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This secondary analysis of a randomized clinical trial assesses whether screening for prostate-specific antigen reduces prostate cancer mortality at 15-year follow-up. Key Points: Question: In men aged 50 to 69 years, does a single invitation for a prostate-specific antigen (PSA) screening test reduce prostate cancer mortality at 15-year follow-up compared with no invitation for testing? Findings: In this secondary analysis of a randomized clinical trial of 415 357 men aged 50 to 69 years randomized to a single invitation for PSA screening (n = 195 912) or a control group without PSA screening (n = 219 445) and followed up for a median of 15 years, risk of death from prostate cancer was lower in the group invited to screening (0.69% vs 0.78%; mean difference, 0.09%) compared with the control group. Meaning: Compared with no invitation for routine PSA testing, a single invitation for a PSA screening test reduced prostate cancer mortality at a median follow-up of 15 years, but the absolute mortality benefit was small. Importance: The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) reported no effect of prostate-specific antigen (PSA) screening on prostate cancer mortality at a median 10-year follow-up (primary outcome), but the long-term effects of PSA screening on prostate cancer mortality remain unclear. Objective: To evaluate the effect of a single invitation for PSA screening on prostate cancer–specific mortality at a median 15-year follow-up compared with no invitation for screening. Design, Setting, and Participants: This secondary analysis of the CAP randomized clinical trial included men aged 50 to 69 years identified at 573 primary care practices in England and Wales. Primary care practices were randomized between September 25, 2001, and August 24, 2007, and men were enrolled between January 8, 2002, and January 20, 2009. Follow-up was completed on March 31, 2021. Intervention: Men received a single invitation for a PSA screening test with subsequent diagnostic tests if the PSA level was 3.0 ng/mL or higher. The control group received standard practice (no invitation). Main Outcomes and Measures: The primary outcome was reported previously. Of 8 prespecified secondary outcomes, results of 4 were reported previously. The 4 remaining prespecified secondary outcomes at 15-year follow-up were prostate cancer–specific mortality, all-cause mortality, and prostate cancer stage and Gleason grade at diagnosis. Results: Of 415 357 eligible men (mean [SD] age, 59.0 [5.6] years), 98% were included in these analyses. Overall, 12 013 and 12 958 men with a prostate cancer diagnosis were in the intervention and control groups, respectively (15-year cumulative risk, 7.08% [95% CI, 6.95%-7.21%] and 6.94% [95% CI, 6.82%-7.06%], respectively). At a median 15-year follow-up, 1199 men in the intervention group (0.69% [95% CI, 0.65%-0.73%]) and 1451 men in the control group (0.78% [95% CI, 0.73%-0.82%]) died of prostate cancer (rate ratio [RR], 0.92 [95% CI, 0.85-0.99]; P =.03). Compared with the control, the PSA screening intervention increased detection of low-grade (Gleason score [GS] ≤6: 2.2% vs 1.6%; P <.001) and localized (T1/T2: 3.6% vs 3.1%; P <.001) disease but not intermediate (GS of 7), high-grade (GS ≥8), locally advanced (T3), or distally advanced (T4/N1/M1) tumors. There were 45 084 all-cause deaths in the intervention group (23.2% [95% CI, 23.0%-23.4%]) and 50 336 deaths in the control group (23.3% [95% CI, 23.1%-23.5%]) (RR, 0.97 [95% CI, 0.94-1.01]; P =.11). Eight of the prostate cancer deaths in the intervention group (0.7%) and 7 deaths in the control group (0.5%) were related to a diagnostic biopsy or prostate cancer treatment. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, a single invitation for PSA screening compared with standard practice without routine screening reduced prostate cancer deaths at a median follow-up of 15 years. However, the absolute reduction in deaths was small. Trial Registration: isrctn.org Identifier: ISRCTN92187251 [ABSTRACT FROM AUTHOR]

Earlier diagnosis and more effective treatments mean that the estimated number of cancer survivors in the United Kingdom is expected to reach 4 million by 2030. However, there is an increasing realisation that excess body fatness (EBF) is likely to influence the quality of cancer survivorship and disease-free survival. For decades, the discussion of weight management in patients with cancer has been dominated by concerns about unintentional weight loss, low body weight and interventions to increase weight, often re-enforced by the existence of the obesity paradox, which indicates that high body weight is associated with survival benefits for some types of cancer. However, observational evidence provides strong grounds for testing the hypothesis that interventions for promoting intentional loss of body fat and maintaining skeletal muscle in overweight and obese cancer survivors would bring important health benefits in terms of survival outcomes and long-term impact on treatment-related side effects. In this paper, we outline the need for studies to improve our understanding of the health benefits of weight-loss interventions, such as hypocaloric healthy-eating plans combined with physical activity. In particular, complex intervention trials that are pragmatically designed are urgently needed to develop effective, clinically practical, evidence-based strategies for reducing EBF and optimising body composition in people living with and beyond common cancers. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) have discovered 27 loci associated with glioma risk. Whether these loci are causally implicated in glioma risk, and how risk differs across tissues, has yet to be systematically explored. We integrated multi-tissue expression quantitative trait loci (eQTLs) and glioma GWAS data using a combined Mendelian randomisation (MR) and colocalisation approach. We investigated how genetically predicted gene expression affects risk across tissue type (brain, estimated effective n = 1194 and whole blood, n = 31,684) and glioma subtype (all glioma (7400 cases, 8257 controls) glioblastoma (GBM, 3112 cases) and non-GBM gliomas (2411 cases)). We also leveraged tissue-specific eQTLs collected from 13 brain tissues (n = 114 to 209). The MR and colocalisation results suggested that genetically predicted increased gene expression of 12 genes were associated with glioma, GBM and/or non-GBM risk, three of which are novel glioma susceptibility genes (RETREG2/FAM134A, FAM178B and MVB12B/FAM125B). The effect of gene expression appears to be relatively consistent across glioma subtype diagnoses. Examining how risk differed across 13 brain tissues highlighted five candidate tissues (cerebellum, cortex, and the putamen, nucleus accumbens and caudate basal ganglia) and four previously implicated genes (JAK1, STMN3, PICK1 and EGFR). These analyses identified robust causal evidence for 12 genes and glioma risk, three of which are novel. The correlation of MR estimates in brain and blood are consistently low which suggested that tissue specificity needs to be carefully considered for glioma. Our results have implicated genes yet to be associated with glioma susceptibility and provided insight into putatively causal pathways for glioma risk. [ABSTRACT FROM AUTHOR]

The evidence that fetal life and early infancy are "critical" or "sensitive" ages for later development of cardiometabolic disease is based on flawed methods for comparing different age periods. Moreover, most previous studies have limited their focus to weight gain, rather than growth in length/height or body mass index (weight (kg)/height (m)2). We undertook a secondary analysis of data from the Promotion of Breastfeeding Intervention Trial (1996–2010), a birth cohort study nested within a large cluster-randomized trial in the Republic of Belarus, that had repeated measurements of weight and length/height taken from birth to 11.5 years of age. We used mixed-effects linear models to analyze associations of changes in standardized weight, length/height, and body mass index during 5 age periods (conception to birth, birth to age 3 months, ages 3–12 months, ages 12 months–6.5 years, and ages 6.5–11.5 years) with fasting glucose, insulin, insulin resistance, β-cell function, and adiponectin at age 11.5 years. We observed strong associations between the metabolic markers and all 3 growth measures, with the largest magnitudes being observed during the latest age period (ages 6.5–11.5 years) and negligible associations during gestation and the first year of life. Later age periods appear more "sensitive" than earlier periods to the adverse metabolic association with rapid growth in childhood. [ABSTRACT FROM AUTHOR]

Background: Evidence on the long-term effect of breastfeeding on neurocognitive development is based almost exclusively on observational studies. In the 16-year follow-up study of a large, cluster-randomized trial of a breastfeeding promotion intervention, we evaluated the long-term persistence of the neurocognitive benefits of the breastfeeding promotion intervention previously observed at early school age.Methods and Findings: A total of 13,557 participants (79.5% of the 17,046 randomized) of the Promotion of Breastfeeding Intervention Trial (PROBIT) were followed up at age 16 from September 2012 to July 2015. At the follow-up, neurocognitive function was assessed in 7 verbal and nonverbal cognitive domains using a computerized, self-administered test battery among 13,427 participants. Using an intention-to-treat (ITT) analysis as our prespecified primary analysis, we estimated cluster- and baseline characteristic-adjusted mean differences between the intervention (prolonged and exclusive breastfeeding promotion modelled on the Baby-Friendly Hospital Initiative) and control (usual care) groups in 7 cognitive domains and a global cognitive score. In our prespecified secondary analysis, we estimated mean differences by instrumental variable (IV) analysis to account for noncompliance with the randomly assigned intervention and estimate causal effects of breastfeeding. The 16-year follow-up rates were similar in the intervention (79.7%) and control groups (79.3%), and baseline characteristics were comparable between the two. In the cluster-adjusted ITT analyses, children in the intervention group did not show statistically significant differences in the scores from children in the control group. Prespecified additional adjustment for baseline characteristics improved statistical precision and resulted in slightly higher scores among children in the intervention for verbal function (1.4 [95% CI 0.3-2.5]) and memory (1.2 [95% CI 0.01-2.4]). IV analysis showed that children who were exclusively breastfed for ≥3 (versus <3) months had a 3.5-point (95% CI 0.9-6.1) higher verbal function, but no differences were observed in other domains. While our computerized, self-administered cognitive testing reduced the cluster-level variability in the scores, it may have increased individual-level measurement errors in adolescents.Conclusions: We observed no benefit of a breastfeeding promotion intervention on overall neurocognitive function. The only beneficial effect was on verbal function at age 16. The higher verbal ability is consistent with results observed at early school age; however, the effect size was substantially smaller in adolescence.Probit Trial Registration: ClinicalTrials.gov NCT01561612. [ABSTRACT FROM AUTHOR]

