Using genetic variants to evaluate the causal effect of cholesterol lowering on head and neck cancer risk: A Mendelian randomization study.

Head and neck squamous cell carcinoma (HNSCC), which includes cancers of the oral cavity and oropharynx, is a cause of substantial global morbidity and mortality. Strategies to reduce disease burden include discovery of novel therapies and repurposing of existing drugs. Statins are commonly prescribed for lowering circulating cholesterol by inhibiting HMG-CoA reductase (HMGCR). Results from some observational studies suggest that statin use may reduce HNSCC risk. We appraised the relationship of genetically-proxied cholesterol-lowering drug targets and other circulating lipid traits with oral (OC) and oropharyngeal (OPC) cancer risk using two-sample Mendelian randomization (MR). For the primary analysis, germline genetic variants in HMGCR, NPC1L1, CETP, PCSK9 and LDLR were used to proxy the effect of low-density lipoprotein cholesterol (LDL-C) lowering therapies. In secondary analyses, variants were used to proxy circulating levels of other lipid traits in a genome-wide association study (GWAS) meta-analysis of 188,578 individuals. Both primary and secondary analyses aimed to estimate the downstream causal effect of cholesterol lowering therapies on OC and OPC risk. The second sample for MR was taken from a GWAS of 6,034 OC and OPC cases and 6,585 controls (GAME-ON). Analyses were replicated in UK Biobank, using 839 OC and OPC cases and 372,016 controls and the results of the GAME-ON and UK Biobank analyses combined in a fixed-effects meta-analysis. We found limited evidence of a causal effect of genetically-proxied LDL-C lowering using HMGCR, NPC1L1, CETP or other circulating lipid traits on either OC or OPC risk. Genetically-proxied PCSK9 inhibition equivalent to a 1 mmol/L (38.7 mg/dL) reduction in LDL-C was associated with an increased risk of OC and OPC combined (OR 1.8 95%CI 1.2, 2.8, p = 9.31 x10-05), with good concordance between GAME-ON and UK Biobank (I2 = 22%). Effects for PCSK9 appeared stronger in relation to OPC (OR 2.6 95%CI 1.4, 4.9) than OC (OR 1.4 95%CI 0.8, 2.4). LDLR variants, resulting in genetically-proxied reduction in LDL-C equivalent to a 1 mmol/L (38.7 mg/dL), reduced the risk of OC and OPC combined (OR 0.7, 95%CI 0.5, 1.0, p = 0.006). A series of pleiotropy-robust and outlier detection methods showed that pleiotropy did not bias our findings. We found limited evidence for a role of cholesterol-lowering in OC and OPC risk, suggesting previous observational results may have been confounded. There was some evidence that genetically-proxied inhibition of PCSK9 increased risk, while lipid-lowering variants in LDLR, reduced risk of combined OC and OPC. This result suggests that the mechanisms of action of PCSK9 on OC and OPC risk may be independent of its cholesterol lowering effects; however, this was not supported uniformly across all sensitivity analyses and further replication of this finding is required.

Surgical sequence, timing and volume, and variation in dento-facial outcome, speech and secondary surgery in children with unilateral cleft lip and palate: The Cleft Care UK Study.

OBJECTIVES: To estimate both the association of surgical variables in complete unilateral cleft lip and palate (cUCLP) in the UK with outcomes at age 5 years, and the association of secondary speech surgery, volume of surgery, and surgeon with the same outcomes. SETTING AND SAMPLE POPULATION: The Cleft Care UK study, a cross-sectional study of 268 5-year-olds, born from 2005 to 2007, with cUCLP. MATERIALS AND METHODS: Information on surgical variables was extracted from a standardized questionnaire. Dento-facial outcomes were derived from dental study casts of dental arch relationships. Three speech outcomes - intelligibility, structure and articulation - were derived using the Cleft Audit Protocol for Speech-Augmented tool. RESULTS: Surgical and outcome data were available for 211 (79%) children from all cleft centres in the UK. Later soft palate surgery was associated with a 17% increased chance of a poor intelligibility score (P = .02), and high volume surgery with a 249% increased chance of a good articulation score (P = .01). There were no between surgeon effects identified. No association between the surgical variables examined and dento-facial outcome, or secondary speech surgery by the age of 5 years were found. CONCLUSION: This study found associations between surgical variables and speech outcomes at 5 years of age, but not between surgical variables and dento-facial outcome, nor between surgical variables and secondary speech surgery. High surgical volume should be maintained, and any changes towards later surgery monitored for changes in speech outcome.

Investigating the effect of sexual behaviour on oropharyngeal cancer risk: a methodological assessment of Mendelian randomization.

BACKGROUND: Human papilloma virus infection is known to influence oropharyngeal cancer (OPC) risk, likely via sexual transmission. However, sexual behaviour has been correlated with other risk factors including smoking and alcohol, meaning independent effects are difficult to establish. We aimed to evaluate the causal effect of sexual behaviour on the risk of OPC using Mendelian randomization (MR). METHODS: Genetic variants robustly associated with age at first sex (AFS) and the number of sexual partners (NSP) were used to perform both univariable and multivariable MR analyses with summary data on 2641 OPC cases and 6585 controls, obtained from the largest available genome-wide association studies (GWAS). Given the potential for genetic pleiotropy, we performed a number of sensitivity analyses: (i) MR methods to account for horizontal pleiotropy, (ii) MR of sexual behaviours on positive (cervical cancer and seropositivity for Chlamydia trachomatis) and negative control outcomes (lung and oral cancer), (iii) Causal Analysis Using Summary Effect estimates (CAUSE), to account for correlated and uncorrelated horizontal pleiotropic effects, (iv) multivariable MR analysis to account for the effects of smoking, alcohol, risk tolerance and educational attainment. RESULTS: In univariable MR, we found evidence supportive of an effect of both later AFS (IVW OR = 0.4, 95%CI (0.3, 0.7), per standard deviation (SD), p = < 0.001) and increasing NSP (IVW OR = 2.2, 95%CI (1.3, 3.8) per SD, p = < 0.001) on OPC risk. These effects were largely robust to sensitivity analyses accounting for horizontal pleiotropy. However, negative control analysis suggested potential violation of the core MR assumptions and subsequent CAUSE analysis implicated pleiotropy of the genetic instruments used to proxy sexual behaviours. Finally, there was some attenuation of the univariable MR results in the multivariable models (AFS IVW OR = 0.7, 95%CI (0.4, 1.2), p = 0.21; NSP IVW OR = 0.9, 95%CI (0.5 1.7), p = 0.76). CONCLUSIONS: Despite using genetic variants strongly related sexual behaviour traits in large-scale GWAS, we found evidence for correlated pleiotropy. This emphasizes a need for multivariable approaches and the triangulation of evidence when performing MR of complex behavioural traits.

