Risk-Based and Central Monitoring of Clinical Trials


This week, our friends at The Society For Clinical Research Sites sponsored a Top Tier Topic Webinar withTranscelerate Biopharma on Transcelerate’s Collaborative Approach to Risk-Based Monitoring (RBM). The Webinar focused on the impact of RBM on the clinical research sites. Last year we wrote a paper on this topic with Accumed Research Associates, a clinical research site under the direction of Mitchell Efros, MD and Kerri Weingard, ANP.  The article demonstrates, with supportive data, that when done properly, RBM and central monitoring, tied in with direct data entry (DDE) at the time of the office visit, can double productivity at the clinical research site. The main reason is that there is virtually no additional work once the study subject leaves the clinic and there is no need for source document verification, as “the data are the data.“ Here is the conclusion from the article:


With the adoption of RBM and DDE at the time of the office visit, the paradigm for conducting and monitoring clinical trials is changing dramatically. DDE significantly reduces the workload of the clinical research sites and there is no need for the CRAs to verify data transcription errors. When data are entered directly at the time of the subject’s visit, online and real time business logic and range checks identify any potential data entry errors or inconsistencies. Generic and study-specific reporting on metadata and study data (e.g., batch edit-checks, IMP management) will lead to greater value-added data management activities, while the less valuable elements of traditional monitoring (e.g., SDV), will disappear. The focus of monitoring will switch from checking data transcription to assurance that the site staff are trained on and following the protocol. The business benefits have potential to be transformative.


ON TARGET is the newsletter of Target Health Inc., a NYC-based contract research organization (CRO), providing strategic planning, regulatory affairs, clinical research, data management, biostatistics, medical writing and software services, including the paperless clinical trial, to the pharmaceutical and device industries.


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 Chief Editor of On Target

Jules Mitchel, Editor

Harvesting Sunshine


SOLAR ROOF: As photovoltaics on rooftops become more affordable, they have become more and more of a threat to traditional electric utilities. Courtesy of U.S. Department of Energy


Editor’s note: Although this space usually presents new medical research, we know that the sooner we all adopt solar, wind and gas as sources for our electricity, the sooner all facets of life will feel less financial pressure, including medical research.


Even as an alternative, solar is the fastest growing electricity source in the world. As the cost of solar power drops, more consumers find that they hold the upper hand as utilities fight to maintain paying customers and the relevance of the grid. Americans have begun to battle over sunshine. In sun-scorched Arizona a regulatory skirmish has broken out over arrays of blue-black silicon panels on rooftops, threatening the local utilities that have ruled electricity generation for a century or more. With some of the best access to sunshine on the planet, Arizona boasts the second-most solar power in the U.S. – more than 1,000 megawatts and counting. The state hosts vast photovoltaic arrays in the desert as well as the nation’s first commercial power plant with the technology to use sunshine at night – by storing daytime heat in molten 1) ___. In terms of infrastructure, such big solar fits as comfortably as a coal-fired power plant in the traditional electricity business model, which involves large plants transmitting electricity over a grid of conducting lines through transformers and into individual homes and businesses. The trouble, from an electric utility’s perspective, is the tens of thousands of Arizona’s total of three million or so homes that have installed small solar:photovoltaic panels made from wafers of semiconducting material, typically silicon, that use incoming sunlight to create an electric current. With these homes making their own 2) ___, utilities lose their most lucrative customers and confront a dwindling base over which to spread big infrastructure costs, like building new power plants or maintaining the grid. “The net-metered customer does not share equally in the overhead costs associated with the grid or other services provided by the utility, producing a very substantial ‘cross-subsidy’ funded by all other utility customers who must pay proportionately more,“ wrote James Hughes, CEO of solar panel maker First Solar, in an op-ed in support of the utility Arizona Public Service Co. (APS) position this past June. These homeowners have installed photovoltaic panels on their rooftops with the help of cash incentives and a state law that requires the local electricity provider – APS – to buy any excess power produced by an individual home. Such “net metering“ programs allow homeowners to zero out monthly or even annual electric bills. That means APS gets nothing from these former customers, and their number is growing. More than 15 rooftop arrays go onto Arizona homes each day, according to the Phoenix-area utility, and the number of such solar independents grew from 4,770 in 2010 to 14,524 in 2012. In response APS and other utility companies across the country have launched a propaganda war against an energy source that still accounts for less than one quarter of 1% of U.S. electricity. In Arizona that fight became very public in 2013, as APS took on such residential solar power in a television ad campaign and mailings. But the utility met resistance from a coalition of liberals and libertarians decrying monopoly or wanting to help cut greenhouse 3) ___ pollution.


More than 40 states now allow property owners to sell excess energy generated by solar panels onto the electric grid, and many utilities must pay a premium for this resource. Utility companies warn that the lost revenue from solar-powered costumers will necessitate price increases for people without solar panels, because the electric grid and other critical infrastructure must still be maintained. Solar homeowners, on the other hand, love their lower bills and independence from utility companies. “Why should they be allowed to hold the monopoly on this power source?“ asks Tom Morrissey, former chairman of the Arizona Republican Party. “Why should they be the only providers? Why can’t we provide for ourselves, while easing the burden on the power 4) ___


However, the utilities do have a point. If solar rooftop arrays became as ubiquitous in home design as chimneys, the U.S. grid could indeed cease to exist – an end to power lines, electrical substations and transformers atop equally archaic wooden utility poles. The key of a decentralized system is the cost of a power producing system to the individual homeowner, and the price of solar power keeps dropping. As a result, solar proponents push for the switch for a variety of reasons that cut across political party lines. This war over solar has pitted Republican against Republican, and formed new alliances between libertarians and liberals. The first intimations of war started with Solyndra. The bankruptcy of the would-be manufacturer of innovative tubular solar arrays heralded the arrival of cheap photovoltaic panels, many of them from China. Such modules can be bought in bulk now for as little as 25 cents per watt. Even the electric utility industry recognizes that where residential electricity costs reach 15 cents per kilowatt-hour, or roughly 16% of the U.S. retail electricity market 5) ___ is already as cheap as grid electricity.



Semiconductor — The scintillating crystals of silicon in each cell are the core of these devices. (The silicon appears blue because of an antireflection coating.) Each panel contains a grid of many such silicon solar cells, and the silicon itself is doped with other chemicals so that it can generate a current when hit by light. Photo courtesy of futureatlas: Photo of photovoltaic array at Oberlin College courtesy of Robb Williamson.


