Thursday, March 28, 2013

3 Key Issues for the Future Global Energy Infrastructure

One of the concerns with the environmental movement is the myopic view that establishing a solar and wind energy infrastructure is the correct path without actually proving that it is the correct path. Unfortunately the lack of evidence for the viability of a solar and wind energy infrastructure should be a concern in environmental groups, but it is an issue they typically ignore. Instead most think that the chief problem facing the environment in the future is the current lack of will and sense of sacrifice in society, thus getting people to realize the severity of the situation is the only genuine issue of importance for everything else will fall in place afterwards. This post is a challenge to the environmental community to PROVE that the common strategy points they champion are the correct ones. The three key points that must be addressed by environmentalists are as followed:

1. Argue that both components of geo-engineering (solar radiation management and carbon remediation) will not be needed for decades in the future; as it stands the more vocal environmentalists claim that geo-engineering is a non-starter no matter what due to uncertainty fears with the popular opinion of planting trees and creating some small amount of bio-char being sufficient.

Note – Remember the elimination of coal as an energy source will eliminate a percentage of negative radiative forcing aerosols that are released into the atmosphere through coal combustion. So is there confidence that society can manage an addition 0.2-0.7 degrees C of warming while global emission profiles are still around 60-70% of current levels? If so, what is the origin of this confidence?

2. Argue that building a solar and wind energy infrastructure (65-80% is the range most environmentalists envision) is more economically and structurally viable than building a small modular nuclear reactor and generation III nuclear energy infrastructure.

Note – Be wary of citing anything from Mark Jacobson for this issue. Jacobson’s solar and wind analyses (along with basically everyone else) fail on three major levels:

A. They do not use detailed real numbers when calculating actual required energy and its integration into a future grid; instead he utilizes broad concepts like smart grid, widespread multi-geographical integration, demand-response management, etc. to “magically” eliminate future energy concerns or changes like network congestion and other grid-level system costs. Without using actual numbers in an in-depth analysis of costs and methodological action it is difficult to view legitimacy in his claims largely due only to scale issues let alone other problems. The few analyses that actually use numbers are plagued by optimistic assumptions addressed in the next two points.

B. They fail to address anything remotely specific about the required energy storage for a solar/wind energy infrastructure simply stating that some storage will be required (hypothesized amounts are not mentioned). Also little mention of what it will be (beyond pumped hydro which is supply short), how much it will cost, how it materializes and how its construction will affect other industries. The failure to discuss the intermittency aspect when calculating cost is especially prevalent when wind and solar supporters make claims like wind and/or solar costs in country x are now lower than coal costs. Wind/solar proponents seem not to understand that 1 GW of solar is not equivalent to 1 GW of coal when taking operational capacities into consideration over nameplate capacities (i.e. what occurs in the real world 10 –35% for solar or wind (depending on the country and time of year) of nameplate versus 75-90% for coal.)

C. They fail to address supply shortages that will be created when constructing a solar/wind infrastructure, especially for rare earths (most notably heavy REs like dysprosium), concrete, steel and aluminum. These shortages will significantly increase costs for the construction of this infrastructure largely because of the low generation per unit ratios that solar and wind installations have due to their scale capacity and intermittency limitations.

Due to these problems, only citing Jacobson demonstrates a lack of caring about these critical issues and thus place the future of the planet in the “hope and pray” column. Basically a mindset that is similar to that of a global warming denier.

3. How will the creation of a large (40%+) electrical vehicle fleet and a large (40%+) wind energy infrastructure be created at economic cost when both utilize the same rare earths (dysprosium, neodymium and praseodymium) to significantly limit costs? Basically as of now it is most probable that one will have to be sacrificed for the other, so if electrical vehicles and wind are deemed necessary for the future, how will this be achieved at feasible costs?

Answers to these questions need to be as specific as possible because simply stating broad concepts like “smart grid” or “rare earth substitutes” does little good without the specifics of how those concept would actually solve certain problems within the core issues. For those who would suggest that this blog do the work, this blog has posted a good portion of discussion about these issues coming to conclusions that oppose the common belief that pursuing a generic solar and wind energy infrastructure is viable and appropriate given the available time remaining to confront global warming. Also because these concerns embody elements critical to the viability of the common environmentalist argument for the future global energy infrastructure the burden of proof is on the environmentalists that support this infrastructure to demonstrate that it will have a significant probability of being successful. It is imperative that these issues be resolved as soon as possible with a significant probability of certainty because the time to act is now and acting with the wrong strategy is just as useless as not acting at all.