Omega-3 fatty acids for depression in adults.

BACKGROUND: Major depressive disorder (MDD) is highly debilitating, difficult to treat, has a high rate of recurrence, and negatively impacts the individual and society as a whole. One potential treatment for MDD is n-3 polyunsaturated fatty acids (n-3PUFAs), also known as omega-3 oils, naturally found in fatty fish, some other seafood, and some nuts and seeds. Various lines of evidence suggest a role for n-3PUFAs in MDD, but the evidence is far from conclusive. Reviews and meta-analyses clearly demonstrate heterogeneity between studies. Investigations of heterogeneity suggest different effects of n-3PUFAs, depending on the severity of depressive symptoms, where no effects of n-3PUFAs are found in studies of individuals with mild depressive symptomology, but possible benefit may be suggested in studies of individuals with more severe depressive symptomology. Hence it is important to establish their effectiveness in treating MDD. This review updates and incorporates an earlier review with the same research objective (Appleton 2015). OBJECTIVES: To assess the effects of n-3 polyunsaturated fatty acids (also known as omega-3 fatty acids) versus a comparator (e.g. placebo, antidepressant treatment, standard care, no treatment, wait-list control) for major depressive disorder (MDD) in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled trials (CENTRAL), Ovid MEDLINE, Embase and PsycINFO together with trial registries and grey literature sources (to 9 January 2021). We checked reference lists and contacted authors of included studies for additional information when necessary. SELECTION CRITERIA: We included studies in the review if they: used a randomised controlled trial design; provided n-3PUFAs as an intervention; used a comparator; measured depressive symptomology as an outcome; and were conducted in adults with MDD. Primary outcomes were depressive symptomology (continuous data collected using a validated rating scale) and adverse events. Secondary outcomes were depressive symptomology (dichotomous data on remission and response), quality of life, and non-completion of studies. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by Cochrane. We assessed the certainty of the evidence using GRADE criteria. MAIN RESULTS: The review includes 35 relevant studies: 34 studies involving a total of 1924 participants investigated the impact of n-3PUFA supplementation compared to placebo, and one study involving 40 participants investigated the impact of n-3PUFA supplementation compared to antidepressant treatment. For the placebo comparison, n-3PUFA supplementation resulted in a small to modest benefit for depressive symptomology, compared to placebo: standardised mean difference (SMD) (random-effects model) -0.40 (95% confidence interval (CI) -0.64 to -0.16; 33 studies, 1848 participants; very low-certainty evidence), but this effect is unlikely to be clinically meaningful. An SMD of 0.40 represents a difference between groups in scores on the HDRS (17-item) of approximately 2.5 points (95% CI 1.0 to 4.0), where the minimal clinically important change score on this scale is 3.0 points. The confidence intervals include both a possible clinically important effect and a possible negligible effect, and there is considerable heterogeneity between studies. Sensitivity analyses, funnel plot inspection and comparison of our results with those of large well-conducted trials also suggest that this effect estimate may be biased towards a positive finding for n-3PUFAs. Although the numbers of individuals experiencing adverse events were similar in intervention and placebo groups (odds ratio (OR) 1.27, 95% CI 0.99 to 1.64; 24 studies, 1503 participants; very low-certainty evidence), the confidence intervals include a small decrease to a modest increase in adverse events with n-3PUFAs. There was no evidence for a difference between n-3PUFA and placebo groups in remission rates (OR 1.13, 95% CI 0.74 to 1.72; 8 studies, 609 participants, low-certainty evidence), response rates (OR 1.20, 95% CI 0.80 to 1.79; 17 studies, 794 participants; low-certainty evidence), quality of life (SMD -0.38 (95% CI -0.82 to 0.06), 12 studies, 476 participants, very low-certainty evidence), or trial non-completion (OR 0.92, 95% CI 0.70 to 1.22; 29 studies, 1777 participants, very low-certainty evidence). The evidence on which these results are based was also very limited, highly heterogeneous, and potentially biased. Only one study, involving 40 participants, was available for the antidepressant comparison. This study found no differences between treatment with n-3PUFAs and treatment with antidepressants in depressive symptomology (mean difference (MD) -0.70, 95% CI -5.88 to 4.48), rates of response to treatment (OR 1.23, 95% CI 0.35 to 4.31), or trial non-completion (OR 1.00, 95% CI 0.21 to 4.71). Confidence intervals are however very wide in all analyses, and do not rule out important beneficial or detrimental effects of n-3PUFAs compared to antidepressants. Adverse events were not reported in a manner suitable for analysis, and rates of depression remission and quality of life were not reported. AUTHORS' CONCLUSIONS: At present, we do not have sufficient high-certainty evidence to determine the effects of n-3PUFAs as a treatment for MDD. Our primary analyses may suggest a small-to-modest, non-clinically beneficial effect of n-3PUFAs on depressive symptomology compared to placebo; however the estimate is imprecise, and we judged the certainty of the evidence on which this result is based to be low to very low. Our data may also suggest similar rates of adverse events and trial non-completion in n-3PUFA and placebo groups, but again our estimates are very imprecise. Effects of n-3PUFAs compared to antidepressants are very imprecise and uncertain. More complete evidence is required for both the potential positive and negative effects of n-3PUFAs for MDD.

Effects of maternal, gestational, and perinatal variables on neonatal line width observed in a modern UK birth cohort.

OBJECTIVES: The objective of this study was to explore potential relationships between neonatal line (NNL) width and early life history variables such as maternal health, gestation, the birth process, and perinatal health. MATERIALS AND METHODS: Histological thin sections of deciduous canines were studied from 71 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). The width of the NNL was measured in three locations on the tooth crown using spatial mapping techniques (ArcGIS) from digital images from an Olympus VS-120 microscope. Life history variables were collected prospectively through a combination of clinical observations and questionnaires. RESULTS: Infants born late term or post term had narrower neonatal lines than those born prematurely or at full term. Infants born in Autumn (September to November) had narrower NNLs than those born at other times of year. NNLs in infants born to mothers with hypertension were wider than those without. Infants resuscitated at birth or born to obese mothers had narrower NNLs than those that were not. There was no association between NNL width and either the type or duration of delivery. DISCUSSION: The NNL in enamel is an irregular accentuated line, but the factors underlying its formation and width remain unclear. In contrast to some previous studies, we found no association between wider NNLs and long or difficult births. Instead, we found that the width of the neonatal line NNL varied in relation to parameters that reflected the prenatal environment and length of gestation.

