Search

OBJECTIVE Maternal glycemic dysregulation during pregnancy increases the risk of adverse health outcomes in her offspring; a risk thought to be linearly related to maternal hyperglycemia. It is hypothesized that changes in offspring DNA methylation (DNAm) underline these associations. RESEARCH DESIGN AND METHODS To address this hypothesis, we conducted fixed-effect meta-analyses of epigenome-wide association study (EWAS) results from eight birth cohorts investigating relationships between cord blood DNAm and fetal exposure to maternal glucose (Nmax= 3,503), insulin (Nmax= 2,062), and the area under the curve of glucose (AUCgluc) following oral glucose tolerance tests (OGTT, Nmax= 1,505). We performed look-up analyses for identified CpG dinucleotides (CpGs) in independent observational cohorts to examine associations between DNAm and cardiometabolic traits as well as tissue-specific gene expression. RESULTS Greater maternal AUCgluc was associated with lower cord blood DNAm at neighboring CpGs cg26974062 (β= -0.013 [SE=2.1x10-3], PFDR= 5.1x10-3) and cg02988288 (β= -0.013 [SE=2.3x10-3], PFDR =0.031) in TXNIP. These associations were attenuated in women with GDM. Lower blood DNAm at these two CpGs near TXNIP was associated with multiple metabolic traits later in life, including type 2 diabetes. TXNIP DNAm in liver biopsies was associated with hepatic expression of TXNIP. We observed little evidence of associations between either maternal glucose or insulin and cord blood DNAm. CONCLUSION Maternal hyperglycemia, as reflected by AUCgluc, was associated with lower cord blood DNAm at TXNIP. Associations between DNAm at these CpGs and metabolic traits in subsequent look-up analyses suggest that these may be candidate loci to investigate in future causal and mediation analyses.

Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy Consortium assembled genome-wide association studies of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (P

Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy (GenDIP) Consortium assembled genome-wide association studies (GWAS) of diverse ancestry in a total of 5,485 women with GDM and 347,856 without GDM. Through trans-ancestry meta-analysis, we identified five loci with genome-wide significant association (p−8) with GDM, mapping to/near MTNR1B (p=4.3×10−54), TCF7L2 (p=4.0×10−16), CDKAL1 (p=1.6×10−14), CDKN2A-CDKN2B (p=4.1×10−9) and HKDC1 (p=2.9×10−8). Multiple lines of evidence pointed to genetic contributions to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D; and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomisation analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.

OBJECTIVE Gestational diabetes mellitus (GDM) is associated with an increased risk of obesity and insulin resistance in offspring later in life, which might be explained by epigenetic changes in response to maternal hyperglycemic exposure. RESEARCH DESIGN AND METHODS We explored the association between GDM exposure and maternal blood and newborn cord blood methylation in 536 mother-offspring pairs from the prospective FinnGeDi cohort using Illumina MethylationEPIC 850K BeadChip arrays. We assessed two hypotheses. First, we tested for shared maternal and offspring epigenetic effects resulting from GDM exposure. Second, we tested whether GDM exposure and maternal methylation had an epigenetic effect on the offspring. RESULTS We did not find any epigenetic marks (differentially methylated CpG probes) with shared and consistent effects between mothers and offspring. After including maternal methylation in the model, we identified a single significant (false discovery rate 1.38 × 10−2) CpG at the cg22790973 probe (TFCP2) associated with GDM. We identified seven additional FDR-significant interactions of maternal methylation and GDM status, with the strongest association at the same cg22790973 probe (TFCP2), as well as cg03456133, cg24440941 (H3C6), cg20002843 (LOC127841), cg19107264, and cg11493553 located within the UBE3C gene and cg17065901 in FAM13A, both susceptibility genes for type 2 diabetes and BMI, and cg23355087 within the DLGAP2 gene, known to be involved in insulin resistance during pregnancy. CONCLUSIONS Our study reveals the potential complexity of the epigenetic transmission between mothers with GDM and their offspring, likely determined by not only GDM exposure but also other factors indicated by maternal epigenetic status, such as maternal metabolic history.