Friction costs are the costs of finding a solar panel maker and installer, and then filing the appropriate paperwork with the appropriate state and local authorities as well as the local utility, then making sure the solar array is installed properly and safely. Such installation costs at least double the cost of a residential solar system, meaning a typical system costs at least $25,000 to put on a roof and hook up. As it stands, the average solar system in the U.S. costs roughly $4.50 per watt to purchase and install, according to the U.S. National Renewable Energy Laboratory. But that cost is coming down, too, and in some cases to near zero thanks to solar companies that essentially rent the equipment, such as SolarCity, Sungevity, SunRun and Vivint. The contracts differ but, essentially, these companies pay to install solar panels on a roof and reap any attendant tax credits. Homeowners pay a set rate for the electricity used as well as a lease price, resulting in a total bill that is less than their current 6) ___ electric bill. Most of these companies contract with the homeowner for 15-year leases, which include maintenance, for example, or a power purchase agreement that guarantees a certain rate (the same contract used between a utility and the developer of a big desert solar project).


The idea is to remove the “stigma,“ that solar is expensive. Solar City, for one, expects to deploy at least 475 megawatts of rooftop solar in 2014, or nearly double its expected installations for all of 2013. It’s a system pioneered by SunEdison with large companies that owned hectares of rooftop space on stores or warehouses, resulting in the creation of what some have called “solar bonds.“ SolarCity, in fact, is planning to sell more than $54 million worth of such solar bonds pegged to the company’s thousands of installations across 14 states that will come due in December 2026. The only traditional utility to do something similar: NRG and its residential solar division. Other utilities, such as Duke and Southern Co., have attempted to block such changes by implementing their own solar-at-home programs that leave the utility in charge.


Now, with solar more than a boutique product for those rich in both kinds of green, utilities have something to worry about. Waking up to the looming threat, utility-funded research outfit the Edison Electric Institute released a report in January 2013 called “Disruptive Challenges“. In essence, EEI noted that home solar, dubbed “distributed energy resources“ could allow Americans to get off the grid, putting their member utilities into a death spiral of fewer and fewer electricity sales to cover more and more grid maintenance costs. That would drive up electricity prices and, as a result, drive more and more people to install rooftop solar. The parallel is drawn with the telephone monopolies of the 1970s that are, in the words of the report, “not recognizable today nor are the names of many of the players and the service they once provided (‘the plain old telephone service’).“ The roughly 3,000 electric utilities that now control U.S. electricity may be as dim a memory in a decade or two.



Wiring — An electrical current is only useful in a circuit that allows it to flow to where it can be put to work. Solar panels include a cross-hatch of metallic material, typically made from silver or copper, that conduct the electricity away from the solar cells. Photo courtesy of Andreas Demmelbauer



Current — On striking a crystal in the panel, an incoming photon from the sun dislodges a spare electron in the silicon layer that has been chemically tweaked to donate electrons, which allows them to roam (referred to as the N-doped silicon). That electron migrates down to an adjacent layer of silicon that has been treated to accept the negative particle (P-doped silicon), thereby creating an electric current. But silicon can only transform the energy of certain wavelengths of light. An antireflective coating composed of thin layers of metals like silver gives the panel its blue hue and ensures that stray photons are redirected back into the photovoltaic silicon layers. A reflective aluminum backing serves a similar role for sunlight that penetrates through the cell as well as provides structural support.



Grid Connection — A single solar cell becomes useful when connected to a device powered by electricity, whether a motor or a lightbulb. Typical solar power systems also include an inverter to convert direct current to the alternating current used in a home, as well as, potentially, batteries to store solar electricity. Photo courtesy of MikieMike


Spurred by projections of 500% growth for solar in the U.S., Arizona Public Services mounted a public relations campaign against its own obsolescence. Backed by EEI and other outside interest groups, APS spent nearly $4 million on TV, print and Internet ads depicting solar homeowners as freeloaders on the grid, and an economic burden to all the households without such solar panels. According to APS ads, such solar homes cost the rest of the utility’s customers at least $1,000 a year, what they dubbed a “cost shift“ in anodyne bureaucratic terminology concealing real malice. APS therefore proposed a surcharge, or “sun tax“ in the words of opponents, of as much as $100 per month that solar homeowners would pay as their fair share of grid maintenance costs. Some Arizona residents described such ads as “deceptive at best“ or “false advertising,“ among other, less mild epithets.


The solar industry, consumers and homeowners fought back over the course of 2013, running their own ads touting the benefits of solar, including increased competition for sclerotic monopolies such as APS, self-reliance and less 7) ___ in smoggy Phoenix. They decried the campaign by APS to blame solar homeowners for doing the fiscally and environmentally responsible thing. It should be noted that in a decade of home improvements prior to installing solar, like better insulation and more energy-efficient light bulbs, electricity use has dropped by roughly 18% whereas bills from APS increased by 33%, largely because of the shared cost of grid maintenance. In fact, utilities may be underpaying solar homeowners for the benefits of rooftop electricity, at least according to an analysis run by Texas’s Austin Energy. The municipal utility’s analysis concluded that it should pay to solar 8) ___ 3 cents more than the retail electricity rate, for savings in transmission losses and the ability to delay building large, centralized power plants that can require multibillion-dollar investments.


Solar is only going to get cheaper. Richard Swanson, the founder of solar panel manufacturer SunPower, has argued that the cost of a photovoltaic cell drops by 20% every time global manufacturing capacity for such cells doubles. This “Swanson’s Law“ for photovoltaics suggests that photovoltaic prices are now less than 75 cents per watt. Even in the face of a significant solar tax, photovoltaics might win as harvesting 9) ___ for electricity grows ever cheaper. The U.S. Department of Energy hopes to help with that. Its SunShot program aims to make solar power cheaper than burning fossil 10) ___, such as coal and natural gas. So far SunShot has awarded $87 million to projects that could reduce the cost of solar power to 50 cents per watt to make a module, and 50 cents per watt to install a module. That includes the $10-million SunShot prize for the first three “teams“ that achieve $1 per watt for the messy paperwork side of installing solar. Projects also include efforts to build novel types of photovoltaics via the Advanced Research Projects Agency – Energy’s “Full-Spectrum Optimized Conversion and Utilization of Sunlight“ or FOCUS program as well as manufacturing processes that could bring down costs. That includes 1366 Technologies’s bid to directly grow the individual silicon wafers in traditional solar panels rather than shaving them from ingots and wasting the expensive material. Such specially treated silicon is responsible for more than half the final price of the photovoltaic module, and sawing off the wafers turns as much as half of that expensive silicon into dust. Growing such wafers individually from melted silicon could cut wafer costs by 80%, according to the company named after the wattage of sunlight that hits each square meter of Earth’s atmosphere. And if wafer costs fall, so, too, should photovoltaic prices.