Importance: Prostate cancer screening remains controversial because potential mortality or quality-of-life benefits may be outweighed by harms from overdetection and overtreatment.Objective: To evaluate the effect of a single prostate-specific antigen (PSA) screening intervention and standardized diagnostic pathway on prostate cancer-specific mortality.Design, Setting, and Participants: The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) included 419 582 men aged 50 to 69 years and was conducted at 573 primary care practices across the United Kingdom. Randomization and recruitment of the practices occurred between 2001 and 2009; patient follow-up ended on March 31, 2016.Intervention: An invitation to attend a PSA testing clinic and receive a single PSA test vs standard (unscreened) practice.Main Outcomes and Measures: Primary outcome: prostate cancer-specific mortality at a median follow-up of 10 years. Prespecified secondary outcomes: diagnostic cancer stage and Gleason grade (range, 2-10; higher scores indicate a poorer prognosis) of prostate cancers identified, all-cause mortality, and an instrumental variable analysis estimating the causal effect of attending the PSA screening clinic.Results: Among 415 357 randomized men (mean [SD] age, 59.0 [5.6] years), 189 386 in the intervention group and 219 439 in the control group were included in the analysis (n = 408 825; 98%). In the intervention group, 75 707 (40%) attended the PSA testing clinic and 67 313 (36%) underwent PSA testing. Of 64 436 with a valid PSA test result, 6857 (11%) had a PSA level between 3 ng/mL and 19.9 ng/mL, of whom 5850 (85%) had a prostate biopsy. After a median follow-up of 10 years, 549 (0.30 per 1000 person-years) died of prostate cancer in the intervention group vs 647 (0.31 per 1000 person-years) in the control group (rate difference, -0.013 per 1000 person-years [95% CI, -0.047 to 0.022]; rate ratio [RR], 0.96 [95% CI, 0.85 to 1.08]; P = .50). The number diagnosed with prostate cancer was higher in the intervention group (n = 8054; 4.3%) than in the control group (n = 7853; 3.6%) (RR, 1.19 [95% CI, 1.14 to 1.25]; P < .001). More prostate cancer tumors with a Gleason grade of 6 or lower were identified in the intervention group (n = 3263/189 386 [1.7%]) than in the control group (n = 2440/219 439 [1.1%]) (difference per 1000 men, 6.11 [95% CI, 5.38 to 6.84]; P < .001). In the analysis of all-cause mortality, there were 25 459 deaths in the intervention group vs 28 306 deaths in the control group (RR, 0.99 [95% CI, 0.94 to 1.03]; P = .49). In the instrumental variable analysis for prostate cancer mortality, the adherence-adjusted causal RR was 0.93 (95% CI, 0.67 to 1.29; P = .66).Conclusions and Relevance: Among practices randomized to a single PSA screening intervention vs standard practice without screening, there was no significant difference in prostate cancer mortality after a median follow-up of 10 years but the detection of low-risk prostate cancer cases increased. Although longer-term follow-up is under way, the findings do not support single PSA testing for population-based screening.Trial Registration: ISRCTN Identifier: ISRCTN92187251. [ABSTRACT FROM AUTHOR]

A new approach to constitutive modeling for non-Newtonian liquids is presented, with a particular application to a dilute suspension of spheroids (prolate and oblate) subject to Brownian rotations at finite PéPclet numbers, but with a general framework that can be applied to other complex fluids, including concentrated suspensions and emulsions. A generalized traceless Oldroyd model is used for the particle contribution to the stress, with five material parameters as functions of one instantaneous flow invariant: the intrinsic energy dissipation rate. All five parameters are found from simultaneously fitting the model to numerical results for two base flows at arbitrary flow intensities: planar extensional flow and simple shear flow. Precise numerical solutions of the Fokker-Planck-Smoluchowski equation for the orientation distribution function are used to prepare the database rheological functions, and also to validate the resulting model in flows with arbitrary kinematics. The present work also verifies the accuracy of various closure models in the literature for dilute suspensions of spheroids in several test flows. Although these closure models give excellent results and are often more accurate than the present approach in the test cases, they are relevant specifically to fiber suspensions, and it is not clear how to generalize the closure approach to other types of non-Newtonian, microstructurally complex liquids. In contrast, the present approach to constitutive modeling is more general and does not hinge on a particular microstructure; it can be applied to various systems with strong hydrodynamical interactions (highly concentrated suspensions, emulsions, etc.). [ABSTRACT FROM AUTHOR]

Case-control studies are potentially open to misclassification of disease outcome which may be unrelated to risk factor exposure (non-differential), thus underestimating associations, or related to risk factor exposure (differential), thus causing more serious bias.We conducted a systematic literature review for methods of adjusting for outcome misclassification in case-control studies. We also applied methods to simulated data with known outcome misclassification to assess performance of these methods. Finally, real data from the Prostate Testing for Cancer and Treatment (ProtecT) randomised controlled trial gauged the usefulness of these methods.Adjustment methods range from recalculating cell frequencies to probabilistic sensitivity modelling and Bayesian models, which incorporate uncertainty in sensitivity and specificity estimates. Simulated data indicated that substantial bias in either direction resulted from differential misclassification. More sophisticated methods, incorporating uncertainty into estimates of misclassification, provided appropriately wide confidence intervals for corrected estimates of risk factor-disease association.Method choice depends on whether the objective is to assess if an observed association can be explained by bias, or to provide a 'corrected' estimate for the primary analysis. Accurate estimation of the degree of misclassification is important for the latter; otherwise further bias may be introduced. [ABSTRACT FROM AUTHOR]

Genetic evidence suggests glioma risk is altered by leukocyte telomere length, allergic disease (asthma, hay fever or eczema), alcohol consumption, childhood obesity, low-density lipoprotein cholesterol (LDLc) and triglyceride levels. DNA methylation (DNAm) variation influences many of these glioma-related traits and is an established feature of glioma. Yet the causal relationship between DNAm variation with both glioma incidence and glioma risk factors is unknown. We applied a two-step Mendelian randomization (MR) approach and several sensitivity analyses (including colocalization and Steiger filtering) to assess the association of DNAm with glioma risk factors and glioma incidence. We used data from a recently published catalogue of germline genetic variants robustly associated with DNAm variation in blood (32,851 participants) and data from a genome-wide association study of glioma risk (12,488 cases and 18,169 controls, sub-divided into 6191 glioblastoma cases and 6305 non-glioblastoma cases). MR evidence indicated that DNAm at 3 CpG sites (cg01561092, cg05926943, cg01584448) in one genomic region (HEATR3) had a putative association with glioma and glioblastoma risk (False discovery rate [FDR] < 0.05). Steiger filtering provided evidence against reverse causation. Colocalization presented evidence against genetic confounding and suggested that differential DNAm at the 3 CpG sites and glioma were driven by the same genetic variant. MR provided little evidence to suggest that DNAm acts as a mediator on the causal pathway between risk factors previously examined and glioma onset. To our knowledge, this is the first study to use MR to appraise the causal link of DNAm with glioma risk factors and glioma onset. Subsequent analyses are required to improve the robustness of our results and rule out horizontal pleiotropy. [ABSTRACT FROM AUTHOR]

There is currently no population screening programme for prostate cancer in the UK, a position that is reflected internationally (e.g. the USA Preventative Services Taskforce recommends shared decision-making [1]). Second, the CAP trial observed that PSA screening misses lethal cancers: 36% (68/188) of men who died from prostate cancer attended the PSA-screening clinic, highlighting that clinically significant prostate cancer is not uncommon among men with low PSA levels. [Extracted from the article]

Objective To conduct a systematic review and meta-analysis of artificial urinary sphincter ( AUS) placement after radical prostatectomy ( RP) and external beam radiotherapy ( EBRT). Patients and Methods There were 1 886 patients available for analysis of surgical revision outcomes and 949 for persistent urinary incontinence ( UI) outcomes from 15 and 11 studies, respectively. The mean age ( sd) was 66.9 (1.4) years and the number of patients per study was 126.6 (41.7). The mean ( sd, range) follow-up was 36.7 (3.9, 18-68) months. A systematic database search was conducted using keywords, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses ( PRISMA) guidelines. Published series of AUS implantations were retrieved, according to the inclusion criteria. The Newcastle-Ottawa Score was used to ascertain the quality of evidence for each study. Surgical results from each case series were extracted. Data were analysed using CMA® statistical software. Results AUS revision was higher in RP + EBRT vs RP alone, with a random effects risk ratio of 1.56 (95% confidence interval [ CI] 1.02-2.72; P < 0.050; I2 = 82.0%) and a risk difference of 16.0% (95% CI 2.05-36.01; P < 0.080). Infection/erosion contributed to the majority of surgical revision risk compared with urethral atrophy ( P = 0.020). Persistent UI after implantation was greater in patients treated with EBRT ( P < 0.001). Conclusions Men receiving RP + EBRT appear at increased risk of infection/erosion and urethral atrophy, resulting in a greater risk of surgical revision compared with RP alone. Persistent UI is more common with RP + EBRT. [ABSTRACT FROM AUTHOR]

