Demonstration Evaluation Form: Fill & Download for Free

In a word, incorrectly.The economic mainstream rejects the labor theory of value (LTV) and has since the late 19th century.What is the LTV?Before we get into the mainstream critique of the LTV and why it is incorrect, we must first define the LTV. Thus, David Ricardo (long quote, I’ll explain in simpler language below):"Let us suppose that all commodities are at their natural price, and consequently that the profits of capital in all employments are exactly at the same rate, or differ only so much as, in the estimation of the parties, is equivalent to any real or fancied advantage which they possess or forego. Suppose now that a change of fashion should increase the demand for silks, and lessen that for woollens; their natural price, the quantity of labour necessary to their production, would continue unaltered, but the market price of silks would rise, and that of woollens would fall; and consequently the profits of the silk manufacturer would be above, whilst those of the woollen manufacturer would be below, the general and adjusted rate of profits. Not only the profits, but the wages of the workmen, would be affected in these employments. This increased demand for silks would however soon be supplied, by the transference of capital and labour from the woollen to the silk manufacture; when the market prices of silks and woollens would again approach their natural prices, and then the usual profits would be obtained by the respective manufacturers of those commodities. It is then the desire, which every capitalist has, of diverting his funds from a less to a more profitable employment, that prevents the market price of commodities from continuing for any length of time either much above, or much below their natural price”The LTV states, in other words, that input costs determine price in the long term. While consumer demand might cause brief shifts in the price of commodities, in the long term as capitalists adjust investment from less profitable to more profitable industries, the profit rates in each industry will over time approach each other. Therefore, in the long term, in a free market without barriers to competition, ultimately input costs and price will directly correlate.Further, because the initial input in creating anything we value that is scarce and therefore has a cost is human labor, ultimately it is the labor involved in creating any commodity that in the long term determines its price.What is the mainstream critique of the LTV?Okay, with that established, what is the mainstream critique of the LTV? Primarily, that the LTV fails to realize that the value of a commodity is subjective, and that their prices are based on the subjective evaluations of consumers. (This, by the way is called either marginalism, or the subjective theory of value (STV))You'll often see examples given like someone spending hours digging a ditch and filling it back up, or, as one previous answerer of this question provided, folding a paper airplane and unfolding it to disprove the LTV.The point of these examples is to show that just because creating something requires labor, it doesn’t necessarily make it more valuable. What makes goods valuable is the subjective utility they provide consumers.Why is this criticism incorrect?Hopefully for those of you who have understood this far, you realize the problem with this critique. Namely, that it’s based on a misrepresentation of the LTV. In fact, the two supposedly competing theories are completely consistent with one another. They just describe different things.The STV is a static description of price; the LTV is a dynamic description of price.The STV describes a snapshot of what determines the price of a good at any one moment in a capitalist economy. Namely the subjective evaluations of consumers and suppliers that form supply and demand curves that intersect at the equilibrium price.Meanwhile, the LTV accepts this description of static prices (with a disequilibrium analysis though, which we’ll get into later). However the LTV goes on further to explain what happens to these prices over time under the capitalist mode of production, and what they’ll tend toward in the long term.The mainstream theory of value sees capitalism as merely a form of exchange; the heterodox LTV sees capitalism more fully as a form of production.What caused the mainstream rejection of the LTV?The LTV has an interesting history. Thought the late 18th and early and mid-19th century, it was about as mainstream in the field of economics as it gets. Adam Smith used it, David Ricardo used it, John Stewart Mill used it. All the notorious fathers of classical liberalism and capitalist economics used the LTV. However, suddenly in the 1870s it started to be replaced by the STV.Why, you might ask? Well think about what very