Paul Fahey

Maternal ethanol consumption alters the epigenotype and the phenotype of offspring in a mouse model.

Recent studies have shown that exposure to some nutritional supplements and chemicals in utero can affect the epigenome of the developing mouse embryo, resulting in adult disease. Our hypothesis is that epigenetics is also involved in the gestational programming of adult phenotype by alcohol. We have developed a model of gestational ethanol exposure in the mouse based on maternal ad libitum ingestion of 10% (v/v) ethanol between gestational days 0.5–8.5 and observed changes in the expression of an epigenetically-sensitive allele, Agouti viable yellow (Avy), in the offspring. We found that exposure to ethanol increases the probability of transcriptional silencing at this locus, resulting in more mice with an agouti-colored coat. As expected, transcriptional silencing correlated with hypermethylation at Avy. This demonstrates, for the first time, that ethanol can affect adult phenotype by altering the epigenotype of the early embryo. Interestingly, we also detected postnatal growth restriction and craniofacial dysmorphology reminiscent of fetal alcohol syndrome, in congenic a/a siblings of the Avy mice. These findings suggest that moderate ethanol exposure in utero is capable of inducing changes in the expression of genes other than Avy, a conclusion supported by our genome-wide analysis of gene expression in these mice. In addition, offspring of female mice given free access to 10% (v/v) ethanol for four days per week for ten weeks prior to conception also showed increased transcriptional silencing of the Avy allele. Our work raises the possibility of a role for epigenetics in the etiology of fetal alcohol spectrum disorders, and it provides a mouse model that will be a useful resource in the continued efforts to understand the consequences of gestational alcohol exposure at the molecular level.

A systematic review and meta-analysis of interventions designed to increase moderate-to-vigorous physical activity in school physical education lessons

OBJECTIVES Physical education (PE) that allows students to engage in moderate-to-vigorous physical activity (MVPA) can play an important role in health promotion. Unfortunately, MVPA levels in PE lessons are often very low. In this review, we aimed to determine the effectiveness of interventions designed to increase the proportion of PE lesson time that students spend in MVPA. METHODS In March 2012, we searched electronic databases for intervention studies that were conducted in primary or secondary schools and measured the proportion of lesson time students spent in MVPA. We assessed risk of bias, extracted data, and conducted meta-analyses to determine intervention effectiveness. RESULTS From an initial pool of 12,124 non-duplicate records, 14 studies met the inclusion criteria. Students in intervention conditions spent 24% more lesson time in MVPA compared with students in usual practice conditions (standardized mean difference=0.62). CONCLUSIONS Given the small number of studies, moderate-to-high risk of bias, and the heterogeneity of results, caution is warranted regarding the strength of available evidence. However, this review indicates that interventions can increase the proportion of time students spend in MVPA during PE lessons. As most children and adolescents participate in PE, these interventions could lead to substantial public health benefits.

Bidirectional Associations Between Clinically Relevant Depression or Anxiety and COPD: A Systematic Review and Meta-analysis

BACKGROUND The longitudinal associations between depression or anxiety and COPD, and their comorbid effect on prognosis, have not been adequately addressed by previous reviews. We aimed to systematically assess these associations to inform guidelines and practice. METHODS We searched electronic databases for articles published before May 2012. Longitudinal studies in adult populations that reported an association between clinically relevant depression or anxiety and COPD, or that reported their comorbid effect on exacerbation and/or mortality, were eligible. Risk ratios (RRs) were pooled across studies using random-effects models and were verified using fixed-effects models. Heterogeneity was explored with subgroup and metaregression analyses. RESULTS Twenty-two citations yielded 16 studies on depression or anxiety as predictors of COPD outcomes (incident COPD/chronic lung disease or exacerbation) and/or mortality, in 28,759 participants followed for 1 to 8 years, and six studies on COPD as a predictor of depression in 7,439,159 participants followed for 1 to 35 years. Depression or anxiety consistently increased the risk of COPD outcomes (RR, 1.43; 95% CI, 1.22-1.68), particularly in higher-quality studies and in people aged ≤ 66 years. Comorbid depression increased the risk of mortality (RR, 1.83; 95% CI, 1.00-3.36), particularly in men. Anxiety (or psychologic distress) increased the risk of COPD outcomes/mortality in most studies (RR, 1.27; 95% CI, 1.02-1.58). Finally, COPD consistently increased the risk of depression (RR, 1.69; 95% CI, 1.45-1.96). CONCLUSIONS Depression and anxiety adversely affect prognosis in COPD, conferring an increased risk of exacerbation and possibly death. Conversely, COPD increases the risk of developing depression. These bidirectional associations suggest potential usefulness of screening for these disease combinations to direct timely therapeutic intervention.