Introduction: Prostate-specific antigen (PSA) testing is a widely accepted screening method for prostate cancer, but with low specificity at thresholds giving good sensitivity. Previous research identified four single nucleotide polymorphisms (SNPs) principally associated with circulating PSA levels rather than with prostate cancer risk (TERT rs2736098, FGFR2 rs10788160, TBX3 rs11067228, KLK3 rs17632542). Removing the genetic contribution to PSA levels may improve the ability of the remaining biologically-determined variation in PSA to discriminate between high and low risk of progression within men with identified prostate cancer. We investigate whether incorporating information on the PSA-SNPs improves the discrimination achieved by a single PSA threshold in men with raised PSA levels. Materials and Methods: Men with PSA between 3-10ng/mL and histologically-confirmed prostate cancer were categorised as high or low risk of progression (Low risk: Gleason score≤6 and stage T1-T2a; High risk: Gleason score 7–10 or stage T2C). We used the combined genetic effect of the four PSA-SNPs to calculate a genetically corrected PSA risk score. We calculated the Area under the Curve (AUC) to determine how well genetically corrected PSA risk scores distinguished men at high risk of progression from low risk men. Results: The analysis includes 868 men with prostate cancer (Low risk: 684 (78.8%); High risk: 184 (21.2%)). Receiver operating characteristic (ROC) curves indicate that including the 4 PSA-SNPs does not improve the performance of measured PSA as a screening tool for high/low risk prostate cancer (measured PSA level AU C = 59.5% (95% CI: 54.7,64.2) vs additionally including information from the 4 PSA-SNPs AUC = 59.8% (95% CI: 55.2,64.5) (p-value = 0.40)). Conclusion: We demonstrate that genetically correcting PSA for the combined genetic effect of four PSA-SNPs, did not improve discrimination between high and low risk prostate cancer in men with raised PSA levels (3-10ng/mL). Replication and gaining more accurate estimates of the effects of the 4 PSA-SNPs and additional variants associated with PSA levels and not prostate cancer could be obtained from subsequent GWAS from larger prospective studies. [ABSTRACT FROM AUTHOR]

Rapid diagnostic pathways for cancer have been implemented, but evidence whether shorter diagnostic intervals (time from primary care presentation to diagnosis) improves survival is lacking. Using the Clinical Practice Research Datalink, we identified patients diagnosed with female breast (8,639), colorectal (5,912), lung (5,737) and prostate (1,763) cancers between 1998 and 2009, and aged >15 years. Presenting symptoms were classified as alert or non-alert, according to National Institute for Health and Care Excellence guidance. We used relative survival and excess risk modeling to determine associations between diagnostic intervals and five-year survival. The survival of patients with colorectal, lung and prostate cancer was greater in those with alert, compared with non-alert, symptoms, but findings were opposite for breast cancer. Longer diagnostic intervals were associated with lower mortality for colorectal and lung cancer patients with non-alert symptoms, (colorectal cancer: Excess Hazards Ratio, EHR >6 months vs <1 month: 0.85; 95% CI: 0.72-1.00; Lung cancer: EHR 3-6 months vs <1 month: 0.87; 95% CI: 0.80-0.95; EHR >6 months vs <1 month: 0.81; 95% CI: 0.74-0.89). Prostate cancer mortality was lower in patients with longer diagnostic intervals, regardless of type of presenting symptom. The association between diagnostic intervals and cancer survival is complex, and should take into account cancer site, tumour biology and clinical practice. Nevertheless, unnecessary delay causes patient anxiety and general practitioners should continue to refer patients with alert symptoms via the cancer pathways, and actively follow-up patients with non-alert symptoms in the community. [ABSTRACT FROM AUTHOR]

Background and Objective: Most guidelines in the UK, Europe and North America do not recommend organised population-wide screening for prostate cancer. Prostate-specific antigen-based screening can reduce prostate cancer-specific mortality, but there are concerns about overdiagnosis, overtreatment and economic value. The aim was therefore to assess the cost effectiveness of eight potential screening strategies in the UK. Methods: We used a cost-utility analysis with an individual-based simulation model. The model was calibrated to data from the 10-year follow-up of the Cluster Randomised Trial of PSA Testing for Prostate Cancer (CAP). Treatment effects were modelled using data from the Prostate Testing for Cancer and Treatment (ProtecT) trial. The participants were a hypothetical population of 10 million men in the UK followed from age 30 years to death. The strategies were: no screening; five age-based screening strategies; adaptive screening, where men with an initial prostate-specific antigen level of < 1.5 ng/mL are screened every 6 years and those above this level are screened every 4 years; and two polygenic risk-stratified screening strategies. We assumed the use of pre-biopsy multi-parametric magnetic resonance imaging for men with prostate-specific antigen ≥ 3 ng/mL and combined transrectal ultrasound-guided and targeted biopsies. The main outcome measures were projected lifetime costs and quality-adjusted life-years from a National Health Service perspective. Results: All screening strategies increased costs compared with no screening, with the majority also increasing quality-adjusted life-years. At willingness-to-pay thresholds of £20,000 or £30,000 per quality-adjusted life-year gained, a once-off screening at age 50 years was optimal, although this was sensitive to the utility estimates used. Although the polygenic risk-stratified screening strategies were not on the cost-effectiveness frontier, there was evidence to suggest that they were less cost ineffective than the alternative age-based strategies. Conclusions: Of the prostate-specific antigen-based strategies compared, only a once-off screening at age 50 years was potentially cost effective at current UK willingness-to-pay thresholds. An additional follow-up of CAP to 15 years may reduce uncertainty about the cost effectiveness of the screening strategies. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer survival in the UK is lower than in other developed countries, but the association of time interval between diagnosis and treatment on excess mortality remains unclear. Methods: Using data from cancer registries in England, we identified 46,511 patients with localised colorectal cancer between 1996-2009, who were 15 years and older, and who underwent a major surgical resection within 62 days of diagnosis. We used relative survival and excess risk modeling to investigate the association of time between diagnosis and major resection (exposure) with survival (outcome). Results: Compared to patients who had major resection within 25-38 days of diagnosis, patients with a shorter time interval between diagnosis and resection and those waiting longer for resection had higher excess mortality (Excess Hazards Ratio, EHR <25 vs 25-38 days: 1.50; 95% Confidence Interval, CI: 1.37 to 1.66; EHR 39-62 vs 25-38 days : 1.16; 95% CI: 1.04 to 1.29). Excess mortality was associated with age (EHR 75+ vs. 15-44 year olds: 2.62; 95% CI: 2.00 to 3.42) and deprivation (EHR most vs. least deprived: 1.27; 95% CI: 1.12 to 1.45), but time between diagnosis and resection did not explain these differences. Conclusion: Within 62 days of diagnosis, a U-shaped association of time between diagnosis and major resection with excess mortality for localised colorectal cancer was evident. This indicates a complicated treatment pathway, particularly for patients who had resection earlier than 25 days, and requires further investigation. [ABSTRACT FROM AUTHOR]

Background: The duration and exclusivity of breastfeeding in infancy have been inversely associated with future cardiometabolic risk. We investigated the effects of an experimental intervention to promote increased duration of exclusive breastfeeding on cardiometabolic risk factors in childhood.Methods and Results: We followed-up children in the Promotion of Breastfeeding Intervention Trial, a cluster-randomized trial of a breastfeeding promotion intervention based on the World Health Organization/United Nations Children's Fund Baby-Friendly Hospital Initiative. In 1996 to 1997, 17 046 breastfeeding mother-infant pairs were enrolled from 31 Belarusian maternity hospitals and affiliated polyclinics (16 intervention versus 15 control sites); 13 879 (81.4%) children were followed up at 11.5 years, with 13 616 (79.9%) who had fasted and did not have diabetes mellitus. The outcomes were blood pressure; fasting insulin, adiponectin, glucose, and apolipoprotein A1; and the presence of metabolic syndrome. Analysis was by intention to treat, accounting for clustering within hospitals/clinics. The intervention substantially increased breastfeeding duration and exclusivity in comparison with the control arm (43% versus 6% and 7.9% versus 0.6% exclusively breastfed at 3 and 6 months, respectively). Cluster-adjusted mean differences at 11.5 years between experimental versus control groups were as follows: 1.0 mm Hg (95% confidence interval, -1.1 to 3.1) for systolic and 0.8 mm Hg (-0.6 to 2.3) for diastolic blood pressure; -0.1 mmol/L (-0.2 to 0.1) for glucose; 8% (-3% to 34%) for insulin; -0.3 μg/mL (-1.5 to 0.9) for adiponectin; and 0.0 g/L (-0.1 to 0.1) for apolipoprotein A1. The cluster-adjusted odds ratio for metabolic syndrome, comparing experimental versus control groups, was 1.21 (0.85 to 1.72).Conclusions: An intervention to improve breastfeeding duration and exclusivity among healthy term infants did not influence cardiometabolic risk factors in childhood.Clinical Trial Registration: Current Controlled Trials: ISRCTN37687716 (http://www.controlled-trials.com/ISRCTN37687716). URL: http://clinicaltrials.gov. Unique identifier: NCT01561612. [ABSTRACT FROM AUTHOR]

