Search

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]

Background: The associations of adiposity with aggressive prostate cancer risk are unclear. Using two‐sample Mendelian randomization, we assessed the association of metabolically unfavourable adiposity (UFA), favourable adiposity (FA) and for comparison body mass index (BMI), with prostate cancer, including aggressive prostate cancer. Methods: We examined the association of these genetically predicted adiposity‐related traits with risk of prostate cancer overall, aggressive and early onset disease using outcome summary statistics from the PRACTICAL consortium (including 15,167 aggressive cases). Results: In inverse‐variance weighted models, there was little evidence that genetically predicted one standard deviation higher UFA, FA and BMI were associated with aggressive prostate cancer [OR: 0.85 (95% CI:0.61–1.19), 0.80 (0.53–1.23) and 0.97 (0.88–1.08), respectively]; these associations were largely consistent in sensitivity analyses accounting for horizontal pleiotropy. There was no strong evidence that genetically determined UFA, FA or BMI were associated with overall prostate cancer or early age of onset prostate cancer. Conclusions: We did not find differences in the associations of UFA and FA with prostate cancer risk, which suggest that adiposity is unlikely to influence prostate cancer via the metabolic factors assessed; however, these did not cover some aspects related to metabolic health that may link obesity with aggressive prostate cancer, which should be explored in future studies. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to systematically evaluate the direction of any potential causal effect between sleep and adiposity traits. Methods: Two‐sample Mendelian randomization was used to assess the association of genetically predicted sleep traits with adiposity and vice versa. Using data from UK Biobank and 23andMe, the sleep traits explored were morning preference (chronotype; N = 697,828), insomnia (N = 1,331,010), sleep duration (N = 446,118), napping (N = 452,633), and daytime sleepiness (N = 452,071). Using data from the Genetic Investigation of ANthropometric Traits (GIANT) and Early Growth Genetics (EGG) consortia, the adiposity traits explored were adult BMI, hip circumference (HC), waist circumference (WC), waist‐hip ratio (WHR; N = 322,154), and childhood BMI (N = 35,668). Results: This study found evidence that insomnia symptoms increased mean WC, BMI, and WHR (difference in means, WC = 0.39 SD [95% CI: 0.13‐0.64], BMI = 0.47 SD [95% CI: 0.22‐0.73], and WHR = 0.34 SD [95% CI: 0.16‐0.52]). Napping increased mean WHR (0.23 SD [95% CI: 0.08‐0.39]). Higher HC, WC, and adult BMI increased odds of daytime sleepiness (HC = 0.02 SD [95% CI: 0.01‐0.04], WC = 0.04 SD [95% CI: 0.01‐0.06], and BMI 0.02 SD [95% CI: 0.00‐0.04]). This study also found that higher mean childhood BMI resulted in lower odds of napping (−0.01 SD [95% CI: 0.02‐0.00]). Conclusions: The effects of insomnia on adiposity and of adiposity on daytime sleepiness suggest that poor sleep and weight gain may contribute to a feedback loop that could be detrimental to overall health. [ABSTRACT FROM AUTHOR]

Deucravacitinib, a novel, selective inhibitor of TYK2 is currently under review at the FDA and EMA for treatment of moderate‐to‐severe plaque psoriasis. It is unclear whether recent safety concerns (ie, elevated rates of lung cancer and lymphoma) related to similar medications (ie, other JAK inhibitors) are shared with this novel TYK2 inhibitor. We used a partial loss‐of‐function variant in TYK2 (rs34536443), previously shown to protect against psoriasis and other autoimmune diseases, to evaluate the potential effect of therapeutic TYK2 inhibition on risk of lung cancer and non‐Hodgkin lymphoma. Summary genetic association data on lung cancer risk were obtained from a GWAS meta‐analysis of 29 266 cases and 56 450 controls in the Integrative Analysis of Lung Cancer Risk and Aetiology (INTEGRAL) consortium. Summary genetic association data on non‐Hodgkin lymphoma risk were obtained from a GWAS meta‐analysis of 8489 cases and 374 506 controls in the UK Biobank and InterLymph consortium. In the primary analysis, each copy of the minor allele of rs34536443, representing partial TYK2 inhibition, was associated with an increased risk of lung cancer (OR 1.15, 95% CI 1.09‐1.23, P = 2.29 × 10−6) and non‐Hodgkin lymphoma (OR 1.18, 95% CI 1.05‐1.33, P = 5.25 × 10−3). Our analyses using an established partial loss‐of‐function mutation to mimic TYK2 inhibition provide genetic evidence that therapeutic TYK2 inhibition may increase risk of lung cancer and non‐Hodgkin lymphoma. These findings, consistent with recent reports from postmarketing trials of similar JAK inhibitors, could have important implications for future safety assessment of deucravacitinib and other TYK2 inhibitors in development. What's new? Increased rates of lymphoma and lung cancer associated with Janus kinase (JAK) inhibitors used in the treatment of chronic inflammatory conditions have raised significant concern. A promising alternative, particularly for the treatment of plaque psoriasis, is deucravacitinib, a selective inhibitor of JAK family member TYK2. Here, the authors explored possible carcinogenic effects of TYK2 inhibition by genetic proxy based on a partial loss‐of‐function variant in TYK2 that provides protection against psoriasis. Analyses show that genetically proxied TYK2 inhibition increases lung cancer and non‐Hodgkin lymphoma risk. The findings could impact safety assessments of deucravacitinib and future novel TYK2 inhibitors. [ABSTRACT FROM AUTHOR]

Previous studies had limited power to assess the associations of testosterone with aggressive disease as a primary endpoint. Further, the association of genetically predicted testosterone with aggressive disease is not known. We investigated the associations of calculated free and measured total testosterone and sex hormone‐binding globulin (SHBG) with aggressive, overall and early‐onset prostate cancer. In blood‐based analyses, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression from prospective analysis of biomarker concentrations in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group (up to 25 studies, 14 944 cases and 36 752 controls, including 1870 aggressive prostate cancers). In Mendelian randomisation (MR) analyses, using instruments identified using UK Biobank (up to 194 453 men) and outcome data from PRACTICAL (up to 79 148 cases and 61 106 controls, including 15 167 aggressive cancers), ORs were estimated using the inverse‐variance weighted method. Free testosterone was associated with aggressive disease in MR analyses (OR per 1 SD = 1.23, 95% CI = 1.08‐1.40). In blood‐based analyses there was no association with aggressive disease overall, but there was heterogeneity by age at blood collection (OR for men aged <60 years 1.14, CI = 1.02‐1.28; Phet =.0003: inverse association for older ages). Associations for free testosterone were positive for overall prostate cancer (MR: 1.20, 1.08‐1.34; blood‐based: 1.03, 1.01‐1.05) and early‐onset prostate cancer (MR: 1.37, 1.09‐1.73; blood‐based: 1.08, 0.98‐1.19). SHBG and total testosterone were inversely associated with overall prostate cancer in blood‐based analyses, with null associations in MR analysis. Our results support free testosterone, rather than total testosterone, in the development of prostate cancer, including aggressive subgroups. [ABSTRACT FROM AUTHOR]