Even as an “expensive“ alternative, solar is the fastest growing electricity source in the world. Globally, more than 100 gigawatts of solar power have been installed to date, including some 400 million solar panels, the majority in Europe where subsidies are highest. And although investments were down in 2012 to just over $140 billion globally, total installed capacity was up, thanks to the declining technology prices. Solar power may be finally beginning to follow a 25-year path similar to that of now ubiquitous cell phones, from an oddity in the 1990s to world domination in the next decade or so. Solar might be growing even faster, if not for another innovation funded by the U.S. Department of Energy: fracking to free natural gas in deep shale. Such shale gas has flooded the market and reduced natural gas prices, resulting in natural gas-fired turbines becoming the technology of choice for producing electricity. Natural gas is killing off nuclear power, slowing the rise of wind and solar, and even shoving aside old, dirty coal.


But natural gas doesn’t have to be tied to big turbines. Most homes in the U.S. are already connected to a distribution system for such natural gas, using it for 11) ___ cooking or heating. That buried distribution system could end up replacing the old electric grid, still carried from place to place atop weather-exposed steel pylons and more than 100 million dead trees, aka utility poles. Novel devices, such as some types of fuel cell, could instead use natural gas to produce electricity cheaply in the home. Or battery systems, like those offered by Tesla, could serve as backup and electricity storage system. Paired with solar cells on the roof, such “disruptive energy resources“ could result in one nation, off the grid.


The past few decades’ severe weather caused by climate change, itself largely an outcome of the old electricity model of a big, centralized grid powered by coal-fired plants, may help hasten that transition, blowing down the world’s largest machine, the U.S. electric grid, again and again, until it becomes obvious that reinvesting in an antiquated technology that Thomas Edison himself would recognize is no longer smart or sustainable. Solar can help insulate people from the vagaries of a changing climate (as well as reducing the greenhouse gas pollution causing the changes by replacing fossil-fuel burning to produce electricity.) The battle lines over this transformation are forming. In Georgia a Southern Co. subsidiary has blocked solar power development. That caused the local Tea Party, led by activist Debbie Dooley, to form what she called the “Green Tea Coalition“ with local environmentalists from the Natural Resources Defense Council, Sierra Club and other groups to push for more solar in the state, rather than costly projects such as the new nuclear reactors being built at the Vogtle power plant, the first new nuclear to be approved in the U.S. since 1978. It’s a similar coalition to the one that has achieved the legalization of marijuana in states like Colorado and Washington. “Solar is a natural fit for conservatives,“ Dooley says, noting her amazement at conservatives who claim to be in favor of a free market but support a government-mandated monopoly like local utilities. “The bottom line is energy has to compete on a level playing field and let the consumer decide.“ As a result of this unlikely alliance, the Georgia Public Service Commission, an all-Republican committee that regulates the electricity monopoly in the state, voted to require Georgia Power to include more solar power in its plans for future generation. Georgia Power also dropped a plan, at least for the moment, to charge solar homeowners a grid fee. But it remains to be seen whether a state law that blocks homeowners from leasing solar power from companies like SolarCity or SunRun will be overturned. A schism of sorts is forming within the Republican Party: Libertarians and Tea Partiers like Dooley who support a homeowner’s property rights have sided against other conservative groups like Americans for Prosperity (a group largely funded by oil magnates the Koch brothers) and think tanks like the Heartland Institute. Grover Norquist of the Republican-group Americans for Tax Reform has decried the Georgia “green tea“ alliance. “The rooftop solar industry has attempted to co-opt countless conservative groups in its fight to protect crony capitalism,“ he wrote in a November submission to the Arizona regulators. “Solar homes effectively avoid paying for the fixed costs of the grid. These costs are like taxes being shifted to non-solar homes.“ But property rights and self-reliance seem to be issues that Americans of most political persuasions can support, from the primarily blue state of California to the reliably red state of Georgia, and has led to “solar rights“ laws in purple Midwestern states such as Wisconsin and Iowa. Barry Goldwater, Jr., son of the famed conservative presidential candidate and a former congressman in his own right, heads the Tell Utilities Solar won’t be Killed, or TUSK, coalition in Arizona. “Rather than innovate or find ways to profit from solar power, APS decries the solar industry and opines that its revenue is heading downward. That’s not the ratepayers problem,“ he wrote in a June op-ed. “Instead of trying to fix the problem, APS is trying to fix the game. It’s looking to rig the system so the utility doesn’t have to pay fair market value for the excess electricity that rooftop solar customers send back to the grid.“


The full costs and benefits of solar rooftops on homes remain unknown. But a survey of home sales in California found that photovoltaic systems boosted home sale prices by nearly $25,000 in 2009, according to research from Lawrence Berkeley National Laboratory. And solar advocates point to the fact that photovoltaics on rooftops save on the costs of investing in new conventional power plants and grid infrastructure as well as the cost of meeting pollution limits or other regulations, while reducing electricity loss. Beyond the U.S., solar energy leaders such as Germany and Spain are also now considering a kind of “solar tax“ for access to the grid in order to ensure maintenance of their legacy infrastructure. In the end, solar may prove an unstoppable force. If solar module prices drop to 50 cents per watt, then solar power becomes as cheap as other forms of electricity in all 50 states, once installation costs are included. In addition, the technology offers some additional benefits, from far fewer climate-changing greenhouse gas emissions than even power plants burning natural gas to reduced use of water compared with the cooling needs of a big coal-fired or nuclear power plant. As the Edison Electric Institute notes, the proportion of regions where solar at home will be cheaper than electricity purchased from the grid could grow to as much as one third of the nation as soon as 2017. Nowhere is that more true than the desert Southwest of the U.S., in states like Arizona.