Background--The duration and exclusivity of breastfeeding in infancy have been inversely associated with future cardiometabolic risk. We investigated the effects of an experimental intervention to promote increased duration of exclusive breastfeeding on cardiometabolic risk factors in childhood. Methods and Results--We followed-up children in the Promotion of Breastfeeding Intervention Trial, a cluster-randomized trial of a breastfeeding promotion intervention based on the World Health Organization/United Nations Children's Fund Baby-Friendly Hospital Initiative. In 1996 to 1997, 17 046 breastfeeding mother-infant pairs were enrolled from 31 Belarusian maternity hospitals and affiliated polyclinics (16 intervention versus 15 control sites); 13 879 (81.4%) children were followed up at 11.5 years, with 13 616 (79.9%) who had fasted and did not have diabetes mellitus. The outcomes were blood pressure; fasting insulin, adiponectin, glucose, and apolipoprotein A1; and the presence of metabolic syndrome. Analysis was by intention to treat, accounting for clustering within hospitals/clinics. The intervention substantially increased breastfeeding duration and exclusivity in comparison with the control arm (43% versus 6% and 7.9% versus 0.6% exclusively breastfed at 3 and 6 months, respectively). Cluster-adjusted mean differences at 11.5 years between experimental versus control groups were as follows: 1.0 mm Hg (95% confidence interval, -1.1 to 3.1) for systolic and 0.8 mm Hg (-0.6 to 2.3) for diastolic blood pressure; -0.1 mmol/L (-0.2 to 0.1) for glucose; 8% (-3% to 34%) for insulin; -0.3 μg/mL (-1.5 to 0.9) for adiponectin; and 0.0 g/L (-0.1 to 0.1) for apolipoprotein A1. The cluster-adjusted odds ratio for metabolic syndrome, comparing experimental versus control groups, was 1.21 (0.85 to 1.72). Conclusions--An intervention to improve breastfeeding duration and exclusivity among healthy term infants did not influence cardiometabolic risk factors in childhood. Clinical Trial Registration--Current Controlled Trials: ISRCTN37687716 (http://www.controlled-trials.com/ISRCTN37687716). URL: http://clinicaltrials.gov. Unique identifier: NCT01561612. [ABSTRACT FROM AUTHOR]

Background: A diagnosis of prostate cancer leads to emotional distress and anxiety, prompting calls for rapid diagnostic pathways. Nevertheless, it remains unclear what impact time between diagnosis and surgery has upon prostate cancer survival.Methods: Using national databases for England (cancer registries, Hospital Episode Statistics and Office of National Statistics), we identified 17,043 men with prostate cancer, aged 15 years and older, diagnosed in 1996-2009, and who had surgical resection with curative intent within 6 months of diagnosis. We used relative survival to investigate associations between waiting times and five- and ten-year survival.Results: Five- and ten-year relative survival estimates for the total study sample were 1.04 (95% CI: 1.04 to 1.05) and 1.08 (95% CI: 1.06-1.09), respectively. There were no notable differences in survival between patients who had surgery at 0-3 and 4-6 months after diagnosis. Relative survival was higher among the elderly (>65) and those with well and moderately differentiated tumours.Conclusion: The high relative survival in our cohort probably reflects adherence to selection criteria for surgery among men with localised prostate cancer. Among men treated with surgery within 6 months of diagnosis, we found little evidence of an association between time from diagnosis to surgery and survival. [ABSTRACT FROM AUTHOR]

Background Colorectal cancer (CRC) is the third-most-common cancer worldwide and its rates are increasing. Elevated body mass index (BMI) is an established risk factor for CRC, although the molecular mechanisms behind this association remain unclear. Using the Mendelian randomization (MR) framework, we aimed to investigate the mediating effects of putative biomarkers and other CRC risk factors in the association between BMI and CRC. Methods We selected as mediators biomarkers of established cancer-related mechanisms and other CRC risk factors for which a plausible association with obesity exists, such as inflammatory biomarkers, glucose homeostasis traits, lipids, adipokines, insulin-like growth factor 1 (IGF1), sex hormones, 25-hydroxy-vitamin D, smoking, physical activity (PA) and alcohol consumption. We used inverse-variance weighted MR in the main univariable analyses and performed sensitivity analyses (weighted-median, MR–Egger, Contamination Mixture). We used multivariable MR for the mediation analyses. Results Genetically predicted BMI was positively associated with CRC risk [odds ratio per SD (5 kg/m2) = 1.17, 95% CI: 1.08–1.24, P -value = 1.4 × 10−5] and robustly associated with nearly all potential mediators. Genetically predicted IGF1, fasting insulin, low-density lipoprotein cholesterol, smoking, PA and alcohol were associated with CRC risk. Evidence for attenuation was found for IGF1 [explained 7% (95% CI: 2–13%) of the association], smoking (31%, 4–57%) and PA (7%, 2–11%). There was little evidence for pleiotropy, although smoking was bidirectionally associated with BMI and instruments were weak for PA. Conclusions The effect of BMI on CRC risk is possibly partly mediated through plasma IGF1, whereas the attenuation of the BMI–CRC association by smoking and PA may reflect confounding and shared underlying mechanisms rather than mediation. [ABSTRACT FROM AUTHOR]

Background: Adiponectin is an adipocyte-derived hormone that acts as a marker of insulin sensitivity. Bloodspot sampling by fingerstick onto filter paper may increase the feasibility of large-scale studies of the determinants of insulin sensitivity. We first describe the validation of an enzyme-linked immunoassay (ELISA) for quantifying adiponectin from dried blood spots and then demonstrate its application in a large trial (PROBIT). Methods: We quantified adiponectin from 3-mm diameter discs (≈3 µL of blood) punched from dried blood spots obtained from: i) whole blood standards (validation); and ii) PROBIT trial samples (application) in which paediatricians collected blood spots from 13,879 children aged 11.5 years from 31 sites across Belarus. We examined the distribution of bloodspot adiponectin by demographic and anthropometric factors, fasting insulin and glucose. Results: In the validation study, mean intra-assay coefficients of variation (n = 162) were 15%, 13% and 10% for ‘low’ (6.78 µg/ml), ‘medium’ (18.18 µg/ml) and 'high’ (33.13 µg/ml) internal quality control (IQC) samples, respectively; the respective inter-assay values (n = 40) were 23%, 21% and 14%. The correlation coefficient between 50 paired whole bloodspot versus plasma samples, collected simultaneously, was 0.87 (95% CI: 0.78 to 0.93). Recovery of known quantities of adiponectin (between 4.5 to 36 µg/ml) was 100.3–133%. Bloodspot adiponectin was stable for at least 30 months at −80°C. In PROBIT, we successfully quantified fasting adiponectin from dried blood spots in 13,329 of 13,879 (96%) children. Mean adiponectin (standard deviation) concentrations were 17.34 µg/ml (7.54) in boys and 18.41 µg/ml (7.92) in girls and were inversely associated with body mass index, fat mass, triceps and subscapular skin-fold thickness, waist circumference, height and fasting glucose. Conclusions: Bloodspot ELISA is suitable for measuring adiponectin in very small volumes of blood collected on filter paper and can be applied to large-scale studies. [ABSTRACT FROM AUTHOR]

Background: National Institute for Health and Clinical Excellence (NICE) clinical guidelines and subsequent NICE issued 'recommendation reminders' advocate discontinuing two fertility procedures and caesarean sections in women with hepatitis. We assess whether NICE guidance in 2004 and recommendation reminders were associated with a change in the rate of clinical procedures performed. Methods: Routine inpatient Hospital Episode Statistics (HES) data were extracted from the HES database for 1st April 1998 to 31st March 2010 using OPCS procedure codes for varicocele operations in infertile men, endometrial biopsies in infertile women and caesarean sections in women with hepatitis B or C. We used Joinpoint regression to identify points in time when the trend in procedure rates changed markedly, to identify any influence of the release of NICE guidance. Results: Between 1998-2010, planned caesarean sections in women with and without hepatitis B or C increased yearly (annual percentage change (APC) 4.9%, 95% CI 2.1% to 7.7%) in women with hepatitis, compared with women without (APC 4.0% [95% CI 2.7% to 5.3%] up to 2001, APC -0.6% [95% CI -2.8% to 1.8%] up to 2004 and 1.3% [95% CI 0.8% to 1.8%] up to 2010). In infertile women under 40 years of age, endometrial biopsies for investigation of infertility increased, APC 6.0% (95% CI 3.6% to 8.4%) up to 2003, APC 1.5% (95% CI -4.3% to 7.7%) to 2007 followed by APC 12.8% (95% CI 1.0% to 26.0%) to 2010. Varicocele procedures remained relatively static between 1998 and 2010 (APC -0.5%, 95% CI -2.3% to 1.3%). Conclusions: There was no decline in use of the three studied procedures, contrary to NICE guidance, and no change in uptake associated with the timing of NICE guidance or recommendation reminders. 'Do not do' recommendation reminders may be ineffective at improving clinical practice or achieving disinvestment. [ABSTRACT FROM AUTHOR]

