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

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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.

 

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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.

 

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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

 

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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.

 

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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

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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.

 

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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

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Ingredients

 

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)

 

 

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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.

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

 

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

 

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

 

Directions 

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

 

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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 !