Catherine Allard

Risk of Clostridium difficile Infection after Perioperative Antibacterial Prophylaxis before and during an Outbreak of Infection due to a Hypervirulent Strain

BACKGROUND Perioperative antibacterial prophylaxis (PAP) is an important component of surgical site infection prevention but may be associated with adverse effects, such as Clostridium difficile infection (CDI). Since the emergence of a hypervirulent strain of C. difficile, the risk of development of CDI after PAP has not been evaluated. The purpose of this study was to determine the risk of PAP-induced CDI after selected surgical procedures and to compare such risk before with such risk after the emergence of the hypervirulent strain of C. difficile. METHODS We performed a retrospective cohort study including all patients aged > or = 18 years who underwent either abdominal hysterectomy, hip arthroplasty, craniotomy, or colon, cardiac, or vascular surgery from August 1999 through May 2005 in a tertiary care hospital in Quebec, Canada. RESULTS A total of 8373 surgical procedures were performed, and PAP was used in 7600 of these interventions. Of 98 CDI episodes identified, 40 occurred after patients received PAP only. The risk of CDI was 14.9 cases per 1000 surgical procedures among patients who received PAP only during the period 2003-2005, compared with 0.7 cases per 1000 surgical procedures during the period 1999-2002 (P < .001). The independent risk factors associated with CDI in patients given PAP only were older age, administration of cefoxitin (rather than cefazolin) alone or in combination with another drug, and year of surgery. CONCLUSIONS In the context of a large epidemic of CDI associated with the emergence of a novel strain, 1.5% of patients who received PAP as their sole antibiotic treatment developed CDI. In situations in which the only purpose of PAP is to prevent infrequent and relatively benign infections, the risks may outweigh the benefits in some elderly patients.

Mendelian randomization supports causality between maternal hyperglycemia and epigenetic regulation of leptin gene in newborns

Leptin is an adipokine that acts in the central nervous system and regulates energy balance. Animal models and human observational studies have suggested that leptin surge in the perinatal period has a critical role in programming long-term risk of obesity. In utero exposure to maternal hyperglycemia has been associated with increased risk of obesity later in life. Epigenetic mechanisms are suspected to be involved in fetal programming of long term metabolic diseases. We investigated whether DNA methylation levels near LEP locus mediate the relation between maternal glycemia and neonatal leptin levels using the 2-step epigenetic Mendelian randomization approach. We used data and samples from up to 485 mother-child dyads from Gen3G, a large prospective population-based cohort. First, we built a genetic risk score to capture maternal glycemia based on 10 known glycemic genetic variants (GRS10) and showed it was an adequate instrumental variable (β = 0.046 mmol/L of maternal fasting glucose per additional risk allele; SE = 0.007; P = 7.8 × 10−11; N = 467). A higher GRS10 was associated with lower methylation levels at cg12083122 located near LEP (β = −0.072 unit per additional risk allele; SE = 0.04; P = 0.05; N = 166). Direction and effect size of association between the instrumental variable GRS10 and methylation at cg12083122 were consistent with the negative association we observed using measured maternal glycemia. Lower DNA methylation levels at cg12083122 were associated with higher cord blood leptin levels (β = −0.17 log of cord blood leptin per unit; SE = 0.07; P = 0.01; N = 170). Our study supports that maternal glycemia is part of causal pathways influencing offspring leptin epigenetic regulation.

Validation of a DNA methylation reference panel for the estimation of nucleated cells types in cord blood

ABSTRACT Cord blood is widely used as surrogate tissue in epigenome-wide association studies of prenatal conditions. Cell type composition variation across samples can be an important confounder of epigenome-wide association studies in blood that constitute a mixture of cells. We evaluated a newly developed cord blood reference panel to impute cell type composition from DNA methylation levels, including nucleated red blood cells (nRBCs). We estimated cell type composition from 154 unique cord blood samples with available DNA methylation data as well as direct measurements of nucleated cell types. We observed high correlations between the estimated and measured composition for nRBCs (r = 0.92, R2 = 0.85), lymphocytes (r = 0.77, R2 = 0.58), and granulocytes (r = 0.72, R2 = 0.52), and a moderate correlation for monocytes (r = 0.51, R2 = 0.25) as well as relatively low root mean square errors from the residuals ranging from 1.4 to 5.4%. These results validate the use of the cord blood reference panel and highlight its utility and limitations for epidemiological studies.

Clostridium difficile Infection in the Intensive Care Unit

Clostridium difficile infection (CDI) is an increasing nosocomial problem in North America and Western Europe, where outbreaks caused by a more virulent, toxin-hyperproducing strain have been recently reported. Clostridium difficile infection is now characterized by a higher incidence, more frequent relapses, and a higher case-fatality ratio. As a consequence, fulminant cases requiring admission to the intensive care unit (ICU) are much more common than previously. In recent years, metronidazole has appeared to lose some of its effectiveness in CDI management and vancomycin is now recognized as the first-line treatment of severe cases. Rapid diagnosis and institution of infection control measures are critical components of CDI management. The current review focuses on recent changes in the epidemiology, diagnostic methods, and treatment of CDI, with special emphasis on complicated cases managed in the ICU.