Objective: To investigate the functional and quality of life (QoL) outcomes of treatments for localised prostate cancer and inform treatment decision‐making. Patients and Methods: Men aged 50–69 years diagnosed with localised prostate cancer by prostate‐specific antigen testing and biopsies at nine UK centres in the Prostate Testing for Cancer and Treatment (ProtecT) trial were randomised to, or chose one of, three treatments. Of 2565 participants, 1135 men received active monitoring (AM), 750 a radical prostatectomy (RP), 603 external‐beam radiotherapy (EBRT) with concurrent androgen‐deprivation therapy (ADT) and 77 low‐dose‐rate brachytherapy (BT, not a randomised treatment). Patient‐reported outcome measures (PROMs) completed annually for 6 years were analysed by initial treatment and censored for subsequent treatments. Mixed effects models were adjusted for baseline characteristics using propensity scores. Results: Treatment‐received analyses revealed different impacts of treatments over 6 years. Men remaining on AM experienced gradual declines in sexual and urinary function with age (e.g., increases in erectile dysfunction from 35% of men at baseline to 53% at 6 years and nocturia similarly from 20% to 38%). Radical treatment impacts were immediate and continued over 6 years. After RP, 95% of men reported erectile dysfunction persisting for 85% at 6 years, and after EBRT this was reported by 69% and 74%, respectively (P < 0.001 compared with AM). After RP, 36% of men reported urinary leakage requiring at least 1 pad/day, persisting for 20% at 6 years, compared with no change in men receiving EBRT or AM (P < 0.001). Worse bowel function and bother (e.g., bloody stools 6% at 6 years and faecal incontinence 10%) was experienced by men after EBRT than after RP or AM (P < 0.001) with lesser effects after BT. No treatment affected mental or physical QoL. Conclusion: Treatment decision‐making for localised prostate cancer can be informed by these 6‐year functional and QoL outcomes. [ABSTRACT FROM AUTHOR]

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]

Background and aims: Varenicline and nicotine replacement therapy (NRT) are the most commonly used medications to quit smoking. Given their widespread use, monitoring adverse risks remains important. This study aimed to estimate the neuropsychiatric and cardiovascular risks associated with varenicline and NRT as used in routine UK care. Design Case–cross‐over study. Setting: UK‐based electronic primary care records in the Clinical Practice Research Datalink from 2006 to 2015 linked to hospital and mortality data sets. Participants: Adult smokers (n =282,429) observed during periods when exposed and not exposed to either varenicline or NRT. Measurements Main outcomes included suicide, self‐harm, myocardial infarction (MI), all‐cause death and cause‐specific death [MI, chronic obstructive pulmonary disease (COPD)]. In primary analyses, conditional logistic regression was used to compare the chance of varenicline or NRT exposure during the risk period (90 days prior to the event) with the chance of exposure during an earlier single reference period (91–180 days prior to the event) or multiple 90‐day reference periods to increase statistical power. Findings In the primary analyses, findings were inconclusive for the associations between varenicline and the main outcomes using a single reference period, while NRT was associated with MI [odds ratio (OR) = 1.40, 95% confidence interval (CI) = 1.18–1.67]. Using multiple reference periods, varenicline was associated with an increased risk of self‐harm (OR = 1.32, 95% CI = 1.12–1.56) and suicide (OR = 3.56, 95% CI = 1.32–9.60) but a reduction in all‐cause death (OR = 0.75, 95% CI = 0.61–0.93). NRT was associated with MI (OR = 1.54, 95% CI = 1.36–1.74), self‐harm (OR = 1.30, 95% CI = 1.18–1.44) and deaths from MI (OR = 1.53, 95% CI = 1.11–2.10), COPD (OR = 1.33, 95% CI = 1.14–1.56) and all causes (OR = 1.28, 95% CI = 1.18–1.40) when using multiple reference periods. Conclusions: There appear to be positive associations between (1) nicotine replacement therapy (NRT) and myocardial infarction, death and risk of self‐harm and (2) varenicline and increased risk of self‐harm and suicide, as well as a negative association between varenicline and all‐cause death. The associations may not be causal. They may reflect health changes at the time of smoking cessation (nicotine replacement therapy is prescribed for people with cardiac problems) or be associated with quit attempts (exposure to both medicines was associated with self‐harm). [ABSTRACT FROM AUTHOR]

Insulin‐like growth factor‐I (IGF‐I) and testosterone have been implicated in prostate cancer aetiology. Using data from a large prospective full‐cohort with standardised assays and repeat blood measurements, and genetic data from an international consortium, we investigated the associations of circulating IGF‐I, sex hormone‐binding globulin (SHBG), and total and calculated free testosterone concentrations with prostate cancer incidence and mortality. For prospective analyses, risk was estimated using multivariable‐adjusted Cox regression in 199 698 male UK Biobank participants. Hazard ratios (HRs) were corrected for regression dilution bias using repeat hormone measurements from a subsample. Two‐sample Mendelian randomisation (MR) analysis of IGF‐I and risk used genetic instruments identified from UK Biobank men and genetic outcome data from the PRACTICAL consortium (79 148 cases and 61 106 controls). We used cis‐ and all (cis and trans) SNP MR approaches. A total of 5402 men were diagnosed with and 295 died from prostate cancer (mean follow‐up 6.9 years). Higher circulating IGF‐I was associated with elevated prostate cancer diagnosis (HR per 5 nmol/L increment = 1.09, 95% CI 1.05‐1.12) and mortality (HR per 5 nmol/L increment = 1.15, 1.02‐1.29). MR analyses also supported the role of IGF‐I in prostate cancer diagnosis (cis‐MR odds ratio per 5 nmol/L increment = 1.34, 1.07‐1.68). In observational analyses, higher free testosterone was associated with a higher risk of prostate cancer (HR per 50 pmol/L increment = 1.10, 1.05‐1.15). Higher SHBG was associated with a lower risk (HR per 10 nmol/L increment = 0.95, 0.94‐0.97), neither was associated with prostate cancer mortality. Total testosterone was not associated with prostate cancer. These findings implicate IGF‐I and free testosterone in prostate cancer development and/or progression. What's new? Testosterone, insulin‐like growth factor‐I (IGF‐I), and sex hormone‐binding globulin (SHBG) all have been associated with prostate‐cancer risk. In this large, prospective study, the authors analyzed how these circulating hormones might impact mortality as well as risk. They found that men with higher IGF‐I had a higher risk of both prostate‐cancer diagnosis and mortality. Men with higher free testosterone had an increased risk of prostate cancer, while men with higher SHBG had a decreased risk. These results support the roles of IGF‐I and testosterone in prostate cancer development. [ABSTRACT FROM AUTHOR]

The epidemiological literature reports inconsistent associations between consumption or circulating concentrations of micronutrients and breast cancer risk. We investigated associations between genetically predicted concentrations of 11 micronutrients (beta‐carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B6, vitamin B12 and zinc) and breast cancer risk using Mendelian randomization (MR). A two‐sample MR study was conducted using 122 977 women with breast cancer and 105 974 controls from the Breast Cancer Association Consortium. MR analyses were conducted using the inverse variance‐weighted approach, and sensitivity analyses were conducted to assess the impact of potential violations of MR assumptions. A value of 1 SD (SD: 0.08 mmol/L) higher genetically predicted concentration of magnesium was associated with a 17% (odds ratio [OR]: 1.17, 95% confidence interval [CI]: 1.10‐1.25, P value = 9.1 × 10−7) and 20% (OR: 1.20, 95% CI: 1.08‐1.34, P value = 3.2 × 10−6) higher risk of overall and ER+ve breast cancer, respectively. An inverse association was observed for a SD (0.5 mg/dL) higher genetically predicted phosphorus concentration and ER−ve breast cancer (OR: 0.84, 95% CI: 0.72‐0.98, P value =.03). There was little evidence that any other nutrient was associated with breast cancer. The results for magnesium were robust under all sensitivity analyses and survived correction for multiple comparisons. Higher circulating concentrations of magnesium and potentially phosphorus may affect breast cancer risk. Further work is required to replicate these findings and investigate underlying mechanisms. What's new? The epidemiological literature reports inconsistent associations between the consumption or circulating concentrations of micro‐nutrients and breast cancer risk. Evidence from clinical trials is also lacking. Here, the authors conducted a Mendelian randomization study to investigate whether genetically‐predicted concentrations of 11 micro‐nutrients are associated with risk of breast cancer. An increased risk of overall and oestrogen‐receptor positive disease was observed for genetically‐predicted higher concentrations of magnesium that was robust to sensitivity analyses and correction for multiple comparisons. [ABSTRACT FROM AUTHOR]