Background Time spent in hospital (length of stay) is an important component of patient experience and the financial cost of cancer care. This study documents the length of stay across English cancer diagnoses at a national level and reports on variation by patient demographics and tumour characteristics. Methods Data on all diagnoses of malignant neoplasms from the English National Cancer Registration and Analysis Service for 252,202 patients first diagnosed in 2015 was linked with NHS Digital’s Admitted Patient Care and Outpatient Hospital Episode Statistics datasets to quantify length of stay within one year following diagnosis. Length of stay was modelled using linear regression adjusted for sex, age, tumour type, stage, time spent alive during the study period, vital status at end of study period, region, deprivation and ethnicity. Results Patients spend a mean of 25 days (median = 17 days; IQR = 8–34 days) in hospital in their first year. Tumour type, stage, age and vital status corrections had the strongest effects in the model adjusting for other independent variables. Younger patients tended towards longer stays. Conclusion Length of stay varies among patients by tumour type, age and stage. Estimating future health service demands should account for changes in incident tumour characteristics.

BackgroundThere are various maternal prenatal biopsychosocial (BPS) predictors of birth weight, making it difficult to quantify their cumulative relationship.MethodsWe studied two birth cohorts: Northern Finland Birth Cohort 1986 (NFBC1986) born in 1985–1986 and the Generation R Study (from the Netherlands) born in 2002–2006. In NFBC1986, we selected variables depicting BPS exposure in association with birth weight and performed factor analysis to derive latent constructs representing the relationship between these variables. In Generation R, the same factors were generated weighted by loadings of NFBC1986. Factor scores from each factor were then allocated into tertiles and added together to calculate a cumulative BPS score. In all cases, we used regression analyses to explore the relationship with birth weight corrected for sex and gestational age and additionally adjusted for other factors.ResultsFactor analysis supported a four-factor structure, labelled closely to represent their characteristics as ‘Factor1-BMI’ (body mass index), ‘Factor2-DBP’ (diastolic blood pressure), ‘Factor3-Socioeconomic-Obstetric-Profile’ and ‘Factor4-Parental-Lifestyle’. In both cohorts, ‘Factor1-BMI’ was positively associated with birth weight, whereas other factors showed negative association. ‘Factor3-Socioeconomic-Obstetric-Profile’ and ‘Factor4-Parental-Lifestyle’ had the greatest effect size, explaining 30% of the variation in birth weight. Associations of the factors with birth weight were largely driven by ‘Factor1-BMI’. Graded decrease in birth weight was observed with increasing cumulative BPS score, jointly evaluating four factors in both cohorts.ConclusionOur study is a proof of concept for maternal prenatal BPS hypothesis, highlighting the components snowball effect on birth weight in two different European birth cohorts.

This project received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 633595

This study compared the costs of home palliative with conventional hospital care for cancer haematological patients in Greece. The study was a retrospective cost-minimisation analysis using data from the finance department and from patient notes for the period from January to June 2002. A non-parametric bootstrap method was used to estimate the incremental cost between home and conventional care. A sensitivity analysis was also used. The estimated incremental cost was euro 522 (95% confidence interval: euro 516-528). This was not substantially affected by varying the unit costs within reasonable limits and remained statistically significant under all scenarios tested in the sensitivity analysis. Our findings show that home palliative care is more expensive than conventional hospital care. Further studies should be carried out to examine the cost-effectiveness of the particular scheme as well as the preferences of patients and carers.

We determined the diagnostic significance of IgM anti-HBc by a rapid, fully automated microparticle enzyme immunoassay (IMx CORE-M) in acute HBsAg positive hepatitis.We studied prospectively for at least 6 months 100 patients with acute self-limited hepatitis B (group A) and 40 patients with acute hepatitis superimposed on histologically confirmed chronic hepatitis B (group B). On admission, all patients in group A were positive and those in group B were negative for IgM anti-HBc by a commercially available enzyme immunoassay.Based on the assay criteria, the rates of IMx CORE-M (1.2) positive serum samples on admission, 4, 12 and 24 weeks later were: in group A: 100%, 95%, 72%, 44% and in group B: 20%, 27.5%, 17.5%, and 15%, respectively. Misclassification was observed in 20-27.5% of the acute on chronic hepatitis B cases. However, the mean IMx CORE-M index value was found to be significantly higher in group A during the whole follow-up. In particular, on admission the mean IMx CORE-M index value was 2.504 +/- 0.435 (range: 1.508-3.482) in group A and 0.747 +/- 0.346 (range: 0.062-1.384) in group B (p0.001). Discriminant function analysis showed that the cutoff level between the two groups for IMxCORE-M index on admission was 1.5. Four to 12 weeks from admission, in the group with acute on chronic hepatitis B cases, 13 patients with HDV and/or HCV superinfection had significantly lower IMx-CORE M index values compared with 27 patients with acute hepatitis due to exacerbation of chronic hepatitis B.IMx CORE-M appears to be an accurate diagnostic test to differentiate acute from acute on chronic HBsAg positive hepatitis, but the cut-off level seems to be higher (1.5 instead of 1.2).