influential thinker wrote his magnum opus on political economy right in the lead up to the 1870s.For those of you who know you’re intellectual history or history of economic though, you’ll know that I am of course speaking of Karl Marx’s notorious three volume examination of capitalism, Das Kapital, the first volume of which was originally published in 1867.In it Marx takes the LTV that had been used for nearly a century by economists advocating for capitalism and used it to write his three volume work criticizing capitalism and advocating revolutionary socialism. The book sparked an international revolutionary socialist movement known as Marxism that was highly influential throughout the 20th century and to this very day.Shortly after that, capitalist economists decided to discard it.What are some other criticisms of the LTV?We’ll go through 4 major ones and address each of them. These are critiques generally made outside the mainstream paradigm, but they still merit a response:The LTV predicts that worker’s standard of living would never increaseThe LTV can’t explain the value of natural goodsThe LTV relies on equilibrium analysisThe LTV is just an abstract modelCriticism #1: The LTV predicts that worker’s standard of living would never increaseThis criticism actually has some basis in socialist literature. Sometimes socialists, in moments of rhetorical flourish, would use the LTV to argue this.The argument is based in the idea that the LTV demonstrates that wages are based on the cost of reproducing the labor power of workers. In other words, providing them the standard of living necessary to cover the cost of surviving and remaining healthy and able enough to do the labor they do.Some will argue this can’t be the case because in many places the standard of living of workers has risen under capitalism. However, this does not necessarily contradict the LTV.Thus Adam Smith, in defense of himself and the LTV of this charge:"By necessaries I understand, not only the commodities that are indispensably necessary for the support of life, but whatever the custom of the country renders it indecent for creditable people, even of the lowest order, to be without. A linen shirt, for example, is, strictly speaking, not a necessary of life. The Greeks and Romans lived, I suppose, very comfortably, though they had no linen. But in the present times, through the greater part of Europe, a creditable day-labourer would be ashamed to appear in public without a linen shirt, the want of which would be supposed to denote that disgraceful degree of poverty, which, it is presumed, no body can well fall into without extreme bad conduct."As you can see, Smith, despite believing that wages are meant to cover the cost of reproducing labor power, says that changing customs and standards of decency that emerge as societies progress can change the costs of labor power and thus wages. He believes, in other words, that standards of living can change as societies progress even if we accept the LTV.I’d add that the demand for skilled and educated labor can also increase living standards as education and training of humans require investment in their livelihoods and ability to cover expenses. Therefore, even under the framework of the LTV, increasing living standards for workers are not ruled out.Criticism #2: The LTV can’t explain the value of natural goodsThis criticism is rather simple to refute. It requires labor to acquire natural goods like water, food, and diamonds. If, for example, diamonds were as easy to acquire as grass they wouldn’t be as valuable, and vice versa.Criticism #3: The LTV relies on equilibrium analysisThis one is popular with fellow critics of the neoclassical economic consensus who reject the LTV. Namely that is relies on the neoclassical motion of static equilibrium, which is clearly nonsense. (The reason it is nonsense is that there are plenty of markets, like the labor market, that clearly aren’t in equilibrium)However, even if equilibrium analysis is incorrect, which it is, the LTV holds up.The reason for this is that it doesn’t particularly matter how static prices are determined in capitalism. The LTV is a dynamic theory of price. All that matters is that the explanation of how production and investment work and how they effect prices in the long term under capitalism the LTV provides holds up, which it does.The way static prices are determined could be anything, and as long as industries with higher rates of profit received greater investment at the expense of relatively profit poor industries, the LTV holds up. So even if you reject equilibrium analysis, as I do, and prefer a post-Keynesian disequilibrium analysis, as I do, you can still accept the LTV.Criticism #4: The LTV is just an abstract modelTrue, however, that is not a reason to completely reject it.Some thinkers, including