Circulating adipokines and C‐reactive protein (CRP) have been linked to breast cancer risk in observational epidemiological studies. The causal nature of these associations is unclear because of the susceptibility of conventional observational designs to residual confounding, reverse causation and other forms of bias. Mendelian randomisation (MR) uses genetic variants as proxies for risk factors to strengthen causal inference in observational settings. We performed a MR analysis to evaluate the causal relevance of six previously reported circulating adipokines [adiponectin, hepatocyte growth factor (HGF), interleukin‐6, leptin receptor, plasminogen activator inhibitor‐1 and resistin] and CRP in risk of overall and oestrogen receptor‐stratified breast cancer in up to 122,977 cases and 105,974 controls of European ancestry. Genetic instruments were constructed from single‐nucleotide polymorphisms robustly (p < 5 × 10−8) associated with risk factors in genome‐wide association studies. Colocalisation was performed as a sensitivity analysis to examine whether findings reflected shared causal variants or genomic confounding. In MR analyses, there was evidence for an association of HGF with oestrogen receptor‐negative cancer (odds ratio per standard deviation increase: 1.17, 95% confidence interval: 1.01–1.35; p = 0.035) but little evidence for associations of other adipokines or CRP with overall or oestrogen receptor‐stratified breast cancer. Colocalisation analysis suggested that the association of HGF with oestrogen receptor‐negative breast cancer was unlikely to reflect a causal association. Collectively, these findings do not support an important aetiological role of various adipokines or CRP in overall or oestrogen receptor‐specific breast cancer risk. What's new? Adipokines and C‐reactive protein have been linked to breast cancer risk in observational studies. But while these molecular mediators potentially connect excess adiposity with breast cancer, whether the associations are causal in nature is uncertain. Here, a Mendelian randomization approach was employed to estimate the causal effect of six circulating adipokines and C‐reactive protein on breast cancer risk. Overall, among 122,977 cases and 105,974 controls, analyses provided little evidence supporting a causal role for these molecular markers in breast cancer etiology. The findings warrant investigation of other mediators that could explain apparent links between adiposity and increased breast cancer risk. [ABSTRACT FROM AUTHOR]

Objective: To test the hypothesis that the baseline clinico‐pathological features of the men with localized prostate cancer (PCa) included in the ProtecT (Prostate Testing for Cancer and Treatment) trial who progressed (n = 198) at a 10‐year median follow‐up were different from those of men with stable disease (n = 1409). Patients and Methods: We stratified the study participants at baseline according to risk of progression using clinical disease stage, pathological grade and PSA level, using Cox proportional hazard models. Results: The findings showed that 34% of participants (n = 505) had intermediate‐ or high‐risk PCa, and 66% (n = 973) had low‐risk PCa. Of 198 participants who progressed, 101 (51%) had baseline International Society of Urological Pathology Grade Group 1, 59 (30%) Grade Group 2, and 38 (19%) Grade Group 3 PCa, compared with 79%, 17% and 5%, respectively, for 1409 participants without progression (P < 0.001). In participants with progression, 38% and 62% had baseline low‐ and intermediate‐/high‐risk disease, compared with 69% and 31% of participants with stable disease (P < 0.001). Treatment received, age (65–69 vs 50–64 years), PSA level, Grade Group, clinical stage, risk group, number of positive cores, tumour length and perineural invasion were associated with time to progression (P ≤ 0.005). Men progressing after surgery (n = 19) were more likely to have a higher Grade Group and pathological stage at surgery, larger tumours, lymph node involvement and positive margins. Conclusions: We demonstrate that one‐third of the ProtecT cohort consists of people with intermediate‐/high‐risk disease, and the outcomes data at an average of 10 years' follow‐up are generalizable beyond men with low‐risk PCa. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate the relationship of BMI with subsequent statural growth among children born in the era of the obesity epidemic.Methods: Among 18,271 children from Belarus (n = 16,781, born 1996 to 1997) and the United States (n = 1,490, born 1999 to 2002), multivariable linear and ordinal logistic regression was used to analyze associations of BMI z score from infancy to adolescence with subsequent standardized length and height velocity, standing height and its components (trunk and leg lengths), and pubertal timing.Results: The prevalence of early adolescent obesity was 6.2% in Belarus and 12.8% in the United States. In both Belarusian and US children, higher BMI z scores in infancy and childhood were associated with faster length and height velocity in early life, while higher BMI z scores during middle childhood were associated with slower length and height velocity during adolescence. Associations with greater standing height and trunk length and earlier pubertal development in adolescence were stronger for BMI z scores at middle childhood than BMI z scores at birth or infancy.Conclusions: These findings in both Belarus and the United States support the role of higher BMI in accelerating linear growth in early life (taller stature and longer trunk length) but earlier pubertal development and slower linear growth during adolescence. [ABSTRACT FROM AUTHOR]

Background: Conflicting findings from studies evaluating associations of allergic disease with child behaviour require longitudinal studies to resolve. Objective: To estimate the magnitude of associations of atopic dermatitis (AD) in infancy, and symptoms of asthma and AD at 6.5 years, with child behaviour at 6.5 years. Methods: Secondary cohort analysis of the Promotion of Breastfeeding Intervention Trial (PROBIT). PROBIT enrolled 17 046 infants at birth and followed them up at 6.5 years (n = 13 889). Study paediatricians collected data on infantile AD at repeated follow‐up examinations during the first year of life. At 6.5 years, paediatricians performed skin prick tests and parents reported asthma and AD symptoms during the prior year. In addition, parents and teachers completed the Strength and Difficulties Questionnaire, which includes scales on hyperactivity/inattention, emotional problems, conduct problems, peer problems and prosocial behaviours. Results: Physician‐diagnosed AD in the first year of life was not associated with increased risk for behavioural problems at 6.5 years. Emotional problems at 6.5 years were more common among children with AD symptoms (OR: 2.24, 95% CI: 1.62‐3.12) and asthma symptoms (OR: 1.45; 95% CI: 1.07‐1.96) during the past year at 6.5 years and ORs for children with symptoms of more severe AD and asthma were also higher. AD in the past year was also associated with probable hyperactivity/inattention disorder at 6.5 years (OR: 2.05; 95% CI: 1.09‐3.84). Other subscales of the SDQ were not related to asthma or AD symptoms during the past year. Conclusions and clinical relevance: Children with AD symptoms were at higher risk for concomitant hyperactivity/inattention and emotional disorder, and children with asthma symptoms were at higher risk of having concomitant emotional problems. However, AD during infancy did not predict childhood behaviours. [ABSTRACT FROM AUTHOR]

Objective: The Children's Eating Attitudes Test (ChEAT) is a self‐report questionnaire that is conventionally summarized with a single score to identify "problematic" eating attitudes, masking informative variability in different eating attitude domains. This study evaluated the empirical support for single‐ versus multifactor models of the ChEAT. For validation, we compared how well the single‐ versus multifactor‐based scores predicted body mass index (BMI). Method: Using data from 13,674 participants of the 11.5 year‐follow‐up of the Promotion of Breastfeeding Intervention Trial (PROBIT) in the Republic of Belarus, we conducted confirmatory factor analysis to evaluate the performance of 3‐ and 5‐factor models, which were based on past studies, to a single‐factor model representing the conventional summary of the ChEAT. We used cross‐validated linear regression models and the reduction in mean squared error (MSE) to compare the prediction of BMI at 11.5 and 16 years by the conventional and confirmed factor‐based ChEAT scores. Results: The 5‐factor model, based on 14 of the original 26 ChEAT items, had good fit to the data whereas the 3‐ and single‐factor models did not. The MSE for concurrent (11.5 years) BMI regressed on the 5‐factor ChEAT summary was 35% lower than that of the single‐score models, which reduced the MSE from the null model by only 1%–5%. The MSE for BMI at 16 years was 20% lower. Discussion: We found that a parsimonious 5‐factor model of the ChEAT explained the data collected from healthy Belarusian children better than the conventional summary score and thus provides a more discriminating measure of eating attitudes. [ABSTRACT FROM AUTHOR]

