passed through the nose and down the throat into the stomach. The study described below developed an intervention to help mothers stimulate their infant's alertness before feeding so that the infants would be better able to feed by mouth. The intervention also sought to spur the infants' social behaviors, such as keeping alert and looking at the mother, and neurological development, in hopes of offsetting at least some of the developmental delays often seen in preterm infants. The study was published on line in Advances in Neonatal Care (30 Mar 2015).
The intervention, Hospital to Home Transition — Optimizing Premature Infant's Environment (H-HOPE) instructs mothers on how to provide behavioral, social, and physical stimulation designed to engage the baby's attention and spur brain development. Compared to a term infant, preterm infants spend much more time sleeping and much less time awake and aware of what's going on around them. They're also are less able to communicate their needs than is a term infant. For this reason, the authors devised the H-HOPE intervention to show new mothers how to provide appropriate stimulation for their newborns, and how to pick up on their often times cues indicating that the baby is hungry. The intervention is made up of two parts. The first part, called the Auditory, Tactile, Visual and Vestibular (ATVV) intervention, teaches mothers how to interact socially with their infants and gently stimulate their senses. The other part teaches the mothers how to interpret and respond to their infants' behavioral cues while giving the ATVV intervention and when feeding them. The ATVV consists of a 15 minute intervention, undertaken twice daily, just before feeding. A nurse and community health worker team teaches the mother the steps involved. The mother is first taught to begin speaking to the infant in calm, soothing tones, before touching the infant. The sound of a female voice is intended to gently alert the infant that the caregiver is present. For the next ten minutes, the mother places the infant on his or her back, and gently massages the infant's head, chest, abdomen and arms, and then turns the infant over to massage the head and back. For the final five minutes, the infant is swaddled, held in the mother's arms, and rocked horizontally. Throughout the procedure, the mother is taught to make eye contact with the baby when the baby is awake. This sequence is repeated twice a day, from the time the baby reaches 31 weeks and continues after the baby is discharged from the hospital until 1 month after the approximate date the baby would have been born, had the pregnancy reached term. The other part of the intervention teaches the mother how to recognize, interpret, and respond to her preterm infant's subtle behavioral cues. For example, a term infant will cry loudly when he is hungry, and perhaps put his hand in his mouth. In contrast, a preterm infant may not cry, may only weakly pull his hand toward his mouth to signal that he is hungry.
The study enrolled 183 mothers and their preterm infants, born from the 29th through the 34th week of pregnancy. Half of the mothers were Hispanic. Roughly half of the mother-infant pairs were assigned at random to the H-HOPE intervention, and roughly half to another program that provided instruction on how to care for preterm infants. The study took place at two hospitals serving impoverished neighborhoods. Mothers received two visits from the nurse-community health advocate team while they were in the hospital to teach them the intervention's procedures and to monitor the mothers to make sure they carried out the steps correctly. The mothers also received two at-home visits from the nurse-community health advocate team after their infants had been discharged from the hospital. Study results showed that after the infants had completed the study, those who received the H-HOPE intervention weighed more, on average, than those who did not receive it. Infants in the H-HOPE group also grew more rapidly in length, especially during the last five days of their hospital stay. The study also found that the feeding abilities of the pre-term infants improved immediately after they received the ATVV intervention. Pre-term infants were fed with a modified bottle connected to a sensor that measured their mouth movements. Infants alternate periods of active sucking (bursts) with rest periods where they hold a nipple in their mouths but refrain from actively feeding. Among the specialized metrics the authors cataloged were the total number of times the infant sucked on the nipple during a feeding, as well as the number of sucks per burst. All infants were tested with the bottle and sensor just after they began oral feeding and each week while they remained in the hospital. By all of the recorded measurements, the infants in the ATVV group outpaced the control group in the ability to perform the mouth movements needed to feed on their own.
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Experimental Ebola Vaccine Safe, Prompts Immune Response
According to an article published online in The New England Journal of Medicine (1 April 2015), an early-stage clinical trial of an experimental Ebola vaccine conducted at the National Institutes of Health and the Walter Reed Army Institute of Research (WRAIR) found that the vaccine, called VSV-ZEBOV, was safe and elicited robust antibody responses in all 40 of the healthy adults who received it. The most common side effects were injection site pain and transient fever that appeared and resolved within 12 to 36 hours after vaccination. The VSV-ZEBOV candidate is one of two experimental Ebola vaccines now being tested in the phase 2/3 PREVAIL clinical trial that is enrolling volunteers in Liberia.