Saturday, March 16, 2013

Placebos in Clinical Trials

The placebo effect has been an important consideration in medical treatment and clinical drug trials since its official identification in 1955.1 Placebos are typically regarded as inert agents or procedures designed to facilitate action against a given detrimental condition regardless of whether the action will have any positive effect on the condition. Some quibble with the use of the word ‘inert’ because the placebo effect encompasses an effect derived from the placebo. However, such a thought takes the word ‘inert’ to an unreasonable extreme. Clearly for the purposes of the definition, inert is assigned to the placebo element not having a direct biological effect against the targeted condition. Thus the placebo effect is regarded as any improvement of a detrimental condition without the aid of direct treatment under the presumption that such a treatment is being given.

One of the most troublesome areas of drug research complicated by the placebo effect is pain management or pain analgesia. For analgesia the biochemical methodology that governs the placebo effect is thought to occur through the release of endorphins stemming from signals derived from the prefrontal cortex with additional activity in the orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DLPFC), rostral anterior cingulate cortex (rACC), and midbrain periaqueductal gray (PAG).2 This belief is further supported by information from Alzheimer’s patients in that neuronal degeneration of the DLPFC, OFC and rACC results in a loss of the placebo effect.3 The endorphin component of the placebo effect regarding analgesia was identified when such analgesia was neutralized by naloxone, an opioid antagonist.4 Follow up research confirmed this relationship between endorphins and placebo analgesia through the use of cholecystokinin (CCK), an anti-opioid peptide.5-7 Direct demonstration of opioid released occurred in 2005 through the PET observation of increased μ-opioid receptor neurotransmission in the ACC, OFC, the insula, and the nucleus accumbens.8

Despite a somewhat better understanding of the psychological and physiological mechanisms behind the placebo response there is still questions regarding its lack of universal application. For example in randomized controlled trials the drug-placebo difference has been reported at 40% for functional disorders,9 29% in depression, 31% in bipolar mania, 21% for treatment of migraines.10,11 Some conclude that the variable placebo rates involve differences in sample size, study time, patient recruitment and design characteristics. The best option seems to be design characteristics.12,13

Design characteristics are important because the placebo effect also has a conditioning expectation component, which exists in two separate parts beyond pure biological activation. The first component is the inherent anticipatory psychological reaction of a potential new stimuli and its influence. Basically if one is given an unknown drug by an individual of expertise and/or authority and is told that it will have a certain effect then one expects that effect to occur regardless of whether or not it actually will. Basically there is a value association with the treatment. The value impact is also applicable in that more expensive drugs are thought to have more positive influence.14

The second component is a conditioning physiological/psychological reaction derived from multiple exposures to a single given element. One of the chief examples of this placebo effect response is after numerous doses of morphine-like compound (buprenorphine), which had a side effect of reduced respiration, at a specific time in a specific manner, individuals were then given an inert compound in the same manner at the same time and the body responded by reducing respiration.15,16 Thus, there appears to be a Pavlovian biological response, which can induce a placebo effect beyond conscious psychological expectations. This response is somewhat mysterious in that it overcomes even an opioid inhibitory treatment, like naloxone, when using a non-opioid primer.16 Overall this behavior implies a ‘mimicry’ effect perhaps associated with long term potentiation (LTP).

One significant element that dictates the strength of these elements is the concentration and interaction rates of two separate neurotransmitters: dopamine and norepinephrine. In essence while dopamine is given chief credit as the ‘reward’ molecule its influence is augmented or dampened, depending on the situation, by norepinephrine. Basically dopamine determines what elements/actions are characterized as rewarding and norepinephrine grants the required focus, both consciously and seemingly unconsciously, to achieve and recognize the rewarding action. Therefore, if norephinephrine is not at a sufficient concentration the placebo effect ceases to operate. If this is the case then enzymes catechol-O-methyltransferase (COMT) and monoamine oxidase A (MAO-A) are also important because they are responsible for the destruction of dopamine and norepinephrine respectively.17

Destruction of dopamine is important because the placebo effect has association with expectation. This expectation, either conscious or unconscious, will create an acute and significant increase in dopamine concentration; however, if dopamine concentrations are already high the additional increase provided by the placebo effect will not induce significant biochemical change because the percentage change will be small. For the placebo effect the percentage change is more important than the absolute change. Thus, in the context of treating pain and also depression the ‘ideal’ placebo effect candidate has high COMT activity (low dopamine concentration) and low MAO-A activity (high norepinephrine concentration).