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 [β (standard deviation difference vs. placebo): 0.69; 95% CI = 0.24, 1.15; p = 0.003], valine (β: −0.62; −1.03, −0.02; p = 0.004), pyruvate (β: −0.56; −0.95, −0.16; p = 0.006) and docosahexaenoic acid (β: −0.50; −085, −0.14; p = 0.006). Valine and diacylglycerol were lower in the lycopene dietary advice group (β: −0.65; −1.04, −0.26; p = 0.001 and β: −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. What's new? Prostate cancer incidence varies by geographic region, suggesting that environmental factors, such as diet, play a role. Here, the authors investigated how green tea and lycopene intake affects prostate cancer risk. They conducted a 6‐month intervention on men with raised PSA levels but no cancer, testing levels of 159 serum metabolites by NMR. Lycopene supplementation, they found, reduced levels of circulating pyruvate, and Mendelian randomisation analysis suggests pyruvate may boost PC risk. These results suggest a possible mechanism of action by which consuming dietary lycopene may reduce prostate cancer risk. [ABSTRACT FROM AUTHOR]

Tobacco smoking and alcohol consumption are well‐established risk factors for head and neck cancer. The prognostic role of smoking and alcohol intake at diagnosis have been less well studied. We analysed 1,393 people prospectively enrolled into the Head and Neck 5000 study (oral cavity cancer, n=403; oropharyngeal cancer, n=660; laryngeal cancer, n=330) and followed up for a median of 3.5 years. The primary outcome was all‐cause mortality. We used Cox proportional hazard models to derive minimally adjusted (age and gender) and fully adjusted (age, gender, ethnicity, stage, comorbidity, body mass index, HPV status, treatment, education, deprivation index, income, marital status, and either smoking or alcohol use) mortality hazard ratios (HR) for the effects of smoking status and alcohol intake at diagnosis. Models were stratified by cancer site, stage and HPV status. The fully‐adjusted HR for current versus never‐smokers was 1.7 overall (95% confidence interval [CI] 1.1, 2.6). In stratified analyses, associations of smoking with mortality were observed for oropharyngeal and laryngeal cancers (fully adjusted HRs for current smokers: 1.8 (95% CI=0.9, 3.40 and 2.3 (95% CI=0.8, 6.4)). We found no evidence that people who drank hazardous to harmful amounts of alcohol at diagnosis had a higher mortality risk compared to non‐drinkers (HR=1.2 (95% CI=0.9, 1.6)). There was no strong evidence that HPV status or tumour stage modified the association of smoking with survival. Smoking status at the time of a head and neck cancer diagnosis influenced all‐cause mortality in models adjusted for important prognostic factors. [ABSTRACT FROM AUTHOR]

Circulating 25‐hydroxyvitamin D (25OHD) is an appealing potential intervention for cancer risk and has been associated with oral and oropharyngeal cancer risk but evidence is inconsistent. The availability of genetic variants, uncorrelated with known confounders, but predictive of 25OHD and genetic data in a large oral and oropharyngeal cancer collaboration aids causal inference when assessing this association. A total of 5,133 oral and oropharyngeal cancer cases and 5,984 controls with genetic data were included in the study. Participants were based in Europe, North America and South America and were part of the Genetic Associations and Mechanisms in Oncology (GAME‐ON) Network. Five genetic variants reliably associated with circulating 25OHD were used to create a relative genetic measure of 25OHD. In the absence of measured 25OHD, two‐sample Mendelian randomization using individual level outcome data were used to estimate causal odds ratios (OR) for cancer case status per standard deviation increase in log25OHD. Analyses were replicated in an independent population‐based cohort (UK Biobank). In the GAME‐ON study, there was little evidence of a causal association between circulating 25OHD and oral cancer (OR = 0.86 [0.68;1.09], p = 0.22), oropharyngeal cancer (OR = 1.28 [0.72;2.26], p = 0.40) or when sites were combined (OR = 1.01 [0.74;1.40], p = 0.93). Replication in UK Biobank and pooled estimates produced similar results. Our study suggests that a clinically relevant protective effect of 25OHD on oral and oropharyngeal cancer risk is unlikely and supplementation of the general population with 25OHD is unlikely to be beneficial in preventing these cancers. [ABSTRACT FROM AUTHOR]

Abstract: Background: Smoking and alcohol increase the risk of head and neck cancer and affect treatment outcomes. Interventions modifying these behaviors may improve posttreatment outcomes and survival. We systematically reviewed evidence of the effectiveness of smoking/alcohol interventions in head and neck cancer and oral dysplasia. Methods: The AMED, CINAHL, Embase, MEDLINE, and Web of Science databases were searched for randomized controlled trials (RCTs) of smoking/alcohol interventions in people with head and neck cancer. A qualitative synthesis of the studies was conducted. Results: Three RCTs were identified: 2 smoking interventions and 1 smoking and alcohol intervention. One intervention, which was comprised of a smoking intervention based on Cognitive Behavioral Therapy and pharmacologic management compared to usual care, reduced smoking prevalence. Conclusion: Further research is required into the underlying mechanisms that lead to cessation and interventions that include both pharmacological and behavioral therapy. Future RCTs should include suitable control conditions and sufficient power to assess clinical outcomes. [ABSTRACT FROM AUTHOR]

Abstract: Aims: To investigate whether smokers prescribed varenicline had lower risks of serious ill‐health during the 4 years following treatment compared with those prescribed nicotine replacement therapy (NRT). Design: Observational cohort study of electronic medical records. Setting: A total of 370 UK general practices sampled from the Clinical Practice Research Datalink. Participants: A total of 126 718 patients aged 18 and over who were issued smoking cessation prescriptions between 1 September 2006 and 31 March 2014. Measurements: Our primary outcome was all‐cause mortality within 2 years of first prescription as indicated by linked Office of National Statistics data. Our secondary outcomes were cause‐specific mortality, all‐cause, cause‐specific hospitalization, primary care diagnosis of myocardial infarction or chronic obstructive pulmonary disease (COPD), body mass index and attendance rate to primary care within 2 years of first prescription. Risk differences and 95% confidence intervals were estimated by multivariable adjusted regression and propensity score matched regression. We used instrumental variable analysis to overcome residual confounding. Findings: People prescribed varenicline were healthier at baseline than those prescribed NRT in almost all characteristics, highlighting the potential for residual confounding. Our instrumental variable analysis results found that people prescribed varenicline had a similar risk of mortality at 2 years [risk difference per 100 patients treated = 0.67, 95% confidence interval (CI) = ‐0.11 to 1.46)] to those prescribed NRT, and there were similar rates of all‐cause hospitalization, incident primary‐care diagnoses of myocardial infarction and COPD. People prescribed varenicline subsequently attended primary care less frequently. Conclusions: Smokers prescribed varenicline in primary care in the United Kingdom do not appear to be less likely to die, be hospitalized or experience a myocardial infarction or chronic obstructive pulmonary disease during the following 2 years compared with smokers prescribed nicotine replacement therapy, but they gain more weight and attend primary care less frequently. [ABSTRACT FROM AUTHOR]

Meta-analyses combine the results of multiple studies of a common question. Approaches based on effect size estimates from each study are generally regarded as the most informative. However, these methods can only be used if comparable effect sizes can be computed from each study, and this may not be the case due to variation in how the studies were done or limitations in how their results were reported. Other methods, such as vote counting, are then used to summarize the results of these studies, but most of these methods are limited in that they do not provide any indication of the magnitude of effect. We propose a novel plot, the albatross plot, which requires only a 1-sided P value and a total sample size from each study (or equivalently a 2-sided P value, direction of effect and total sample size). The plot allows an approximate examination of underlying effect sizes and the potential to identify sources of heterogeneity across studies. This is achieved by drawing contours showing the range of effect sizes that might lead to each P value for given sample sizes, under simple study designs. We provide examples of albatross plots using data from previous meta-analyses, allowing for comparison of results, and an example from when a meta-analysis was not possible. [ABSTRACT FROM AUTHOR]