Investigating the effects of lycopene and green tea on the metabolome of men at risk of prostate cancer: The ProDiet randomised controlled trial.

Lycopene and green tea consumption have been observationally associated with reduced prostate cancer risk, but the underlying mechanisms have not been fully elucidated. We investigated the effect of factorial randomisation to a 6-month lycopene and green tea dietary advice or supplementation intervention on 159 serum metabolite measures in 128 men with raised PSA levels (but prostate cancer-free), analysed by intention-to-treat. The causal effects of metabolites modified by the intervention on prostate cancer risk were then assessed by Mendelian randomisation, using summary statistics from 44,825 prostate cancer cases and 27,904 controls. The systemic effects of lycopene and green tea supplementation on serum metabolic profile were comparable to the effects of the respective dietary advice interventions (R2 = 0.65 and 0.76 for lycopene and green tea respectively). Metabolites which were altered in response to lycopene supplementation were acetate [ß (standard deviation difference vs. placebo): 0.69; 95% CI = 0.24, 1.15; p = 0.003], valine (ß: -0.62; -1.03, -0.02; p = 0.004), pyruvate (ß: -0.56; -0.95, -0.16; p = 0.006) and docosahexaenoic acid (ß: -0.50; -085, -0.14; p = 0.006). Valine and diacylglycerol were lower in the lycopene dietary advice group (ß: -0.65; -1.04, -0.26; p = 0.001 and ß: -0.59; -1.01, -0.18; p = 0.006). A genetically instrumented SD increase in pyruvate increased the odds of prostate cancer by 1.29 (1.03, 1.62; p = 0.027). An intervention to increase lycopene intake altered the serum metabolome of men at risk of prostate cancer. Lycopene lowered levels of pyruvate, which our Mendelian randomisation analysis suggests may be causally related to reduced prostate cancer risk.

Early enteral nutrition within 24 hours of lower gastrointestinal surgery versus later commencement for length of hospital stay and postoperative complications.

BACKGROUND: This is an update of the review last published in 2011. It focuses on early postoperative enteral nutrition after lower gastrointestinal surgery. Traditional management consisted of 'nil by mouth', where patients receive fluids followed by solids after bowel function has returned. Although several trials have reported lower incidence of infectious complications and faster wound healing upon early feeding, other trials have shown no effect. The immediate advantage of energy intake (carbohydrates, protein or fat) could enhance recovery with fewer complications, and this warrants a systematic evaluation. OBJECTIVES: To evaluate whether early commencement of postoperative enteral nutrition (within 24 hours), oral intake and any kind of tube feeding (gastric, duodenal or jejunal), compared with traditional management (delayed nutritional supply) is associated with a shorter length of hospital stay (LoS), fewer complications, mortality and adverse events in patients undergoing lower gastrointestinal surgery (distal to the ligament of Treitz). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library 2017, issue 10), Ovid MEDLINE (1950 to 15 November 2017), Ovid Embase (1974 to 15 November 2017). We also searched for ongoing trials in ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform (15 November 2017). We handsearched reference lists of identified studies and previous systematic reviews. SELECTION CRITERIA: We included randomised controlled trials (RCT) comparing early commencement of enteral nutrition (within 24 hours) with no feeding in adult participants undergoing lower gastrointestinal surgery. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study quality using the Cochrane 'Risk of bias' tool tailored to this review and extracted data. Data analyses were conducted according to the Cochrane recommendations.We rated the quality of evidence according to GRADE.Primary outcomes were LoS and postoperative complications (wound infections, intraabdominal abscesses, anastomotic dehiscence, pneumonia).Secondary outcomes were: mortality, adverse events (nausea, vomiting), and quality of life (QoL).LoS was estimated using mean difference (MD (presented as mean +/- SD). For other outcomes we estimated the common risk ratio (RR) and calculated the associated 95% confidence intervals. For analysis, we used an inverse-variance random-effects model for the primary outcome (LoS) and Mantel-Haenszel random-effects models for the secondary outcomes. We also performed Trial Sequential Analyses (TSA). MAIN RESULTS: We identified 17 RCTs with 1437 participants undergoing lower gastrointestinal surgery. Most studies were at high or unclear risk of bias in two or more domains. Six studies were judged as having low risk of selection bias for random sequence generation and insufficient details were provided for judgement on allocation concealment in all 17 studies. With regards to performance and deception bias; 14 studies reported no attempt to blind participants and blinding of personnel was not discussed either. Only one study was judged as low risk of bias for blinding of outcome assessor. With regards to incomplete outcome data, three studies were judged to be at high risk because they had more than 10% difference in missing data between groups. For selective reporting, nine studies were judged as unclear as protocols were not provided and eight studies had issues with either missing data or incomplete reporting of results.LOS was reported in 16 studies (1346 participants). The mean LoS ranged from four days to 16 days in the early feeding groups and from 6.6 days to 23.5 days in the control groups. Mean difference (MD) in LoS was 1.95 (95% CI, -2.99 to -0.91, P < 0.001) days shorter in the early feeding group. However, there was substantial heterogeneity between included studies (I2 = 81, %, Chi2 = 78.98, P < 0.00001), thus the overall quality of evidence for LoS is low. These results were confirmed by the TSA showing that the cumulative Z-curve crossed the trial sequential monitoring boundary for benefit.We found no differences in the incidence of postoperative complications: wound infection (12 studies, 1181 participants, RR 0.99, 95%CI 0.64 to 1.52, very low-quality evidence), intraabdominal abscesses (6 studies, 554 participants, RR 1.00, 95%CI 0.26 to 3.80, low-quality evidence), anastomotic leakage/dehiscence (13 studies, 1232 participants, RR 0.78, 95%CI 0.38 to 1.61, low-quality evidence; number needed to treat for an additional beneficial outcome (NNTB) = 100), and pneumonia (10 studies, 954 participants, RR 0.88, 95%CI 0.32 to 2.42, low-quality evidence; NNTB = 333).Mortality was reported in 12 studies (1179 participants), and showed no between-group differences (RR = 0.56, 95%CI, 0.21 to 1.52, P = 0.26, I2 = 0%, Chi2 = 3.08, P = 0.96, low-quality evidence). The most commonly reported cause of death was anastomotic leakage, sepsis and acute myocardial infarction.Seven studies (613 participants) reported vomiting (RR 1.23, 95%CI, 0.96 to 1.58, P = 0.10, I2 = 0%, Chi2 = 4.98, P = 0.55, low-quality evidence; number needed to treat for an additional harmful outcome (NNTH) = 19), and two studies (118 participants) reported nausea (RR 0.95, 0.71 to 1.26, low-quality evidence). Four studies reported combined nausea and vomiting (RR 0.94, 95%CI 0.51 to 1.74, very low-quality evidence). One study reported QoL assessment; the scores did not differ between groups at 30 days after discharge on either QoL scale EORTC QLQ-C30 or EORTC QlQ-OV28 (very low-quality evidence). AUTHORS' CONCLUSIONS: This review suggests that early enteral feeding may lead to a reduced postoperative LoS, however cautious interpretation must be taken due to substantial heterogeneity and low-quality evidence. For all other outcomes (postoperative complications, mortality, adverse events, and QoL) the findings are inconclusive, and further trials are justified to enhance the understanding of early feeding for these. In this updated review, only a few additional studies have been included, and these were small and of poor quality.To improve the evidence, future trials should address quality issues and focus on clearly defining and measuring postoperative complications to allow for better comparison between studies. However due to the introduction of fast track protocols which already include an early feeding component, future trials may be challenging. A more feasible trial may be to investigate the effect of differing postoperative energy intake regimens on relevant outcomes.

