Issue Of IJE Research Articles

Commentary: Far-reaching hypothesis or a step too far: the inheritance of acquired characteristics.

A quarter of a century ago, Eva Jablonka and Marion J Lamb put forward a model (reprinted in this issue of IJE) to explain how the functional history of a gene might influence its expression in subsequent generations. They were particularly interested in the idea that an environmental stimulus acting on the parent could alter the behaviour of a gene in the offspring. The model is simple and is depicted in Figure 1. The environment stimulates a change in transcription that is associated with chemical modifications to the DNA or to the proteins that package the DNA.These modifications are inherited via the germ line and influence transcriptional activity in the next generation. In other words, epigenetic marks, generally considered to be cleared between generations, are retained at some loci and convey a memory of the altered activity state to the offspring. This model emerged in conjunction with the developing interest among biologists in epigenetics, in particular the finding that demethylation of DNA could result in gene activation and that, at least in cell culture, the addition of an environmental stimulus, 5-azacytidine, could change the level of DNA methylation. Patterns of DNA methylation had already been shown to be mitotically heritable in vitro. At the same time, observations that the expression of some autosomal genes is dependent on the sex of the parent from which they are inherited, termed genomic imprinting, were being made. The latter requires that ‘epigenetic marks’ be inherited across meiosis to enable the zygote (fertilized egg) to discriminate between the paternal and maternal alleles. From these and other findings, Eva Jablonka and Marion J Lamb speculated on the existence of a form of ‘Lamarckian’ inheritance that involved an adaptive response to the environment based on epigenetic variations. This bold hypothesis has generated a great deal of interest and has driven experiments in the field for the last couple of decades. Here we review the current evidence for and against the inheritance of acquired characteristics. Does it ever happen?

Commentary: The hidden and not so hidden benefits of work: identity, income and interaction.

Work provides people with an income, and income is important for health. We know this. It is obvious, but work does much more. Work provides most of us with one of our primary roles in society: as a worker. We may see ourselves as mechanics, nurses, teachers, construction workers, farmers, scientists, architects or additional identities, but at the core we are all workers. We provide for ourselves and often for others. Work is not the only role that provides identity and meaning. Traditionally family, friendship and community roles add important dimensions in defining our basic societal roles. When we are robbed of such significant roles, particularly when we are older and less likely to be resilient to such shocks, we experience loss—and loss in many realms, both material and non-material. Clearly we experience a loss in income, and such losses close to retirement may be particularly challenging since they will not be replaceable with a short-time horizon, nor are opportunities easily available to work ‘double shifts’ to regain such financial loss. In this issue of IJE is an important article on the impact of job loss during the Great Recession in the USA and Europe, by Riumallo-Herl, Basu, Stuckler, Courtin and Avendano.1 The authors document in a compelling way the impact of job loss on depression for older men and women in advanced industrialized countries. They show that financial loss is important, but financial loss alone does not explain the whole story of the impact of job loss. The authors are insightful and provocative and set an agenda for the future. They suggest some solutions in the policy realm related to social protection, and find some problems harder to identify solutions for. Here I discuss three kinds of loss that they suggest may accompany the loss of a job in later adulthood. I speculate about what may be critical for health and well being so that we can move forward from the important foundation that Riumallo Herl et al. have laid. The three kinds of loss that may be central to affecting health and well-being include: (i) financial loss with social protection as a potential buffer; (ii) loss of identity and meaning with loss of such a major role; and (iii) loss of social interaction and engagement with a community of workers.