Coffee consumption has been shown in some studies to be associated with lower risk of prostate cancer. However, it is unclear if this association is causal or due to confounding or reverse causality. We conducted a Mendelian randomisation analysis to investigate the causal effects of coffee consumption on prostate cancer risk and progression. We used two genetic variants robustly associated with caffeine intake (rs4410790 and rs2472297) as proxies for coffee consumption in a sample of 46,687 men of European ancestry from 25 studies in the PRACTICAL consortium. Associations between genetic variants and prostate cancer case status, stage and grade were assessed by logistic regression and with all-cause and prostate cancer-specific mortality using Cox proportional hazards regression. There was no clear evidence that a genetic risk score combining rs4410790 and rs2472297 was associated with prostate cancer risk (OR per additional coffee increasing allele: 1.01, 95% CI: 0.98,1.03) or having high-grade compared to low-grade disease (OR: 1.01, 95% CI: 0.97,1.04). There was some evidence that the genetic risk score was associated with higher odds of having nonlocalised compared to localised stage disease (OR: 1.03, 95% CI: 1.01, 1.06). Amongst men with prostate cancer, there was no clear association between the genetic risk score and all-cause mortality (HR: 1.00, 95% CI: 0.97,1.04) or prostate cancer-specific mortality (HR: 1.03, 95% CI: 0.98,1.08). These results, which should have less bias from confounding than observational estimates, are not consistent with a substantial effect of coffee consumption on reducing prostate cancer incidence or progression. [ABSTRACT FROM AUTHOR]

Prostate cancer is the most common cancer in men in developed countries, and is a target for risk reduction strategies. The effects of alcohol consumption on prostate cancer incidence and survival remain unclear, potentially due to methodological limitations of observational studies. In this study, we investigated the associations of genetic variants in alcohol-metabolising genes with prostate cancer incidence and survival. We analysed data from 23,868 men with prostate cancer and 23,051 controls from 25 studies within the international PRACTICAL Consortium. Study-specific associations of 68 single nucleotide polymorphisms (SNPs) in 8 alcohol-metabolising genes (Alcohol Dehydrogenases (ADHs) and Aldehyde Dehydrogenases (ALDHs)) with prostate cancer diagnosis and prostate cancer-specific mortality, by grade, were assessed using logistic and Cox regression models, respectively. The data across the 25 studies were meta-analysed using fixed-effect and random-effects models. We found little evidence that variants in alcohol metabolising genes were associated with prostate cancer diagnosis. Four variants in two genes exceeded the multiple testing threshold for associations with prostate cancer mortality in fixed-effect meta-analyses. SNPs within ALDH1A2 associated with prostate cancer mortality were rs1441817 (fixed effects hazard ratio, HRfixed = 0.78; 95% confidence interval (95%CI):0.66,0.91; p values = 0.002); rs12910509, HRfixed = 0.76; 95%CI:0.64,0.91; p values = 0.003); and rs8041922 (HRfixed = 0.76; 95%CI:0.64,0.91; p values = 0.002). These SNPs were in linkage disequilibrium with each other. In ALDH1B1, rs10973794 (HRfixed = 1.43; 95%CI:1.14,1.79; p values = 0.002) was associated with prostate cancer mortality in men with low-grade prostate cancer. These results suggest that alcohol consumption is unlikely to affect prostate cancer incidence, but it may influence disease progression. [ABSTRACT FROM AUTHOR]

Objective To determine whether there are differences in prostate-specific antigen ( PSA) levels at diagnosis or changes in PSA levels between US and European populations of men with and without prostate cancer ( PCa). Subjects and Methods We analysed repeated measures of PSA from six clinically and geographically diverse cohorts of men: two cohorts with PSA-detected PCa, two cohorts with clinically detected PCa and two cohorts without PCa. Using multilevel models, average PSA at diagnosis and PSA change over time were compared among study populations. Results The annual percentage PSA change of 4-5% was similar between men without cancer and men with PSA-detected cancer. PSA at diagnosis was 1.7 ng/ mL lower in a US cohort of men with PSA-detected PCa (95% confidence interval 1.3-2.0 ng/mL), compared with a UK cohort of men with PSA-detected PCa, but there was no evidence of a different rate of PSA change between these populations. Conclusion We found that PSA changes over time are similar in UK and US men diagnosed through PSA testing and even in men without PCa. Further development of PSA models to monitor men on active surveillance should be undertaken in order to take advantage of these similarities. We found no evidence that guidelines for using PSA to monitor men cannot be passed between US and European studies. [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]

We discuss six questions related to the recent 'strongly constrained and appropriately normed' (SCAN) meta-generalized gradient approximation (meta-GGA): (1) When and why should a semilocal approximation to the density functional for the exchange-correlation energy be accurate? (2) What is the right dimensionless ingredient for a meta-GGA, and why? (3) In the construction of density functional approximations, should we satisfy more or fewer exact constraints? (4) Is there a tight lower bound on the exchange energy for all spin-unpolarized densities? (5) Should a semilocal approx- imation yield any intermediate-range van der Waals interaction? (6) Do semilocal functionals make consistent predictions for the energy differences between different molecules (and thus presumably for reaction and formation energies)? © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

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]

Associations between certain lifestyle characteristics and prostate cancer risk have been reported, and continuation post-diagnosis can adversely affect prognosis. We explored whether men make spontaneous changes to their physical activity and alcohol intake, body mass index (BMI) and smoking status, following a diagnosis of localised prostate cancer. A detailed diet, health and lifestyle questionnaire was completed by 511 participants within the Prostate Testing for Cancer and Treatment (ProtecT) randomised controlled trial, both before and 9 months after a diagnosis of prostate cancer. Of 177 men who were insufficiently active before their diagnosis (median 0 activity units/week; IQR 0-9), 40.7% had increased their activity by a median of 22 U week−1 (IQR 15-35) 9 months later, and there was weak evidence that men were more active after diagnosis than before ( p = 0.07). Men categorised as 'working' occupational social class and who were insufficiently active before diagnosis were 2.03 (95%, CI = 1.03-3.99, p = 0.04) times more likely to have increased their physical activity levels compared to men classified as 'managerial or professional.' Similarly, men who were insufficiently active pre-diagnosis and with T-stage 2 compared with T-stage 1 prostate cancer were 2.47 (95%, CI = 1.29-4.71, p = 0.006) times more likely to be sufficiently active post-diagnosis. Following diagnosis, there was an overall reduction in alcohol intake ( p = 0.03) and the proportion of current smokers ( p = 0.09), but no overall change in BMI. We conclude that some men spontaneously change certain lifestyle behaviours on receiving a diagnosis of prostate cancer. For many men, however, additional support through lifestyle interventions is probably required to facilitate and maintain these changes. [ABSTRACT FROM AUTHOR]