socialists like Peter Kropotkin, think it is. He even went as far as to call it one of:"the metaphysical definitions of the academical economists"Kropotkin thought, in other words, that any economic model was essentially “metaphysical” in that it does not perfectly describe the real world, and therefore shouldn’t be adhered too.Kropotkin is right that the LTV doesn’t perfectly describe prices under really-existing capitalism. It describes them in the long term in a free market with free competition. However, often there are state interventions and barriers to entry and monopolies that interfere with this long term process. Additionally, the LTV even under such circumstances only describes a long-term tendency. Therefore perhaps it is better to think of labor costs as the regulator of price, rather than the determiner of price.However, it is still, in my opinion, a useful tool for analyzing capitalism. And it is a tool that has helped millions understand why it is so insidious and how it can be overthrown.For further reading:Unfinished appendix on economicsThe Labor Theory of Value

My sympathy to Wendy Barker, whose reaction to this question is very understandable. Her reply is, in a nutshell, correct. But in case you'd be more reassured by a little bit more information:I'm not seeing anything new on this topic in the news, only rehashings that date back to the fear-mongering news reports about a study, published in July 2012, that claimed to have shown that diacetyl, microwave popcorn's butter flavoring, causes brain proteins to misfold into the "Alzheimer's-linked form" called β-amyloid (beta amyloid, Abeta, Aβ, etc), can pass through the blood-brain barrier, and can inhibit the brain's natural amyloid-clearing mechanisms.More SS, Vartak AP, Vince R. The butter flavorant, diacetyl, exacerbates β-amyloid cytotoxicity. Chemical research in toxicology. 2012 Jul 6;25(10):2083-91.The studies that were done involved (a) incubating diacetyl with β-amyloid peptide 1-42 (Aβ1-42) in solution, and using thioflavin T fluorescence to monitor aggregation and circular dichroism to detect changes in the secondary solution structure of Aβ1-42; (b) in vitro cytotoxicity studies involving incubating SH-SY-5Y in diacetyl and/or Aβ1-42 and then using 2,5-diphenyltetrazolium bromide (MTT) to detect mitochondrial function of the viable cells as a reflection of cell growth; and (c) a simplistic, MDR1-MDCK cell monolayer model of the blood-brain barrier to detect diacetyl permeation. The paper states:"Due caution must, however, be exercised while extrapolating the results of this study to phenomenon in the intact animal. Although the in vitro data in this study show toxicity of [diacetyl] at concentrations actually recorded physiologically, extension of this toxicity in the in vivo environment is influenced by a plethora of factors ranging from transport across compartments to its possible metabolism of [diacetyl] by dicarbonyl reductases. A study of the effects of such factors requires greatly expanded investigations employing animal models."In other words ... all sorts of things can happen in solution and/or in cell culture that do not happen in a living organism.And one further word of caution: no study should be relied on until it has been replicated by other laboratories.So why, you ask, would anyone think to study a possible (very tenuous) link between between diacetyl flavored microwave popcorn and Alzheimer's in the first place?The line of reasoning in More et al is roughly this: It is “unequivocally” agreed upon that Aβ aggregation is a pathogenic event. Aβ peptides equilibrate between three major conformations: random-coil, α-helix, and β-strand. Only the β-strand structure is prone to aggregation and is the conformation of interest in Aβ pathology. Reactive carbonyl species such as methylglyoxal (MEG) form covalent adducts with proteins, called advanced glycation end products (AGEs). Inception and progression of Alzheimer's have been linked to the formation of AGEs. Solution studies have shown that modification of Aβ by MEG increases the percentage of β-strand structure and therefore its aggregation propensity. Diacetyl has been a focus of toxicological research because of its ability to induce bronchiolitis obliterans in popcorn factory workers chronically exposed to it. The structural similarity of diacetyl to physiologically occurring dicarbonyl species suggests that it may form AGEs. More et al sum it up: "In light of chronic exposure of popcorn factory workers to [diacetyl] and the structural similarity of [diacetyl] to MEG, a known Aβ1-42 aggregation inducer, an investigation into the amyloidogenic effects of [diacetyl] is clearly warranted."Which, I suppose, might sound good if you read it very quickly and didn't question any of the individual statements, let alone whether there are any logical