This research is financially supported by the Hellenic Center for Disease Control and Prevention (H.C.D.C.P.). The authors would like to thank the Hellenic Statistical Authority for providing valuable data for this publication. Background: Hexavalent chromium is a known carcinogen when inhaled, but its carcinogenic potential when orally ingested remains controversial. Water contaminated with hexavalent chromium is a worldwide problem, making this a question of significant public health importance. Methods: We conducted an ecological mortality study within the Oinofita region of Greece, where water has been contaminated with hexavalent chromium. We calculated gender, age, and period standardized mortality ratios (SMRs) for all deaths, cancer deaths, and specific cancer types of Oinofita residents over an 11-year period (1999 - 2009), using the greater prefecture of Voiotia as the standard population. Results: A total of 474 deaths were observed. The SMR for all cause mortality was 98 (95% CI 89-107) and for all cancer mortality 114 (95% CI 94-136). The SMR for primary liver cancer was 1104 (95% CI 405-2403, p-value < 0.001). Furthermore, statistically significantly higher SMRs were identified for lung cancer (SMR = 145, 95% CI 100203, p-value = 0.047) and cancer of the kidney and other genitourinary organs among women (SMR = 368, 95% CI 119-858, p-value = 0.025). Elevated SMRs for several other cancers were also noted (lip, oral cavity and pharynx 344, stomach 121, female breast 134, prostate 128, and leukaemias 168), but these did not reach statistical significance. Conclusions: Elevated cancer mortality in the Oinofita area of Greece supports the hypothesis of hexavalent chromium carcinogenicity via the oral ingestion pathway of exposure. Further studies are needed to determine whether this association is causal, and to establish preventive guidelines and public health recommendations. Hellenic Center for Disease Control and Prevention (H.C.D.C.P.)

In this article, three alternative Bayesian hierarchical latent factor models are described for spatially and temporally correlated multivariate health data. The fundamentals of factor analysis with ideas of space— time disease mapping to provide a flexible framework for the joint analysis of multiple-related diseases in space and time with a view to estimating common and disease-specific trends in cancer risk are combined. The models are applied to area-level mortality data on six diet-related cancers for Greece over the 20-year period from 1980 to 1999. The aim of this study is to uncover the spatial and temporal patterns of any latent factor(s) underlying the cancer data that could be interpreted as reflecting some aspects of the habitual diet of the Greek population.

