Does the response to aspirin and clopidogrel vary over 6 months in patients with ischemic heart disease?

BACKGROUND: Dual-antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor, mostly clopidogrel, is the default therapy in both acute coronary syndrome (ACS) and after intracoronary stents. It is well established that responses to antiplatelet therapy (APT), particularly clopidogrel, are subject to considerable interindividual variability. OBJECTIVES: We investigated whether responses to APT in individuals vary significantly over time. METHODS: Simultaneous assay with VerifyNow(™) and short thrombelastography (s-TEG) was performed before and at four time points over 6 months after hospital discharge in 40 patients receiving DAPT. Serum thromboxane B2 levels were also measured. RESULTS: While aspirin response units (ARU) by VerifyNow(™) and serum thromboxane B2 levels remained stable over time, arachidonic acid (AA)-mediated platelet aggregation with s-TEG (i.e. area under the curve at 15 min in AA channel, AUC15AA ) increased at 1 week compared with predischarge (P < 0.008). In addition, platelet reactivity units (PRU) by VerifyNow(™) (P = 0.046) and adenosine diphosphate (ADP)-mediated platelet aggregation with s-TEG (i.e. AUC15ADP ) also increased at 1 week compared with predischarge (P = 0.026). There were no significant changes in either platelet reactivity or rates of high on-treatment platelet reactivity while receiving clopidogrel beyond 1 week. CONCLUSIONS: This study demonstrates important variability in responses to APT within individuals between predischarge and 1 week but not thereafter. The use of a single early (predischarge) platelet function assay as an indicator of future response may therefore be flawed. The design of future strategies to assess individual responses for tailored therapy needs to take this into account.

The rising incidence of anal cancer in England 1990-2010: a population-based study.

AIM: Although anal cancer is rare, its incidence has been reported to be rising in several countries. This study aimed to determine whether there have been any changes in incidence over time in England. METHOD: In the cancer registry component of the English National Cancer Data Repository, 13 940 patients were identified with a primary diagnosis of anal cancer made between 1990 and 2010. Tumours were grouped according to the ICD-O morphology codes into squamous cell carcinoma, basaloid and cloacogenic carcinoma, adenocarcinoma and other cancer types. The incidence over this period was investigated in relation to type of tumour, age and sex. RESULTS: In men there was a 69% increase in squamous cell anal carcinoma from 0.43 per 100 000 population in 1990-94 to 0.73 in 2006-10. For women these rates were 0.50 in 1990-94 and 1.13 in 2006-10, a rise of 126%. CONCLUSION: The study showed that between 1990 and 2010 there was a substantial rise in the incidence of anal cancer in England. This effect was more marked in women than men.

Population-based study of laparoscopic colorectal cancer surgery 2006-2008.

BACKGROUND: Clinical guidelines recommend that, where clinically appropriate, laparoscopic tumour resections should be available for patients with colorectal cancer. This study aimed to examine the introduction of laparoscopic surgery in the English National Health Service. METHODS: Data were extracted from the National Cancer Data Repository on all patients who underwent major resection for a primary colorectal cancer diagnosed between 2006 and 2008. Laparoscopic procedures were identified from codes in the Hospital Episode Statistics and National Bowel Cancer Audit Project data in the resource. Trends in the use of laparoscopic surgery and its influence on outcomes were examined. RESULTS: Of 58 135 resections undertaken over the study period, 10 955 (18·8 per cent) were attempted laparoscopically. This increased from 10·0 (95 per cent confidence interval (c.i.) 8·1 to 12·0) per cent in 2006 to 28·4 (25·4 to 31·4) per cent in 2008. Laparoscopic surgery was used less in patients with advanced disease (modified Dukes' stage 'D' versus A: odds ratio (OR) 0·45, 95 per cent c.i. 0·40 to 0·50), rectal tumours (OR 0·71, 0·67 to 0·75), those with more co-morbidity (Charlson score 3 or more versus 0: OR 0·69, 0·58 to 0·82) or presenting as an emergency (OR 0·15, 0·13 to 0·17). A total of 1652 laparoscopic procedures (15·1 per cent) were converted to open surgery. Conversion was more likely in advanced disease (modified Dukes' stage 'D' versus A: OR 1·56, 1·20 to 2·03), rectal tumours (OR 1·29, 1·14 to 1·46) and emergencies (OR 2·06, 1·54 to 2·76). Length of hospital stay (OR 0·65, 0·64 to 0·66), 30-day postoperative mortality (OR 0·55, 0·48 to 0·64) and risk of death within 1 year (hazard ratio 0·60, 0·55 to 0·65) were reduced in the laparoscopic group. CONCLUSION: Laparoscopic surgery was used more frequently in low-risk patients.