associations among them. Since I got hung up on the statement that "it is unequivocally agreed upon that Aβ aggregation is a pathogenic event" -- that may have been the case in the past, but certainly not nowadays -- and still can't see how a possible link between a lung disease and chronic exposure to very high levels of diacetyl in factory workers leads to a hypothesis there's a link between a neurodegenerative brain disorder and occasional exposure to very low levels of diacetyl in the general public ... well, I didn't find it to be very compelling.When one gets into the details, it makes even less sense.The concern about the potential of diacetyl to cause pulmonary disease associated with microwave popcorn began in May of 2000, when an unusual cluster of fixed airway obstructions was reported in workers in a microwave popcorn plant in Missouri. Eight workers who had formerly worked in the plant were reported by the Missouri Department of Health as having bronchiolitis obliterans, which is a very rare disorder. Investigators from NIOSH conducted medical examinations and environmental surveys and concluded that the estimated cumulative diacetyl exposure correlated with lung disease in a factory. (Remember that correlation does not imply causation.) Since then, NIOSH has conducted at least 16 additional industrial hygiene and medical Health Hazard Evaluations in food production, food preparation, and flavoring manufacturing facilities related to diacetyl. However, ever since the first NIOSH report, numerous investigators, including those associated with the initial research, have questioned whether diacetyl alone can be singled out as a causative agent in lung ailments in microwave popcorn plant employees. More recently, a re‐analysis conducted on the Health Hazard Evaluation that was performed by NIOSH (using the NIOSH spirometry results and employment histories) concluded that exposures to flavoring chemicals in the workplace, including diacetyl, did not produce an increased risk of abnormal spirometric findings. Moreover, experts have agreed that other components of artificial butter flavoring and microwave popcorn manufacture may contribute to respiratory disease -- diacetyl has gained the most attention simply because it is the most prevalent. Yet relationship or association does not mean causation, and just because a compound is most prevalent does not mean that it is the cause of an ailment. On top of that, the data have been significantly confounded by nonoccupational diacetyl exposure from cigarette smoke and hundreds of other volatile organic compounds.Animal inhalation toxicity studies appeared to support the concept that diacetyl exposures cause respiratory injury. However, the levels selected for these studies were unrealistic extremes, orders of magnitude higher than typical TWA values measured in popcorn plant mixing rooms. Given that exposure levels of popcorn consumers are not nearly as high as those who work in manufacturing plants, the results cannot be extrapolated to the bronchiolitis obliterans risk for consumers ... let alone the risk of, sigh, Alzheimer's.Clark and Winter conclude: "Numerous foods, particularly fermented foods, have been a source of consumer exposure to diacetyl for millennia. The appealing aroma characteristics of diacetyl include both orthonasal and retronasal pathways. Consumers are regularly and intermittently exposed to moderate levels of diacetyl in the diet. Dietary exposure to diacetyl under exaggerated conditions representing abnormally high levels of diacetyl in several foods still represents exposure levels far below those considered to be of toxicological significance. In addition, typical levels of airborne diacetyl resulting from [microwave] popcorn are significantly below levels of occupational health and safety concern. The levels of diacetyl in food products are not dangerous and special warning labels are not warranted. Diacetyl, at the levels found in many foods and beverages, including [microwave] popcorn, does not present a risk to consumers and should not be implicated as a cause of lung disease for consumers of [microwave] popcorn or other foods."Clark S, Winter CK. Diacetyl in foods: a review of safety and sensory characteristics. Comprehensive Reviews in Food Science and Food Safety. 