Depressive symptoms in relation to overall survival in people with head and neck cancer: A longitudinal cohort study.

OBJECTIVE: The objective of the study is to investigate the relation between pretreatment depressive symptoms (DS) and the course of DS during the first year after cancer diagnosis, and overall survival among people with head and neck cancer (HNC). METHODS: Data from the Head and Neck 5000 prospective clinical cohort study were used. Depressive symptoms were measured using the Hospital Anxiety and Depression Scale (HADS) pretreatment, at 4 and 12-month follow-up. Also, socio-demographic, clinical, lifestyle, and mortality data were collected. The association between before start of treatment DS (HADS-depression > 7) and course (never DS, recovered from DS, or persistent/recurrent/late DS at 12-month follow-up) and survival was investigated using Cox regression. Unadjusted and adjusted analyses were performed. RESULTS: In total, 384 of the 2144 persons (18%) reported pretreatment DS. Regarding DS course, 63% never had DS, 16% recovered, and 20% had persistent/recurrent/late DS. People with pretreatment DS had a higher risk of earlier death than people without DS (hazard ratio (HR) = 1.65; 95% confidence interval (CI) 1.33-2.05), but this decreased after correcting for socio-demographic, clinical, and lifestyle-related factors (HR = 1.21; 95% CI 0.97-1.52). Regarding the course of DS, people with persistent/recurrent/late DS had a higher risk of earlier death (HR = 2.04; 95% CI 1.36-3.05), while people who recovered had a comparable risk (HR = 1.12; 95% CI 0.66-1.90) as the reference group who never experienced DS. After correcting for socio-demographic and clinical factors, people with persistent/recurrent/late DS still had a higher risk of earlier death (HR = 1.66; 95% CI 1.09-2.53). CONCLUSIONS: Pretreatment DS and persistent/recurrent/late DS were associated with worse survival among people with HNC.

Early enteral nutrition within 24 hours of lower gastrointestinal surgery versus later commencement for length of hospital stay and postoperative complications.

BACKGROUND: This is an update of the review last published in 2011. It focuses on early postoperative enteral nutrition after lower gastrointestinal surgery. Traditional management consisted of 'nil by mouth', where patients receive fluids followed by solids after bowel function has returned. Although several trials have reported lower incidence of infectious complications and faster wound healing upon early feeding, other trials have shown no effect. The immediate advantage of energy intake (carbohydrates, protein or fat) could enhance recovery with fewer complications, and this warrants a systematic evaluation. OBJECTIVES: To evaluate whether early commencement of postoperative enteral nutrition (within 24 hours), oral intake and any kind of tube feeding (gastric, duodenal or jejunal), compared with traditional management (delayed nutritional supply) is associated with a shorter length of hospital stay (LoS), fewer complications, mortality and adverse events in patients undergoing lower gastrointestinal surgery (distal to the ligament of Treitz). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library 2017, issue 10), Ovid MEDLINE (1950 to 15 November 2017), Ovid Embase (1974 to 15 November 2017). We also searched for ongoing trials in ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform (15 November 2017). We handsearched reference lists of identified studies and previous systematic reviews. SELECTION CRITERIA: We included randomised controlled trials (RCT) comparing early commencement of enteral nutrition (within 24 hours) with no feeding in adult participants undergoing lower gastrointestinal surgery. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study quality using the Cochrane 'Risk of bias' tool tailored to this review and extracted data. Data analyses were conducted according to the Cochrane recommendations.We rated the quality of evidence according to GRADE.Primary outcomes were LoS and postoperative complications (wound infections, intraabdominal abscesses, anastomotic dehiscence, pneumonia).Secondary outcomes were: mortality, adverse events (nausea, vomiting), and quality of life (QoL).LoS was estimated using mean difference (MD (presented as mean +/- SD). For other outcomes we estimated the common risk ratio (RR) and calculated the associated 95% confidence intervals. For analysis, we used an inverse-variance random-effects model for the primary outcome (LoS) and Mantel-Haenszel random-effects models for the secondary outcomes. We also performed Trial Sequential Analyses (TSA). MAIN RESULTS: We identified 17 RCTs with 1437 participants undergoing lower gastrointestinal surgery. Most studies were at high or unclear risk of bias in two or more domains. Six studies were judged as having low risk of selection bias for random sequence generation and insufficient details were provided for judgement on allocation concealment in all 17 studies. With regards to performance and deception bias; 14 studies reported no attempt to blind participants and blinding of personnel was not discussed either. Only one study was judged as low risk of bias for blinding of outcome assessor. With regards to incomplete outcome data, three studies were judged to be at high risk because they had more than 10% difference in missing data between groups. For selective reporting, nine studies were judged as unclear as protocols were not provided and eight studies had issues with either missing data or incomplete reporting of results.LOS was reported in 16 studies (1346 participants). The mean LoS ranged from four days to 16 days in the early feeding groups and from 6.6 days to 23.5 days in the control groups. Mean difference (MD) in LoS was 1.95 (95% CI, -2.99 to -0.91, P < 0.001) days shorter in the early feeding group. However, there was substantial heterogeneity between included studies (I2 = 81, %, Chi2 = 78.98, P < 0.00001), thus the overall quality of evidence for LoS is low. These results were confirmed by the TSA showing that the cumulative Z-curve crossed the trial sequential monitoring boundary for benefit.We found no differences in the incidence of postoperative complications: wound infection (12 studies, 1181 participants, RR 0.99, 95%CI 0.64 to 1.52, very low-quality evidence), intraabdominal abscesses (6 studies, 554 participants, RR 1.00, 95%CI 0.26 to 3.80, low-quality evidence), anastomotic leakage/dehiscence (13 studies, 1232 participants, RR 0.78, 95%CI 0.38 to 1.61, low-quality evidence; number needed to treat for an additional beneficial outcome (NNTB) = 100), and pneumonia (10 studies, 954 participants, RR 0.88, 95%CI 0.32 to 2.42, low-quality evidence; NNTB = 333).Mortality was reported in 12 studies (1179 participants), and showed no between-group differences (RR = 0.56, 95%CI, 0.21 to 1.52, P = 0.26, I2 = 0%, Chi2 = 3.08, P = 0.96, low-quality evidence). The most commonly reported cause of death was anastomotic leakage, sepsis and acute myocardial infarction.Seven studies (613 participants) reported vomiting (RR 1.23, 95%CI, 0.96 to 1.58, P = 0.10, I2 = 0%, Chi2 = 4.98, P = 0.55, low-quality evidence; number needed to treat for an additional harmful outcome (NNTH) = 19), and two studies (118 participants) reported nausea (RR 0.95, 0.71 to 1.26, low-quality evidence). Four studies reported combined nausea and vomiting (RR 0.94, 95%CI 0.51 to 1.74, very low-quality evidence). One study reported QoL assessment; the scores did not differ between groups at 30 days after discharge on either QoL scale EORTC QLQ-C30 or EORTC QlQ-OV28 (very low-quality evidence). AUTHORS' CONCLUSIONS: This review suggests that early enteral feeding may lead to a reduced postoperative LoS, however cautious interpretation must be taken due to substantial heterogeneity and low-quality evidence. For all other outcomes (postoperative complications, mortality, adverse events, and QoL) the findings are inconclusive, and further trials are justified to enhance the understanding of early feeding for these. In this updated review, only a few additional studies have been included, and these were small and of poor quality.To improve the evidence, future trials should address quality issues and focus on clearly defining and measuring postoperative complications to allow for better comparison between studies. However due to the introduction of fast track protocols which already include an early feeding component, future trials may be challenging. A more feasible trial may be to investigate the effect of differing postoperative energy intake regimens on relevant outcomes.