Early mortality from colorectal cancer in England: a retrospective observational study of the factors associated with death in the first year after diagnosis.

BACKGROUND: The United Kingdom performs poorly in international comparisons of colorectal cancer survival with much of the deficit owing to high numbers of deaths close to the time of diagnosis. This retrospective cohort study investigates the patient, tumour and treatment characteristics of those who die in the first year after diagnosis of their disease. METHODS: Patients diagnosed with colon (n=65,733) or rectal (n=26,123) cancer in England between 2006 and 2008 were identified in the National Cancer Data Repository. Multivariable logistic regression was used to investigate the odds of death within 1 month, 1-3 months and 3-12 months after diagnosis. RESULTS: In all, 11.5% of colon and 5.4% of rectal cancer patients died within a month of diagnosis: this proportion decreased significantly over the study period. For both cancer sites, older age, stage at diagnosis, deprivation and emergency presentation were associated with early death. Individuals who died shortly after diagnosis were also more likely to have missing data about important prognostic factors such as disease stage and treatment. CONCLUSION: Using routinely collected data, at no inconvenience to patients, we have identified some important areas relating to early deaths from colorectal cancer, which merit further research.

A retrospective observational study examining the characteristics and outcomes of tumours diagnosed within and without of the English NHS Bowel Cancer Screening Programme.

BACKGROUND: Colorectal cancer is common in England and, with long-term survival relatively poor, improving outcomes is a priority. A major initiative to reduce mortality from the disease has been the introduction of the National Health Service (NHS) Bowel Cancer Screening Programme (BCSP). Combining data from the BCSP with that in the National Cancer Data Repository (NCDR) allows all tumours diagnosed in England to be categorised according to their involvement with the BCSP. This study sought to quantify the characteristics of the tumours diagnosed within and outside the BCSP and investigate its impact on outcomes. METHODS: Linkage of the NCDR and BCSP data allowed all tumours diagnosed between July 2006 and December 2008 to be categorised into four groups; screen-detected tumours, screening-interval tumours, tumours diagnosed in non-participating invitees and tumours diagnosed in those never invited to participate. The characteristics, management and outcome of tumours in each category were compared. RESULTS: In all, 76 943 individuals were diagnosed with their first primary colorectal cancer during the study period. Of these 2213 (2.9%) were screen-detected, 623 (0.8%) were screening-interval cancers, 1760 (2.3%) were diagnosed in individuals in non-participating invitees and 72 437 (94.1%) were diagnosed in individuals not invited to participate in the programme due to its ongoing roll-out over the time period studied. Screen-detected tumours were identified at earlier Dukes' stages, were more likely to be managed with curative intent and had significantly better outcomes than tumours in other categories. CONCLUSION: Screen-detected cancers had a significantly better prognosis than other tumours and this would suggest that the BCSP should reduce mortality from colorectal cancer in England.

Community-based service provision for the prevention and management of maternal obesity in the North East of England: a qualitative study.

OBJECTIVES: This study was conducted to develop a better understanding of community-based initiatives relating to maternal obesity, and to gain community service providers' views on maternal obesity services and their perceived role in the management and prevention of maternal obesity. STUDY DESIGN: An interpretive constructionist approach using semi-structured interviews and focus groups. METHODS: Semi-structured interviews and focus groups were carried out with community service providers in the North East of England, UK. Data were analysed using thematic content analysis. RESULTS: Five dominant themes emerged: community-based obesity services, understanding maternal obesity services, participation in maternal obesity services, challenges in the development of community maternal obesity services, and factors contributing to successful maternal obesity services. Community service providers identified their role in tackling maternal obesity alongside maternity services. Participants identified a lack of community maternal obesity services, distinct training requirements, and felt that a multi-agency approach was likely to be required. CONCLUSIONS: Increasing rates of maternal obesity and the relationship between maternal obesity and childhood obesity mean that the preconception, pregnancy and postnatal periods are important and timely stages in the life course for public health intervention. However, current public health and community service provision lacks structured maternal obesity objectives.