2015 Sep;14(5):634-43.On top of that, other researchers have noted that bronchiolitis obliterans is a rare disease involving concentric bronchiolar fibrosis that develops rapidly following inhalation of certain irritant gases at sufficiently high acute doses. Irritant gases known to cause bronchiolitis obliterans (e.g., chlorine, hydrochloric acid, ammonia, nitrogen oxides, sulfur oxides, sulfur or nitrogen mustards, and phosgene) all follow a similar pathologic process and time course of disease onset in humans. Failure to clearly define the clinical features and pathological characteristics can easily lead to misdiagnoses. To date, animal and human studies on diacetyl have not identified a coherent pattern of pathology and latency that would be expected based on studies of other known causes of bronchiolitis obliterans disease.I would also emphasize that microwave popcorn is hardly the only source of diacetyl exposure that consumers face. Many products contain high levels of diacetyl, including unsalted butter, cheese, flour mixes, shortening, food oils, flavored wines and liquors, yogurt and ice cream flavors, fragrance, gum, and flavorings.The Food and Drug Administration (FDA) categorizes diacetyl as a generally recognized as safe (GRAS) substance and that the ingestion of diacetyl in food has not shown any human health risks. (I checked again today, to make sure there hasn't been any change in its status.)Now. Back to More et al and their hypothesized link to Alzheimer's. Remember my earlier word of caution, that no study should be relied on until it has been replicated by other laboratories. Just a few days ago, Das and Smid published the results of a new study:Das S, Smid SD. Small molecule diketone flavorants diacetyl and 2,3-pentanedione promote neurotoxicity but inhibit amyloid β aggregation. Toxicology letters. 2019 Jan 1;300:67-72.Like diacetyl, 2,3-pentanedione and acetoin are used to impart buttery flavors in processed foods such as popcorn. The authors note that, "while many small organic molecule inhibitors of Aβ aggregation have been identified, including many bioactive polyphenols (Das et al., 2016), small organic molecules that actively promote Aβ fibrillisation have been less well characterised. This is made more difficult by a lack of understanding in whether small molecule-Aβ interactions affecting aggregation generate non-toxic or 'off-target' Aβ conformations, probably best exemplified by the curcuminoids (Ahmad et al., 2017). From this perspective, further insight into small molecule flavorant interactions promoting Aβ aggregation would be valuable."In contrast to More et al, Das and Smid found that diacetyl inhibited Aβ1-42 fibril and aggregate formation -- even though they used the same Thioflavin T (ThT)-based assay to measure aggregation kinetics. Using electron microscopy -- which provides much more detailed structural information than circular dichroism -- they also showed that diacetyl reduced aggregate and fibril density, and turned Aβ1-42 into amorphous small aggregates. 2,3-Pentanedione also reduced overall aggregate formation, but to a lesser extent than diacetyl, and retained the presence of a meshwork of Aβ1-42 aggregates and fibrils. Acetoin did not alter Aβ1-42 fibril density or morphology.Das and Smid used two neuroblastoma cell lines, SH-SY5Y (used by More et al) and Neuro 2a (N2a), to begin studying possible mechanisms of neurotoxicity. Diacetyl and 2,3-pentanedione both elicited a concentration-dependent loss of cell viability in N2a cells after 48h incubation over the 10–100 μM range, while acetoin was without significant effect. Diacetyl was the most neurotoxic, with less than 10% N2a cell viability remaining at 50μM. IC50 values were 2.0μM and 5.3 μM for diacetyl and 2,3-pentanedione respectively; acetoin’s toxicity was insufficient for an IC50 determination.Similar to N2a cells, SH-SY5Y cells were also susceptible to diacetyl, exhibiting a concentration-dependent loss of cell viability at 48h. In contrast to N2a cells however, 2,3-pentanedione was without significant effect on SH-SY5Y cells, where only the highest concentration (100μM) induced a modest, albeit significant reduction in viability after 48 h.In order to compare the cell viability response with the More et al study, which used a 24 h exposure period with diacetyl in SH-SY5Y cells, Das and Smid incubated SH-SY5Y cells with each flavorant for 24 h prior to the MTT assay. After 24 h incubation, diacetyl still evoked significant and concentration-dependent reductions in cell viability, with a maximum loss of over 90% at 50 μM. Incubation with 2,3pentanedione for 24 h also caused concentration-dependent reductions in SH-SY5Y cell viability, but overall toxicity was reduced to a maximum of less than 50% at 50 μM. Interestingly, SH-SY5Y cells displayed diminished toxicity after 48 h versus 24 h from exposure to both diketones and in comparison to N2a cells at 48 h, indicating the development of some resistance to toxicity. This may be due to induction of glyoxalase I, which has been demonstrated to occur from 24 to 48 h following neuronal damage in SH-SY5Y cells, but also from recruitment of alternate metabolic pathways such as aldose reductase. I.e., More et al used too short an incubation period to fully characterize the neurotoxicity of the diacetyl, as well as relying on a single cell line to establish