Closing the Loop on Centralization of Cleft Care in the United Kingdom.

OBJECTIVE: We highlight a major study that investigated the impact of reconfigured cleft care in the United Kingdom some 15 years after centralization. We argue that centralization as an intervention has a major impact on outcomes. SETTING: Audit clinics held in Cleft Centers in the United Kingdom. PATIENTS, PARTICIPANTS: Five-year-olds born between April 1, 2005, and March 31, 2007, with nonsyndromic unilateral cleft lip and palate. INTERVENTIONS: Centralization of cleft care. MAIN OUTCOME MEASURE(S): We collected routine clinical measures (speech recordings, hearing, photographs, models, oral health, psychosocial factors) in a very similar way to a previous survey. RESULTS: We identified 359 eligible children and recruited 268 (74.7%) to the study. Overall, their outcomes were better post-centralization. There have been marked improvements in dentoalveolar arch relationships and in speech whereas the prevalence of dental caries and hearing loss are unchanged. CONCLUSIONS: Centralized cleft care has changed UK outcomes considerably and there is no argument for returning to a dispersed model of treatment.

Omega-3 fatty acids for depression in adults.

BACKGROUND: Major depressive disorder (MDD) is highly debilitating, difficult to treat, has a high rate of recurrence, and negatively impacts the individual and society as a whole. One emerging potential treatment for MDD is n-3 polyunsaturated fatty acids (n-3PUFAs), also known as omega-3 oils, naturally found in fatty fish, some other seafood, and some nuts and seeds. Various lines of evidence suggest a role for n-3PUFAs in MDD, but the evidence is far from conclusive. Reviews and meta-analyses clearly demonstrate heterogeneity between studies. Investigations of heterogeneity suggest differential effects of n-3PUFAs, depending on severity of depressive symptoms, where no effects of n-3PUFAs are found in studies of individuals with mild depressive symptomology, but possible benefit may be suggested in studies of individuals with more severe depressive symptomology. OBJECTIVES: To assess the effects of n-3 polyunsaturated fatty acids (also known as omega-3 fatty acids) versus a comparator (e.g. placebo, anti-depressant treatment, standard care, no treatment, wait-list control) for major depressive disorder (MDD) in adults.  SEARCH METHODS: We searched the Cochrane Depression, Anxiety and Neurosis Review Group's Specialised Registers (CCDANCTR) and International Trial Registries over all years to May 2015. We searched the database CINAHL over all years of records to September 2013. SELECTION CRITERIA: We included studies in the review if they: were a randomised controlled trial; provided n-3PUFAs as an intervention; used a comparator; measured depressive symptomology as an outcome; and were conducted in adults with MDD. Primary outcomes were depressive symptomology (continuous data collected using a validated rating scale) and adverse events. Secondary outcomes were depressive symptomology (dichotomous data on remission and response), quality of life, and failure to complete studies. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by Cochrane. MAIN RESULTS: We found 26 relevant studies: 25 studies involving a total of 1438 participants investigated the impact of n-3PUFA supplementation compared to placebo, and one study involving 40 participants investigated the impact of n-3PUFA supplementation compared to antidepressant treatment.For the placebo comparison, n-3PUFA supplementation results in a small to modest benefit for depressive symptomology, compared to placebo: standardised mean difference (SMD) -0.32 (95% confidence interval (CI) -0.12 to -0.52; 25 studies, 1373 participants, very low quality evidence), but this effect is unlikely to be clinically meaningful (an SMD of 0.32 represents a difference between groups in scores on the HDRS (17-item) of approximately 2.2 points (95% CI 0.8 to 3.6)). The confidence intervals include both a possible clinically important effect and a possible negligible effect, and there is considerable heterogeneity between the studies. Although the numbers of individuals experiencing adverse events were similar in intervention and placebo groups (odds ratio (OR) 1.24, 95% CI 0.95 to 1.62; 19 studies, 1207 participants; very low-quality evidence), the confidence intervals include a significant increase in adverse events with n-3PUFAs as well as a small possible decrease. Rates of remission and response, quality of life, and rates of failure to complete studies were also similar between groups, but confidence intervals are again wide.The evidence on which these results are based is very limited. All studies contributing to our analyses were of direct relevance to our research question, but we rated the quality of the evidence for all outcomes as low to very low. The number of studies and number of participants contributing to all analyses were low, and the majority of studies were small and judged to be at high risk of bias on several measures. Our analyses were also likely to be highly influenced by three large trials. Although we judge these trials to be at low risk of bias, they contribute 26.9% to 82% of data. Our effect size estimates are also imprecise. Funnel plot asymmetry and sensitivity analyses (using fixed-effect models, and only studies judged to be at low risk of selection bias, performance bias or attrition bias) also suggest a likely bias towards a positive finding for n-3PUFAs. There was substantial heterogeneity in analyses of our primary outcome of depressive symptomology. This heterogeneity was not explained by the presence or absence of comorbidities or by the presence or absence of adjunctive therapy.Only one study was available for the antidepressant comparison, involving 40 participants. This study found no differences between treatment with n-3PUFAs and treatment with antidepressants in depressive symptomology (mean difference (MD) -0.70 (95% CI -5.88 to 4.48)), rates of response to treatment or failure to complete. Adverse events were not reported in a manner suitable for analysis, and rates of depression remission and quality of life were not reported. AUTHORS' CONCLUSIONS: At present, we do not have sufficient high quality evidence to determine the effects of n-3PUFAs as a treatment for MDD. Our primary analyses suggest a small-to-modest, non-clinically beneficial effect of n-3PUFAs on depressive symptomology compared to placebo; however the estimate is imprecise, and we judged the quality of the evidence on which this result is based to be low/very low. Sensitivity analyses, funnel plot inspection and comparison of our results with those of large well-conducted trials also suggest that this effect estimate is likely to be biased towards a positive finding for n-3PUFAs, and that the true effect is likely to be smaller. Our data, however, also suggest similar rates of adverse events and numbers failing to complete trials in n-3PUFA and placebo groups, but again our estimates are very imprecise. The one study that directly compares n-3PUFAs and antidepressants in our review finds comparable benefit. More evidence, and more complete evidence, are required, particularly regarding both the potential positive and negative effects of n-3PUFAs for MDD.