Public health genomics: the interface with public health intelligence and the role of public health observatories.

BACKGROUND: Public health genomics is a new field that brings the findings of research in genetic and molecular technologies together with public health. The purpose of this paper is to examine the interface between this new emerging field and that of public health intelligence. We describe the possible areas of integration between genomics and public health, suggesting a future potential role for the Public Health Observatories. METHODS: A small group comprising of a public health geneticist and representatives from Public Health Observatories met and discussed the ways in which the public health information and intelligence community might contribute to the developing agenda of public health genomics. RESULTS: The results of the deliberations are presented in this paper, and a combination of short, medium and longer term possibilities are described. Also, necessary changes and additions to routinely collected data are proposed. CONCLUSIONS: The emerging field of public health genomics has implications for the collection, management and analysis of routine data. The benefits of this will accrue over time, but changes need to be made now in order to make the best use of these developments. A possible supporting action plan for the development of public health genomics within Public Health Observatories is proposed.

Public health observatories on the international stage.

This article reviews the involvement of public health observatories in the UK in international public health. It does not aim to be a comprehensive review, but to offer some examples of work in an international context.

Workplace-based assessment in radiology-where to now?

Assessment of doctors is in a state of flux. Traditional methods of assessment have been critically examined and found inherently limited. The wholesale shift towards outcome-orientated education in the last 10 years has led to the relatively rapid development of a radically different method of assessment. This method focuses on assessing what doctors do in everyday practice rather than written or practical simulations. Known collectively as "workplace-based assessment" tools, these have been embraced in North America, whereas they have been more cautiously adopted in the UK. However, many of these assessment tools have not been rigorously studied and, moreover, few have been specifically developed for assessing radiologists. However, they are likely to be incorporated into radiology training in the near future. This paper critically analyses both the underpinning assumptions behind this method and the evidence behind existing tools, and looks at the work that is required to develop, adopt or adapt such tools for use in radiology.

A nationally representative study of maternal obesity in England, UK: trends in incidence and demographic inequalities in 619 323 births, 1989-2007.

BACKGROUND: There is an absence of national statistics for maternal obesity in the UK. This study is the first to describe a nationally representative maternal obesity research data set in England. DESIGN: Retrospective epidemiological study of first trimester obesity. METHODS: Data from 34 maternity units were analysed, including 619 323 births between 1989 and 2007. Data analysis included trends in first trimester maternal body bass index status over time, and geographical distribution of maternal obesity. Population demographics including maternal age, parity, ethnic group, deprivation and employment were analysed to identify any maternal obesity-associated health inequalities. All demographics were tested for multicollinearity. Logistic regression analyses were adjusted for all demographics as confounders. RESULTS: First trimester maternal obesity is significantly increasing over time, having more than doubled from 7.6% to 15.6% over 19 years (P<0.001), and shows geographic variation in incidence. There are also demographic health inequalities associated with maternal obesity, including increased odds of being obese with increasing age, parity, Black ethnic group and deprivation. There is also an association between morbid obesity and increased levels of unemployment. CONCLUSIONS: The increase in maternal obesity has serious implications for the health of mothers, infants and service providers, yielding an additional 47 500 women per year requiring high dependency care in England. The demography of women most at risk of first trimester obesity highlights health inequalities associated with maternal obesity, which urgently needs to be addressed.

Duration of daily bull exposure on resumption of ovulatory activity in postpartum, primiparous, suckled, beef cows.