In that future of cheap solar the home would be a self-sufficient energy fortress, and perhaps self-driving electric cars would plug in there, to recharge from sunshine. Batteries or even technologies that transform newly abundant natural gas to electricity inside the home could serve as backup for cloudy days. In fact, solar systems paired with batteries or fuel cells could become cost-effective in states besides Hawaii (where it is already so) by the 2020s, according to a new analysis from energy think tank the Rocky Mountain Institute, and partners. “How shockingly stupid is it to build a 21st-century electricity system based on a system of 130 million wooden poles?“ asked NRG’s David Crane at the ARPA-E summit on February 25. “The day is coming, within a generation, where the grid is, at best, an antiquated backup system.“ His company helped open the world’s largest solar thermal power plant on February 20, where 347,000 mirrors concentrate sunlight on three nearly five story-tall central power towers at Ivanpah in the California desert, near Bakersfield. But he sees an even bigger future for photovoltaics, and NRG has already installed them at football stadiums across the country, including at Lincoln Field in Philadelphia. Last year nearly one third of new U.S. electric capacity was solar power. At the same time, NRG is investing in natural gas generators to fit in people’s basements that could either provide all the electricity a house needs or to be paired with rooftop solar 12) ___to offer electricity after sunset, freeing homes in Arizona, Georgia or anywhere else from the grid forever. War is coming, and when it comes, it may sweep away not only the American electric utility as it has been for the last century, the world’s largest machine, but also the legacy car companies and even the most recent iteration of the American way of life, making the bucolic lifestyle of the suburbs sustainable in a novel way. Source: http://www.scientificamerican.com/article/fight-over-rooftop-solar-forecasts-a-bright-future-for-cleaner-energy/


ANSWERS: 1) salts; 2) electricity; 3) gas; 4) grid; 5) solar; 6) monthly; 7) pollution; 8) homeowners; 9) sunshine; 10) fuels; 11) cooking; 12) cells

Remaking History: A New Take on How Evolution Has Shaped Modern Europeans



Investigators reporting in the Cell Press journal Trends in Genetics say that analytical techniques are changing long-held, simplistic views about the evolutionary history of humans in Europe. Their findings indicate that many cultural, climatic, and demographic events have shaped genetic variation among modern-day European populations and that the variety of those mechanisms is more diverse than previously thought.


Recent advances in paleogenetics are providing never-before-seen glimpses into the complex evolution of humans in Europe, helping researchers piece together the events that ultimately created what is now known as modern man. Following the period when ice sheets were at their maximum extension across Earth (between 27,000 and 16,000 years ago), hunter-gatherer populations re-colonized most parts of Europe. Then around 8,000 years ago, the first farming populations appeared on the continent during the so-called Neolithic transition. For several thousand years, two separate modes of life coexisted in Europe: hunter-gatherer populations continued to rely on wild food resources, while farming populations had an entirely different demographic profile and lifestyle that consisted of domesticated crops and livestock, pottery, housing, and storage technology.


For some decades, it was assumed that the genetic diversity of contemporary Europeans was shaped mainly during the Neolithic transition; however, it now appears that it was also affected both before and after this key event. Moreover, the spread of farming is likely to have varied to a great extent by region, leading to varying impacts of migrating farmers’ and local hunter-gatherers’ genetic contributions to future populations. “We are currently at a stage in which next-generation sequencing technologies, ancient DNA analyses, and computer simulation modeling allow us to obtain a much more accurate and detailed perspective on the nature and timing of major prehistoric processes such as the colonization of Europe by modern humans, the survival of human populations during the ice age, the Neolithic transition, and the rise and fall of complex societies and empires,“ says first author Dr. Ron Pinhasi, of Trinity College Dublin, in Ireland. “The development of inter-disciplinary approaches is crucial to elaborate realistic models of human evolution.“ explains Dr. Mathias Currat. “These methods and technologies hold great potential to shed new light on past genetic variation, the onset of major cultural and technological changes that left their imprint on past and present genomes, and potentially on the impact of changes in lifestyle and demography on the appearance of certain diseases and genetic disorders“ says Dr. Pinhasi.


Why did humans replace Neanderthals? Paleo diet didn’t change, the climate did


Why were Neanderthals replaced by anatomically modern humans around 40,000 years ago? One popular hypothesis states that a broader dietary spectrum of modern humans gave them a competitive advantage on Neanderthals. Geochemical analyses of fossil bones seemed to confirm this dietary difference. Indeed, higher amounts of nitrogen heavy isotopes were found in the bones of modern humans compared to those of Neanderthals. However, these studies did not look at possible isotopic variation of nitrogen isotopes in the food resource themselves. In fact, environmental factors such as aridity can increase the heavy nitrogen isotope amount in plants, leading to higher nitrogen isotopic values in herbivores and their predators even without a change of subsistence strategy.



Fragment of jaw of a wolf from Le Moustier that was analyzed during the investigation.
Credit: Herve Bocherens/University of Tubingen


Why were Neanderthals replaced by anatomically modern humans around 40,000 years ago? One popular hypothesis states that a broader dietary spectrum of modern humans gave them a competitive advantage on Neanderthals. Geochemical analyses of fossil bones seemed to confirm this dietary difference. Indeed, higher amounts of nitrogen heavy isotopes were found in the bones of modern humans compared to those of Neanderthals, suggesting at first that modern humans included fish in their diet while Neanderthals were focused on the meat of terrestrial large game, such as mammoth and bison. However, these studies did not look at possible isotopic variation of nitrogen isotopes in the food resource themselves. In fact, environmental factors such as aridity can increase the heavy nitrogen isotope amount in plants, leading to higher nitrogen isotopic values in herbivores and their predators even without a change of subsistence strategy.


A recent study published in Journal of Human Evolution by researchers from the University of Tubingen (Germany) and the Musee national de Prehistoire in Les Eyzies-de-Tayac (France) revealed that the nitrogen isotopic content of animal bones, both herbivores, such as reindeer, red deer, horse and bison, and carnivores such as wolves, changed dramatically at the time of first occurrence of modern humans in southwestern France. The changes are very similar to those seen in human fossils during the same period, showing that there was not necessarily a change in diet between Neanderthals and modern humans, but rather a change in environment that was responsible for a different isotopic signature of the same food resources. Moreover, this isotopic event coinciding in timing with the replacement of Neanderthals by modern humans may indicate that environmental changes, such as an increase of aridity, could have helped modern humans to overcome the Neanderthals.


These new results, together with recently published research showing that Neanderthals had more skills and exploited more diverse food resources than previously thought, makes the biological differences between these two types of prehistoric humans always smaller. In this context, the exact circumstances of the extinction of Neanderthals by modern humans remain unclear and they are probably more complex than just a behavioral superiority of one type of humans compared to the other.

Sources:  Universitaet Tubingen. “Why did humans replace Neanderthals? Paleo diet didn’t change, the climate did.“ Herve Bocherens, Dorothee G. Drucker, Stephane Madelaine. Evidence for a 15N positive excursion in terrestrial foodwebs at the Middle to Upper Palaeolithic transition in south-western France: Implications for early modern human palaeodiet and palaeoenvironment. Journal of Human Evolution, 2014; DOI: 10.1016/j.jhevol.2013.12.015 and ScienceDaily.com


Underlying Genetics, Marker for Stroke, Cardiovascular Disease


Stroke is the fourth leading cause of death and a major cause of adult disability in this country, yet its underlying genetics have been difficult to understand. Numerous genetic and environmental factors can contribute to a person having a stroke.