Association of Helicobacter pylori Infection With Reduced Risk for Esophageal Cancer Is Independent of Environmental and Genetic Modifiers

BACKGROUND & AIMS Infection with Helicobacter pylori is associated with reduced risk of esophageal adenocarcinoma (EAC), but it is not clear whether this reduction is modified by genotype, other host characteristics, or environmental factors. Furthermore, little is known about the association between H pylori and adenocarcinomas of the esophagogastric junction (EGJAC) or squamous cell carcinomas (ESCC). We sought to measure the association between H pylori infection and esophageal cancer and identify potential modifiers. METHODS In an Australian, population-based, case-control study, we compared the prevalence of H pylori seropositivity and single nucleotide polymorphisms in interleukin (IL)-1B (-31, -511) and tumor necrosis factor (TNF)-alpha (-308, -238) among 260 EAC, 298 EGJAC, and 208 ESCC patients and 1346 controls. To estimate relative risks, we calculated odds ratios (OR) and 95% confidence intervals (CI) using multivariable logistic regression in the entire sample and within strata of phenotypic and genotypic risk factors. RESULTS H pylori infection was associated with significantly reduced risks of EAC (OR, 0.45; 95% CI: 0.30-0.67) and EGJAC (OR, 0.41; 95% CI: 0.27-0.60) but not ESCC (OR, 1.04; 95% CI: 0.71-1.50). For each cancer subtype, risks were of similar magnitude across strata of reflux frequency and smoking status. We found no evidence that polymorphisms in IL-1B or TNF-alpha modified the association between H pylori and EAC or EGJAC. CONCLUSIONS H pylori infection is inversely associated with risks of EAC and EGJAC (but not ESCC); the reduction in risk is similar across subgroups of potential modifiers.

Oral hygiene program for orthodontic patients

The gingival and periodontal health of 62 adolescent orthodontic patients was assessed before and again after orthodontic treatment in a controlled clinical study. Before the commencement of orthodontic treatment, the experimental group received an oral hygiene program consisting of 4 weekly sessions of oral health education, instruction on plaque-control techniques and reviews in plaque removal performance. The control group did not receive this program. It was found that there was a general trend in the study population for improved gingival health as measured by the bleeding index, gingival index, plaque index and gingival crevicular fluid volume. Furthermore, the oral hygiene program induced in the experimental group significantly lower scores in the measured clinical indices compared to the control group. However, no significant difference was noted in the measured probing depths in all subjects before or after the study period.

Impact of treatment with raltegravir during primary or chronic HIV infection on RNA decay characteristics and the HIV viral reservoir

Background:Eradication of HIV-1 is prevented by the formation of viral reservoirs in peripheral blood, lymphoid tissues and other sanctuary sites. In most patients, rebound upon treatment cessation is prompt. We assessed whether early treatment with raltegravir can impact on the formation of the viral reservoir. Methods:We conducted an open-label, nonrandomized study, and assessed in detail the decay characteristics of HIV-1 RNA in plasma, HIV DNA in CD4+ T cells and colon tissue biopies (CTBs) in 16 treatment-naive patients during either primary (PHI, n = 8) or chronic (CHI, n = 8) HIV-1 infection after treatment with raltegravir and Truvada for 52 weeks. Results:HIV-1 RNA decreased rapidly with treatment in all patients; first and second phase levels were lower in PHI patients with no appreciable difference in residual viremia between the two groups at 52 weeks. Episomal HIV-1 DNA increased sharply in both groups with peak levels at 3–4 weeks. Total HIV-1 DNA levels were reduced in both groups with similar kinetics, but were markedly lower in PHI patients after 52 weeks. Integrated HIV-1 DNA levels were significantly lower at baseline in PHI patients and this difference widened on treatment. Finally, total HIV-1 DNA decayed substantially in both groups in CTB. Conclusion:Treatment with raltegravir resulted in a large number of abrogated integration events, reflected by the increase of episomal HIV-1 DNA after treatment initiation. Levels of total and integrated HIV-1 DNA were lower in PHI patients at the end of the study period.

Collaborative care for comorbid depression and diabetes: a systematic review and meta-analysis

Objective The collaborative care model is recommended for depression in adults with a chronic physical health problem like diabetes. We sought to systematically assess the effect of collaborative care on depression and glycaemia in adults with comorbid depression and diabetes to inform guidelines and practice. Design Systematic review and meta-analysis. Data sources We searched PubMed, Scopus, Cochrane Library, CINAHL, Health Source Nursing, MEDLINE, PsychINFO and reference lists of retrieved articles published before August 2013. Inclusion criteria Randomised controlled trials (RCTs) on collaborative care (ie, coordinated multidisciplinary model of care) for depression that reported the effects on depression and glycaemic outcomes in adults with comorbid clinically relevant depression and diabetes were eligible. Data extraction and analysis Data on the mean difference in depression and glycaemic outcomes were extracted and pooled using random effects meta-analysis. Results Seven RCTs included for review reported effects on depression outcomes in 1895 participants, and glycated haemoglobin (HbA1c) level in 1556 participants. Collaborative care significantly improved the depression score (standardised mean difference was −0.32 (95% CI −0.53 to −0.11); I2=79%) and HbA1c level (weighted mean difference was −0.33% (95% CI −0.66% to −0.00%); I2=72.9%) compared with control conditions. Depression remission did not predict better glycaemic control across studies. Conclusions Limited evidence from short-to-medium term RCTs predominantly conducted in the USA suggests that collaborative care for depression significantly improves both depression and glycaemia outcomes, independently, in people with comorbid depression and diabetes.