Identifying potential placebo beneficial or detrimental genetic agents produces a useful secondary treatment strategy. For example individuals who are the ideal placebo candidates have an advantage in that they could be treated for pain through the placebo effect if other direct pain mitigation methods are unavailable due to bad reactions and/or excessive side effects. Also with this new information pertaining to the function of the placebo effect with regards to pain management one can design diets to augment this aspect of the placebo effect. Clearly there are ethical concerns with giving a known placebo to a patient in lieu of actual medication, but there are numerous situations where the side effects associated with the standard pain medication may reduce the quality of life of the patient to a level where taking the medication is not viewed as significantly beneficial. Therefore, individuals who have mid to high COMT activity and low to mid MAO-A activity could be candidates for an enhanced placebo effect either using direct placebos or even simple changes in diet which would augment dompaine and norepinephrine levels.

Another important consideration of the placebo effect beyond actual treatment is how it can influence results in clinical trials. Most pharmaceutical companies know that the clinical trial is the most frustrating part of creating a new drug because after spending hundreds of thousands to millions on research and development if clinical trial results are ambiguous or inconclusive the developed drug enters a state of limbo which can be even worse than if it simply fails to demonstrate improvement.

Part of the problem with identifying the placebo effects is the idea of responders and non-responders (those who exhibit a placebo effect and those who do not) is typically ignored. Instead in both clinical studies and placebo studies differences between group averages are analyzed over individual responses. Such practice creates situations where the identical mean change between a placebo group and non-treatment group can be demonstrated either by large number of individuals showing an average response or a small number of individuals showing a large response and others showing no response. This is one of numerous statistical situations where averages without standard deviations are dangerous.

When individual results are taken one of the big problems with confirming the placebo effect is the nature of pain progression relative to regression to the mean. Extremes in self-reported pain intensity, either high or low, eventually shifts towards average because they are extreme and more than likely short-lived. With regards to the placebo effect clearly the high extreme is more relevant than the low because individuals involved in these trials are in pain. However, the pain will abate over time from a self-reporting standpoint as the body adapts to the pain regardless whether or not the placebo effect activates. Therefore, in such a situation it is difficult to differentiate between the placebo effect reducing pain or regression to the mean adaptation to the pain.

There are a number of strategies designed to “neutralize” the placebo effect in clinical trails. The crossover design is where individuals serve as their own controls reducing inter-subject variability. Another focuses on eliminating expectations through concealing the psychological component by either initiating the medical treatment without the knowledge of the patient or by introducing uncertainty in its administration. Basically hiding the injection or infusion method from the patient eliminating knowledge of its administration or telling the patient that the treatment could make the patient feel better, but there are no guarantees.

However, as mentioned above despite strategies to reduce psychological triggering of the placebo effects the one thing that cannot be concealed is that patients do receive some form of treatment. Therefore, genetic elements like COMT and MAO-A will still play a significant role in driving the placebo effect. Identifying individuals who possess these genetic characteristics would allow for better post-experiment analysis regarding potential placebo effects pertaining to pain treatment and other treatments given the particular genetic agent. There are two immediate questions regarding the collection of this genetic information: first, the screenings would have to comprise of only the above agents, not a complete genetic analysis to ensure the privacy of the research subject. Second, the research must remain a double-blind study, thus the genetic information should only be used post-analysis and not revealed to anyone prior to or during the experiment.

Finally there has been some question to the legitimacy of the placebo effect.18 The problem with this critical analysis is it is too expansive coving too many different disease and treatment methodologies. Such analysis method makes it more difficult to see the statistical nuances in each separate study, which could muddle results and conclusions. For example it would be akin to judging the quality of an orange when eating it in a fruit salad. Therefore, it is difficult to view conclusions questioning the placebo effect without skepticism.

Overall the use of genetic mapping and better statistical analysis techniques should allow researchers to better separate real changes between drugs versus artificial changes like the placebo effect. Analysis accuracy is obviously important because if analysis remains suspect then society wastes time, money and resources on statistically insignificant drugs. The most important element to a more robust analysis methodology would be to standardize it through all laboratories. Such standardization would ensure effective analysis checking to maximize the probability of correct conclusions and effective drug action.

Citations –

1. Beecher, H. “The powerful placebo.” JAMA. 1955. 159(17):1602-1606.

2. Miller, E and Cohen, J. “An integrative theory of prefrontal cortex function.” Annu. Rev. Neurosci. 2001. 24:167-202.

3. Thompson, P, et Al. “Dynamics of gray matter loss in Alzheimer’s disease.” 2003. J. Neurosci. 23:994-1005.

4. Levine, J, Gordon, N, and Fields, H. “The mechanisms of placebo analgesia.” Lancet. 1978. 2:654-657.

5. Levine, J and Gordon, N. “Influence of the method of drug administration on analgesic response.” Nature. 1984. 312:755-756.