According to an article published in PLoS Genetics (20 March 2014), a study of the genomes of nearly 5,000 people has pinpointed a genetic variant tied to an increased risk for stroke, as well as new details about an important metabolic pathway that plays a major role in several common diseases. Together, these findings may provide new clues to underlying genetic and biochemical influences in the development of stroke and cardiovascular disease, and may also help lead to new treatment strategies. This study was supported by theNational Human Genome Research Institute (NHGRI) Genomics and Randomized Trials Network (GARNET) program.


The study focused on one particular biochemical pathway called the folate one-carbon metabolism (FOCM) pathway. They knew that abnormally high blood levels of the amino acid homocysteine are associated with an increased risk of common diseases such as stroke, cardiovascular disease and dementia. Homocysteine is a breakdown product of methionine, which is part of the FOCM pathway. The same pathway can affect many important cellular processes, including the methylation of proteins, DNA and RNA. DNA methylation is a mechanism that cells use to control which genes are turned on and off, and when. But clinical trials of homocysteine-lowering therapies have not prevented disease, and the genetics underlying high homocysteine levels — and methionine metabolism gone awry — are not well defined.


As a result, the authors conducted genome-wide association studies (GWAS) of participants from two large long-term projects: the Vitamin Intervention for Stroke Prevention (VISP), a trial looking at ways to prevent a second ischemic stroke, and the Framingham Heart Study (FHS), which has followed the cardiovascular health and disease in a general population for decades. They also measured methionine metabolism – the ability to convert methionine to homocysteine – in both groups. In all, they studied 2,100 VISP participants and 2,710 FHS subjects.


In a GWAS, researchers scan the genome to identify specific genomic variants associated with a disease. In this case, the scientists were trying to identify variants associated with a trait — the ability to metabolize methionine into homocysteine. Results from the study identified variants in five genes in the FOCM pathway that were associated with differences in a person’s ability to convert methionine to homocysteine. They found that among the five genes, one — the ALDH1L1 gene — was also strongly associated with stroke in the Framingham study. When the gene is not working properly, it has been associated with a breakdown in a normal cellular process called programmed cell death, and cancer cell survival. The authors also made important discoveries about the methionine-homocysteine process. According to the authors, the GNMT gene produces a protein that converts methionine to homocysteine, and of the 5 genes that were identified, it was the one most significantly associated with this process. The authors added that the study results suggest that differences in GNMT are the major drivers behind the differences in methionine metabolism in humans.


The study determined that the 5 genes accounted for 6% of the difference in individuals’ ability to process methionine into homocysteine among those in the VISP trial. The genes also accounted for 13% of the difference in those participants in the FHS, a remarkable result given the complex nature of methionine metabolism and its impact on cerebrovascular risk. In many complex diseases, genomic variants often account for less than 5% of such differences.


The authors stated that this is a great example of the kinds of successful research efforts coming out of the GARNET program, in that the goal of the program is to identify variants that affect treatment response by doing association studies in randomized trials. The association of the ALDH1L1 gene variant with stroke is just one example of how the findings may potentially lead to new prevention efforts, and help develop new targets for treating stroke and heart disease.

Mutation Linked to Severe Form of Cushing’s Syndrome


Cushing’s syndrome results when the body is exposed to too much of the stress hormone cortisol. The syndrome may result when the body itself produces excess cortisol, causing symptoms that may include high blood pressure, muscle weakness or osteoporosis.


According to a paper published online in the New England Journal of Medicine (27 February 20014), mutations in a gene containing part of the information needed to make an enzyme that provides energy for governing basic cell functions appear to contribute to a severe form of Cushing’s syndrome. In a letter to the editor of the same journal, members of the NIH research team and researchers in Italy reported that a mutation in another gene containing information needed to make yet another portion of the enzyme appears to be central to Carney Complex, a rare disease that causes multiple tumors and which is characterized by increased cortisol levels.


For the study on Cushing’s syndrome, the authors examined tissue from patients having a subtype of Cushing’s syndrome, in which the source of the excess cortisol is a noncancerous tumor confined to only one of the body’s two adrenal glands. When samples from nearly 200 such adrenal gland tumors were examined, it was found that 37% contained a mutation in the gene known as PRKACA. The PRKACA gene contains the information needed to make a portion, or subunit, of the PKA (protein kinase A) enzyme. The enzyme is involved in numerous chemical reactions in the cell. For these patients, the mutant PRKACA gene was found only in the tumor cells, and not in other cells of the body. Because the gene was not found in other cells of the body, the mutation likely arose spontaneously in the adrenal tissue. According to the authors, the mutant PRKACA gene appears to give rise to one of the most common kinds of adrenal tumors seen in Cushing’s syndrome, and that the discovery suggests a clear path forward for investigating medications that might block the production of excess cortisol.


The authors also examined tissue from patients who had non-cancerous growths on both adrenal glands. In samples from these patients, an extra copy of the PRKACA gene was found. This extra copy was present in all of the patients’ cells, and was not limited to the tumor tissue. Because the mutation was found in all the cells of the body, the authors concluded that it was likely hereditary. However, in both the cases involving the spontaneous mutation and the inherited mutation, the activity of the PKA enzyme was increased.


In a letter to the editor of the same issue of the New England Journal of Medicine, it was reported that a patient with Carney Complex, who had a tumor in the pituitary gland and elevated growth hormone, had an extra copy of the PRKACB gene. This gene codes for another subunit of Protein Kinase A. In addition to elevated growth hormone levels, people with Carney Complex often have skin spots and increased risk of tumors in the pituitary, adrenals as well as other parts of the body. According to the authors, it is likely that the extra copy of this gene also increases the activity of protein kinase A, essentially setting the stage for increased cell proliferation and higher production of hormones.

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


FDA Approves First Long-Acting Recombinant Coagulation Factor IX Concentrate for Patients with Hemophilia B


Hemophilia B is an inherited blood-clotting disorder, which primarily affects males, and is caused by defects in the Factor IX gene. Hemophilia B affects about 3,300 people in the United States. People with Hemophilia B can experience repeated episodes of potentially serious bleeding, mainly into the joints, which can be destroyed by the bleeding.


The FDA has approved Alprolix, Coagulation Factor IX (Recombinant), Fc Fusion Protein, for use in adults and children who have Hemophilia B. Alprolix is the first Hemophilia B treatment designed to require less frequent injections when used to prevent or reduce the frequency of bleeding. Alprolix is approved to help control and prevent bleeding episodes, manage bleeding during surgical procedures, and prevent or reduce the frequency of bleeding episodes (prophylaxis). Alprolix consists of the Factor IX molecule linked to a protein fragment, Fc, which is found in antibodies. This makes the product last longer in circulation.