Importance: Evidence that longer-term and exclusive breastfeeding reduces child obesity risk is based on observational studies that are prone to confounding.Objective: To investigate effects of an intervention to promote increased duration and exclusivity of breastfeeding on child adiposity and circulating insulin-like growth factor (IGF)-I, which regulates growth.Design, Setting, and Participants: Cluster-randomized controlled trial in 31 Belarusian maternity hospitals and their affiliated clinics, randomized into 1 of 2 groups: breastfeeding promotion intervention (n = 16) or usual practices (n = 15). Participants were 17,046 breastfeeding mother-infant pairs enrolled in 1996 and 1997, of whom 13,879 (81.4%) were followed up between January 2008 and December 2010 at a median age of 11.5 years.Intervention: Breastfeeding promotion intervention modeled on the WHO/UNICEF Baby-Friendly Hospital Initiative (World Health Organization/United Nations Children's Fund).Main Outcome Measures: Body mass index (BMI), fat and fat-free mass indices (FMI and FFMI), percent body fat, waist circumference, triceps and subscapular skinfold thicknesses, overweight and obesity, and whole-blood IGF-I. Primary analysis was based on modified intention-to-treat (without imputation), accounting for clustering within hospitals and clinics.Results: The experimental intervention substantially increased breastfeeding duration and exclusivity when compared with the control (43% vs 6% exclusively breastfed at 3 months and 7.9% vs 0.6% at 6 months). Cluster-adjusted mean differences in outcomes at 11.5 years of age between experimental vs control groups were: 0.19 (95% CI, -0.09 to 0.46) for BMI; 0.12 (-0.03 to 0.28) for FMI; 0.04 (-0.11 to 0.18) for FFMI; 0.47% (-0.11% to 1.05%) for percent body fat; 0.30 cm (-1.41 to 2.01) for waist circumference; -0.07 mm (-1.71 to 1.57) for triceps and -0.02 mm (-0.79 to 0.75) for subscapular skinfold thicknesses; and -0.02 standard deviations (-0.12 to 0.08) for IGF-I. The cluster-adjusted odds ratio for overweight/obesity (BMI ≥ 85th vs <85th percentile) was 1.18 (95% CI, 1.01 to 1.39) and for obesity (BMI ≥ 95th vs <85th percentile) was 1.17 (95% CI, 0.97 to 1.41).Conclusions: AND RELEVANCE Among healthy term infants in Belarus, an intervention that succeeded in improving the duration and exclusivity of breastfeeding did not prevent overweight or obesity, nor did it affect IGF-I levels at age 11.5 years. Breastfeeding has many advantages but population strategies to increase the duration and exclusivity of breastfeeding are unlikely to curb the obesity epidemic.Trial Registration: isrctn.org: ISRCTN37687716; and clinicaltrials.gov: NCT01561612. [ABSTRACT FROM AUTHOR]

The article focuses on a randomized-controlled trial which aims to investigate effects of an intervention to promote increased duration and exclusivity of breastfeeding on child adiposity and circulating insulin-like growth factor (IGF)-I in Belarus. It mentions that the participants of this study included 17,046 breastfeeding mothers enrolled in 1996 and 1997, of whom 13,879 were followed up between January 2008 and December 2010 at a median age of 11.5 years. The main outcome measures included body mass index, percent body fat and waist circumference. The results indicated that breastfeeding has many advantages but population strategies to increase the duration and exclusivity of breastfeeding are unlikely to curb the obesity epidemic.

Background: In large-scale epidemiology, bloodspot sampling by fingerstick onto filter paper has many advantages, including ease and low costs of collection, processing and transport. We describe the development of an enzyme-linked immunoassay (ELISA) for quantifying insulin from dried blood spots and demonstrate its application in a large trial. Methods: We adapted an existing commercial kit (Mercodia Human Insulin ELISA, 10-1113-01) to quantify insulin from two 3-mm diameter discs (≈6 µL of blood) punched from whole blood standards and from trial samples. Paediatricians collected dried blood spots in a follow-up of 13,879 fasted children aged 11.5 years (interquartile range 11.3-11.8 years) from 31 trial sites across Belarus. We quantified bloodspot insulin levels and examined their distribution by demography and anthropometry. Results: Mean intra-assay (n = 157) coefficients of variation were 15% and 6% for 'low' (6.7 mU/L) and 'high' (23.1 mU/L) values, respectively; the respective inter-assay values (n = 33) were 23% and 11%. The intraclass correlation coefficient between 50 paired whole bloodspot versus serum samples, collected simultaneously, was 0.90 (95% confidence interval 0.85 to 0.95). Bloodspot insulin was stable for at least 31 months at -80°C, for one week at +30°C and following four freeze-thaw cycles. Paediatricians collected a median of 8 blood spots from 13,487 (97%) children. The geometric mean insulin (log standard deviation) concentrations amongst 12,812 children were 3.0 mU/L (1.1) in boys and 4.0 mU/L (1.0) in girls and were positively associated with pubertal stage, measures of central and peripheral adiposity, height and fasting glucose. Conclusions: Our simple and convenient bloodspot assay is suitable for the measurement of insulin in very small volumes of blood collected on filter paper cards and can be applied to large-scale epidemiology studies of the early-life determinants of circulating insulin. [ABSTRACT FROM AUTHOR]

Background: Previous studies suggest that over-nutrition in early infancy may programme long-term susceptibility to insulin resistance. Objective: To assess the association of breast milk and quantity of infant formula and cows' milk intake during infancy with insulin resistance measures in early adulthood. Design: Long-term follow-up of the Barry Caerphilly Growth cohort, into which mothers and their offspring had originally been randomly assigned, between 1972-1974, to receive milk supplementation or not. Participants were the offspring, aged 23-27 years at follow-up (n = 679). Breastfeeding and formula/cows' milk intake was recorded prospectively by nurses. The main outcomes were insulin sensitivity (ISI0) and insulin secretion (CIR30). Results: 573 (84%) individuals had valid glucose and insulin results and complete covariate information. There was little evidence of associations of breastfeeding versus any formula/cows' milk feeding or of increasing quartiles of formula/cows' milk consumption during infancy (<3 months) with any outcome measure in young adulthood. In fully adjusted models, the differences in outcomes between breastfeeding versus formula/cows' milk feeding at 3 months were: fasting glucose (-0.07 mmol/l; 95% CI: -0.19, 0.05); fasting insulin (8.0%; -8.7, 27.6); ISI0 (-6.1%; -11.3, 12.1) and CIR30 (3.8%; -19.0, 32.8). There was also little evidence that increasing intakes of formula/cows' milk at 3 months were associated with fasting glucose (increase per quartile of formula/cows' milk intake = 0.00 mmol/l; -0.03, 0.03); fasting insulin (0.8%; -3.2, 5.1); ISI0 (-0.9%; -5.1, 3.5) and CIR30 (-2.6%; -8.4, 3.6). Conclusions: We found no evidence that increasing consumption of formula/cows' milk in early infancy was associated with insulin resistance in young adulthood. [ABSTRACT FROM AUTHOR]

Background Socio-economic influences over a lifetime impact on health and may contribute to poor physical functioning in old age. Methods The authors examined the impact of both childhood and adulthood socio-economic factors on locomotor function at 63-86 years (measured with the get up and go timed walk and flamingo balance test) in the UK-based Boyd Orr (n=405) and Caerphilly (n=1196) prospective cohorts. Results There was a marked reduction in walking speed and balance time with increasing age. Each year of age was associated with a 1.7% slower walk time and a 14% increased odds of poor balance. Participants who moved from a low socio-economic position in childhood to a high socio-economic position in adulthood had 3% slower walking times (95% CI -- 2% to 8%) than people with a high socio-economic position in both periods. Participants who moved from a high socio-economic position in childhood to a low adulthood socio-economic position had 5% slower walking times (95% CI --2% to 12%). Participants with a low socio-economic position in both periods had 10% slower walking times (95% CI 5% to 16%; p for trend<0.001). In Boyd Orr, low socio-economic position in childhood was associated with poor balance in old age (OR per worsening category=1.26; 95% CI 1.01 to 1.57; p=0.043), as was socio-economic position in adulthood (OR=1.71; 95% CI 1.20 to 2.45; p=0.003). Similar associations were not observed in Caerphilly. Conclusion Accumulating socio-economic disadvantage from childhood to adulthood is associated with slower walking time in old age, with mixed results for balance ability. [ABSTRACT FROM AUTHOR]

Background: It is suggested that maternal adiposity has a stronger association with offspring adiposity than does paternal adiposity. Furthermore, a recent small study reported gender assortment in parental-offspring adiposity associations. We aimed to examine these associations in one of the largest studies to date using data from a low-middle income country that has recently undergone a major political and economic transition. Methods and Principal Findings: In a cross-sectional study of 12,181 parental-offspring trios from Belarus (mean age (SD) of mothers 31.7 (4.9), fathers 34.1 (5.1) and children 6.6 (0.3) at time of assessment), we found positive graded associations of mother's and father's BMI with offspring adiposity. There was no evidence that these associations differed between mothers and fathers. For example, the odds ratio of offspring overweight or obesity (based on BMI) comparing obese and overweight mothers to normal weight mothers was 2.03 (95%CI 1.77, 2.31) in fully adjusted models; the equivalent result for father's overweight/obesity was 1.81 (1.58, 2.07). Equivalent results for offspring being in the top 10% waist circumference were 1.91 (1.67, 2.18) comparing obese/overweight to normal weight mothers and 1.72 (1.53, 1.95) comparing obese/ overweight to normal weight fathers. Similarly, results for offspring being in the top 10% of percent fat mass were 1.58 (1.36, 1.84) and 1.76 (1.49, 2.07), for mother's and father's obese/overweight exposures respectively. There was no strong or consistent evidence of gender assortment - i.e. associations of maternal adiposity exposures with offspring outcomes were similar in magnitude for their daughters compared to equivalent associations in their sons and paternal associations were also similar in sons and daughters. Conclusions/Significance: These findings suggest that genetic and/or shared familial environment explain family clustering of adiposity. Interventions aimed at changing overall family lifestyle are likely to be important for population level obesity prevention. [ABSTRACT FROM AUTHOR]