neurotoxicity.Moreover, More et al found that 50μM diacetyl alone (without β amyloid) was innocuous to SH-SY5Y cells. However, at an equivalent concentration, Das and Smid found ~40% loss of viability. Both studies used the MTT assay. One reason for the difference may be methodological, in that More et al used a diacetyl washout and 24 h recovery period prior to the MTT assay. During this time, the cells may have restored proliferative density and mitochondrial capacity and function, upon which the MTT assay is most dependent. There are known limitations in using the MTT assay as an index of mitochondrial activity as a surrogate for neuronal viability. The MTT assay is, however, noted as a reliable biochemical indicator of neuronal apoptosis. In support of the Das and Smid findings, there were good morphological correlates to the assay results, such as microscopic evidence of blebbing, floating, and rounded and shrunken appearance of cells.Both Das and Smid, and More et al, agree on one thing: their in vitro findings may not be at all relevant to what happens in the human body. Bare minimum, in vivo studies need to be undertaken in appropriate animal models to establish a plausible exposure link and risk. What those "appropriate animal models" might be if researchers intend to establish a link between diacetyl and Alzheimer's are unknown. They sure do not include mice.

Based on a general 18th century observation that farm maids in England, France, Germany, Holland, Italy and Mexico who came in contact and got infected with cowpox appeared resistant to smallpox (1), cowpox, the original smallpox vaccine, was intended to prevent, not cure, smallpox.The world's last naturally occurring smallpox case was in Somalia in October 1977 (Ali Maow Maalin - Wikipedia).The last reported laboratory-acquired infection was in England in September 1978 (1978 smallpox outbreak in the United Kingdom - Wikipedia).The WHO officially declared smallpox eradicated from the global human population in 9 December, 1979 (2).Smallpox vaccine in the form of cowpox was first introduced in the mid-to-late 18th – early 19th centuries when little was known about the causes of infectious diseases, certainly long before the discovery of micro-organisms. Since then a variety of vaccines have been used against smallpox including horsepox, and in the 20th century, attentuated (weakened) vaccinia virus and inactivated vaccines. Thus the biggest obstacle in the quest for smallpox vaccine efficacy data is it was eradicated from Europe and North America by mid-20th century and the world over by 1977 without the kind of controlled clinical trial that would now be mandated to evaluate the efficacy of a new vaccine (2), and proof of its efficacy is perforce largely based on historical records. Also important to bear in mind that even in the 18th century, vaccination wasn't the only game in town.This answer outlinesHistorical smallpox prevention measures included not just cowpox vaccination but also smallpox inoculation (variolation), strict case isolation and contact quarantine, all of which contributed to its decline and eventual eradication.Historical smallpox vaccination efforts began long before micro-organisms were discovered, its causative agent identified, and standardized vaccine manufacture, quality control and distribution methods developed.Some historical data on smallpox vaccine efficacy.Historical Smallpox Prevention Measures Were Many: Not just Cowpox Vaccination But Also Smallpox Inoculation (Variolation), Case Isolation & Contact QuarantineInoculation (Variolation - Wikipedia) was the competing approach to try and prevent smallpox outbreaks.Inoculation is reported to have been long practiced in China, India (see below from 3) and the Ottoman empire.Consisting of exposure to a mild dose of the disease itself by placing a small piece of infective smallpox material, typically under the skin (2), inoculation was obviously a double-edged sword since it might itself cause disease. Vaccination, OTOH, was based on an entirely different principle, exposure to a related, less dangerous animal disease, cowpox. Though common credit for the cowpox vaccination is usually ascribed to Edward Jenner - Wikipedia, it was apparently first innovated by the English farmer Benjamin Jesty - Wikipedia (4, 5, 6).Thus, at the time cowpox vaccination appeared on the scene, smallpox inoculation was already being practiced, for example by roving bands of 'itinerant inoculators' (7) in England, Scottish Highlands and Ireland (8). However, historical data suggests vaccination soon overtook inoculation in popularity. The WHO treatise on the subject (2) states,'Jenner stated that by 1801 over 100 000 persons had been vaccinated in Great Britain, whereas by 1730, 8 years after the introduction of variolation, less than 1000 people had been variolated