Chewing gum for postoperative recovery of gastrointestinal function.

BACKGROUND: Ileus commonly occurs after abdominal surgery, and is associated with complications and increased length of hospital stay (LOHS). Onset of ileus is considered to be multifactorial, and a variety of preventative methods have been investigated. Chewing gum (CG) is hypothesised to reduce postoperative ileus by stimulating early recovery of gastrointestinal (GI) function, through cephalo-vagal stimulation. There is no comprehensive review of this intervention in abdominal surgery. OBJECTIVES: To examine whether chewing gum after surgery hastens the return of gastrointestinal function. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (via Ovid), MEDLINE (via PubMed), EMBASE (via Ovid), CINAHL (via EBSCO) and ISI Web of Science (June 2014). We hand-searched reference lists of identified studies and previous reviews and systematic reviews, and contacted CG companies to ask for information on any studies using their products. We identified proposed and ongoing studies from clinicaltrials.gov, World Health Organization (WHO) International Clinical Trials Registry Platform and metaRegister of Controlled Trials. SELECTION CRITERIA: We included completed randomised controlled trials (RCTs) that used postoperative CG as an intervention compared to a control group. DATA COLLECTION AND ANALYSIS: Two authors independently collected data and assessed study quality using an adapted Cochrane risk of bias (ROB) tool, and resolved disagreements by discussion. We assessed overall quality of evidence for each outcome using Grades of Recommendation, Assessment, Development and Evaluation (GRADE). Studies were split into subgroups: colorectal surgery (CRS), caesarean section (CS) and other surgery (OS). We assessed the effect of CG on time to first flatus (TFF), time to bowel movement (TBM), LOHS and time to bowel sounds (TBS) through meta-analyses using a random-effects model. We investigated the influence of study quality, reviewers' methodological estimations and use of Enhanced Recovery After Surgery (ERAS) programmes using sensitivity analyses. We used meta-regression to explore if surgical site or ROB scores predicted the extent of the effect estimate of the intervention on continuous outcomes. We reported frequency of complications, and descriptions of tolerability of gum and cost. MAIN RESULTS: We identified 81 studies that recruited 9072 participants for inclusion in our review. We categorised many studies at high or unclear risk of the bias' assessed. There was statistical evidence that use of CG reduced TFF [overall reduction of 10.4 hours (95% CI: -11.9, -8.9): 12.5 hours (95% CI: -17.2, -7.8) in CRS, 7.9 hours (95% CI: -10.0, -5.8) in CS, 10.6 hours (95% CI: -12.7, -8.5) in OS]. There was also statistical evidence that use of CG reduced TBM [overall reduction of 12.7 hours (95% CI: -14.5, -10.9): 18.1 hours (95% CI: -25.3, -10.9) in CRS, 9.1 hours (95% CI: -11.4, -6.7) in CS, 12.3 hours (95% CI: -14.9, -9.7) in OS]. There was statistical evidence that use of CG slightly reduced LOHS [overall reduction of 0.7 days (95% CI: -0.8, -0.5): 1.0 days in CRS (95% CI: -1.6, -0.4), 0.2 days (95% CI: -0.3, -0.1) in CS, 0.8 days (95% CI: -1.1, -0.5) in OS]. There was statistical evidence that use of CG slightly reduced TBS [overall reduction of 5.0 hours (95% CI: -6.4, -3.7): 3.21 hours (95% CI: -7.0, 0.6) in CRS, 4.4 hours (95% CI: -5.9, -2.8) in CS, 6.3 hours (95% CI: -8.7, -3.8) in OS]. Effect sizes were largest in CRS and smallest in CS. There was statistical evidence of heterogeneity in all analyses other than TBS in CRS.There was little difference in mortality, infection risk and readmission rate between the groups. Some studies reported reduced nausea and vomiting and other complications in the intervention group. CG was generally well-tolerated by participants. There was little difference in cost between the groups in the two studies reporting this outcome.Sensitivity analyses by quality of studies and robustness of review estimates revealed no clinically important differences in effect estimates. Sensitivity analysis of ERAS studies showed a smaller effect size on TFF, larger effect size on TBM, and no difference between groups for LOHS.Meta-regression analyses indicated that surgical site is associated with the extent of the effect size on LOHS (all surgical subgroups), and TFF and TBM (CS and CRS subgroups only). There was no evidence that ROB score predicted the extent of the effect size on any outcome. Neither variable explained the identified heterogeneity between studies. AUTHORS' CONCLUSIONS: This review identified some evidence for the benefit of postoperative CG in improving recovery of GI function. However, the research to date has primarily focussed on CS and CRS, and largely consisted of small, poor quality trials. Many components of the ERAS programme also target ileus, therefore the benefit of CG alongside ERAS may be reduced, as we observed in this review. Therefore larger, better quality RCTS in an ERAS setting in wider surgical disciplines would be needed to improve the evidence base for use of CG after surgery.