The AIDS epidemic is now more than a decade old, and new estimates by the Joint United Nations Programme on HIV/AIDS (UNAIDS) and the World Health Organization (WHO) indicate that infection with HIV is far more common in the world than previously thought.1 By the beginning of 1998 over 30 million people were living with HIV/AIDS (Table 1). That is one in every 100 sexually active adults aged 15 to 49 years old, yet only a tiny fraction know about their infection. During 1997 alone it is estimated that 5.8 million new HIV infections occurred (that is an average of 16,000 new infections daily during the year) despite the fact that more is known now than ever about preventing spread of the epidemic. Over 90% of these individuals are concentrated in the developing world, mostly in countries least able to afford to care for infected people. Over 50% of the newly infected adults are in the age bracket 15 to 24 years old and more than 40% are women. Overall, by the beginning of 1998, it is estimated that over 12 million women are living with HIV/AIDS, of whom 2 million were infected in 1997 alone (Table 1). The global HIV epidemic in women continues to expand at an alarming rate. The primary risk factor for HIV infection in women is unprotected heterosexual intercourse. Several cofactors may influence a women’s risk for acquisition, including the presence of other STDs, the prevalence of HIV in the population engaging in high-risk sexual behaviors at a young age, and the increased number of sexual partners.2 Of the 30 million people living with HIV/AIDS, 1.1 million are children under 15 years of age. Both UNAIDS and WHO estimate that the number of children who have been infected with HIV since the start of the epidemic has reached about 3.8 million, of whom 2.7 million have already died (Table 1). Nearly 600,000 children were infected with HIV in 1997. The overwhelming majority of these children live in the developing world and acquired the infection from their mothers during pregnancy, during delivery, or through breast feeding. It is estimated that altogether 11.7 million people died of AIDS and HIV-related causes since the beginning of the epidemic and 2.3 million deaths occurred during the course of 1997 (Table 1). Community studies in less developed countries show a twoto threefold increase in total adult mortality, with an even larger increase in mortality among young adults in communities with adult HIV prevalence levels below 10%.3,4 HIV/AIDS is among the top ten leading causes of death worldwide, and according to the current situation of HIV infection, it may soon move into the top five.5 In the United States, after combination therapy was introduced in 1996, AIDS dropped into second place for the first time since 1992 as the leading cause of death in people 25 to 44 years old. It is apparent that AIDS is systematically cutting down life expectancy in the countries where the disease is most common. In a study of a rural area of Uganda, which has an adult HIV prevalence of 8%, life expectancy has dropped from just under 60 years to 42.5 years.6 There is evidence that HIV-infected women die at an earlier age than HIV-infected men and thereby lose significantly more productive years of life.3 In addition, the high mortality of AIDS and HIVrelated causes has major impacts on families. Both UNAIDS and WHO estimate that more than 8 million children under the age of 15 have lost their mothers to AIDS since the start of the epidemic and many of these have also lost their fathers (Table 2). It is estimated that this figure will double by the year 2000. Life expectancy in children has already been greatly affected by HIV. Despite the fact that developing nations have made great efforts in increasing infant and child survival in recent years, these gains are threatened by HIV. A mortality rate of 25% in babies under 12 months old was observed in Zimbabwe and Zambia because of HIV. Zimbabwe’s infant mortality rate is expected to rise by 138% because of AIDS by the year 2010.7 It is becoming increasingly apparent that, although almost every country is touched by HIV, the features of the pandemic differ from country to country (Fig 1). Variations in prevalence reflect the timing of the emerFrom the Department of Dermatology, University of Athens, and Hellenic Center for Infectious Disease Control, Athens, Greece. Address correspondence to Evangelia Tzala, MSc, HIV/AIDS Epidemiology Section, Hellenic Centre for Infectious Diseases Control (KEEL), 6-8 Macedonias Street, GR 104 33 Athens, Greece.

Background/Aims: The aim of this study was to determine the frequency of hepatitis E virus infection in a cohort of patients with acute non-A, non-B hepatitis in Greece. Methods: Serial serum samples of 198 patients with acute non-A, non-B hepatitis and a single serum specimen from 316 healthy subjects were tested for IgG and IgM antibodies to hepatitis E virus (anti-HEV). Results: Anti-HEV IgG was found in 15198 (7.6%) of acute non-A, non-B hepatitis patients and 7316 (2.2%) of healthy controls ( p =0.007). Anti-HEV IgM was found in 2198 (1.0%) acute non-A, non-B hepatitis patients and in none of the healthy subjects. Neither anti-HEV IgM (+) case reported any risk factor and neither had travelled in areas endemic for hepatitis E virus infection. HEV-RNA was detected by reverse transcription polymerase chain reaction in one patient. The prevalence of anti-HEV IgG was 745 (15.6%), 146 (2.2%), 530 (16.7%) and 277 (2.6%) in acute non-A, non-B hepatitis reporting transfusion, intravenous drug use, occupational/hospitalization, and unknown transmission, respectively ( p =0.007). Anti-HEV IgG was found in 13122 (10.7%) and 276 (2.6%) of acute non-A, non-B hepatitis patients positive and negative for anti-HCV, respectively ( p =0.03). A similar association was found with anti-HBc ( p =0.007). The prevalence of anti-HEV IgG was significantly higher in cases reporting transfusion [OR=7.3, 95% C.I. 1.4–37.7, p =0.017] and occupational/hospitalization [OR=6.8, 95% C.I. 1.2–38.2, p =0.029], as transmission category after controlling for age. Conclusions: These findings indicate that: (a) hepatitis E virus may be a cause - although not a frequent one - of sporadic or community-acquired acute non-A, non-B hepatitis in Greece; (b) hepatitis E virus may share transmission routes with hepatitis B and C viruses; and (c) the hypothesis that hepatitis E virus may be transmitted by parenteral routes deserves careful consideration.