The objective of this experiment was to determine if duration of daily bull exposure influences length of postpartum anestrus in primiparous, anovular, suckled, beef cows. The null hypotheses were that intervals from calving or the start of bull exposure (D 0) to resumption of ovulatory activity (OA), and proportions of cows that resumed OA during the experiment does not differ among cows exposed to bulls for 0h, 6h, or 12h daily, and that there is no relationship between the duration of bull exposure and interval to resumption of OA in cows exposed to bulls for 0h, 6h, or 12h daily. At 51.5+/-2.3d (+/-SE) after calving, cows were assigned randomly to be exposed for 12h (BE12; n=15) or 6h daily (BE6; n=14) to bulls, or not exposed to bulls (NE; n=10) for 45 d. Interval from calving or from D 0 to resumption of OA was shorter (P<0.05) and the proportion of cows that resumed OA during the experiment was greater (P<0.05) for BE12 than for NE cows. Interval from D 0 to resumption of OA did not differ (P>0.10) between BE6 cows and either BE12 or NE cows. However, interval from calving to resumption of OA was shorter (P<0.05) for BE6 than NE cows. The proportion of cows that resumed OA did not differ (P>0.10) between BE6 cows and BE12 cows; however, the proportion of cows that resumed OA during the experiment tended (P=0.08) to be greater for BE6 cows than for NE cows. There was a linear relationship between intervals from calving (b(1)=-7.64 d/h; P<0.05) and D 0 (b(1)=-3.3 d/h; P<0.05) to resumption of OA and duration of daily bull exposure. Thus, the duration of bull-pheromone stimuli that cows perceive each day is related to when primiparous, postpartum, anestrous, suckled cows respond to this stimulus and undergo the physiological changes necessary to resume ovulatory activity.

Integration of ethylene and jasmonic acid signaling pathways in the expression of maize defense protein Mir1-CP.

In plants, ethylene and jasmonate control the defense responses to multiple stressors, including insect predation. Among the defense proteins known to be regulated by ethylene is maize insect resistance 1-cysteine protease (Mir1-CP). This protein is constitutively expressed in the insect-resistant maize (Zea mays) genotype Mp708; however, its abundance significantly increases during fall armyworm (Spodoptera frugiperda) herbivory. Within 1 h of herbivory by fall armyworm, Mir1-CP accumulates at the feeding site and continues to increase in abundance until 24 h without any increase in its transcript (mir1) levels. To resolve this discrepancy and elucidate the role of ethylene and jasmonate in the signaling of Mir1-CP expression, the effects of phytohormone biosynthesis and perception inhibitors on Mir1-CP expression were tested. Immunoblot analysis of Mir1-CP accumulation and quantitative reverse-transcriptase polymerase chain reaction examination of mir1 levels in these treated plants demonstrate that Mir1-CP accumulation is regulated by both transcript abundance and protein expression levels. The results also suggest that jasmonate functions upstream of ethylene in the Mir1-CP expression pathway, allowing for both low-level constitutive expression and a two-stage defensive response, an immediate response involving Mir1-CP accumulation and a delayed response inducing mir1 transcript expression.

Health indicators in the European regions: expanding regional comparisons to the new countries of the European Union - ISARE III.

OBJECTIVES: Most comparisons of health in Europe take place at the national level. However, there is increased interest in looking at health data at a sub-national level. This study aimed to establish the availability of health data at a regional level and to develop a methodology for the comparisons of health indicators at a sub-national level. In previous work on indicators at a regional level in the European Union, the authors recommended the development of such indicators. This paper takes into account the expansion of the European Union which took place in 2004. STUDY DESIGN: Observational study using routinely available data. METHODS: Similar to previous projects, a network of country correspondents was used and data were collected on a similar range of topics. In addition, a supplementary list of data was collected from one region of each country. RESULTS: Twenty-three countries out of the 25 member states of the European Union participated in the study. Where available, data were of relatively good quality. Data on mortality were most readily available, but data on important public health topics such as obesity were much more difficult to obtain. CONCLUSIONS: A database and a set of indicators for relevant sub-national areas of countries in the European Union, including new countries, were constructed. Data collection from the new countries was more straightforward due to the requirement for them to adhere to the nomenclature of territorial units for statistics (NUTS) levels. The lack of adherence to NUTS levels in the 'old' countries of the European Union continues to create problems. There remains an urgent need to introduce comprehensive sub-national data collection on important public health topics such as obesity and smoking.

Aspergillus flavus aflatoxin occurrence and expression of aflatoxin biosynthesis genes in soil.