Summary: Background: There is no conclusive evidence that screening based on serum prostate-specific antigen (PSA) tests decreases prostate-cancer mortality. Since its introduction in the USA around 1990, uptake of PSA testing has been rapid in the USA, but much less common in the UK. Our aim was to study trends over time in prostate-cancer mortality and incidence in the USA and UK in 1975–2004, and compare these patterns with trends in screening and treatment. Methods: Joinpoint regression analysis of cancer-mortality statistics from Cancer Research UK (London, UK) and from the US National Cancer Institute Surveillance, Epidemiology and End Results (SEER) programme from 1975 to 2004 was used to estimate the annual percentage change in prostate-cancer mortality in both countries and the points in time when trends changed. The ratio of USA to UK age-adjusted prostate-cancer incidence was also assessed. Findings: Age-specific and age-adjusted prostate-cancer mortality peaked in the early 1990s at almost identical rates in both countries, but age-adjusted mortality in the USA subsequently declined after 1994 by −4·17% (95% CI −4·34 to −3·99) each year, four-times the rate of decline in the UK after 1992 (−1·14% [−1·44 to −0·84]). The mortality decline in the USA was greatest and most sustained in patients aged 75 years or older (−5·32% [−8·23 to −2·32]), whereas death rates had plateaued in this age group in the UK by 2000. The mean ratio of USA to UK age-adjusted prostate-cancer incidence rates in 1975–2003 was 2·5, with a pronounced peak around the time that PSA testing was introduced in the USA. Numbers needed to treat to prevent one death from prostate cancer were 33 000 in the 55–64-year age group. Interpretation: The striking decline in prostate-cancer mortality in the USA compared with the UK in 1994–2004 coincided with much higher uptake of PSA screening in the USA. Explanations for the different trends in mortality include the possibility of an early effect of initial screening rounds on men with more aggressive asymptomatic disease in the USA, different approaches to treatment in the two countries, and bias related to the misattribution of cause of death. Speculation over the role of screening will continue until evidence from randomised controlled trials is published. Funding: ProMPT (Prostate Cancer: Mechanisms of Progression and Treatment) collaborative (UK National Cancer Research Institute, London, UK, and UK Medical Research Council, London, UK). [Copyright &y& Elsevier]

Background One commonly held theory of ageing is that it is caused by oxidative damage to critical molecules in the body, including proteins, lipids and nucleic acids. Accumulation of oxidative DNA damage with age will occur if there is an increase in reactive oxygen species in the body, or a decline in antioxidant defences, or a reduced efficiency of DNA repair. Subjects and Methods Using the comet assay, we have measured DNA breaks and oxidised purines in lymphocytes from subjects of different age groups: 20-35 (n = 40), 63-70 (n = 35), and 75-82 (n = 22). We also measured the resistance of lymphocyte DNA to H2O2-induced oxidative damage, and the repair activity of cell-free lymphocyte extracts on a substrate containing 8-oxoguanine. Results We found an increase in oxidative base damage in old age, but this apparently does not result from deterioration of either antioxidant defence or DNA repair. In fact, both of these tend to increase with age. There were few age-related differences in plasma levels of dietary antioxidants: tocopherols and retinol were higher in the older subjects, while lycopene was highest in the youngest age group. Conclusions It is possible, that in old age, antioxidant defences and DNA repair are induced, in response to a higher level of oxidative damage, as mitochondria become more leaky and release more reactive oxygen. It is equally possible that older people, as survivors, had relatively high levels of antioxidant defences and DNA repair earlier in their lives, compared with those who did not survive to such an age. [ABSTRACT FROM AUTHOR]

Objective: To assess the association of having been breast fed with social class mobility between childhood and adulthood. Design: Historical cohort study with a 60-year follow-up from childhood into adulthood. Setting: 16 urban and rural centres in England and Scotland. Participants: 3182 original participants in the Boyd Orr Survey of Diet and Health in Pre-War Britain (1937–39) were sent follow-up questionnaires between 1997 and 1998. Analyses are based on 1414 (44%) responders with data on breast feeding measured in childhood and occupational social class in both childhood and adulthood. Main outcome: Odds of moving from a lower to a higher social class between childhood and adulthood in those who were ever breast fed versus those who were bottle fed. Results: The prevalence of breast feeding varied by survey district (range 45-86%) but not with household income (p=0.7), expenditure on food (p=0.3), number of siblings (p=0.7), birth order (p=0.5) or social class (p=0.4) in childhood. Participants who had been breast fed were 41% (95% CI 10% to 82%) more likely to move up a social class in adulthood (p=0.007) than bottle-fed infants. Longer breastfeeding duration was associated with greater odds of upward social mobility in fully adjusted models (p for trend=0.003). Additionally controlling for survey district, household income and food expenditure in childhood, childhood height, birth order or number of siblings did not attenuate these associations. In an analysis comparing social mobility among children within families with discordant breastfeeding histories, the association was somewhat attenuated (OR 1.16; 95% CI 0.74 to 1.8). Conclusions: Breast feeding was associated with upward social mobility. Confounding by other measured childhood predictors of social class in adulthood did not explain this effect, but we cannot exclude the possibility of residual or unmeasured confounding. [ABSTRACT FROM AUTHOR]

The article evaluates the efficacy and tolerability of oxycodone drug in the relief of pains in cancer. In the course of the research, it made to analyze the efficacy between the drugs of choice, the analgesic, oxycodone and morphine use. The data revealed that many favored the essence of oxycodone, with the adverse effects of mouth drying and drowsiness, than the use of analgesic and morphine which are administered intramuscularly due to its faster results and the extent of the relief.

Aim To document the impact on clinical practice in England of media attention around possible adverse effects of paroxetine. Design Analysis of national selective serotonin reuptake inhibitor (SSRI) prescribing trends and yellow-card adverse drug reaction reports, 2001–2004. Results From a steady state in 2001, paroxetine prescribing declined sharply from April 2002, coinciding with a USA regulatory action; the subsequent decline in paroxetine prescribing was 1.87% per month (95% confidence interval − 2.06, −1.68). Other SSRI prescribing increased by 1% per month until a major UK review of SSRIs in children in December 2003, after which prescribing plateaued. Media publicity was associated with short-term peaks in yellow-card reports related to paroxetine. Conclusion Falls in paroxetine and other SSRI prescribing in the UK coincided, respectively, with regulatory communications from the USA and the UK, but associations may have noncausal or other explanations. Reports of adverse reactions to paroxetine appeared to increase after adverse media publicity about the drug. [ABSTRACT FROM AUTHOR]

Background: Having been breast-fed has been suggested to influence cancer risk in adulthood. We investigated associations between breast-feeding during infancy and adult cancer incidence and mortality in a cohort study and meta-analyses of published studies. Methods: The Boyd Orr cohort consisted of 4999 subjects who were originally surveyed in 1937–39, when they were 0–19 years of age. Cancer outcomes from 1948 through 2003 were available for 4379 (88%) subjects, and 3844 had complete data on all covariates. Associations of breast-feeding with cancer were investigated using proportional hazards models. We also identified 14 studies on infant feeding and cancer published from 1966 through July 2005, of which 10 could be combined with the Boyd Orr cohort results in a meta-analysis of breast cancer using random-effect models. Results: In the Boyd Orr cohort, ever having been breast-fed, compared with never having been breast-fed, was not associated with the incidence of all cancers (hazard ratio [HR] = 1.07, 95% confidence interval [CI] = 0.89 to 1.28) or of any individual cancer type examined (prostate HR = 1.43, 95% CI = 0.58 to 3.52; breast HR = 1.62, 95% CI = 0.89 to 2.94; colorectal HR = 0.86, 95% CI = 0.45 to 1.63; gastric HR = 1.22, 95% CI = 0.47 to 3.15). In the meta-analysis, there was also no association between breast-feeding and breast cancer (regardless of menopausal status) (relative risk [RR] = 0.94, 95% CI = 0.85 to 1.04). However, breast-fed women had a reduced risk of premenopausal breast cancer (RR = 0.88, 95% CI = 0.79 to 0.98) but not of postmenopausal breast cancer (RR = 1.00, 95% CI = 0.86 to 1.16). Conclusion: Ever having been breast-fed was not associated with overall breast cancer risk, although the meta-analysis revealed a reduced risk of premenopausal breast cancer in women who had been breast-fed. [ABSTRACT FROM AUTHOR]

The influence of infant feeding method (breast/formula) on growth factor levels could underlie associations of breastfeeding with childhood growth and risk factors for cardiovascular disease. We investigated associations of having been breastfed with serum IGF-I and IGFBP-3 in childhood.Prospective birth cohort study (subsample of the Avon Longitudinal Study of Parents and Children, UK) based on 871 children born in 1991/1992 who underwent clinical follow-up and blood tests at age 7–8 years. A total of 488 (56%) children had complete data.In children with complete data, the age- and sex-standardized IGF-I levels of those who were partially or exclusively breastfed were 6·1 and 13·8 ng/ml higher, respectively, than those who were never breastfed (increase in IGF-I levels per category of breastfeeding exclusivity: 7·1 ng/ml; 95% CI: 0·3–13·9;P = 0·04). In models also controlling for birthweight, gestational age, mother's age, and socioeconomic and dietary factors, the breastfeeding–IGF-I association was attenuated (regression coefficient: 3·3 ng/ml;−4·2–10·7;P = 0·4); further adjustment for IGFBP-3 made little difference (regression coefficient: 4·1 ng/ml;−2·8–10·9;P = 0·2). There was little evidence for an association between breastfeeding and IGFBP-3 or the molar ratio IGF-I/IGFBP-3.The positive association between breastfeeding and IGF-I could be due to residual confounding or to chance. Nevertheless, the magnitude of the fully adjusted effect estimate and the novelty of the association suggest that larger studies should now be conducted to confirm or refute the hypothesis that variations in IGF-I by infant feeding mode explain associations of breastfeeding with health in later life. [ABSTRACT FROM AUTHOR]