Scientists at the Public Health Agency of Canada developed the candidate vaccine. It was licensed to NewLink Genetics Corp. of Ames, Iowa, a company collaborating with Merck & Co. Inc., of Kenilworth, New Jersey, which is responsible for advancing this vaccine towards regulatory approval. The investigational vaccine is based on a genetically modified and attenuated vesicular stomatitis virus (VSV), a virus that mainly affects cattle. In the investigational vaccine, a gene for a VSV protein is replaced with a gene segment from a key protein in the Zaire species of Ebola virus. The vaccine does not contain the whole Ebola virus and therefore cannot infect vaccinated persons with Ebola.
The article summarizes results of the first 52 volunteers enrolled in the study: 26 at the NIH Clinical Center in Bethesda, Maryland, and 26 at the WRAIR clinic in Silver Spring, Maryland. Six volunteers at each site received a placebo injection of saline solution, and the remaining 40 received the experimental vaccine at either one of two different dosages (2×107 or 3×106 in 20 volunteers at each site.) The candidate vaccine's ability to stimulate immune responses was assessed by sampling the volunteers' blood at multiple time points following injection. (The blood sampling schedule differed between the two trial sites.) Of those volunteers tested at 14 days after injection, 93% (26 out of 28) of whose who had received vaccine developed antibodies against Zaire species of Ebola virus. Antibodies were detected in the remaining 14 volunteers who had received vaccine by 28 days after injection. Antibody responses were approximately three-fold greater in those who received the higher vaccine dose. This information was available to the designers of the PREVAIL trial and was used to guide the decision to use VSV-ZEBOV at the higher dosage level in that trial.
The volunteers tolerated the vaccine well. Thirty percent (12 out of 40) of those who received the vaccine experienced mild or moderate fever; in all but one case, fever appeared and resolved within 24 hours of vaccination. The VSV-ZEBOV vaccine is made from live, weakened VSV and self-limiting fever following immunization with a live virus vaccine is not unexpected. Some volunteers in a separate, Swiss study of this candidate vaccine reported experiencing arthritis that started in the second week after vaccination. Therefore, volunteers in the NIH-WRAIR study were specifically queried about new arthritis symptoms. No episodes of frank arthritis were reported by any volunteer.
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Providing Timely Patient Access to High-Quality, Safe and Effective Medical Devices
Again and again, FDA is a head of the curve promoting innovative concepts to accelerate products to the market to fulfill unmet needs.
The following was abstracted from a blog by Jeffrey Shuren, M.D., J.D., Director of FDA's Center for Devices and Radiological Health (CDRH) and posted inFDA Voice.
Patients with life-threatening or irreversibly debilitating conditions often lack treatment and diagnostic options. For these patients, earlier access to promising new devices is critically important. At the same time, delayed access may mean the difference between life and death, or may result in irreversible disability. In weighing the benefits and risks of new technologies for these patients, FDA understands the need to place greater weight on the benefit of earlier access, and to also account for the risks of delayed access. That's why FDA has developed the Expedited Access Program (EAP) to speed qualifying devices to patients with life-threatening or irreversibly debilitating conditions without compromising FDA's high standards for safety and effectiveness.
Under this voluntary program, sponsors of devices for life-threatening or irreversibly debilitating conditions that meet an unmet need can request an EAP designation. Also under this program, CDRH staff, including senior management, work collaboratively with developers of such devices earlier and more often. These efforts include the creation of a Data Development Plan that provides predictability and leverages postmarket data collection. The Data Development Plan will shift premarket data collection to the postmarket setting, to the extent appropriate, taking into account the public health benefit of these devices, while still meeting the U.S. approval standard of reasonable assurance of safety and effectiveness. Starting April 15th, this program will be up and running and we will begin to accept requests for EAP designation.
The premarket data must be adequate to support FDA's high standard for premarket review but can include data based on an intermediate endpoint or a surrogate endpoint reasonably likely to predict clinical benefit. Another important feature of the EAP is how FDA decides that the benefits of a novel device for patients with life-threatening or irreversibly debilitating conditions outweigh its risks. Under the EAP, FDA may accept a greater degree of uncertainty if it is sufficiently balanced by other factors, including the probable benefits to having earlier access to the device. If, after careful analysis, FDA determines that some data can be collected after the device is on the market, then patients in need will benefit sooner. A few of the factors that can enter into this analysis include a low probability of serious harm, a high likelihood that postmarket surveillance can quickly identify instances of serious patient harm and a high likelihood that postmarket data collection will be completed in a timely manner.