Aims The UK Clinical Practice Research Datalink ( CPRD) is increasingly being used to investigate suicide-related adverse drug reactions. No studies have comprehensively validated the recording of suicide and nonfatal self-harm in the CPRD. We validated general practitioners' recording of these outcomes using linked Office for National Statistics ( ONS) mortality and Hospital Episode Statistics ( HES) admission data. Methods We identified cases of suicide and self-harm recorded using appropriate Read codes in the CPRD between 1998 and 2010 in patients aged ≥15 years. Suicides were defined as patients with Read codes for suicide recorded within 95 days of their death. International Classification of Diseases codes were used to identify suicides/hospital admissions for self-harm in the linked ONS and HES data sets. We compared CPRD-derived cases/incidence of suicide and self-harm with those identified from linked ONS mortality and HES data, national suicide incidence rates and published self-harm incidence data. Results Only 26.1% ( n = 590) of the 'true' ( ONS-confirmed) suicides were identified using Read codes. Furthermore, only 55.5% of Read code-identified suicides were confirmed as suicide by the ONS data. Of the HES-identified cases of self-harm, 68.4% were identified in the CPRD using Read codes. The CPRD self-harm rates based on Read codes had similar age and sex distributions to rates observed in self-harm hospital registers, although rates were underestimated in all age groups. Conclusions The CPRD recording of suicide using Read codes is unreliable, with significant inaccuracy (over- and under-reporting). Future CPRD suicide studies should use linked ONS mortality data. The under-reporting of self-harm appears to be less marked. [ABSTRACT FROM AUTHOR]

Background It has been hypothesised that postnatal weight and length/height gain are variously related to wheeze, asthma and atopy; however, supporting evidence is limited and inconsistent. Methods Weights and lengths/heights of 12,171 term infants were measured from birth to 12 months and at 6.5 yr and extracted from polyclinic records prospectively obtained between 12 and 60 months. Atopic phenotypes were ascertained at 6.5 yr with the International Study of Asthma and Allergy in Childhood questionnaire and skin prick tests. Logistic regression models investigated whether rates of weight and length/height gain from infancy to mid-childhood were associated with atopy phenotypes that have occurred ever or in the last 12 months. Results After controlling for confounders and prior weight and length/height gain, all weight gain variables except birth weight were positively associated with ever having wheezed (p < 0.1). A one s.d. increase in weight gain rate between 0 and 3 months was associated with a 12% increase (2-23%) in allergic rhinitis ever. No other consistent patterns of association were found for weight gain or length/height gain rate between 0 and 60 months with atopic outcomes at 6.5 yr. In contrast, all atopy outcomes except for ever having asthma were associated with current weight and height, even after controlling for prior growth. Conclusion Current height and weight are more strongly associated with the development of atopic phenotypes in childhood than patterns of infant and early childhood growth, which may well reflect reverse causality (atopy effects on growth) or residual confounding by an unknown common cause of growth and atopy. [ABSTRACT FROM AUTHOR]

Epidemiological studies suggest that vitamin D protects against prostate cancer, although evidence is limited and inconsistent. We investigated associations of circulating total 25-hydroxyvitamin D (25(OH)D) with prostate specific antigen-detected prostate cancer in a case-control study nested within the prostate testing for cancer and treatment (ProtecT) trial. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) quantifying the association between circulating total 25(OH)D and prostate cancer. In case-only analyses, we used unconditional logistic regression to quantify associations of total 25(OH)D with stage (advanced vs. localized) and Gleason grade (high-grade (≥7) vs. low-grade (<7)). Predetermined categories of total 25(OH)D were defined as: high: ≥30 ng/mL; adequate: 20 - <30 ng/mL; insufficient: 12 - <20 ng/mL; deficient: <12 ng/mL. Fractional polynomials were used to investigate the existence of any U-shaped relationship. We included 1,447 prostate cancer cases (153 advanced, 469 high-grade) and 1,449 healthy controls. There was evidence that men deficient in vitamin D had a 2-fold increased risk of advanced versus localized cancer (OR for deficient vs. adequate total 25(OH)D = 2.33, 95% CI: 1.26, 4.28) and high-grade versus low-grade cancer (OR for deficient vs. adequate total 25(OH)D = 1.78, 95% CI: 1.15, 2.77). There was no evidence of a linear association between total 25(OH)D and prostate cancer ( p = 0.44) or of an increased risk of prostate cancer with high and low vitamin D levels. Our study provides evidence that lower 25(OH)D concentrations were associated with more aggressive cancers (advanced versus localized cancers and high- versus low-Gleason grade), but there was no evidence of an association with overall prostate cancer risk. [ABSTRACT FROM AUTHOR]

Study Type - Practice patterns (retrospective cohort) Level of Evidence 2b What is known on the subject? and what does the study add? There is no organized screening programme for prostate cancer in the UK, although men can request a PSA test at their general practice. The testing rate had been estimated at 6% per year among 45-84 year old men during 2001 to 2007. Our study estimated the annual practice-based PSA testing rate for men aged 45-89 years with no previous diagnosis of prostate cancer at 6.2% during 2007. This is very similar to the rate found in the earlier study. Older men and men at general practices situated in more affluent areas were found to be most likely to undergo a PSA test, suggesting that uptake of the test is not reflecting clinical need. OBJECTIVE • To estimate rates of prostate-specific antigen (PSA) testing in UK general practices by age, deprivation index and geographical location. SUBJECTS AND METHODS • Practice-based, retrospective data on PSA testing patterns in 2007 were collected from a random sample of 87 general practices using EMIS LV computer systems within the passively observed non-intervention arm of a cluster-randomized controlled trial. • Information for a total of 126 716 men aged 45-89 years with no recorded diagnosis of prostate cancer prior to 1 January 2007 was collected. RESULTS • In all, 7902 (6.2%) of 126 716 men aged 45-89 without a prior diagnosis of prostate cancer underwent at least one PSA test from their general practitioner during 2007 [95% confidence interval (CI) 5.6-7.0%; practice-based inter-quartile range 3.6-8.4%]. • PSA testing rates were 1.4% (95% CI 1.1-1.6%) in men aged 45-49, rising to 11.3% (95% CI 10.0-12.9%) at age 75-79 years ( P for trend <0.001). • Testing rates were lowest in the three northern centres (3.5-5.7%) vs the three more southern centres (7.1-8.9%; P < 0.001). • For every 20 points increase in the index of multiple deprivation score, the proportion of men tested fell by 1.7% (95% CI −2.5 to −0.8%; P < 0.001). • Lower proportions of men were subsequently diagnosed with prostate cancer in practices testing more men (odds ratio for a one unit increase in the natural log of testing 0.76; 95% CI 0.60-0.97; P= 0.025). CONCLUSION • Overall levels of PSA testing in UK general practice remain low, but for those tested there are important variations by age, deprivation and geographical location that do not appear to reflect clinical need or the intention of current policy. • PSA testing in general practice is currently skewed towards older men, and current policy enabling all men to make an informed choice about PSA testing is not being effectively implemented as uptake clearly varies by socioeconomic status. • This reinforces the need for robust evidence regarding the costs and benefits of using the PSA test for the detection of localized prostate cancer in the UK, a full assessment of the health economic implications and a revision of the current policy. [ABSTRACT FROM AUTHOR]

Study Type - Aetiology (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Evidence for seasonal or climatic effects on PSA levels is mixed and inconclusive. In this large, long-term study, no seasonal or climatic patterns in PSA levels were identified. OBJECTIVE • To assess whether a seasonal change in prostate specific antigen (PSA) levels can be detected in men recruited to a large clinical trial. PATIENTS AND METHODS • A total of 66 969 men aged 50-69 years were drawn from a large study conducted at general practices across the UK between 2002 and 2007. • Trigonometric algorithms and regression methods were used to assess the relationship between the time of year and serum PSA and blood pressure measurements. • We obtained local daily mean temperatures and hours of sunlight per day to assess whether these factors were potential mechanisms for seasonal variation in PSA levels or blood pressure. • The proportion of participants who would be considered clinically at risk according to their PSA or blood pressure measurement, by month, was also assessed. • The strength of associations between time of year and blood pressure were used to reinforce conclusions from the PSA models. RESULTS • There was no relationship between time of year and PSA levels ( P= 0.11) or between climate and PSA levels ( P= 0.42). • No difference was found in the prevalence of clinically raised PSA content by month ( P= 0.50). • This lack of an association with PSA content was despite our data being sufficient to provide clear evidence of an association between blood pressure and time of year (systolic P < 0.001; diastolic P < 0.001), and to show that this association was largely explained by climatic factors (temperature and sunlight). CONCLUSION • There was no pattern in PSA levels by time of year, air temperature or levels of sunlight in this cohort, so there is no need to take these factors into account when reviewing PSA results. [ABSTRACT FROM AUTHOR]