Objective. To examine the influence of initial infant feeding on obesity in later life. Methods. A systematic review of published studies investigating the association between infant feeding and a measure of obesity was performed with Medline (1966 onward) and Embase (1980 onward) databases, supplemented with manual searches. Data extraction was conducted by 2 authors. Analyses were based on odds ratios of obesity among initially breastfed subjects, compared with formula-fed subjects, pooled with fixed-effects models. Results. Sixty-one studies reported on the relationship of infant feeding to a measure of obesity in later life; of these, 28 (298 900 subjects) provided odds ratio estimates. In these studies, breastfeeding was associated with a reduced risk of obesity, compared with formula feeding (odds ratio: 0.87; 95% confidence interval [CI]: 0.85 - 0.89). The inverse association between breastfeeding and obesity was particularly strong in 11 small studies of <500 subjects (odds ratio: 0.43; 95% CI: 0.33--0.55) but was still apparent in larger studies of ≥500 subjects (odds ratio: 0.88; 95% CI: 0.85--0.90). In 6 studies that adjusted for all 3 major potential confounding factors (parental obesity, maternal smoking, and social class), the inverse association was reduced markedly (from an odds ratio of 0.86 to 0.93) but not abolished. A sensitivity analysis examining the potential impact of the results of 33 published studies (12 505 subjects) that did not provide odds ratios (mostly reporting no relationship between breastfeeding and obesity) showed little effect on the results. Conclusions. Initial breastfeeding protects against obesity in later life. However, a further review including large unpublished studies exploring the effect of confounding factors in more detail is needed. [ABSTRACT FROM AUTHOR]

Study objective: To investigate the association of having been breast fed with cardiovascular disease risk factors, incidence, and mortality. Design: Prospective cohort study. Setting: Caerphilly, South Wales. Participants: All men aged 45-59 years living in and around the study area. Of 2818 eligible men, 2512 (89%) were seen. Altogether 1580 men (63%) obtained details of how they had been fed in infancy (ever breast fed or only bottle fed) from their mother or a close female relative. A subset of 1062 subjects reported on whether bottle fed or the duration of breast feeding if breast fed. Main results: Breast feeding was not associated with stature, blood pressure, insulin resistance, total cholesterol, or fibrinogen. In fully adjusted models (controlling for age, birth order, and social position in childhood and adulthood), breast feeding was associated with greater body moss index than bottle feeding (difference: 0.41 kg/m² (95% CI: 0.01 to 0.81). There was a positive association between breast feeding and coronary heart disease mortality (hazard ratio: 1.73; 1.17 to 2.55) and incidence (1.54; 1 .17 to 2.04) (fully adjusted models). There was no evidence of a duration-response effect, which might be expected if an adverse effect of breast feeding was causal. Conclusion: These data provide little evidence of a protective influence of breast feeding on cardiovascular disease risk factors, incidence, or mortality. A possible adverse effect of breast feeding on coronary heart disease incidence was observed but may have a number of explanations, including selection and information bias. In view of these limitations, further long term studies with improved measures of infant feeding are required to confirm or refute these findings. [ABSTRACT FROM AUTHOR]

Objective: We analyzed the value of topoisomerase IIα (Topo II) in predicting the clinical response to anthracycline-based neoadjuvant chemotherapy in breast cancers and the potential changes in Topo II after chemotherapy. In parallel, HER2, which is commonly coexpressed with Topo II, and p53, a modulator of chemotherapy activity, were also analyzed. Methods: Forty-one patients with primary breast cancer and treated with neoadjuvant anthracycline-based chemotherapy (FAC or FEC) were included for the present study. Topo II, HER2 and p53 expression were measured by immunohistochemistry in pre and post chemotherapy (at the time of surgery), tumor specimens and the results were correlated with the clinical response. Results: Topo II was overexpressed in 16 of 41 (31%) tumors before treatment, and this overexpression was significantly associated with clinical response (p = 0.03). HER2 and p53 were unrelated to response. Notably, Topo II overexpression, but not HER2 or p53, was lost in specimens after chemotherapy (p = 0.01). Conclusion: The observed link between Topo II and the clinical response to neoadjuvant anthracycline-based chemotherapy, together with its loss after chemotherapy, implies that Topo II deserves further testing in a prospective setting as a predictive marker. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

We have performed a density functional study of 15 different structural models of the Si(5 5 7)–Au surface reconstruction. Here we present a brief summary of the main structural trends obtained for the more favourable models, focusing afterwards in a detailed description of the atomic structure, electronic properties and simulated STM images of the most stable model predicted by our calculations. This structure is in very good agreement with that recently proposed from X-ray diffraction measurements by Robinson et al. [Phys. Rev. Lett. 88 (2002) 096194]. [Copyright &y& Elsevier]

Objectives: To investigate the national distribution of prolonged waiting for elective day case and inpatient surgery, and to examine associations of prolonged waiting with markers of NHS capacity, activity in the independent sector, and need. Setting: NHS hospital trusts in England. Population: People waiting for elective treatment in the specialties of general surgery; ear, nose and throat surgery; ophthalmic surgery; and trauma and orthopaedic surgery. Main outcome measure: Numbers of people waiting six months or longer (prolonged waiting). Characteristics of trusts with large numbers waiting six months or longer were examined by using logistic regression. Results: The distribution of numbers of people waiting for day case or elective surgery in all the specialties examined was highly positively skewed. Between 52% and 83% of patients waiting longer than six months in the specialties studied were found in one quarter of trusts, which in turn contributed 23-45% of the national throughput specific to the specialty. In general, there was little evidence to show that capacity (measured by numbers of operating theatres, dedicated day case theatres, available beds, and bed occupancy rate) or independent sector activity were associated with prolonged waiting, although exceptions were noted for individual specialties. There was consistent evidence showing an increase in prolonged waiting, with increased numbers of anaesthetists across all specialties and with increased bed occupancy rates for ear, nose, and throat surgery. Markers of greater need for health care, such as deprivation score and rate of limiting long term illness, were inversely associated with prolonged waiting. Conclusion: In most instances, substantial numbers of patients waiting unacceptably long periods for elective surgery were limited to a small number of hospitals. Little and inconsistent support was found for associations of prolonged waiting with markers of capacity, independent sector... [ABSTRACT FROM AUTHOR]

Aims To estimate the rates of common adverse events in patients treated with the proton pump inhibitors omeprazole, lansoprazole and pantoprazole in general practice in England. Methods In prescription‐event monitoring cohort studies, data on dispensed prescriptions prescribed by general practitioners in England soon after each drug was launched were linked to subsequent clinical events recorded by the prescriber. 16 205 patients prescribed omeprazole between June 1989 and June 1990, 17 329 patients prescribed lansoprazole between May and November 1994, and 11 541 patients prescribed pantoprazole between December 1996 and June 1997 were studied. Results The commonest adverse events in the omeprazole, lansoprazole and pantoprazole cohorts were diarrhoea (incidence: 0.18, 0.39 and 0.23 per 1000 days of exposure, respectively); nausea/vomiting (incidence: 0.16, 0.22 and 0.18 per 1000 days of exposure, respectively); abdominal pain (incidence: 0.17, 0.21 and 0.17 per 1000 days of exposure, respectively); and headache (incidence rates: 0.10, 0.17 and 0.15 per 1000 days of exposure, respectively). The remaining adverse events occurred at rates of less than 0.11 per 1000 days of exposure. There were little absolute differences in the rates of most events between the three proton pump inhibitors. However, diarrhoea was more commonly associated with lansoprazole compared with omeprazole (rate difference: 0.21 per 1000 days of exposure; 95% CI 0.17, 0.25; rate ratio: 2.11; 1.78, 2.51), and there was a clear age‐response relationship. Conclusions Adverse events occurred relatively infrequently in all three cohorts. There were only small absolute differences in event rates between the three drugs, although these data suggest the hypothesis that lansoprazole is associated with more frequent occurrence of diarrhoea, particularly in the elderly. [ABSTRACT FROM AUTHOR]