Commentary: Liver enzymes and all-cause mortality

Determination of serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] was first introduced in 1955 as a means of diagnosing viral hepatitis and other liver diseases, with gamma glutamyltranspeptidase (GGT) introduced into clinical laboratories some 10 years later. Liver function tests [including alkaline phosphatase (ALP)], as they are commonly and somewhat misleadingly known, are increasingly performed in primary care settings in the UK as part of general health checks as well as in the investigation of potential liver, pancreas, bone and gallbladder disease, alcohol misuse and for monitoring of drug effects. With the growing interest in the epidemiology of non-alcoholic fatty liver disease, liver enzymes—ALT and GGT in particular—also have been increasingly studied in recent years as they are relatively easy to measure in large-scale general population studies. In this issue of IJE, Kunutsor et al. report results of a sound systematic review and meta-analysis of prospective cohorts that examined associations between these enzymes and all-cause mortality over a median follow-up time of 10 years in general populations. In pooled analyses, they found a 60% [95% confidence interval (CI): 42%, 80%; 11 studies] increased mortality risk in the top third of the GGT distribution compared with the bottom third, an equivalent 38% increase (95% CI: 17%, 63%; four studies) for ALP and no strong evidence of overall associations of the transmainases with mortality (eight and four studies of ALT and AST, respectively). They also report: positive linear associations of GGT and ALP with mortality, with a 7% (95% CI: 4%, 10%) and 3% (95% CI: 1%, 6%) increase in risk per 5 U/l, respectively; nonlinear associations of ALT and AST with mortality, with sharp increases in risk observed from 20 U/l of ALT and 15 U/l of AST; and marked heterogeneity in associations in Asian (ALT positively associated with mortality) vs American and European (inverse association) populations. Kunutsor et al. acknowledge the low specificities of liver enzymes but argue that they are sensitive, well standardized, simple, inexpensive and common laboratory tests, and hence the need to assess their associations with all-cause mortality. And indeed their rigorous systematic review and meta-analysis does just that. But where do we go from here? The pathophysiological processes that determine serum liver enzymes levels are not well understood, and this is particularly true with regard to nonextreme levels. Hence the mechanisms and pathways underlying the observed associations of liver enzymes across their distributions with all-cause mortality are not obvious. Kunutsor et al. provide a clear and insightful discussion of potential mechanisms driving the reported associations of liver enzymes with mortality, but they too acknowledge that some are ‘hypothetical’ and ‘may be more complex than generally appreciated’. From an aetiological perspective, the lack of clarity with regard to the pathophysiological mechanisms that determine liver enzyme levels is compounded by the outcome examined, namely all-cause mortality. As opposed to associations with cause-specific mortality that could potentially suggest specific disease processes resulting in variation in liver enzymes’ levels and ultimately in death, all-cause mortality is not informative in this respect. In light of the above, the implications and utility of the association between liver enzyme levels and all-cause mortality, as accurately estimated as it may be, remain at this point somewhat elusive. Granted, understanding disease aetiology is not the only goal of epidemiological research. Risk prediction is important for early detection of potential existing and future adverse health, allowing for early intervention aimed at reducing subsequent morbidity and mortality. As Kunutsor et al. themselves conclude, their work highlights the need for further clinical evaluation of even mildly elevated liver enzymes or Published by Oxford University Press on behalf of the International Epidemiological Association