Obese men appear to have an increased risk of being diagnosed with advanced prostate cancer and of dying from the disease. Few studies have examined the impact of weight gain during adulthood on prostate cancer risk and mortality and these have reported conflicting results. We analysed data from 20,991 Norwegian men who participated in two phases of the Nord-Trøndelag Health Study in 1984/1986 (HUNT-1, when aged at least 20 years) and 1995/1997 (HUNT-2). Weight and height were measured at both HUNT-1 and HUNT-2, allowing each man's change in weight and body mass index (BMI) to be computed. During a median of 9.3 years of follow-up after the end of HUNT-2, 649 (3%) men developed prostate cancer. We observed no increase in prostate cancer incidence amongst men who put on weight between HUNT-1 and HUNT-2. In multivariable models, including adjustment for weight at HUNT-2, the hazard ratio (HR) for prostate cancer per one standard deviation, SD (6.2 kg) gain in weight was 0.98 (95% confidence interval [95% CI] = 0.87-1.10, p-trend = 0.70) and per one SD gain in BMI (1.9 kg/m [ABSTRACT FROM AUTHOR]

Several age-related traits are associated with shorter telomeres, the structures that cap the end of linear chromosomes. A common polymorphism near the telomere maintenance gene TERT has been associated with several cancers, but relationships with other aging traits such as physical capability have not been reported. As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, men and women aged between 44 and 90 years from nine UK cohorts were genotyped for the single-nucleotide polymorphism (SNP) rs401681. We then investigated relationships between the SNP and 30 age-related phenotypes, including cognitive and physical capability, blood lipid levels and lung function, pooling within-study genotypic effects in meta-analyses. No significant associations were found between the SNP and any of the cognitive performance tests (e.g. pooled beta per T allele for word recall z-score = 0.02, 95% CI: −0.01 to 0.04, P-value = 0.12, n = 18 737), physical performance tests (e.g. pooled beta for grip strength = −0.02, 95% CI: −0.045 to 0.006, P-value = 0.14, n = 11 711), blood pressure, lung function or blood test measures. Similarly, no differences in observations were found when considering follow-up measures of cognitive or physical performance after adjusting for its measure at an earlier assessment. The lack of associations between SNP rs401681 and a wide range of age-related phenotypes investigated in this large multicohort study suggests that while this SNP may be associated with cancer, it is not an important contributor to other markers of aging. [ABSTRACT FROM AUTHOR]

The article focuses on a study related to the association of aspirin, nonsteroidal anti-inflammatory drug and paracetamol use with prostate specific antigen (PSA)-detected prostate cancer. The study reveals that chronic inflammation plays a vital role in prostate cancer aetiology. According to the study, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen may reduce prostate cancer risk. Several charts related to the study are also presented.

The article focuses on a study related to prostate-specific antigen (PSA)-detected prostate cancer and the potential for dedifferentiation. The study reflects on the estimation of proportion of the Gleason score tumors with progressive potential. The study reveals that in prostate cancer, the histological grading which is based on the Gleason score is associated with the future biological behavior and prognosis. Several charts and diagrams related to the same are also presented.

Observational studies suggest that diabetes is associated with a decreased risk of prostate cancer, but few are population based or have investigated associations with cancer stage or duration of diabetes. We report a case-control study nested within the population-based Prostate testing for cancer and Treatment (ProtecT) study ISRCTN20141297. Men aged 50-69 years based around 9 UK cities were invited for a prostate-specific antigen (PSA) test between June 2002 and November 2006. Amongst 55,215 PSA-tested men, 1,966 had histologically confirmed prostate cancer; of these, 1,422 (72.3%) completed the questionnaire and 1,291 (65.7%) had complete data for analysis. We randomly selected 6,479 age- (within 5 years) and general practice-matched controls. The prevalence of diabetes was 89/1,291 (6.9%) in cases and 555/6,479 (8.6%) in controls. Diabetes was associated with a reduced risk of prostate cancer (odds ratio = 0.78; 95% confidence interval: 0.61-0.99). There was weak evidence that the inverse association was greater for well- versus poorly differentiated cancers ( p = 0.07). The magnitude of the inverse association did not change with increasing duration of diabetes ( p for trend = 0.95). Diabetes is associated with a decreased risk of PSA-detected prostate cancer. These data add to the evidence of the association of diabetes with prostate cancer in the PSA era. [ABSTRACT FROM AUTHOR]

Purpose To investigate trends in mortality rates due to both myocardial infarction and gastrointestinal haemorrhage before and after rofecoxib withdrawal and the release of regulatory guidance regarding the use of other COX-2 inhibitors. Methods International ecological study of temporal trends in deaths from myocardial infarction and gastrointestinal haemorrhage around 2004 when regulatory activity restricted the use of COX-2 inhibitors. Mortality data in countries with low child and adult male mortality (WHO mortality stratum A) were analysed. Results Comparing, on a country-by-country basis, post-2004 mortality rates with those expected from a continuation of preceding trends, there was no evidence of a deviation from the earlier trends in mortality from gastrointestinal haemorrhage or acute myocardial infarction in 50-69 year olds. Amongst 70+ year olds however, there was evidence of lower gastrointestinal haemorrhage mortality (rate ratio 0.963, 95% confidence interval 0.948 to 0.977) and of lower acute myocardial infarction mortality (rate ratio 0.981, 95% confidence interval 0.977 to 0.986) after 2004. These associations were similar for males and females. Conclusions We did not find evidence of an increase in mortality due to gastrointestinal haemorrhage following the withdrawal of rofecoxib in 2004, and coincident concern amongst regulatory bodies about other COX-2 inhibitors. In fact in men and women aged 70 years or older there appeared to be reduced mortality due to gastrointestinal haemorrhage and acute myocardial infarction compared to what was expected from mortality trends before 2004. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