in Great Britain and North America'Cowpox vaccination had several advantages over smallpox variolation (9; see below from 3)Produced a less severe, local inoculation site lesion.Was not communicable to contacts.Greatly reduced risk of disease from vaccination itself unlike inoculation (variolation).However, all through its history, vaccination wasn't whole-heartedly accepted by the population at large. For example, a review (10) notes the Medical Officer of Health for Whitechapel in London (11) recorded all the way back in 1859 that**'a "deep-rooted" prejudice against vaccination "strongly manifested" in poor neighbourhoods wherever a child had suffered some eruptive disease "syphilitic, eczematous, etc., commonly associated with teething" after vaccination.'Since smallpox started causing cyclical epidemics from the 16th-17th century onward throughout Europe, some as frequent as every 2 years, with death rates ranging in the tens of thousands during each cycle, affected communities evolved rigorous preventive measures, consisting of prompt detection and expedient isolation of cases and quarantine of their contacts, efforts based on the pioneering insights of British physician John Haygarth - Wikipedia in 1793.Haygarth's original insight for exterminating smallpox from Great Britain consisted of 'isolation of cases, variolation and a system of rewards and punishments' (9). It was so spot-on that almost 200 years later the WHO's smallpox eradication program consisting of surveillance and containment only slightly altered from it by switching from variolation to limited vaccination and including strict isolation of contacts. This also means smallpox eradication ensued from not just vaccination but also from breaking transmission through strict quarantine.Inoculation, vaccination, isolation of cases, and quarantine of contacts were thus preventive public health measures brought to bear on smallpox for centuries before it was even known what caused the disease and how it spread (see below from 3).Historical Smallpox Vaccination Efforts Began Long Before Micro-organisms Were Discovered, Its Causative Agent Identified, And Standardized Vaccine Manufacture, Quality Control & Distribution Methods DevelopedAfter the discovery of micro-organisms in the 19th century, bacteria, bacterial spores, protozoa, many organisms were historically suspected of causing smallpox. Not knowing what precisely caused the disease obviously hobbled rigorous assessment of how inoculation or vaccination prevented it even as smallpox vaccination itself became embedded as a widespread public health measure long before modern good manufacturing, clinical and regulatory practices came into existence.Today it would be unthinkable to inject a vaccine into humans without rigorous quality control. Consider then that smallpox vaccination had already been in place >100 years before a potency assay was even established for it in the beginning of the 20th century (12). Thus even though smallpox vaccination had been in theory compulsory in the UK for decades by that point* (7, 10, 13), 'the vaccinator had at best a very rough idea of the quantity of active material in the vaccine' (12) One reviewer estimates that 19th century smallpox vaccines may have been cowpox, horsepox or even attentuated smallpox (9).So many caveats notwithstanding, smallpox vaccination as popularized by Jenner was so successful at bringing down smallpox mortality for several decades that many countries soon made smallpox vaccination, usually of infants, compulsory: Bavaria in 1807, Denmark in 1810, Norway in 1811, Bohemia and Russia in 1812, Sweden in 1816, Hanover in 1821, Great Britain in 1853 and France in 1902 (2). Enforcing such laws was however decidedly problematic since standardized methods for large-scale production and distribution of vaccine were then non-existent.Thus, even though untold numbers of people got inoculated (variolated) or vaccinated against smallpox the world over for > a century, this complicated history means it isn't possible to perform meta-analyses of well-controlled, rigorously collected scientific clinical trials on smallpox vaccine efficacy. Such data simply doesn't exist.Historical records of groups of vaccinated and unvaccinated individuals aren't easy to interpret.What did the vaccinated individuals actually get? Cowpox, smallpox itself, a mix of the two, a mix containing some cowpox with all kinds of other microbes, mainly bacteria, mixed in it? Were they vaccinated or variolated?Lack of standardized vaccination method and doses meant different individuals got different kinds of injections and material, i.e., different routes and doses, two important variables we now know greatly influence the strength and quality of ensuing immunity.Some Compelling Historical Data On Smallpox Vaccine EfficacyEven with the many caveats