On the cause of offence

We continue our celebration of the Snow bicentenary in this issue of the IJE by reprinting John Snow’s paper ‘On the supposed influence of offensive trades on mortality’ originally published in the Lancet in 1856. Of the pieces included in the celebration this is the only one actually written by Snow himself. In 1855 Snow had stirred up controversy and opprobrium, in particular from Thomas Wakley, founder and editor of the Lancet, when he appeared as an expert witness in front of the parliamentary committee assessing the proposed Public Health and Nuisances Removal bills. Snow’s main argument was this: if the offensive trades were indeed harmful to the public health, rates of disease and death among those who worked in them would be high and, as far as he had been able to learn, this was not the case. In his commentary, David Lilienfeld speculates on Snow’s reasons for publishing the paper. Was it a response to Wakley’s stinging attacks the year before? As Jan Vandenbroucke points out, the arguments as presented by Snow to the parliamentary committee do indeed come across as somewhat dogmatic. Maybe this was Snow’s attempt to justify that dogmatism. We will never know for sure. Certainly Snow’s oral-faecal theory of the transmission of cholera proved to be correct; his assumption that the oral-faecal theory would apply to all infectious diseases did not. Wakley’s jibes at members of what he jeeringly calls the ‘Offensive Trades Association’ or the ‘Offensive Association’, ’These unsavoury persons, trembling for the conservation of their right to fatten upon the injury of their neighbours’, display a deep contempt. However, his most vitriolic comments are reserved for Snow. In his own time, Snow was best known for his contribution to anaesthesia. His deep understanding of the diffusion of gases combined with his own theory that cholera was transmitted by the oralfaecal route made it impossible for him to accept the dominant theory that epidemic diseases were caused by miasmas emanating from decaying animal or vegetable matter and spread through the atmosphere. In his editorial attack, reprinted as a Diversion in the current issue of IJE, it seems to be Snow’s refutation of this dominant paradigm that most infuriates Wakley as he targets Snow’s lack of scientific evidence and dogmatism. However, Wakley himself makes a poor case for the miasma theory, his evidence resting on his own observation that ‘failing strength, flabby muscles, pallid cheeks, lassitude of body, and torpidity of mind’ are most frequently the result of noxious gases from leaking drains, and on his assertion that ‘there is hardly a practitioner of experience and average powers of observation who does not daily observe the same thing’. More considered criticism of Snow’s paper can be found in the other Diversion in this issue: a letter to the Lancet by John Tripe, who had been appointed Medical Officer of Health for Hackney in London the year before. Tripe takes issue with Snow on two counts; one is the denominator he uses, which is based on the 1851 census and does not allow for population growth, and the other continues the debate, initiated by Snow, on what we now know as the healthy worker effect. Snow uses the lower mortality rate among workers in the offensive trades to argue against their detrimental effect on health. Careful to state that his comments are in no way intended to denigrate Snow’s work, Tripe argues the case for reverse causality; that people can only engage in the physically demanding work of the offensive trades while they are fit enough and leave to swell the mortality rates of other trades when they are not. Tripe was an active Fellow of the Royal Meteorological Society from 1856 until his death and the Society’s President in 1871. His obituary lauds his contribution to the relationship between meteorology and health, disease and death. However, it seems that Tripe was far from a confirmed miasmatist. During discussion of a paper in the society’s Quarterly Journal, Tripe is reported as stating ‘that the spreading of the disease [cholera] does not always arise from atmospheric conditions, but that to a great extent it spreads from person to person.’ It would be easy to dismiss Wakley merely as an editor who misused his position to vent his spleen on those whose views he held in contempt. Snow’s obituary in the Lancet on the 26 June 1858 was shockingly brief. Devoid of any mention of his work on the transmission of cholera, the Lancet in April 2013 felt the need ‘after an unduly prolonged period of reflection’ to correct the perception that it may have Published by Oxford University Press on behalf of the International Epidemiological Association

Commentary: Jumping the gun or asleep at the switch: is there a middle ground?

Commentary: Jumping the gun or asleep at the switch: is there a middle ground?

Commentary: Infection-related cancers in low- and middle-income countries: challenges and opportunities

As non-communicable diseases (NCDs) rise in prominence as sources of morbidity and mortality in low-income and middle-income countries (LMICs), focus on cancer prevention and control activities has increased. These transitions coincide with improved prevention and treatment of infectious causes of death [e.g., tuberculosis, malaria, and human immunodeficiency virus (HIV) infection], whereas NCDs such as cancer and cardiovascular disease related to tobacco consumption and poor dietary practices have increased. These changes also coincide with population expansion and aging in LMICs. In this issue of IJE, 1 Remais and colleagues discuss some of the factors contributing to ‘the convergence of noncommunicable and infectious diseases in LMICs’ and the importance of aligning existing infectious disease programmes with NCD prevention efforts. Notably, many cancers occurring in LMICs are related to infections that may be prevented and/or treated to preclude the development of cancer. In this commentary we provide a framework with which to consider infection-related cancers, and discuss challenges and opportunities for their control in LMICs. In 2008, infection-related cancers accounted for 22.9% of all cancers in less-developed countries (including 32.7% in sub-Saharan Africa) in contrast to 7.4% in developed countries. 2 Another study found that in 2008, the most common cancers in nations that were low in the Human Development Index (HDI), in which nations are ranked according to life expectancy, education, and gross domestic product, were (in order): cervical, female breast, liver, Kaposi

Commentary: Lifestyle factors and colorectal cancer microsatellite instability--molecular pathological epidemiology science, based on unique tumour principle

Commentary: Lifestyle factors and colorectal cancer microsatellite instability--molecular pathological epidemiology science, based on unique tumour principle