The influence of prediagnostic demographic and lifestyle factors on esophageal squamous cell carcinoma survival

Demographic and lifestyle factors, in particular tobacco smoking and alcohol, are well established causes of esophageal squamous cell carcinoma (ESCC); however, little is known about the effect of these factors on survival. We included all 301 patients with incident ESCC, recruited into a population‐based case–control study of esophageal cancer in Australia. Detailed information about demographic and lifestyle factors was obtained at diagnosis, and deaths were identified using the National Death Index. Median follow‐up for all‐cause mortality was 6.4 years. Hazard ratios (HRs) and 95% confidence intervals (95% CI) were calculated from Cox proportional hazards models, adjusted for age, sex, pretreatment AJCC tumor stage, treatment and presence of comorbidities. Two hundred and thirteen patients (71%) died during follow‐up. High lifetime alcohol consumption was independently associated with poor survival. Relative to life‐long nondrinkers and those consuming <1 drink/week, the HRs for those with average consumption of 7–20 drinks/week or ≥21 drinks/week were 2.21 (95% CI = 1.27–3.84) and 2.08 (95% CI = 1.18–3.69), respectively. There was a suggestion of worse survival among current smokers (HR = 1.42, 95% CI = 0.89–2.28); however, the risk of early death was greatest among current smokers who reported regularly (≥7 drinks/week) consuming alcohol (HR = 3.84, 95% CI = 2.02–7.32). Other lifestyle factors putatively associated with risk of developing ESCC were not associated with survival. In addition to increasing disease risk, heavy alcohol consumption may be independently associated with worse survival among patients with ESCC. Future clinical follow‐up studies should consider alcohol as a potential prognosticator, in addition to known clinicopathologic factors.

Interrater Reliability of Chinese Medicine Diagnosis in People with Prediabetes

Background. Achieving reproducibility in research design is challenging when patient cohorts under study are inconsistently defined. Traditional Chinese medicine (TCM) diagnosis is one example where inconsistency between practitioners has been found. We hypothesise that the use of a validated instrument may improve consistency. Biochemical biomarkers may also be used enhance reliability. Methods. Twenty-seven participants with prediabetes were assessed by two TCM practitioners using a validated instrument (TEAMSI-TCM). Inter-rater reliability was summarised using percentage agreement and the kappa coefficient. One-way ANOVA and Tukeys post hoc test were used to test links between TCM diagnosis and biomarkers. Results. The two practitioners agreed on primary diagnosis of 70% of participants. kappa = 0.56 (P < 0.001). The three predominant TCM diagnostic patterns for people with prediabetes were Yin deficiency, Qi and Yin deficiency and Spleen qi deficiency. The Spleen Qi deficiency with Damp cohort had statistically significant higher fasting glucose, higher insulin, higher insulin resistance, higher HbA1c and lower HDL than those with Qi and Yin deficiency. Conclusions. Using the TEAMSI-TCM resulted in moderate interrater reliability between TCM practitioners. This study provides initial evidence of variation in the biomarkers of people with prediabetes according to the different TCM patterns which may suggest a route to further improving interrater reliability.

Efficient discovery of risk patterns in medical data

OBJECTIVE This paper studies a problem of efficiently discovering risk patterns in medical data. Risk patterns are defined by a statistical metric, relative risk, which has been widely used in epidemiological research. METHODS To avoid fruitless search in the complete exploration of risk patterns, we define optimal risk pattern set to exclude superfluous patterns, i.e. complicated patterns with lower relative risk than their corresponding simpler form patterns. We prove that mining optimal risk pattern sets conforms an anti-monotone property that supports an efficient mining algorithm. We propose an efficient algorithm for mining optimal risk pattern sets based on this property. We also propose a hierarchical structure to present discovered patterns for the easy perusal by domain experts. RESULTS The proposed approach is compared with two well-known rule discovery methods, decision tree and association rule mining approaches on benchmark data sets and applied to a real world application. The proposed method discovers more and better quality risk patterns than a decision tree approach. The decision tree method is not designed for such applications and is inadequate for pattern exploring. The proposed method does not discover a large number of uninteresting superfluous patterns as an association mining approach does. The proposed method is more efficient than an association rule mining method. A real world case study shows that the method reveals some interesting risk patterns to medical practitioners. CONCLUSION The proposed method is an efficient approach to explore risk patterns. It quickly identifies cohorts of patients that are vulnerable to a risk outcome from a large data set. The proposed method is useful for exploratory study on large medical data to generate and refine hypotheses. The method is also useful for designing medical surveillance systems.