The safety and efficacy of Alprolix were evaluated in a multi-center clinical trial that compared each of two prophylactic treatment regimens to on-demand treatment. A total of 123 individuals with severe Hemophilia B, ages 12-71, were followed for up to a year and a half. The studies demonstrated the effectiveness of Alprolix in the prevention and treatment of bleeding episodes and during perioperative management of patients undergoing a surgical procedure. No safety concerns were identified in this trial.


Alprolix received orphan-drug designation for this use by the FDA because it is intended for treatment of a rare disease or condition, and is manufactured by Biogen Idec, Inc., Cambridge, Mass.

Viennese Veal Chops




1.  1/2 cup finely grated parmigiano reggiano
2.  1/2 cup Panko
3.  2-3 egg whites or 2-3 eggs
4.  4 thick veal chops (1 chop per person)
5.  1 egg per person, poached or fried just before serving
6.  Pinch freshly ground black pepper (grind to your taste)
7.  1/3 cup almond flour
8.  2 Tablespoons olive oil
9.  1 lemon, quartered (optional)




Butcher trimmed most of fat, but I’m gonna cut a little more off, before dipping.

I sprinkled a pinch of black pepper on each veal chop.


Bowls lined up for dipping the veal. Top, almond flour, bottom left, beaten eggs,
Bottom right, Panko crumbs



After dipping in almond flour, then beaten eggs, then Panko – ready to cook over stove with medium flame



Beautiful golden brown, makes your mouth water, and smells so-o good, too!



1.  Mix cheese and bread crumbs in medium-size bowl.
2.  Beat egg whites just until foamy.
3.  Wash and dry veal and sprinkle lightly with pepper.
4.  Dip meat into the almond flour and shake off excess, then into egg white and then into Panko/cheese mixture.
5.  Heat oil in non-stick skillet and saute over medium heat until crust is golden brown on one side (7 to 10 minutes); turn and brown on second side (7 to 10 minutes).
6.  Veal chops will take 15 to 20 minutes.
7.  Just before serving the veal chop, poach one egg per person. Don’t break the yolk and keep it fairly loose. Serve one chop on each plate with an egg on top of the veal chop.
8.  For those who don’t want a poached egg on top, put a wedge of fresh lemon on the plate
9. Enjoy






We tried a delicious red Italian with our veal feast. It’s hard to find this wine, because the Muscardini Tuscany vineyard, has expanded to California with their Italian vines and are setting up shop in these two locations. This “cab“ was a great success. It got a 90 in one of the wine newsletters (Wine Spectator or Robert Parker).


This is the second time we had veal, because I needed to experiment with the best way to cook the chops. The first time, I dipped them in flour, egg white and Panko mixed with parmesan. I must admit the veal was too thin, about 1 inch thick. The result was too dry and a waste of time and calories. The second time, I bought much thicker veal chops. I would say about 1 and 1/4 or 1 and 1/2 inches. I also eliminated the parmesan because the cheese made the chops stick to the pan too much.


The second round of veal turned out very well, with a fried egg on top of each chop; along with delicious fresh broccoli sauteed in olive oil and juice of one garlic clove and jasmine/saffron rice made with golden raisins and pine nuts. Take a look (photo above) at the delicious Italian red we discovered to have with this meal.


We started with crudites dipped in hummus, instead of a salad. Dessert was my simple recipe of fresh blueberries pureed and mixed with activa vanilla yogurt and sugar-free cherry jello, topped with a dollop of fat-free cool whip.


Life is good, people. Life is good.


Bon Appetit !

Disruptive Innovation Meeting – September 11-12, 2014, Boston


For those of us committed to change, not for its own sake but to make what we do better and more effective, we want to highlight one of the best conferences in the industry. Our friends at The Conference Forum will be running the 4th annual meeting of Dpharm: Disruptive Innovations to Advance Clinical Trials. This most exciting conference will be held September 11-12, 2014, at The Fairmont Copley Plaza, Boston, MA. Make plans to participate as you will not be disappointed. Check out the website or just send us a note and we will connect you to the organizers (http://theconferenceforum.org/conferences/disruptive-innovations/overview/). We are also pleased to announce that Dr. Jules T. Mitchel, President of Target Health is on the Advisory Board of the conference.  


The conference is designed for leaders in clinical research who are open to new and alternative approaches to making clinical development far more productive and sustainable. The conference brings together a speaking faculty of a diverse community of leading thinkers and practitioners of clinical trials who are experimenting with breakthrough models and approaches. Their case studies will demonstrate examples of transformative and disruptive approaches to advancing clinical trials.


ON TARGET is the newsletter of Target Health Inc., a NYC-based contract research organization (CRO), providing strategic planning, regulatory affairs, clinical research, data management, biostatistics, medical writing and software services, including the paperless clinical trial, to the pharmaceutical and device industries.


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 Chief Editor of On Target

Jules Mitchel, Editor

Anger Is Fast Trigger for Heart Attack or Stroke


A stroke, or cerebrovascular accident (CVA), is the rapid loss of brain function(s) due to disturbance in the blood supply to the brain. This can be due to ischemia (lack of blood flow) caused by blockage (thrombosis, arterial embolism), or a 1) ___. As a result, the affected area of the brain cannot function, which might result in an inability to move one or more limbs on one side of the body, inability to understand or formulate speech, or an inability to see one side of the visual field. A stroke is a medical emergency and can cause permanent neurological damage, complications, and death. Risk factors for stroke include old age, hypertension (high blood pressure), previous stroke or transient ischemic attack (TIA), diabetes, high cholesterol, cigarette smoking and atrial fibrillation. High blood pressure is the most important modifiable risk factor of stroke. It is the second leading cause of 2) ___ worldwide.