Corticosteroids as Adjunctive Therapy in Severe Blastomycosis-Induced Acute Respiratory Distress Syndrome in an Immunosuppressed Patient

We describe the case of an immunosuppressed transplant recipient with disseminated blastomycosis (cutaneous, central nervous system, and pulmonary infection) complicated by septic shock and severe, refractory acute respiratory distress syndrome that improved markedly and rapidly after the addition of corticosteroids to the antifungal regimen.

Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium

&NA; Pre‐pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later in life. Individual studies have shown that epigenetic modifications such as DNA methylation could contribute. Within the Pregnancy and Childhood Epigenetics (PACE) Consortium, we meta‐analysed the association between pre‐pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother‐newborn pairs). We attempted to infer causality by comparing the effects of maternal versus paternal BMI and incorporating genetic variation. In four additional cohorts (1,817 mother‐child pairs), we meta‐analysed the association between maternal BMI at the start of pregnancy and blood methylation in adolescents. In newborns, maternal BMI was associated with small (<0.2% per BMI unit (1 kg/m2), P < 1.06 × 10‐7) methylation variation at 9,044 sites throughout the genome. Adjustment for estimated cell proportions greatly attenuated the number of significant CpGs to 104, including 86 sites common to the unadjusted model. At 72/86 sites, the direction of the association was the same in newborns and adolescents, suggesting persistence of signals. However, we found evidence for acausal intrauterine effect of maternal BMI on newborn methylation at just 8/86 sites. In conclusion, this well‐powered analysis identified robust associations between maternal adiposity and variations in newborn blood DNA methylation, but these small effects may be better explained by genetic or lifestyle factors than a causal intrauterine mechanism. This highlights the need for large‐scale collaborative approaches and the application of causal inference techniques in epigenetic epidemiology.

Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics

Abstract Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother–child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P < 5 × 10−8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.

Genetics of Glucose regulation in Gestation and Growth (Gen3G): a prospective prebirth cohort of mother-child pairs in Sherbrooke, Canada.

Purpose We initiated the Genetics of Glucose regulation in Gestation and Growth (Gen3G) prospective cohort to increase our understanding of biological, environmental and genetic determinants of glucose regulation during pregnancy and their impact on fetal development. Participants Between January 2010 and June 2013, we invited pregnant women aged ≥18 years old who visited the blood sampling in pregnancy clinic in Sherbrooke for their first trimester clinical blood samples: 1034 women accepted to participate in our cohort study. Findings to date At first and second trimester, we collected demographics and lifestyle questionnaires, anthropometry measures (including fat and lean mass estimated using bioimpedance), blood pressure, and blood samples. At second trimester, women completed a full 75 g oral glucose tolerance test and we collected additional blood samples. At delivery, we collected cord blood and placenta samples; obstetrical and neonatal clinical data were abstracted from electronic medical records. We also collected buffy coats and extracted DNA from maternal and/or offspring samples (placenta and blood cells) to pursue genetic and epigenetic hypotheses. So far, we have found that low adiponectin and low vitamin D maternal levels in first trimester predict higher risk of developing gestational diabetes. Future plans We are now in the phase of prospective follow-up of mothers and offspring 3 and 5 years postdelivery to investigate the consequences of maternal dysglycaemia during pregnancy on offspring adiposity and metabolic profile. Trial registration number NCT01623934.

Preeclampsia is associated with an increased pro-inflammatory profile in newborns

Hypertensive disorders of pregnancy (HDP) lead to high rates of maternal and fetal morbidity. Existing studies on inflammatory marker TNFα in HDP offspring are inconsistent. We performed a population-based cohort study of 636 pregnancies, including normotensive (NT) women and women with preeclampsia (PE) or gestational hypertension (GH). TNFα was measured in maternal blood in the first and second trimesters and in cord blood at the time of delivery. Cord blood TNFα was higher in offspring delivered of women with PE (6.53 [4.94-8.38]pg/mL) versus those delivered of NT women (5.13 [4.11-6.72]pg/mL; p=0.01), independent of confounders. Maternal TNFα levels were not different among groups (p>0.1) in either the first or second trimester.

LRP1B, BRD2 and CACNA1D : new candidate genes in fetal metabolic programming of newborns exposed to maternal hyperglycemia

AIM To assess the associations between gestational diabetes mellitus (GDM) and DNA methylation levels at genes related to energy metabolism. PATIENTS & METHODS Ten loci were selected from our recent epigenome-wide association study on GDM. DNA methylation levels were quantified by bisulfite pyrosequencing in 80 placenta and cord blood samples (20 exposed to GDM) from an independent birth cohort (Gen3G). RESULTS We did not replicate association between DNA methylation and GDM. However, in normoglycemic women, glucose levels were associated with DNA methylation changes at LRP1B and BRD2 and at CACNA1D and LRP1B gene loci in placenta and cord blood, respectively. CONCLUSION These results suggest that maternal glucose levels, within the normal range, are associated with DNA methylation changes at genes related to energy metabolism and previously associated with GDM. Maternal glycemia might thus be involved in fetal metabolic programming.