FDA considers this balancing of premarket and postmarket data collection to be so important that we made it one of our three 2014-2015 strategic priorities, along with strengthening the clinical trial enterprise and providing excellent customer service. In addition to issuing a guidance document outlining our EAP program for devices to treat or diagnose life-threatening or irreversibly debilitating conditions, FDA is issuing a guidance on balancing premarket and postmarket data collection. It describes the circumstances under which postmarket data collection is appropriate for PMAs, whether or not they meet the criteria for the EAP, and provides many useful examples. Once EAP products come to FDA for review, they will qualify for priority review. This feature, combined with the other elements of the EAP program, will reduce the time it takes to develop important new medical devices for patients with unmet medical needs and it will do so without ever lowering our standards.
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Baked (Moist) Halibut with Creamy Red Pepper/Miso Sauce & Capers
This delicious sauce keeps the halibut moist ©Joyce Hays, Target Health Inc.
3 red bell peppers roasted in oven
1 yellow pepper roasted in oven
1 can (15 ounces) chickpeas, drained through strainer then on paper towel
1.5 teaspoons golden miso which is the same as traditional white miso
1 container of tofutti (8 ounces of tofu cream cheese)
3 anchovy fillets, minced
2 garlic cloves, minced or sliced
Pinch chili flakes (optional)
Pinch kosher or sea salt
Pinch black pepper (or grind to your taste)
2 (6- to 8-ounce) halibut fillets
2 Tablespoons drained capers, patted dry
Juice of 1/2 to 1 lime, plus first use zest of 1/2 lime
Fresh chopped parsley, for serving
1. Preheat oven to 400.
2. Clean the peppers, cut in half, remove seeds and roast for about 30-40 minutes or until soft, but not burned. Remove and cool slightly
3. Clean your fish.
4. One spray of olive oil or canola, onto a baking dish. With a brush spread the oil around to cover the dish.
5. Combine all the ingredients except fish and the parsley, in a food processor. Pulse until smooth. .
6. Use a spatula to get all of the sauce out and pour all of the sauce over the fish
7. Lower temperature to 350 and bake for 20 minutes.
8. Remove and serve with parsley sprinkled over the fish
Just poured the sauce over the halibut ©Joyce Hays, Target Health Inc.
Going into the oven ©Joyce Hays, Target Health Inc.
Oven to table, and sprinkled fresh parsley on top ©Joyce Hays, Target Health Inc.
Friday night was a fabulous meal.
We started with two different white wines, Hall (Napa)Vineyards Sauvignon Blanc and Cloudy Bay (New Zealand) Sauvignon Blanc, just to compare the two. We both love Hall cabernet, so assumed we'd like the Hall whites.
Jules loved the Hall (I didn't) so he had that and I drank the Cloudy Bay. Hall Vineyards is a highly respected winery and I expected to like their white, and the taste buds in the front of my mouth were okay with it, but then the lingering taste was so sharply acidic (grapefruity), I couldn't go on and had to switch to the Cloudy Bay and then onto my favorite, so far, Te Koko, from the same New Zealand vineyard.
Hall Vineyards Sauvignon Blanc ©Joyce Hays, Target Health Inc.
Cloudy Bay Sauvignon Blanc ©Joyce Hays, Target Health Inc.
After a toast, which we always do, we started with a fresh tomato/avocado salad with a simple lemon/oil dressing; Then the baked halibut with tiny elbow pasta and the baked zucchini circles, which I'm still trying to perfect before presenting in the On Target Newsletter. Jules gave the halibut with red sauce 5 stars (from 1 to 5, with 5 being tops).
I would say that the sauce has secret ingredients, that took a fair amount of experimenting to arrive at. I've found that chick peas pureed, give a dish a certain body and anchovies used in exactly the right amount add a rich flavor that you would never say is fishy. Anchovies are a mysterious ingredient like a spice. In the right amount, the flavor is heightened and you would never guess it was there.
I've been using tofutti for so long I sort of take it for granted, but it's a wonderful addition to many of my recipes; plus perfect for weekend brunch bagels & cream cheese substitute, with our neighborhood's delicate thinly sliced nova salmon.
I'm starting to experiment more with miso and finding it an excellent ingredient. More with miso in recipes to come.
For dessert we are loving my recent discovery of Cara Cara orange segments. First of all, they are a beautiful color, so even before you taste them, they're inviting. We like to spear them with a tiny fork. These oranges are so sweet, that if you were thinking about a fattening sweet dessert, like, say, chocolate layer cake, you would be satisfied after eating these Cara Cara. We shared one container of them, and Jules drinks the small amount of juice down to the last drop.
This was a wonderful dinner!