Aims Meloxicam is a novel nonsteroidal anti‐inflammatory drug (NSAID) which may be associated with fewer adverse upper gastrointestinal events than other NSAIDs because it preferentially inhibits the inducible enzyme cyclo‐oxygenase‐2 relative to the constitutive isoform, cyclo‐oxygenase‐1. The aims of the study were to: determine the rate of adverse events associated with meloxicam in general practice, stratify these rates by selected risk factors, and to identify signals of previously unsuspected adverse events associated with meloxicam. Methods As part of the national prescription‐event monitoring pharmacovigilance system for newly launched drugs in general practice, all patients prescribed meloxicam in England between December 1996 and March 1997 were identified by the central Prescription Pricing Authority. We sent short questionnaires to all prescribers asking about adverse events experienced within 6 months of the first prescription. Results There were 19 087 patients in the study. The rate of dyspepsia during the first month of exposure was 28.3 per 1000 patient‐months. There were 33 reports of upper gastrointestinal haemorrhage during treatment (rate: 0.4 per 1000 months). A history of gastrointestinal disorder in the previous year was associated with an increased rate of dyspepsia (rate ratio: 3.0; 95% confidence interval: 2.6, 3.4), abdominal pain (2.1; 1.6, 2.6), and peptic ulcer (4.0; 1.4, 13.2). Prior NSAID use was associated with a 20–30% decrease in the rate of dyspepsia and abdominal pain in patients starting meloxicam, while patients prescribed concomitant gastroprotective agents had a two to three‐fold increased rate of dyspepsia, abdominal pain and peptic ulceration. Other rare events were thrombocytopenia (n = 2); interstitial nephritis (n = 1) and idiosyncratic liver abnormalities (n = 1). Conclusions In the absence of gastro‐intestinal risk factors the incidence of gastro‐intestinal disturbance was low. Such risk factors should be carefully reviewed prior to prescribing meloxicam. [ABSTRACT FROM AUTHOR]

Background: Some modifiable risk factors for cancer originate during adolescence. While there is evidence indicating relationships between adverse childhood experiences and health risk behaviours generally, little is known about how childhood adversity influences the engagement of adolescents in cancer risk behaviours. This study aimed to determine the relationship between adverse childhood experiences and adolescent cancer risk behaviours. Methods: Data were collected prospectively from birth to age 18 years on children born to mothers enrolled into the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort study. Multivariable linear regression models assessed relationships of a composite exposure measure comprised of adverse childhood experiences (total number of childhood adversities experienced from early infancy until age 9 years) with multiple cancer risk behaviours. The latter was expressed as a single continuous score for tobacco smoking, alcohol consumption, obesity, unsafe sex, and physical inactivity, at ages 11, 14, 16 and 18 years. Analysis was carried out on the complete case and imputation samples of 1,368 and 7,358 participants respectively. Results: All adolescent cancer risk behaviours increased in prevalence as the adolescents grew older, except for obesity. Each additional adverse childhood experience was associated with a 0.25 unit increase in adolescent cancer risk behaviour (95% CI 0.16–0.34; p < 0.001). Individually, parental substance misuse (β 0.64, 95% CI 0.25–1.03, p < 0.001) and parental separation (β 0.56, 95% CI 0.27–0.86, p < 0.001) demonstrated the strongest evidence of association with engagement in adolescent cancer risk behaviour. Conclusion: Childhood adversity was associated with a greater degree of engagement in adolescent cancer risk behaviours. This finding demonstrates the need for targeted primary and secondary prevention interventions that reduce engagement across multiple cancer risk behaviours for children and adolescents who have experienced adversity in childhood, such as parental substance misuse and separation, and reduce exposure to adversity. [ABSTRACT FROM AUTHOR]

Background: Sedentary behaviours have been associated with increased risks of some common cancers in epidemiological studies; however, it is unclear if these associations are causal. Methods: We used univariable and multivariable two-sample Mendelian randomisation (MR) to examine potential causal relationships between sedentary behaviours and risks of breast, colorectal and prostate cancer. Genetic variants associated with self-reported leisure television watching and computer use were identified from a recent genome-wide association study (GWAS). Data related to cancer risk were obtained from cancer GWAS consortia. A series of sensitivity analyses were applied to examine the robustness of the results to the presence of confounding. Results: A 1-standard deviation (SD: 1.5h/day) increment in hours of television watching increased risk of breast cancer (OR per 1-SD: 1.15, 95% confidence interval [CI]: 1.05–1.26) and colorectal cancer (OR per 1-SD: 1.32, 95% CI: 1.16– 1.49) while there was little evidence of an association for prostate cancer risk (OR per 1-SD: 0.94, 95% CI: 0.84–1.06). After adjusting for years of education, the effect estimates for television watching were attenuated (breast cancer, OR per 1-SD: 1.08, 95% CI: 0.92–1.27; colorectal cancer, OR per 1-SD: 1.08, 95% CI: 0.90–1.31). Post hoc analyses showed that years of education might have a possible confounding and mediating role in the association between television watching with breast and colorectal cancer. Consistent results were observed for each cancer site according to sex (colorectal cancer), anatomical subsites and cancer subtypes. There was little evidence of associations between genetically predicted computer use and cancer risk. Conclusions: Our univariable analysis identified some positive associations between hours of television watching and risks of breast and colorectal cancer. However, further adjustment for additional lifestyle factors especially years of education attenuated these results. Future studies using objective measures of exposure can provide new insights into the possible role of sedentary behaviour in cancer development. [ABSTRACT FROM AUTHOR]

Aims Little is known about the frequency with which suspected adverse drug reactions are seen by general practitioners after the prescription of newly marketed drugs. We investigated age and sex specific incidence rates of suspected adverse drug reactions recorded by general practitioners in England after the prescription of selected newly marketed drugs. Methods Information was collected from 48 national cohort studies of newly marketed drugs studied by prescription-event monitoring. Questionnaires were sent to prescribers asking for details of events and suspected adverse drug reactions recorded in the patients’ notes occurring after the drugs were prescribed. Results During the 48 cohort studies, a total of 513 608 patients were investigated, of which 221 781 (43.2%) were males and 285 862 (55.7%) were females. The overall incidence of suspected adverse drug reactions in males was 12.9 per 10 000 patient-months of exposure (95% confidence limits 12.3 to 13.5), and in females was 20.6 per 10 000 patient-months of exposure (95% confidence limits 19.9 to 21.3). The overall age-standardised relative risk of an adverse drug reaction in females compared with males was 1.6 (1.5–1.7). This sex difference was significant in all age groups above 19 years of age, and was relatively consistent across all age groups (χ2 test for heterogeneity=9.2, P=0.3).The highest rate of recording in males was in the 50–59 year age group, and in females was in the 30–39 year age group. Conclusions In general practice in England, suspected adverse drug reactions to newly marketed drugs are recorded more often in adults aged between 30 and 59 years of age and are 60% more common in women than in men. The sex difference occurs in all age groups over 19 years of age. [ABSTRACT FROM AUTHOR]

Using Q-technique, we examined conceptions of representation among a sample of delegates to the 1984 Democratic and Republican National Conventions. Analysis of the data revealed four perspectives on representation in the sample: the "trustee," the belief that group interests should be represented, the belief that representation is a matter of the representative's conscience, and the "delegate-servant." Surprisingly, no delegates saw themselves as representatives of party officials or presidential candidates. We conclude that representation is a subjective process and should be examined from that perspective. [ABSTRACT FROM AUTHOR]

Examines inceptions and discontinuations of antidepressants in general medical practice in Great Britain. Reasons for discontinuation; Proportion of switches to another antidepressant; Selective serotonin reuptake inhibitors; Tricyclic antidepressants.

Examines the second-intentional logic of philosopher Charles Peirce regarding his philosophy of notation. Overview of the icons of algebra; Application of existential and universal quantifiers; Kind of higher-order quantifier in handling of identity; Principle of the existence of a special sum.

Summary: Background: Caesarean delivery has been associated with later adiposity, perhaps via early programming or perhaps because of residual confounding by maternal or birth characteristics. Objectives: Examine associations of caesarean delivery with adiposity and cardio‐metabolic biomarkers. Methods: Observational analysis of 15 069 children in the PROBIT cohort in Belarus. We examined measures of child anthropometry and blood pressure at 6.5, 11.5 and 16 years and fasting blood (11.5 years). Results: Caesarean‐delivered children were slightly heavier at 6.5 (mean BMI 15.8 vs. 15.6 kg/m2), 11.5 (18.4 vs. 18.2) and 16 years (21.5 vs. 21.3). After adjustment for prenatal characteristics including maternal third trimester BMI, however, we observed no association of caesarean versus vaginal delivery with child BMI (β 0.05 kg/m2; 95%CI: −0.03, 0.14), sum of skinfolds (0.14 mm; −0.13, 0.42), waist circumference (−0.07 cm; −0.23, 0.10), obesity (OR 0.99; 0.76, 1.29), or systolic (−0.20 mmHg; −0.70, 0.30) or diastolic (−0.17 mmHg, −0.60, 0.26) blood pressure at 6.5 years; results were similar at 11.5 and 16 years. At 11.5 years, we observed a modest association of caesarean delivery with fasting insulin (0.33 mU/L; 0.00, 0.65). Conclusions: Caesarean delivery had little or no association with adiposity or related cardio‐metabolic biomarkers in childhood. Adjustment for maternal BMI attenuated all outcome effect estimates. [ABSTRACT FROM AUTHOR]

In this article, the author discusses aspects of the significance of science for the development of Africa. The author mentions that scientific education and research is improving on various African countries even though slow translation for important technological improvements is observed. It examines various initiatives and programs for scientific research which were organized by African scientists like the African School on Electronic Structure Methods and Applications (ASESMA).

The article reports on the potential of double clustering to explain the negative results of some cluster randomised trials. Among the advantages of cluster randomised trials is their feasibility based on the fact that group dynamics can make it easier to change practices or behaviours within an overall group. Their disadvantages include reduced statistical power due to within cluster correlation of outcomes. The author also presents a review of an experience with the Promotion of Breastfeeding Intervention Trial to evaluate the effect of measurement error and clustering.