Effects of BMI, fat mass, and lean mass on asthma in childhood: a Mendelian randomization study.

BACKGROUND: Observational studies have reported associations between body mass index (BMI) and asthma, but confounding and reverse causality remain plausible explanations. We aim to investigate evidence for a causal effect of BMI on asthma using a Mendelian randomization approach. METHODS AND FINDINGS: We used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ y in the Avon Longitudinal Study of Parents and Children (ALSPAC). A weighted allele score based on 32 independent BMI-related single nucleotide polymorphisms (SNPs) was derived from external data, and associations with BMI, fat mass, lean mass, and asthma were estimated. We derived instrumental variable (IV) estimates of causal risk ratios (RRs). 4,835 children had available data on BMI-associated SNPs, asthma, and BMI. The weighted allele score was strongly associated with BMI, fat mass, and lean mass (all p-values<0.001) and with childhood asthma (RR 2.56, 95% CI 1.38-4.76 per unit score, p = 0.003). The estimated causal RR for the effect of BMI on asthma was 1.55 (95% CI 1.16-2.07) per kg/m2, p = 0.003. This effect appeared stronger for non-atopic (1.90, 95% CI 1.19-3.03) than for atopic asthma (1.37, 95% CI 0.89-2.11) though there was little evidence of heterogeneity (p = 0.31). The estimated causal RRs for the effects of fat mass and lean mass on asthma were 1.41 (95% CI 1.11-1.79) per 0.5 kg and 2.25 (95% CI 1.23-4.11) per kg, respectively. The possibility of genetic pleiotropy could not be discounted completely; however, additional IV analyses using FTO variant rs1558902 and the other BMI-related SNPs separately provided similar causal effects with wider confidence intervals. Loss of follow-up was unlikely to bias the estimated effects. CONCLUSIONS: Higher BMI increases the risk of asthma in mid-childhood. Higher BMI may have contributed to the increase in asthma risk toward the end of the 20th century. Please see later in the article for the Editors' Summary.

Skin pigmentation, sun exposure and vitamin D levels in children of the Avon Longitudinal Study of Parents and Children.

BACKGROUND: It has been hypothesised that light skin pigmentation has arisen to ensure adequate levels of vitamin D as human populations moved out of Africa and into higher latitudes. Vitamin D, which is primarily obtained through exposure to sunlight (specifically ultraviolet radiation B (UVR-B)), has been inversely associated with several complex diseases. Greater sun exposure, on the other hand, is a well-known cause of skin cancer. The potential of UVR to be beneficial for some health outcomes but detrimental for others has prompted a public health debate on how to balance the positive and negative consequences of sun exposure. In this study we aimed to determine the validity of the evolutionary hypothesis linking lighter skin with higher vitamin D concentrations in a European population. Additionally, we aimed to examine the influence of pigmentation on personal behaviour towards sunlight exposure and the effects of this behaviour on vitamin D. METHODS: We combined genetic variants strongly associated with skin colour, tanning or freckling to create genetic scores for each of these phenotypes. We examined the association of the scores with pigmentary traits, sun exposure and serum 25-hydroxyvitamin D (25(OH)D) levels among children of the Avon Longitudinal Study of Parents and Children (ALSPAC, N = 661 to 5649). RESULTS: We found that fairer-skinned children, i.e. those with higher pigmentation score values, had higher levels of 25(OH)D (0.6 nmol/l; 95% CI 0.2, 1.0; per unit increase in skin colour score; N = 5649). These children also used more protection against the damaging effects of UVR. CONCLUSIONS: In this population taking protective measures against sunburn and skin cancer does not seem to remove the positive effect that having a less pigmented skin has on vitamin D production. Our findings require further replication as skin pigmentation showed only a small effect on circulating 25(OH)D.

Evaluating the effect of metabolic traits on oral and oropharyngeal cancer risk using Mendelian randomization.

A recent World Health Organization report states that at least 40% of all cancer cases may be preventable, with smoking, alcohol consumption, and obesity identified as three of the most important modifiable lifestyle factors. Given the significant decline in smoking rates, particularly within developed countries, other potentially modifiable risk factors for head and neck cancer warrant investigation. Obesity and related metabolic disorders such as type 2 diabetes (T2D) and hypertension have been associated with head and neck cancer risk in multiple observational studies. However, adiposity has also been correlated with smoking, with bias, confounding or reverse causality possibly explaining these findings. To overcome the challenges of observational studies, we conducted two-sample Mendelian randomization (inverse variance weighted [IVW] method) using genetic variants which were robustly associated with adiposity, glycaemic and blood pressure traits in genome-wide association studies (GWAS). Outcome data were taken from the largest available GWAS of 6034 oral and oropharyngeal cases, with 6585 controls. We found limited evidence of a causal effect of genetically proxied body mass index (BMI; OR IVW = 0.89, 95% CI 0.72-1.09, p = 0.26 per 1 standard deviation in BMI [4.81kg/m2]) on oral and oropharyngeal cancer risk. Similarly, there was limited evidence for related traits including T2D and hypertension. Small effects cannot be excluded given the lack of power to detect them in currently available GWAS.

Maternal and offspring fasting glucose and type 2 diabetes-associated genetic variants and cognitive function at age 8: a Mendelian randomization study in the Avon Longitudinal Study of Parents and Children.

BACKGROUND: In observational epidemiological studies type 2 diabetes (T2D) and both low and high plasma concentrations of fasting glucose have been found to be associated with lower cognitive performance. These associations could be explained by confounding. METHODS: In this study we looked at the association between genetic variants, known to be robustly associated with fasting glucose and T2D risk, in the mother and her offspring to determine whether there is likely to be a causal link between early life exposure to glucose and child's intelligence quotient (IQ) scores in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. We generated a fasting glucose (FGGRS) and a T2D (T2DGRS) genetic risk score and used them in a Mendelian randomization approach. RESULTS: We found a strong correlation between the FGGRS and fasting glucose plasma measurements that were available for a subset of children, but no association of either the maternal or the offspring FGGRS with child's IQ was observed. In contrast, the maternal T2DGRS was positively associated with offspring IQ. CONCLUSIONS: Maternal and offspring genetic variants which are associated with glucose levels are not associated with offspring IQ, suggesting that there is unlikely to be a causal link between glucose exposure in utero and IQ in childhood. Further exploration in even larger cohorts is required to exclude the possibility that our null findings were due to a lack of statistical power.