Luscious sweet Cara Cara Orange Segments from California, at their peak right now. ©Joyce Hays, Target Health Inc.
PS: If you're wondering what to buy tickets for, when you come to Manhattan, try the new musical, Dr Zhivago, which we just saw with family from Seattle. The music for the most part is lovely and good voices; the history is correct; and how can a show miss with a plot based on one of the great novels of the 20th Century. (Nobel prize for Boris Pasternak)
If you're in Manhattan, let us know.
From Our Table to Yours!
Bon Appetit!


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Captain: George Fortune
Subject: Maths
Year: 4
Proudest Sporting Moment: Helping the pool team to the top of Division 2 last year to get us promoted into Division 1!
George is working really hard on his website bio right now- check back soon for lots of information about doing pool at Trinity!
Any questions in the meantime? Contact email@example.com.

subset: commoncrawl


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3D InCites Technical Advisory Board
Sitaram R. Arkalgud, Ph.D., VP of 3D Technology, Invensas Corp. San Jose, CA
Sitaram Arkalgud is Vice President of 3D Technology at Invensas Corporation, a complete Interconnectology solutions provider for advanced mobile applications. Previously, Arkalgud started and led 3D IC development at SEMATECH, where the focus was on delivering manufacturable process technologies for 3D interconnects. In addition, he has worked in a variety of roles spanning R&D and manufacturing in memory and logic technologies at Infineon/Qimonda and Motorola. Arkalgud holds a doctorate and master's degree in materials engineering from Rensselaer Polytechnic Institute in Troy, NY, and a bachelor's degree in metallurgical engineering from Karnataka Regional Engineering College, Suratkal, India. He is the author of several publications and holds 14 U.S. patents.
Rozalia Beica, CTO, Dow Electronic Materials
Rozalia Beica is global director for new business development at Dow Electronic Materials. She is an international award (R&D 100) winning scientist with over 60 publications and several patents. For more than 16 years, Rozalia has been involved in the research, application and strategic marketing of Advanced Packaging and 3D IC technologies, with global leading responsibilities at Yole Dévelopeement, and for materials (Rohm and Haas), equipment (Semitool, Applied Materials, Lam Research) and device manufacturing (Maxim IC) organizations. She has a Global Executive MBA from IE Business School (Spain), M. Sc. In Management of Technology from KW University (USA) and a B.Sc/M.Sc in Chemical Engineering from Polytechnic University "Traian Vuia" (Romania)
Pascal Couderc, R&D Manager, 3D PLUS
Research and Development Manager at 3D PLUS since 2002, Pascal Couderc has led the development of 3D technologies, such as wire-free die-on-die (WDoDTM) technology for space, medical and industrial applications. He has been involved in more than ten European projects and has authored or co-authored publications and patents in the field of 3D technology. Prior to 3D Plus, he spent 11 years at Alcatel Group as engineering and technology specialist in the field of thin films, printed circuit boards and hybrid modules for microwave applications. He spent the first five years of his career at Airbus Group as a thin films application engineer. Pascal has a Ph.D. in Material Sciences with a specialty in thin film technology from Nantes University (France).
Yann Guillou, Marketing Manager, UnitySC, France
Yann Guillou is the marketing manager at UnitySC in Grenoble, France, where he is responsible for UnitySC global marketing strategy, product, and marketing communications. Previously, he served as Business Development Manager at SEMI Europe Grenoble Office, where he was responsible for the development of SEMI activities in France & Southern Europe in Semiconductor, PV, and Emerging markets and the coordination of SEMI standard activities in Europe. Previously, Yann worked on Advanced Packaging activities within the Back-End Sourcing and CTO & Strategic Planning office of ST-Ericsson. His main interest was 3D integration and TSV. He started his career at CEA-Leti before joining ST Microelectronics and successively worked at ST-NXP Wireless and ST-Ericsson. Yann holds an MS in materials and nanotechnology from the National Institute of Applied Sciences and a master of management of technology and innovation from Grenoble Business School.
Erik Jan Marinissen, Principal Scientist at IMEC, Leuven, Belgium
Erik Jan Marinissen is Principal Scientist at the world-renowned research institute imec in Leuven, Belgium, where he is responsible for research on test and design-for-test, covering topics as diverse as TSV-based 3D-stacked ICs, silicon photonics, CMOS technology nodes below 10nm, and STT-MRAMs. In addition, he is Visiting Researcher at the Eindhoven University of Technology, the Netherlands. Previously, he worked at NXP Semiconductors and Philips Research Laboratories in Eindhoven. Marinissen holds an MSc degree in Computing Science (1990) and a PDEng degree in Software Technology (1992), both from Eindhoven University of Technology. He is (co-)author of 280+ journal and conference papers and (co-) inventor on twelve granted US/EP patent families. Additionally, he is the recipient of numerous industry awards and serves on a multitude of editorial boards and has chaired numerous workshops on 3D Test.