The carcinogen aflatoxin B1 (AFB1) produced by Aspergillus flavus is a major food safety concern in crops. However, information on AFB1 occurrence in soil and crop residue is scarce. A series of experiments investigated the occurrence of AFB1 in soil and corn residues and ascertained the ecology of A. flavus in a Dundee silt loam soil. Samples of untilled soil (0-2 cm) and residues were collected in March 2007 from plots previously planted with a corn isoline containing the Bacillus thuringiensis (Bt) endotoxin gene or the parental non-Bt isoline. AFB1 levels were significantly different in various corn residues. The highest AFB1 levels were observed in cobs containing grain, with 145 and 275 ng.g-1 in Bt and non-Bt, respectively (P > or = F = 0.001). Aflatoxin levels averaged 3.3 and 9.6 ng.g-1 in leaves and (or) stalks and cobs without grain, respectively. All soils had AFB1 ranging from 0.6 to 5.5 ng.g-1 with similar levels in plots from Bt and non-Bt corn. Based on cultural methods, soil contained from log10 3.1 to 4.5 A. flavus cfu.g-1 with about 60% of isolates producing aflatoxin. Laboratory experiments demonstrated that AFB1 is rapidly degraded in soil at 28 degrees C (half-life < or = 5 days). The potential of the soil A. flavus to produce aflatoxins was confirmed by molecular methods. Transcription of 5 aflatoxin biosynthesis genes, including aflD, aflG, aflP, aflR, and aflS, were detected by reverse transcription - polymerase chain reaction analysis in soil. Although AFB1 appears to be transient in soils, it is clear that AFB1 is produced in surface soil in the presence of corn residues, as indicated by A. flavus cfu levels, AFB1 detection, and expression of aflatoxin biosynthetic genes.

Farmyards, an overlooked source for highly contaminated runoff.

Summer sampling of storm runoff generated from areas of roofs and hardstanding situated on four dairy/beef farms has provided novel information regarding its microbiological and chemical quality. All farm hardstandings generated runoff that was contaminated with respect to those pollutants (faecal coliforms, FC, and faecal streptococci, FS, major nutrients, organic carbon) that are ubiquitously associated with faecal matter and urine. The separate analysis of roof runoff indicated that these can contribute significant concentrations of FS, phosphorus (P) and potentially toxic elements such as zinc (Zn), and suggests a level of 'background' contamination originating from wash-off of bird droppings and in the case of Zn galvanised surfaces. On average hardstanding runoff showed enhanced concentrations of >4 orders of magnitude for FC and 2-3 for major nutrients and carbon relative to roof runoff. Organic forms of nitrogen (N) and P contributed significantly (averaging >40%) to the total dissolved fraction in both roof and hardstanding runoff. Part of the substantial variability in composition of runoff samples could be attributed to differences between farms as well as the timing of sample collection during individual storms. Where situations allowed, a comparison of water upstream and downstream of the farmyard demonstrated they acted as a source of multiple contaminants not only during hydrologically active storm events but also during dry periods. Contamination pathways included a combination of both point (e.g., septic overflows) and non-point (e.g., seepage from livestock housing) sources. Farmyards situated within intensive livestock farming areas such as SW Scotland, would be expected to have significant local and accumulated downstream impacts on the aquatic environment. Localised impacts would be particularly important for headwaters and low order streams.

Aflatoxin formation and gene expression in response to carbon source media shift in Aspergillus parasiticus.

Aflatoxins are toxic and carcinogenic polyketide metabolites produced by fungal species, including Aspergillus flavus and A. parasiticus. The biosynthesis of aflatoxins is modulated by many environmental factors, including the availability of a carbon source. The gene expression profile of A. parasiticus was evaluated during a shift from a medium with low concentration of simple sugars, yeast extract (YE), to a similar medium with sucrose, yeast extract sucrose (YES). Gene expression and aflatoxins (B1, B2, G1, and G2) were quantified from fungal mycelia harvested pre- and post-shifting. When compared with YE media, YES caused temporary reduction of the aflatoxin levels detected at 3-h post-shifting and they remained low well past 12 h post-shift. Aflatoxin levels did not exceed the levels in YE until 24 h post-shift, at which time point a tenfold increase was observed over YE. Microarray analysis comparing the RNA samples from the 48-h YE culture to the YES samples identified a total of 2120 genes that were expressed across all experiments, including most of the aflatoxin biosynthesis genes. One-way analysis of variance (ANOVA) identified 56 genes that were expressed with significant variation across all time points. Three genes responsible for converting norsolorinic acid to averantin were identified among these significantly expressed genes. The potential involvement of these genes in the regulation of aflatoxin biosynthesis is discussed.

Analysis of aflatoxin regulatory factors in serial transfer-induced non-aflatoxigenic Aspergillus parasiticus.