6. Benedetti, F. “The opposite effects of the opiate antagonist naloxone and the cholecystokinin antagonist proglumide on placebo analgesia.” Pain. 1996. 64:535-543.

7. Benedetti, F and Amanzio M. “The neurobiology of placebo analgesia: from endogenous opioids to cholecystokinin.” Prog. Neurobiol. 1997. 52:109-125.

8. Zubieta, J and et Al. “Placebo effects mediated by endogenous opioid activity on u-opioid receptors.” J. Neurosci. 2005. 25:7754-7762.

9. Enck, P and Klosterhalfen, S. “The placebo response in functional bowel disorders: perspectives and putative mechanisms.” Neurogastroenterol Motil. 2005. 17:325-331.

10. Sysko R and Walsh, B. “A systematic review of placebo response in studies of bipolar mania.” J. Clin. Psychiatry. 2007. 68:1213-1270.

11. Macedo, A, Banos, J, and Farre, M. “Placebo response in the prophylaxis of migraine: A meta-analysis.” Eur. J. Pain. 2008. 12:68-75.

12. Walsh, B, et Al. “Placebo response in studies of major depression – variable, substantial and growing.” JAMA. 2002. 287:1840-1847.

13. Kobak, K, et Al. “Why do clinical trials fail? The problem of measurement error in clinical trials: time to test new paradigms?” J. Clin. Psychopharmacol. 2007. 27:1-5.

14. Waber, R, et Al. “Commercial features of placebo and therapeutic efficacy.” JAMA. 2008. 299(9):1016-1017.

15. Benedetti, F, et Al. “The specific effects of prior opioid exposure on placebo analgesia and placebo respiratory depression.” Pain. 1998. 75:313-319.

16. Benedtti, F, et Al. “Inducing placebo respiratory depressant responses in humans via opioid receptors.” Eur. J. Neurosci. 1999. 11:625-631

17. Leuchter, A, et Al. “Monoamine Oxidase A and Catechol-O-Methyltransferase Functional Polymorphisms and the Placebo Response in Major Depressive Disorder.” Journal of Clinical Psychopharmacology. 2009. 29(4):372-377.

18. Hrobjartsson, A and Gotzsche, P. “Placebo interventions for all clinical conditions.” Cochrane Database Syst. Rev. 2010. 106(1).

Thursday, March 14, 2013

A Brief Discussion of Election Voting Reform

The aftermath of any election season brings numerous complaints about the inefficiencies and/or unfairness of the voting process. Voters wait too long, voter ID laws are too stringent, bias against certain voting parties, inconsistencies in the early voting process, etc. Unfortunately while most critics are correct that there is some gross inefficiency in the system, most do not actually consider the entire system and how it reflects on the problem, they simply focus on their specific complaint. Also critics do not seem to provide many solutions to the identified problems beyond, “Fix it!”. An important element that must be considered is that because the ability of the electorate to actually wield power is so scant, hundreds of millions of people will vote during major election season. Therefore, there will be significant wait times to vote in most situations regardless of the designed system; the goal must be to manage those wait times.

A pathetic element regarding the state of the voting system in the U.S. is how overcomplicated it has become. Voting ID requirements are a principle example of this aspect for they are irrelevant and actually exacerbate the problem due to the difficulties some have in acquiring appropriate IDs. The purported purpose of voting IDs is to eliminate voter fraud. Confusingly voter fraud is hardly rampant and it is economically inefficient to demand IDs to combat such an incredibly small problem. However, if combating voter fraud is still regarded as a moral issue then there is a more effective way to combat it; a method that will also significantly reduce any potential inequality associated with the ability to acquire an appropriate ID.

Instead of using voting IDs a simpler and less expensive solution would be to add one additional element to voting registration. When an individual registers to vote he/she will simply declare a 4-digit voter PIN number. Then when this individual goes to vote the identification procedure in acquiring a ballot will simply require giving the correct name and voter PIN number. The election worker will then check the number and if correct hand over a ballot and cross the name off.