Peter Ramm, Department Head, Heterogenous Systems Integration, Fraunhofer EMFT, Munich, Germany
Dr. Peter Ramm is responsible for the key competence "Si Processes, Device, and 3D Integration". He received physics and Dr. rer. nat. degrees from the University of Regensburg and subsequently worked for Siemens in the DRAM facility where he was responsible for process integration. In 1988 he joined Fraunhofer IFT in Munich, focusing for more than 25 years on 3D integration technologies. Peter Ramm is author or co-author of over 100 publications and 24 patents. He received the "Ashman Award 2009" from the International Electronics Packaging Society (IMAPS) "For Pioneering Work on 3D IC Stacking and Integration and leading-edge work on SiGe and Si technologies". Peter is Fellow and Life Member of IMAPS, organizing committee and founding member of IEEE 3DIC conference and co-editor of Wiley´s "Handbook of 3D Integration", vol. 1, 2 & 3 and Wiley´s "Handbook of Wafer Bonding".
Herb Reiter, Founder, eda2asic Consulting, Palo Alto, CA
After more than 20 years in technical and business roles at semiconductor and EDA companies, Herb Reiter founded eda2asic Consulting, Inc. in 2002 to focus on increasing the cooperation between EDA suppliers and ASIC vendors. In this role, Herb introduced innovative IC design tools to the major semiconductor vendors worldwide. In 2008 he expanded his scope into Multi-die ICs. As chair of the GSA's 3D-IC Working Group (2008-2011) and as SEMATECH business development consultant (2012 + '13), he broadened his horizon to include interposers and 3D-ICs technology, semiconductor materials as well as manufacturing, metrology and test equipment. In 2014 + '15 Herb consulted with Si2, to encourage development and standardization of data exchange formats for Interposer and 3D-IC design flows. Since early 2016 he is consulting with the newly formed Electronic System Design Alliance (formerly EDAC), to accelerate market acceptance of Multi-die ICs, the essential building blocks for the emerging System Scaling methodology.
Mark Scannell, Director Business Development Silicon Component Division, Leti, Grenoble, France
Mark Scannell has an engineering degree from National University Ireland. He has 25 years experience in the electronics and semiconductor industry. Starting his career as an electro-mechanical design engineer in 1989; he subsequently worked for one of the world's leading semiconductor equipment suppliers in various engineering positions and as a technology business director. Mark has lived in several countries; notably Japan, Germany, USA, and France. He joined CEA – Léti in 2005. Mark's current position is Business Development Director where his responsibilities include business development for silicon components, industrial contracts, and IP management.
Dr. Maaike M. Visser Taklo, Chief Scientist, SINTEF Digital, Oslo, Norway
Dr. Maaike M. Visser Taklo is a Chief Scientist at SINTEF Digital in Norway at the Department of Smart Sensor Systems which she joined in 2010. Within this department, she is Research Manager for the group "Advanced Packaging and Interconnects". From 1998 until 2010 she wa employed at the Department of Microsystems within SINTEF Digital where she worked on MEMS processing and was responsible for their wafer level bonding activities. She received her Ph.D. degree in Physical Electronics from the University of Oslo in 2002 for her thesis entitled "Wafer bonding for MEMS". She is the author or co-author of more than 50 papers and edited the book "Handbook of Wafer Bonding" (Wiley, 2012) together with P. Ramm and J-Q Lu. She has been part of the management team of several European projects and regularly performs proposal and project reviews for the European Commission.
E. Jan Vardaman, president and founder of TechSearch International, Inc., Austin, TX
E. Jan Vardaman founded TechSearch International Inc. in 1987, and since then has provided licensing and consulting services in semiconductor packaging. She is the co-author of How to Make IC Packages (published in Japanese by Nikkan Kogyo Shinbunsha), a columnist with Circuits Assembly/Printed Circuit Board Fabrication, and the author of numerous publications on emerging trends in semiconductor packaging and assembly. She is a member of IEEE CPMT, SMTA, MEPTEC, IPC, IMAPS, and SEMI. She was elected to two terms on the IEEE CPMT Board of Governors. Before founding TechSearch International, she served on the corporate staff of Microelectronics and Computer Technology Corporation (MCC), the electronics industry's first pre-competitive research consortium. She has made numerous presentations on developments in advanced packaging.