Aflatoxins (AFs) are carcinogenic secondary metabolites of Aspergillus parasiticus. In previous studies, non-toxigenic A. parasiticus sec- (for secondary metabolism negative) variants were generated through serial transfer of mycelia from their toxigenic sec+ (for secondary metabolism positive) parents for genetic and physiological analysis for understanding regulation of AF biosynthesis. Previous studies have shown no difference in the DNA sequence of aflR, a positive regulator of AF production, in the sec+ and sec- strains. In this study, AflJ, another positive regulator of AF production, laeA, a global regulator of secondary metabolism, and the intergenic region between aflR and aflJ, were analysed to determine if they play a role in establishment of the sec- phenotype. The study showed that while this sequence identity extended to the aflJ as well as the aflJ-aflR intergenic region, expression of aflR in the sec- strain was several fold lower than that observed in the sec+ strain, while aflJ expression was barely detectable in the sec- strain. Western blot analysis indicated that despite AflR protein being present in the sec- strain, no toxin production resulted. Introduction of a second copy of aflR into the sec- strain increased aflR expression, but did not restore AF production. Lastly, reverse transcription-PCR analysis revealed that laeA was expressed in both sec+ and sec- strains. These results suggest that although aflR, aflJ and laeA are necessary for AF production, they are not sufficient. We propose that the aflR and aflJ expression may be regulated by element(s) downstream from laeA or from pathways not influenced by laeA.

The effect of elevated temperature on gene transcription and aflatoxin biosynthesis.

The molecular regulation of aflatoxin biosynthesis is complex and influenced by several environmental conditions; one of these is temperature. Aflatoxins are produced optimally at 28-30 C, and production decreases as temperatures approach 37 C, the optimum temperature for fungal growth. To better characterize the influence of temperature on aflatoxin biosynthesis, we monitored the accumulation of aflatoxin and the expression of more than 5000 genes in Aspergillus flavus at 28 C and 37 C. A total of 144 genes were expressed differentially (P < 0.001) between the two temperatures. Among the 103 genes more highly expressed at 28 C, approximately 25% were involved in secondary metabolism and about 30% were classified as hypothetical. Genes encoding a catalase and superoxide dismutase were among those more highly expressed at 37 C. As anticipated we also found that all the aflatoxin biosynthetic genes were much more highly expressed at 28 C relative to 37 C. To our surprise expression of the pathway regulatory genes aflR and aflS, as well as aflR antisense, did not differ between the two temperatures. These data indicate that the failure of A. flavus to produce aflatoxin at 37 C is not due to lack of transcription of aflR or aflS. One explanation is that AFLR is nonfunctional at high temperatures. Regardless, the factor(s) sensing the elevated temperatures must be acute. When aflatoxin-producing cultures are transferred to 37 C they immediately stop producing aflatoxin.

Evidence of an environmental contribution to the aetiology of cryptorchidism and hypospadias?

OBJECTIVES: Evidence suggests that there is geographical variation in the birth prevalence of both cryptorchidism and hypospadias. The aim was to determine if there is evidence of spatial heterogeneity in the prevalence of these conditions and to test the hypothesis that environmental factors may contribute to aetiology. METHODS: A population-based dataset of cryptorchidism and hypospadias cases was constructed from the hospital episodes statistics that covered the Northern Region of England and assigned to a small area based on the residential address at time of admission. Expected numbers of cases for each small area were computed. The ratio of observed to expected cases was determined for each small area and analysed with respect to both geographical heterogeneity and small area level socio-economic deprivation. The Potthoff-Whittinghill method was used to determine if there was localized spatial clustering of cases. RESULTS: There was statistically significant spatial clustering for cases of both cryptorchidism [estimated Extra-Poisson Variation (EPV) = 0.14; 95% CI, 0.03-0.25] and hypospadias (EPV = 0.17; 95% CI, 0.05-0.28). In addition, increased prevalence was associated with lower levels of deprivation for hypospadias (P = 0.06), but there was no such relationship for cryptorchidism (P = 0.61). CONCLUSIONS: The finding of localized spatial heterogeneity in the prevalence of cryptorchidism and hypospadias is consistent with the involvement of a spatially varying environmental risk factor. The apparent social patterning of hypospadias is likely to reflect an association with lifestyle and other factors which underpin social variation in health. However, there also remains a possibility that these findings may be due to variability in ascertainment of cases.