If the name and voter PIN do not match up, the potential voter has one of two actions available. First, the voter can display a valid state or federal ID confirming his/her identity. Second, each voter will be allowed to answer a “security question”, similar to those asked when individuals forget their computer passwords, which was filled out on the new voter registration form. Inability to comply with either of these steps will result in the election worker asking the potential voter to leave. Note that forgetting a voter PIN number will be very difficult because it will be listed on an individual’s voter registration card. For absentee voting the voter PIN number would be required just below the signature and dating portion of the ballot. There is a voter ID number given upon registration, but it is longer and not uniquely determined making it more difficult to manage; however, the issued voter ID number could work fine as well.

Another criticism in both 2010 and 2012 U.S. elections was the reduction of time available to conduct early voting, which some believe was an indirect attack against minority voting capacity. The chief purpose of early voting is to accommodate those who would be unable to vote or face great stress in voting on Election Day. Individuals making criticism against more restrictive early voting must tread carefully because keeping polling areas open on various days obviously requires spending money, money that both state and local governments have in less supply due to the slow recovery from the Great Recession.

Also most local election officials, not surprisingly, see changes in the voting system in terms of cost. Most early voting increases long-term workload, yet states tend not to hire anywhere near the amount of temporary workers to compensate for this increased workload. Therefore, most election officials have to work longer at typically a greater inconvenience level at the same general salary. Also the time between elections does not allow for the creation of a “familiarity groove” of sorts. Basically because elections occur once every two years, most early voting coordination seems like it is happening for the first time, especially if temporary help is new, thus there is little significant consistency; this consistency reduces workload both literally and psychologically.

The best strategy to address early voting seems to be utilizing no excuse absentee ballots, which could be picked up at Federal Buildings, police departments or post offices for no charge. After voting these ballots can be mailed to the appropriate election office. However, there would have to be a minimum date of return for effective early voting processing on the ballot consistent among all states. For example a domestic no-excuse absentee ballot would have to be postmarked no later than five days prior to the election date. Some would argue that online balloting can take the place of mailed ballots, but either security or cost concerns for online balloting will almost always be significant enough to limit its role in major elections. Also despite what some appear to believe wide swatches of the country do not have routine access to the Internet, which could create problems for an unsupervised and unorganized voting period and disenfranchise some voters.

One point of note is that while there are questions to the utility of early voting in increasing turnout rate,1-3 expansion of Election Day registration (EDR) may not be appropriate. There is evidence to suggest that EDR does increase voter turnout rate, but from a logical perspective it offers the highest probability to generate voter fraud.4,5 Also EDR expansion will further increase the workload of election officials and increase wait times for all voters. The purpose of EDR is strange because it validates and encourages laziness. Registering to vote is not difficult, even despite the effort of some to make it so, and people typically have sufficient time (months to years), thus failure to be successfully registered during election season is purely the fault of the unregistered individual.

Finally the Federal government may have to expand its role when states and districts fail at their administrative responsibilities. The Federal government should create a minimum threshold for discrimination complaints against a particular district/state and if that threshold is met, then it should strip the autonomy of that district/state to conduct elections. Some may argue that this is an unjustified reach of government power against state rights, but those making such an argument would be incorrect because those ‘encroached upon’ areas have only themselves to blame because they did not fulfill the responsibilities associated with its afforded power. Also the Elections Clause of the Constitution affords the Federal government the power to circumvent state power when it comes to election regulations.

A voter PIN number should eliminate almost all voter fraud as well as be convenient enough to keep the actual vote casting process fair. A stronger “refereeing” role needs to be taken by the Federal government to ensure that states behave appropriately and fairly when conducting elections. Finally appropriate access to early balloting through availability of absentee ballots should ensure that everyone who wants to vote would have the opportunity to do so. Overall creating and maintaining an effective, fair and honest voting system is rather simple if one does not attempt to derail it through the addition of unnecessary complexities.

Citations –

1. Burden, B, et Al. “The effects and costs of early voting, elections day registration, and same day registration in the 2008 elections.” Pew Charitable Trust. Dec. 21, 2009.

2. Fitzgerald, M. “Greater Convenience but not Greater Turnout: The Impact of Alternative Voting Methods on Electoral Participation in the United States.” American Politics Research 2005. 33:842-67.

3. Gronke, P, Galanes-Rosenbaum, E, and Miller, P. “Early Voting and Turnout.” PS: Political Science and Politics. 2007. 40:639-45.

4. EAC. “The Impact of the National Voter Registration Act of 1993 on the Administration of Elections for Federal Office 2007-2008: A Report to the 111th Congress.” U.S. Election Assistance Commission. June 30, 2009.

5. Leighley, J and Nagler, J. “Electoral Laws and Turnout: 1972-2008.” Paper presented at the Fourth Annual Conference on Empirical Legal Studies, University of Southern California. 2009.