Cardiovascular disease (also called heart disease) is a class of diseases that involve the heart, the blood vessels (arteries, capillaries, and veins) or both. Cardiovascular disease refers to any disease that affects the cardiovascular system, principally cardiac disease, vascular diseases of the brain and kidney, and peripheral arterial disease. The causes of cardiovascular disease are diverse but atherosclerosis and/or hypertension are the most common. In addition, with aging come a number of physiological and morphological changes that alter cardiovascular function and lead to increased risk of cardiovascular disease, even in healthy asymptomatic individuals. Cardiovascular disease is the leading cause of deaths worldwide, though, since the 1970s, cardiovascular 3) ___ rates have declined in many high-income countries. At the same time, cardiovascular deaths and disease have increased at a fast rate in low- and middle-income countries. Although cardiovascular disease usually affects older adults, the antecedents of cardiovascular disease, notably atherosclerosis, begin in early life, making primary prevention efforts necessary from childhood. There is therefore increased emphasis on preventing atherosclerosis by modifying risk factors, such as healthy eating, exercise, and avoidance of smoking tobacco. Some of these risk factors, such as age, gender or family history, are immutable; however, many important cardiovascular risk factors are modifiable by lifestyle change, social change, drug treatment and prevention of Serrano’s Cardiac Triad: hypertension, hyperlipidemia, and 4) ___.


Interesting research is being done on the relationship between a lifestyle change of anger management and cardiovascular event or stroke. A flash of anger may send the body down a path ending in a heart attack or stroke, a systemic review showed. Note that the magnitude of increased risks were higher for individuals who had a greater cardiovascular risk initially. Although relatively few studies have explored the link between short bouts of 5) ___ and cardiovascular events in the hours immediately following the outburst, the evidence is consistent in showing a direct relationship, according to Murray Mittleman, Dr PH, of the Harvard School of Public Health, and colleagues. But it’s not clear how substantial the risk is, the authors reported online in the European Heart Journal. “The relative risks estimated in this meta-analysis indicate that there is a higher risk of cardiovascular 6) ___ after outbursts of anger among individuals at risk of a cardiovascular event, but because each episode may be infrequent and the effect period is transient, the net absolute impact on disease burden is extremely low,“ they wrote. “However, with increasing frequency of anger episodes, these transient effects may accumulate, leading to a larger clinical impact.“


Several smaller studies have examined the link between anger and cardiovascular health, but Mittleman and colleagues set out to explore the consistency of the association. A review of the literature turned up nine independent case-crossover studies conducted in the U.S., Sweden, England, Israel, and the Netherlands. Outcomes included myocardial 7) ___, acute coronary syndromes, stroke, and ventricular arrhythmia in the 2 hours following angry outbursts. In pooled results of four of the studies, the risk of MI or acute coronary syndrome was 4.74-fold higher in the hours after an outburst. In pooled results of two studies, the risk of ischemic stroke was not significantly elevated. One study evaluated intracranial hemorrhage and showed that the risk was higher in the hour after a bout of anger. Two studies had ventricular arrhythmia in patients with implantable cardioverter-defibrillators as an outcome, although the results could not be combined because of differences in the measurement of anger, study design, and hazard periods. One showed that risk was significantly higher in the 15 minutes after an outburst and the other showed that the 8) ___ was higher in the hour after the angry episode. Mittleman and colleagues noted that magnitude of increased risks was higher for individuals who had a greater cardiovascular risk initially. For MI/acute coronary syndrome, for example, “the absolute impact of one episode of anger per month is only one excess cardiovascular event per 10,000 individuals per year at low (5%) 10-year cardiovascular risk and four excess cardiovascular events per 10,000 individuals per year at high (20%) 10-year 9) ___ risk.“ In an accompanying editorial, Suzanne Arnold, MD, of Saint Luke’s Mid America Heart Institute in Kansas City, Mo., and colleagues discussed some of the potential mechanisms tying anger to cardiovascular events and stated that “Mediated through increases in circulating catecholamines, increased myocardial oxygen demand, coronary vasospasm, and increased platelet aggregability, anger can cause transient ischemia, disruption of vulnerable plaques, and increased thrombotic potential, and that these changes can then result in myocardial or cerebral ischemia or malignant arrhythmias.“ They authors also pointed out that the review was limited by the small number of available studies and the significant heterogeneity between them, but said that the findings highlight the consistency of results linking acute anger and increased cardiovascular risk. “However, how to move forward in reducing the burden of these risk factors in patients and, hopefully, its impact on cardiovascular health is still in question,“ they wrote. “Given the lessons we have learned from trying to treat depression after MI, treating anger in isolation is unlikely to be impactful. Instead, a broader and more comprehensive approach to treating acute and chronic mental stress, and its associated psychological stressors, is likely to be needed to heal a hostile heart.“ Mittleman and colleagues noted in their paper that studies of 10) ___ — including beta-blockers and selective serotonin reuptake inhibitors — have not shown substantial benefits, and said that psychological interventions might help.


In an email to MedPage Today, Redford Williams, MD, of Duke University, said that beta-blockers could ease some of the negative consequences of angry outbursts but that their use would be limited by side effects. He agreed the 11) ___ interventions might be worthwhile. “Behavioral interventions that train folks to reduce angry outbursts and/or the accompanying physiological arousal could be an effective means of reducing the health damage associated with angry outbursts,“ he said, backing that up with three prior studies. The first showed that a group-based psychosocial intervention designed to reduce stress, cut mortality among women with coronary heart disease. The second demonstrated that cognitive behavioral therapy with a focus on stress management lowered the risk of recurrent cardiovascular events in men and women with established coronary heart disease. And the final paper cited by Williams showed that a psychosocial skills training workshop reduced anger 12) ___ and the size of the increases in blood pressure and heart rate that accompanied the recall of situations that made men who had undergone CABG, angry.



1.    American Heart Association: Trait Antagonism and the Progression of Arterial Thickening

2.    European Heart Journal: Mostofsky E, et al “Outbursts of anger as a trigger of acute cardiovascular events: a systematic review and meta-analysis“ Eur Heart J 2014; DOI: 10.1093/eurheartj/ehu033.

3.    European Heart Journal: Arnold S, et al “The hostile heart: anger as a trigger for acute cardiovascular events“ Eur Heart J 2014; DOI: 10.1093/eurheartj/ehu097;

4.    MedPageToday.com


ANSWERS: 1) hemorrhage; 2) death; 3)Mortality; 4) diabetes; 5) anger; 6) events; 7) infarction; 8) risk; 9) cardiovascular; 10) medications; 11) psychological; 12) levels

Thomas Willis MD (1621-1625), Father of Neuroscience


Thomas Willis (27 January 1621 – 11 November 1675) was an English doctor who played an important part in the history of anatomy, neurology and psychiatry. He was a founding member of the Royal Society and is often called the father of neuroscience. Willis was born on his parents’ farm in Great Bedwyn, Wiltshire, where his father held the stewardship of the Manor. He was a kinsman of the Willys baronets of Fen Ditton, Cambridgeshire. At Oxford University he did a Bachelors degree, and Masters degree. Once qualified with a B. Med. in 1646, he began as an active physician by regularly attending the market at Abingdon.