to historical smallpox vaccination data, several compelling examples demonstrate its unmistakable efficacy.Some of the most robust historical statistical data for smallpox comes from Sweden which began smallpox vaccination late in 1801, making it compulsory in 1816. In the 18th century, Sweden used to have major smallpox epidemics with 3 to 7000 smallpox deaths per million every 5 years or so. The disease was also endemic meaning an average of 6 to 800 smallpox deaths per million as a matter of course. However, from about 1810, mortality rates declined steeply. In 1822, 6 years after smallpox vaccination was made compulsory, smallpox deaths per million had declined to single digits, i.e., a 100-fold reduction. Even though death rates rose slightly and epidemics recurred in later decades of the 19th century, they occurred at much lower frequency and at a fraction of pre-vaccination amplitude (see below from 2).Lymph that the Empress of Russia obtained from Jenner in 1801 was maintained by arm-to-arm vaccination for >60 years. Infants aged 7 to 8 days at the St. Petersburg Foundling Hospital were vaccinated with this lymph until 1867 when the state switched to vaccines from cows. Compulsory registration of these infants until the age of 25 years meant another historical record with which to assess vaccine efficacy. St. Petersburg had 17 smallpox epidemics between 1826 and 1846. However, out of 15000 foundlings, only 34 (0.23%) got smallpox with only 1 fatality (2).After Prussia instituted compulsory smallpox vaccination of military recruits in 1833, smallpox deaths fell from 88 per year in 1831 to 1834 to <2 per year for the next 30 years (2).Prussia, Bavaria and Wurttemberg made smallpox vaccination and revaccination compulsory in 1874. Smallpox mortality rates declined more steeply in those German states compared to those in Austria which only practiced primary vaccination during the same time period (see below from 2).A 1902 comparison study in Glasgow, Scotland, provides one of the clearest data sets attesting to smallpox vaccine efficacy (see below from 14).* ~42000 deaths between 1837 and 1840 after a smallpox epidemic swept across England and Wales resulted in its first Vaccination Act in 1840. This made the vaccine freely available though not mandatory, even as it made inoculation an imprisonable offense.** Plus ca change, plus c’est la meme chose.Bibliography1. Barquet, Nicolau, and Pere Domingo. "Smallpox: the triumph over the most terrible of the ministers of death." Annals of internal medicine 127.8_Part_1 (1997): 635-642. https://www.researchgate.net/profile/Pere_Domingo2/publication/13887407_Smallpox_The_Triumph_over_the_Most_Terrible_of_the_Ministers_of_Death/links/02e7e514c7b5913bf3000000.pdf2. Fenner, Frank, et al. "Smallpox and its eradication." (1988). http://apps.who.int/iris/bitstream/10665/39485/1/9241561106.pdf3. Fenner, F., et al. "Early efforts at control: variolation, vaccination, and isolation and quarantine." History of International Public Health 6 (1988): 245-276. http://www.leighainslie.com/bigredbook/BigRed_Ch06.pdf4. Crookshank, Edgar March. History and pathology of vaccination. Vol. 2. P. Blackiston, 1889.5. Smith, John R. The speckled monster: smallpox in England, 1670-1970, with particular reference to Essex. Vol. 95. Essex Record Office, 1987.6. Pead, Patrick J. "Benjamin Jesty: new light in the dawn of vaccination." The Lancet 362.9401 (2003): 2104-2109. http://www.jesty.org/no_pead_lancet.pdf7. Oxley, Deborah. "‘The seat of death and terror’: urbanization, stunting, and smallpox." The Economic History Review 56.4 (2003): 623-656.8. Brunton, Deborah. "Smallpox inoculation and demographic trends in eighteenth-century Scotland." Medical history 36.04 (1992): 403-429. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1036632/pdf/medhist00045-0047.pdf9. Baxby, Derrick. "Smallpox vaccine: ahead of its time." Interdisciplinary Science Reviews 26.2 (2001): 125-138.10. Hardy, Anne. "Smallpox in London: Factors in the Decline of the Disease in the Nineteenth Century." Medical History 27.02 (1983): 111-138. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1139298/pdf/medhist00083-0005.pdf11. https://dlcs.io/pdf/wellcome/pdf-item/b19883341/012. Minor, Philip D. "Live attenuated vaccines: historical successes and current challenges." Virology 479 (2015): 379-392. https://www.researchgate.net/profile/Philip_Minor/publication/274736792_Live_attenuated_vaccines_Historical_successes_and_current_challenges/links/557fd10708aeea18b7797231.pdf13. Smith, John R. The speckled monster: smallpox in England, 1670-1970, with particular reference to Essex. Vol. 95. Essex Record Office, 1987.14. McVail, J. C. "Small-Pox in Glasgow—1900-1902." British medical journal 2.2166 (1902): 40. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2401269/pdf/brmedj08463-0041.pdf