Paul Werbaneth, Global Product Marketing Director, Intevac, Inc.
Paul Werbaneth is the Global Product Marketing Director at Intevac, Inc. Since entering the semiconductor industry in 1980 he has been a hands-on Photolithography Process Sustaining Engineer in an Intel wafer fab; a Senior Plasma Etch Process Engineer with Hitachi High Technologies; the Country Manager for Tegal Japan Inc.; the Vice President of Marketing and Applications at Tegal Corporation; a Business Development Manager at EV Group; and an independent consultant and writer. Paul is a member of the SEMI Advanced Semiconductor Manufacturing Conference steering committee and was the ASMC 2004 Conference Co-Chair. He also serves on the steering committee for the NCCAVS Thin Film User Group. Paul's writing activities include his frequent contributions on heterogeneous integration and 2.5-D/3-D IC technology and commercialization to 3D InCites; his work as a Guest Editor for IEEE TRANSACTIONS ON SEMICONDUCTOR MANUFACTURING; the contributed chapter on TSV etching in the book 3D Integration for VLSI Systems. Follow him on Twitter @PFWerbaneth.
M. Juergen Wolf, Head of Division Wafer Level System Integration, Fraunhofer IZM-ASSID
M. Juergen Wolf studied electrical engineering and after an industrial career, he joined Fraunhofer Institute for Reliability and Microintegration (IZM), Berlin in 1994 working in the field of wafer level packaging and System in Package (SiP). Since 2011 he is head of department Wafer Level System Integration and also responsible for the management of ASSID – "All Silicon System Integration Dresden-ASSID" with its 300 mm 3D Wafer Level Integration line. He is also involved in and leading a number of research projects on the national, European and international level. Wolf is, among others, a European representative in the technical working group Assembly & Packaging of ITRS, a board member of EURIPIDES and JISSO as well as a member of IEEE and SMTA. He has authored and co-authored numerous scientific papers and reports in the field of microelectronic packaging and holds a number of patents.


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TWO SECONDARY schools in south Manchester were wrong to close on the day of the funeral of gangster Desmond Noonan, education chiefs have ruled.
The heads of Chorlton High School and St Thomas Aquinas RC High School in Chorlton decided to close on the day of the funeral at nearby Southern Cemetery, after advice from police.
But the move angered some parents and was slammed as a "bad decision" by council leader Cllr Richard Leese - prompting an investigation by council officials.
That investigation has concluded that the closure of the schools was unnecessary and was the result of "poor communications".
Now the council is to draw up new guidelines for such circumstances.
Cllr Jeff Smith, executive member for education, said: "We asked the chief executive to investigate urgently the closure of these schools. He has met the schools and the police and the investigation is now complete.
"Although advice was given to schools with the best of intentions, we are satisfied it was not necessary to close the schools. Poor communications led to youngsters being deprived of a day's education.
"It's a major decision to close a school for a day and we need a full review of how those decisions are made. It should be in only very exceptional circumstances that a school should close."
The heads say they took the decision to close last Friday after being told by the police that between 5,000 and 11,000 mourners were expected to converge on the area for the funeral - although the actual number turned out to be closer to 300.
Peter Kennedy, headteacher at the 1,400-pupil Chorlton High School, said: "I am pleased that it has now been acknowledged that police advice was, indeed, given to the schools, who also acted with the best of intentions and were not prepared to put the safety of their students and staff at risk in the light of that advice."
"I agree completely with the statement that `poor communications' were the root cause of this problem, placing the schools in an extremely difficult position. I hope that the lessons learned from this unfortunate episode will prevent such a situation from recurring in the future."
The police - who said at the time they "did not believe it was necessary" to close the schools - have confirmed that a number of discussions took place between the schools and police officers during the day before the funeral. But they say they believe the content of those discussions may have been "misinterpreted".
Chief Supt Alan Cooper, divisional commander for the south Manchester division, said: "We contacted four schools and one college within the Chorlton area to advise them of the event.
"During the afternoon period one of those schools re-contacted us requesting further details. They also requested an officer make contact with one of the other schools previously spoken to that morning.
"The schools sought clarification of the finer details and timings of the procession, which were provided.
"It is possible some of the content of those discussions was misinterpreted."
Headteacher Mr Kennedy admitted the decision to close sparked a mixed reaction from parents - some complained and others thanked the school for considering the pupils' safety.