Commentary: Postpartum vitamin A supplementation and infant mortality

Maternal vitamin A deficiency during pregnancy and lactation continues to be a concern in many regions of the world. In this issue of IJE, Gogia and Sachdev report a systematic review and meta-analysis of the effect of maternal postpartum vitamin A supplementation on infant mortality and morbidity. A total of six trials from developing countries included in the meta-analysis revealed no impact on infant mortality [relative risk (RR)1⁄4 1.05, 95% confidence interval (CI)1⁄4 0.92–1.20]. Only one trial that reported morbidity found no effect on diarrhoea or respiratory infection. Out of the six postpartum vitamin A supplementation trials included in the meta-analysis, two large ones were cluster-randomized controlled trials that also included routine pre-conceptional and/or pre-natal supplementation using small weekly doses of vitamin A, representing a supplementation regimen that was restricted neither to the postpartum period nor to the large bolus dose as per the existing WHO guidelines for postpartum supplementation with 200 000 IU of vitamin A within 6 weeks. Additionally, for one of the trials in the meta-analysis, the authors selected infants from the placebo arm of a newborn vitamin A supplementation trial, which was nested within the maternal supplementation trial. Also, three other trials included in the meta-analysis had sample sizes of 300 or less per group. Although these trials reported mortality, they did not have this as a pre-specified outcome, nor were they designed or powered to assess mortality as an outcome. The one trial with the appropriate sample size and which used the currently recommended dose of 400 000 IU vitamin A was conducted in an HIV-infected population. Thus, it is evident that the meta-analysis was based on diverse data of limited utility for discerning a mortality impact. Additionally, it mixed different forms of maternal vitamin A dosing (single with routine) over varying periods of time (from pre-conceptional through postpartum) and therefore both cumulative and timing of dosages are variable. The primary motivation for the policy related to prophylactic postpartum dosing of vitamin A did not stem from reducing infant mortality; instead, the two primary goals for this approach were to improve maternal vitamin A status and the vitamin A status of infants <6 months of age via enhancing the vitamin A content of breast milk. Several previous trials of postpartum vitamin A supplementation, not included in the meta-analysis, have demonstrated improvements in biochemical indicators of vitamin A status in mothers and their breast-fed infants, including increased breast milk concentrations of vitamin A. Based on these studies, in 1997, the WHO, UNICEF and the International Vitamin A Consultative Group (IVACG) provided guidelines for postpartum vitamin A supplementation recommending a single dose of 200 000 IU soon after delivery. This recommendation was updated in 2002 to two doses of 200 000 IU (or 400 000 IU) based on an analysis of expected change and adequacy of infant vitamin A stores suggested to be suboptimal with a single 200 000 IU dose. The revised recommendation, however, has not been widely adopted in developing countries. Only two of the six trials included in the meta-analysis tested the revised 400 000 IU of vitamin A. In a parallel meta-analysis effort, these authors have also evaluated neonatal/early infancy dosing with 50 000 IU vitamin A using data from six trials and shown no impact on infant mortality. However, combining trials which provided vitamin A within 48 h of birth vs those in which infants were dosed later during the first month of life may have yielded the null findings. Limiting the analysis to the former studies, at least in the Asian context, has shown to have a beneficial impact. In a meta-regression analysis, it was shown that newborn vitamin A supplementation likely reduces infant mortality in regions where vitamin A deficiency is common. In contrast, studies from Africa, where vitamin A deficiency was not common, have shown an overall null effect, and a potential negative effect among girls. These apparently contradictory findings have resulted in three more trials of newborn vitamin A supplementation being commissioned by the WHO, Published by Oxford University Press on behalf of the International Epidemiological Association

Commentary: Is it time to redefine cognitive epidemiology?

In this issue of IJE,1 Deary and Johnson discuss the association between education and intelligence and argue that their use in epidemiological research as interchangeable entities is incorrect. They highlight at least three areas where this ambiguity is evident: choice of education rather than intelligence as a confounder of the association between an exposure and an outcome, the direction of the causal association between education and intelligence and, finally, their main effects on health outcomes.

Commentary: Challenging public health orthodoxies--prophesy or heresy?

Commentary: Challenging public health orthodoxies--prophesy or heresy?

Commentary: Assessing the effects of the Scottish Smokefree Law--the placebo effect and the importance of obtaining unbiased data

Commentary: Assessing the effects of the Scottish Smokefree Law--the placebo effect and the importance of obtaining unbiased data