Cross-sectional association between smoking depictions in films and adolescent tobacco use nested in a British cohort study.

OBJECTIVE: To assess associations between exposure to smoking depictions in films and adolescent tobacco use in a British population cohort. METHODS: Data on exposure to smoking in films and smoking behaviour were collected from 5166 15-year-old adolescents in the UK. Main outcome measures were smoking initiation (ever tried a cigarette) and current smoking status. Social, family and behavioural factors were adjusted for, together with alcohol use and peer smoking as potential mediators. Data from all existing cross-sectional studies examining the effects of exposure to smoking in films were summarised in a meta-analysis. RESULTS: Higher exposure to smoking in films was associated with a dose-response increase in the risk of smoking initiation even after adjusting for confounders. Adolescents in the highest exposure quartile were 1.73 (95% CI 1.55 to 1.93) times (RR) more likely to initiate smoking than those in the lowest quartile. They were more likely to report current smoking after adjusting for social and familial factors (RR 1.47 (95% CI 1.07 to 2.02)), but the association attenuated after including behavioural factors (RR 1.34 (95% CI 0.95 to 1.87)). The meta-analysis shows that, after aggregation of all relevant data, viewing smoking in films increases the risk of smoking onset by over 100% (combined RR 2.13 (95% CI 1.76 to 2.57)) and the risk of current or established smoking behaviour by 68% (combined RR 1.68 (95% CI 0.40 to 2.01)). CONCLUSIONS: This study provides evidence that adolescents in the UK and elsewhere who are exposed to smoking depictions in films are more likely to initiate smoking. Given the association between smoking and poor health outcomes, these data justify a review of film ratings.

Milk intakes are not associated with percent body fat in children from ages 10 to 13 years.

Epidemiologic studies report conflicting results for the relationship between milk intake and adiposity in children. We examined prospective and cross-sectional associations between milk intake and percent body fat among 2245 children from the Avon Longitudinal Study of Parents and Children. Cross-sectional analyses were performed at age 13 y between total, full-fat, and reduced-fat milk intake assessed using 3-d dietary records and body fat from DXA. Prospective analyses were conducted between milk intakes at age 10 y and body fat at 11 and 13 y. Models were adjusted for age, sex, height, physical activity, pubertal status, maternal BMI, maternal education, and intakes of total fat, sugar-sweetened beverages, 100% fruit juice, and ready-to-eat cereals; baseline BMI was added to prospective models. Subset analyses were performed for those with plausible dietary intakes. Mean milk consumption at 10 and 13 y was (mean ± SD) 0.90 ± 0.73 and 0.85 ± 0.78 servings/d [1 serving = 8 oz of milk (244 g of plain and 250 g flavored milk)], respectively. Cross-sectional results indicated an inverse association between full-fat milk intake and body fat [ß = -0.47 (95% CI = -0.76, -0.19); P = 0.001]. Milk intake at age 10 y was inversely associated with body fat at 11 y [ß = -0.16 g/d (95%CI = -0.28, -0.04); P = 0.01], but not among those with plausible dietary intakes, suggesting that this association was influenced by dietary measurement errors. Milk intake was not associated with body fat at age 13 y after adjustment. Although our prospective results corroborate other findings of a null associations between milk intake and adiposity, our inconsistent findings across analyses suggest further investigation is needed to clarify the relation, and accounting for dietary reporting errors is an important consideration.

Incidence of obesity during childhood and adolescence in a large contemporary cohort.

BACKGROUND AND AIMS: Timing of obesity development during childhood and adolescence is unclear, hindering preventive strategies. The primary aim of the present study was to quantify the incidence of overweight and obesity throughout childhood and adolescence in a large contemporary cohort of English children (the Avon Longitudinal Study of Parents and Children, ALSPAC; children born 1991-1992). A secondary aim was to examine the persistence of overweight and obesity. METHODS: Longitudinal data on weight and height were collected annually from age 7-15 years in the entire ALSPAC cohort (n=4283), and from 3 to 15 years in a randomly selected subsample of the cohort (n=549; 'Children in Focus' CiF). Incidence of overweight and obesity (BMI (Body mass index) at or above the 85th and 95th centiles relative to U.K. reference data) was calculated. Risk ratios (RR) for overweight and obesity at 15 years based on weight status at 3, 7, and 11 years were also calculated. RESULTS: In the entire cohort, four-year incidence of obesity was higher between ages 7 and 11 years than between 11 and 15 years (5.0% vs. 1.4% respectively). In the CiF sub-sample, four-year incidence of obesity was also highest during mid-childhood (age 7-11years, 6.7%), slightly lower during early childhood (3-7 years, 5.1%) and lowest during adolescence (11-15 years 1.6%). Overweight and obesity at all ages had a strong tendency to persist to age 15 years as indicated by risk ratios (95% CI (Confidence interval)) for overweight and obesity at 15 years from overweight and obesity (relative to healthy weight status) at 3 years (2.4, 1.8-3.1), 7 years (4.6, 3.6-5.8), and 11 years (9.3, 6.5-13.2). CONCLUSION: Mid-late childhood (around age 7-11 years) may merit greater attention in future obesity prevention interventions.

Physical activity during pregnancy in a prospective cohort of British women: results from the Avon longitudinal study of parents and children.

We sought to examine the levels, types, and changes of physical activity and their correlates among pregnant women. Data came from 9,889 pregnant women with due dates between April 1, 1991 and December 31, 1992 who were participants of the Avon Longitudinal Study of Parents and Children (ALSPAC) in Bristol, Avon, Southwest England. Self-reported physical activity during pregnancy was collected via questionnaires administered at 18 and 32 weeks of gestation. We found, at 18 weeks of gestation, the prevalence of engaging in physical activity that was sufficient to cause sweating for ≥ 3 h/week (referred to as strenuous physical activity) was 48.8%. This percentage was similar at 32 weeks of gestation. The most common physical activity during pregnancy reported by these women was brisk walking, followed by swimming and ante-natal exercise. In models that mutually adjusted for all characteristics examined, younger women, women in lower social classes, those not employed during pregnancy, married and parous women (compared to those not in each of these groups) were more likely to report engaging in strenuous physical activity. After becoming pregnant, about two out of three of these women reported reducing physical activity levels at 18 weeks of gestation. In mutually adjusted models, women who were younger, fit and well, parous, and women from lower social classes (compared to those not in each of these groups) were less likely to report reducing their physical activity. Our findings provide insights that are relevant to the design of future observational and intervention studies concerned with the effects of physical activity during pregnancy on health outcomes for mothers and offspring.