Before the council's investigation was held, John O'Callaghan, headteacher at St Thomas Aquinas, said: "It's very regrettable and unfortunate that we have to close the school on any occasion. But we made the decision based on the advice given by the police in the best interests of everybody in the school and the local community."
Hundreds of people lined the street for the funeral of Noonan, one of Manchester's most notorious gangsters. A Requiem Mass was held at St Aidan's Catholic Church in Northern Moor and a procession, led by his brother Domenyk, travelled on to Southern Cemetery in Chorlton.
Noonan, 45, died after being stabbed in March.
The funeral was filmed for Channel 5 by documentary maker Donal McIntyre, whose film on the Noonans was shown four days after he died.
Riazat Butt joined hundreds of mourners as Desmond Noonan's funeral cortege wended its way through south Manchester
SHE stood on Wythenshawe Road, dabbing her eyes with a scrunched up paper tissue. With each wipe, the sobs became louder and the shaking more pronounced. "God bless you Dessy," she cries. "You were a lovely man."
The horse-drawn carriage rolls by and, with it, Desmond Noonan's funeral procession. "Hold your heads high," urges the woman. "You have nothing to be ashamed of."
Last Friday, a community mourned the passing of Dessy Noonan.
"I got very upset when he was described as a gangster," says the woman standing on the roadside. "I used to see him in the shops. My son, who's the same age as Dessy, burst into tears when he heard. I was devastated too."
Not everyone shares her sentiments. Not many of the parents who kept their children at home that day, nor the motorists who spent most of the sunny Friday afternoon sitting in traffic wondering why the fixer of a crime family should inspire mile-long tailbacks and the presence of Greater Manchester Police.
Shaven-headed children swarm outside the church. They wear black or fluorescent jackets with "We Serve to Protect" - the motto of the family's security firm - emblazoned on them. They cadge cigarettes off their mates or their mums.
Mourners spill out of the church onto the streets. Women have poured themselves into tight-fitting trouser suits. Their big sunglasses twinkle with interlocked Cs or D&G. Everyone is decked out in chunky gold jewellery.
In the shade, investigative reporter Donal McIntyre is giving back-to-back interviews to TV reporters. He is much shorter in real life. His bouncers hover out of shot.
It was McIntyre's documentary that introduced the crimes and misdemeanours of the Noonan family to the rest of the UK. Dessy's death, four days before the programme was aired on national television, cranked up the excitement and scandal surrounding the documentary.
The Noonan family had given permission to film the day's proceedings so they have a steadicam and a boom, which has been positioned outside the church.
Dessy's funeral took place a little more than a month after he was stabbed to death on the Merseybank Estate in Chorlton. A man has been charged with his murder.
The cortege comprises three hearses, a horse-drawn carriage, 16 pipers, hundreds of friends and relatives and a dozen black Daimlers. Floral tributes in red and white say "Uncle", "Our Kid" and "Dez". Shortly after midday, this elaborate tribute inches away from St Aidan's Church towards Southern Cemetery.
GMP warned motorists of congestion along the route and, sure enough, cars snake back the entire length of Manchester's busiest roads.
There are plenty of bemused people who don't know what's going on.
One mourner thanks drivers for their patience. Some motorists cross themselves or give the thumbs up to people they recognise. Onlookers emerge from their homes and businesses to see what sort of man can be worthy of such a send-off.
"Matt Busby never got this, did he?" someone quips.
His friend replies: "People who didn't know Dessy want to be a part of today. It's about saying you were there. It's like the Pope's funeral. Why do you think so many people wanted to go to Rome?"
However amid the banter there is reflection and crying.
"I miss him," sniffs one woman. "I miss him so much. He was so kind to my kids. If I ever needed anything he'd come straight round. Don't cry love," she says, stroking her daughter's head. "He's in peace now."
For three hours and six miles the funeral procession crosses over the Princess Parkway and fills two lanes while cars, lorries and buses squeeze past in the third lane.
On arrival at the Merseybank Estate the procession halts and the pipers play Amazing Grace. It moves off once more towards the cemetery.
A red-haired lady breaks off from the procession to catch the number 47 bus to the city centre. When she gets off at Oxford Road the driver asks if she knows why the traffic's been backed up all day.
"It was someone's funeral," she says, then adds with pride and sadness in her voice, "it was Dessy Noonan's funeral."
The driver shrugs his shoulders. "Never heard of him."


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Words that start with bolb
Found 10 words that start with bolb. Browse our Scrabble Word Finder, Words With Friends cheat dictionary, and WordHub word solver to find words starting with bolb. Or use our Unscramble word solver to find your best possible play! Related: Words containing bolb
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For jailed ex-Illinois governor Rod Blagojevich, what a difference a year makes.