Willis obtained his medical degree from Christ Church, Oxford. While at Oxford, he became Sedleian Professor of Natural History in 1660, and retained that position until his death. He did much experimental work with his associate Richard Lower. He performed injection experiments on cadavers and noted that if he injected the carotid artery on one side, the dye solution would come forth from the carotid on the opposite side.


He maintained an Anglican position; an Anglican congregation met at his lodgings in the 1650s, including John Fell, John Dolben, and Richard Allestree. Fell’s father Samuel Fell had been expelled as Dean of Christ Church, in 1647; Willis married Samuel Fell’s daughter Mary, and brother-in-law John Fell would later be his biographer. He employed Robert Hooke as an assistant, in the period 1656-58; this probably was another Fell family connection, since Samuel Fell knew Hooke’s father in Freshwater, Isle of Wight.


In 1664 Willis published his monumental work Cerebri Anatome, the most complete and accurate account of the nervous system that had hitherto appeared. In it he contributed the term “neurology“ to medicine, a word derived from the Greek, meaning “sinew,“ “tendon,“ or “bowstring.“ The word was translated and introduced into the English language in 1681 in Samuel Pordage’s translation of Willis’ work. Cerebri Anatome contains a classification of the cerebral nerves, the first description of the eleventh nerve, and a description of the hexagonal network of arteries at the base of the brain that we know as the circle of Willis. Although others had described the circle before Willis, he was the first to grasp its physiological and pathological significance. He records the clinical histories of two patients in whom he suggests that the anatomic configuration of the arteries at the base of the brain could prevent apoplexy. The book was illustrated by Christopher Wren, an associate of Willis at Oxford, later to become England’s leading architect and designer of St Paul’s Cathedral, numerous other English churches, and many historic secular buildings.


Willis moved to London in 1666 where he continued his careful clinical observations and made a number of other important contributions. He was the first to recognize that lesions in the region of the internal capsule will produce hemiplegia. He was the first (after the ancient Greeks and Romans) to notice the characteristic sweetish taste of diabetic urine. He described myasthenia gravis. He gave the first account of epidemic typhoid fever and typhus. He was the first to describe and name puerperal fever. He described the phenomenon of Willis’ paracusis: a deaf person who can hear only in the presence of noise.


One of several Oxford cliques of those interested in science grew up around Willis and Christ Church. Besides Hooke, others in the group were Nathaniel Hodges, John Locke, Richard Lower, Henry Stubbe and John Ward. (Locke went on to study with Thomas Sydenham, who would become Willis’s leading rival, and who both politically and medically held some incompatible views.) In the broader Oxford scene, he was a colleague in the “Oxford Club“ of experimentalists with Ralph Bathurst, Robert Boyle, William Petty, John Wilkins and Christopher Wren. Willis was on close terms with Wren’s sister Susan Holder, skilled in the healing of wounds.


In 1656 and 1659, Willis published two significant medical works, De Fermentatione and De Febribus. These were followed by the 1664 volume on the brain, which was a record of collaborative experimental work. From 1660 until his death, he was Sedleian Professor of Natural Philosophy at Oxford.


At the time of the formation of the Royal Society of London, he was on the 1660 list of priority candidates, and became a Fellow in 1661. Henry Stubbe became a polemical opponent of the Society, and used his knowledge of Willis’s earlier work before 1660 to belittle some of the claims made by its proponents. Willis later worked as a physician in Westminster, London, this coming about after he treated Gilbert Sheldon in 1666. He had a successful medical practice, in which he applied both his understanding of anatomy and known remedies, attempting to integrate the two; he mixed both iatrochemical and mechanical views. Willis combined the physician’s expert anatomical sophistication with the fluent use of an interpretive apparatus that see-sawed between novelty and tradition, Galenism and Gassendist atomism, iatrochemistry and mechanism. Among his patients was the philosopher Anne Conway, whom he had intimate relations with, but although he was consulted, Willis failed to relieve her headaches.


Willis is mentioned in John Aubrey’s Brief Lives; their families became linked generations later through the marriage of Aubrey’s distant cousin Sir John Aubrey, 6th Baronet of Llantrithyd to Martha Catherine Carter, the grand-niece of Sir William Willys, 6th Baronet of Fen Ditton.



Frontispiece to Thomas Willis’ 1663 book “Diatribae duae medico-philosophicae – quarum prior agit de fermentatione“, engraved and published by Gerbrandus Schagen in Amsterdam


His anatomy of the brain and nerves, as described in his Cerebri anatome of 1664, is minute and elaborate. This work coined the term neurology, and was not the result of his own personal and unaided exertions; he acknowledged his debt to Christopher Wren, who provided drawings, Thomas Millington, and his fellow anatomist Richard Lower. It abounds in new information, and presents an enormous contrast with the vaguer efforts of his predecessors. In 1667 he published Pathologicae cerebri, et nervosi generis specimen, an important work on the pathology and neurophysiology of the brain. In it he developed a new theory of the cause of epilepsy and other convulsive diseases, and contributed to the development of psychiatry. In 1672 he published the earliest English work on medical psychology, “Two Discourses concerning The Soul of Brutes, Which is that of the Vital and Sensitive of Man“. Willis could be seen as an early pioneer of the mind-brain supervenience claim, prominent in present day neuropsychiatry and philosophy of mind. Unfortunately, his enlightenment did not affect his treatment of patients, advocating in some cases to hit the patient over the head with sticks.


Willis was the first to number the cranial nerves in the order in which they are now usually enumerated by anatomists. He noted the parallel lines of the mesolobe (corpus callosum), afterwards minutely described by F?lix Vicq-d’Azyr. He seems to have recognized the communication of the convoluted surface of the brain and that between the lateral cavities beneath the fornix. He described the corpora striata and optic thalami; the four orbicular eminences, with the bridge, which he first named annular protuberance; and the white mammillary eminences, behind the infundibulum. In the cerebellum he remarks about the arborescent arrangement of the white and grey matter, and gives a good account of the internal carotids, and the communications which they make with the branches of the basilar artery.


He coined the term mellitus in diabetes mellitus. An old name for the condition is “Willis’s disease“. He observed what had been known for many centuries elsewhere, that the urine is sweet in patients (glycosuria). His observations on diabetes formed a chapter of Pharmaceutice rationalis (1674). Further research came from Johann Conrad Brunner, who had met Willis in London.


Willis’s work gained currency in France through the writings of Daniel Duncan. The philosopher Richard Cumberland quickly applied the findings on brain anatomy to argue a case against Thomas Hobbes’s view of the primacy of the passions.

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