It was a year ago Friday the colorful politician left Illinois amid a national media frenzy in disgrace and facing a 14-year sentence for corruption.
Now, his attorney says after a year of losing his freedom (but washing plenty of dishes and checking out books) the ex-governor's spirits are "good" and he's still optimistic he can clear his name on appeal.
"He believes justice in the end will prevail," Blagojevich attorney Lauren Kaeseberg said to the Chicago Tribune. "He wakes up every day in a horrible place and that's what gets him through every day, is a belief that in the end the right thing will happen."
Politico reports the separation from his wife, Patti, and two young daughters has been the hardest. "His family visit him as often as they can make the trip to Colorado," Blago's appellate lawyer Len Goodman told the site.
In a Facebook post on Friday, Patti wrote that "all that we have been left with is a aching hole in our lives." She also said that her husband runs "miles and miles" around a quarter-mile track, the Associated Press reports, and that they talk often.
Patti Blagojevich visited her husband in the Englewood prison last May and called it "one of the saddest places on earth."
On his last night as a free man in 2012, Blago made a characteristically dramatic scene issuing a final statement to press — complete with media helicopters buzzing over his Ravenswood home, the Sun-Times notes — signed autographs and mugged for the many cameras.
The next day he would grab a pair of patty melts on his way to federal prison near Denver, and continue to grandstand all the way to prison, high-fiving fellow inmates his first night in lockup.
The attention-loving pol has continued to keep what sounds like a high-profile in prison, teaching a history class that WGN reports was so popular with inmates, several had to be turned away because there were too many applicants.
Somewhat surprising is that Blagojevich has not granted any interviews or photos since heading to jail. One possible reason: while family and attorneys haven't confirmed it, the ex-governor is said to be going grey and dyes aren't allowed for inmates at the low-security prison.


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If you ever find yourself in the rapidly gentrified neighborhood of Ballard in Seattle, you might happen across an unusual sight. There is a massive shopping mall there, and right in the middle of one side of it is an adorable little house. How did it get there? The story starts some years ago.
Edith Macefield was around 84 when developers, seeking to build a new mall, bought out all of her neighbors.
Edith, however, refused to sell.
Even after the developers offered her a million dollars for her little bungalow.
Her reasons were not financial. Her family was all gone, and this home was the last connection to them.
Her mother had died on the sofa, and she planned to live out her days in this home as well.
As fate would have it, Edith befriended the construction chief for the new mall, Barry Martin.
Edith slowly became a folk hero, inspiring tattoos...
And even a music festival.
Eventually, Edith passed away. To everyone's shock, she willed the home to Barry Martin, who built the mall that surrounds her home.
The mall was designed to be modified to absorb the space, should Edith ever have changed her mind. Amazingly, Barry didn't sell to the mall developers, and the house is still standing today.
Credit: Roadtrippers


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31' Bertram 1974
V- berth sleeps two followed by a convertible dinette aft to port which also sleeps two for a total of four berths. Opposite the dinette is a small galley area with molded in fiberglass sink and refrigerator.
This 31 Bertram was restored by Dog River Marina several years back. With literally an open checkbook policy she was stripped down to the stringers and the work began. Major refit included: gutted to the stringers, new engines, gears, shafts, propellers, generator, wiring, everything new. Kitchen with high glass teak, counter tops, paint, tower. All new VDO engine gauges 2017. Prop tunnel allows for shallow water.
This is an opportunity to own a spectacular 31 Bertram that had hundreds of thousands of dollars thrown at it for a fraction of the cost.
Northern Lights Generator 6.5kw with 1374 Hours
M6730.3 ZF Gears 1.5 to 1
5004 Dauphin Island Parkway
Mobile, AL 36605
United States


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This Autumn Paragliding Special Offer
This Autumn, were offering to anyone booking Two week s tuition together or a Club pilot and Guiding week together a voucher for 350 pounds cash back on any new glider purchased from us.
Of course we don´t do things by half measures, remember we only offer the best kit on the market so choose from Ozone Buzz z3 to the new and popular Boler 4 or mojo 3 gliders...more infor on the equipment page. Remember all our paragliding courses and paragliding tuition lessons are run by full time BHPa registered instructors offering full Uk qualifications. Flyspain paragliding training centre is the only full time school working all year round here in Spain. With over ten years experience you can put trust in our sound safety record and outstanding qualification rate. Pilots come here with with no experience and two weeks later leave with over fours hours flying time under their belt. See out testimonials for what our students have had to say about us.