OBJECTIVE To determine, within the UK, the stage and grade of prostate cancers that would be found through population-based prostate specific antigen (PSA) testing and biopsy. SUBJECTS AND METHODS In the ‘Prostate Testing for Cancer and Treatment’ trial (ProtecT), men aged 50–69 years were recruited from nine cities in the UK and from randomly selected practices of general practitioners. Those with a PSA level of >3 ng/mL were offered a prostate biopsy. Age, PSA, stage and grade at diagnosis of ProtecT participants with cancer were compared with contemporaneous incident cases aged 50–69 years (age-restricted Cancer Registry cases) registered with the Eastern Cancer Registration and Information Centre (ECRIC). RESULTS Within ProtecT, 94 427 men agreed to be tested (50% of men contacted), 8807 (≈9%) had a raised PSA level and 2022 (23%) had prostate cancer; 229 (≈12%) had locally advanced (T3 or T4) or metastatic cancers, the rest having clinically localized (T1c or T2) disease. Within ECRIC, 12 661 cancers were recorded over the same period; 3714 were men aged 50–69 years at diagnosis. Men in ProtecT had a lower age distribution and PSA level, and the cancers were of lower stage and grade ( P < 0.001 for all comparisons). If population-based PSA testing were introduced in the UK, ≈2660 men per 100 000 aged 50–69 years would be found to have prostate cancer, compared to current rates of ≈130 per 100 000. If half of men accepted PSA testing, ≈160 000 cancers would be found, compared to 30 000 diagnosed each year at present. CONCLUSIONS Population-based PSA testing resulted in a significant downward stage and grade migration, and most such cancers were of low stage and grade, which could lead to risks of over-treatment for some men. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Cyclooxygenase-2 (COX-2) inhibitors are selective nonsteroidal anti-inflammatory drugs (NSAIDs), purported to demonstrate lower gastrointestinal toxicity than nonselective NSAIDs. • Prescriptions of selective COX-2 inhibitors declined internationally after 2004 following voluntary withdrawal and regulatory intervention because of possible cardiovascular side-effects. • A study in Canada indicated that rates of gastrointestinal haemorrhage actually increased during the period of increasing COX-2 inhibitor prescriptions, due to the increased number of people receiving NSAIDs. WHAT THIS STUDY ADDS • The reduction in availability of COX-2 inhibitors in the UK was temporally associated with a favourable reversal of the trend in emergency hospital admissions for acute myocardial infarction among people aged ≥65 years, but there were no related changes in myocardial infarction mortality trends. • There was some indication that hospital admissions for gastrointestinal haemorrhage among people aged 55–64 years started to increase following a previously declining trend, but this change predated withdrawal/regulation of COX-2 inhibitors by up to 2 years. • The withdrawal/regulation of coxibs did not appear to have any adverse impact on population health and may have been beneficial. AIMS To investigate impacts of withdrawal and regulatory advice regarding cyclooxygenase-2 (COX-2) inhibitors on UK population rates of gastrointestinal haemorrhage and acute myocardial infarction (MI). METHODS Ecological time series study of prescribing, mortality and hospital admission trends in people aged ≥55 years. RESULTS Withdrawal and regulatory advice limiting COX-2 inhibitor availability from 2004 were temporally associated with reversal of previously unfavourable trends in emergency MI admissions among people aged ≥65 years. Annual admission rate trends changed from +4.6% to −3.1% ( P < 0.001) among women and from +2.1% to −3.8% ( P= 0.003) among men. Absolute changes in average annual trend in the number of individuals aged ≥65 years admitted following MI were from +981 (1999–2004) to −819 (2004–2006) per year for women and from +713 to −995 for men. No change in trend was apparent among people aged 55–64 years, or in MI mortality trends. There was some suggestion of an unfavourable change in admission trends for gastrointestinal haemorrhage among 55−64-year-olds, although this appeared to occur prior to COX-2 inhibitor withdrawal/regulation by up to 2 years. These trends were not apparent in older people, or in gastrointestinal haemorrhage mortality rates. CONCLUSIONS Withdrawal/regulation of COX-2 inhibitors was temporally associated with a favourable reversal of population-level hospital admission trends in MI among people aged ≥65 years. Unfavourable reversal of previous declines in gastrointestinal haemorrhage admissions probably occurred before changes in COX-2 inhibitor availability. Withdrawal/ regulation of COX-2 inhibitors did not appear to have any adverse impact on population health and may have been beneficial. [ABSTRACT FROM AUTHOR]

There is currently no means of primary prevention for prostate cancer. Increased exposure to ultraviolet-radiation may be protective, but the literature is inconclusive. We investigated associations of life course exposure to sunlight with prostate cancer. The study design was a UK-wide nested case-control study, based on 1,020 prostate specific antigen-detected cases and 5,044 matched population controls and a systematic review with meta-analysis. Men with olive/brown skin (OR = 1.47; 95% CI: 1.00 to 2.17), men who burnt rarely/never (OR = 1.11; 0.95 to 1.29) and men with the lowest levels of intense sun exposure in the 2 years prior to diagnosis (OR = 1.24; 1.03 to 1.50) had an increased prostate cancer risk. However, amongst men with prostate cancer, spending less time outside was associated with a reduced risk of advanced cancer (OR = 0.49; 0.27 to 0.89) and high Gleason grade (OR = 0.62; 0.43 to 0.91), and men who burnt rarely/never had a reduced risk of advanced cancer (OR = 0.71; 0.47 to 1.08). The meta-analysis provided weak evidence that men with the lowest (versus highest) sunlight exposure had an increased prostate cancer risk (4 studies, random-effects pooled relative risk = 1.13; 0.98 to 1.29) and higher advanced or fatal prostate cancer risk (6 studies, random-effects pooled relative risk = 1.14; 0.98 to 1.33). Our data and meta-analyses provide limited support for the hypothesis that increased exposure to sunlight may reduce prostate cancer risk. The findings warrant further investigation because of their implications for vitamin D chemoprevention trials. © 2009 UICC [ABSTRACT FROM AUTHOR]

Purpose Concerns that selective serotonin reuptake inhibitors (SSRIs) may increase the risk of suicidal behaviour amongst young people led to regulatory action in 2003/4 in many countries. Antidepressant prescribing to young people in various countries declined, but subsequent analyses have demonstrated mixed effects on population suicide rates. Methods Annual, national suicide mortality rates from 1990 to 2006 for 10-19 year-olds in World Health Organisation (WHO) Mortality Stratum A countries were studied using the WHO mortality database. Departures from country-specific trends in 2004-2006 relative to overall trends 1990-2006 were calculated to estimate the impact of regulatory actions in 2003/4. Results There was no consistent change in rate after 2003, with some countries experiencing more and some fewer suicides than expected. Amongst 15-19 year olds the rate ratio was 0.999 (95%CI: 0.971-1.028), and in 10-14 year olds was 0.999 (95%CI: 0.929-1.074). There was some evidence of differential results for males and females. In 15-19 year olds there were 1.8% fewer (95%CI: −5.0 to +1.5%) suicides than expected amongst males and 8.1% more (95%CI: +1.9 to +14.6%) suicides than expected amongst females during 2004-2006. Rate ratios for 10-14 year-olds demonstrated a similar pattern, but with much greater uncertainty. Conclusions There was no evidence of an overall effect on suicides of regulatory action to restrict prescribing of SSRIs to young people, although there was weak evidence of an increase in suicide amongst young women internationally. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Insulin-like growth factors (IGF-I, IGF-II) and their binding proteins (IGFBP-1-6) play a key role in cell proliferation, differentiation and apoptosis, suggesting possible involvement in carcinogenesis. Several epidemiological studies show associations of IGFs with prostate cancer. We searched the published literature for all studies relating levels of IGFs or IGFBPs with prostate cancer. We performed random effects meta-analysis to calculate summary odds ratios. The number of studies (prostate cancer cases) included in each meta-analysis were 42 (7,481) IGF-I; 10 (923) IGF-II; 3 (485) IGFBP-1; 5 (577) IGFBP-2; 29 (6,541) IGFBP-3 and 11 (3,545) IGF-1:IGFBP-3 ratio. The pooled odds ratios (95% confidence intervals) per standard deviation increase in peptide were: IGF-I, OR = 1.21 (1.07, 1.36); IGF-II, OR = 1.17 (0.93, 1.47); IGFBP-1, OR = 1.21 (0.62, 2.33); IGFBP-2, OR = 1.18 (0.90, 1.54); IGFBP-3, OR = 0.88 (0.79, 0.98); IGFI:IGFBP-3 ratio, OR = 1.10 (0.97, 1.24). For all exposures, there was substantial heterogeneity (all I [ABSTRACT FROM AUTHOR]

Background: Dementia is at present incurable. It is seen in a range of neurodegenerative diseases, the most common being Alzheimer's disease (AD). The debilitating neurocognitive deficits develop over time and available treatments have limited effectiveness. It is of paramount and economic concern to identify new and safe possibilities for treatment. Current treatments are aimed at managing symptoms, but do not address the underlying cause of disease. Existing medications work to minimise toxicity caused from breakdown of neurons and brain connections, and preserve neurochemical levels important in cognitive function. Hypertension and hypercholesterolemia, have been linked with increased risk of developing AD. Antihypertensive drugs may protect against AD and lead to reduced disease progression through decreasing neuropathological mechanisms. Statins treat high cholesterol. High cholesterol relates with elevated levels of β‐amyloid protein, an accumulation in brain tissue leads to formation of amyloid plaques, toxic to neurons. Cholesterol‐lowering medication lowers amyloid plaques in brain tissue. Method: Data will be obtained from the Clinical Practice Research Datalink (CPRD), an ongoing database of UK primary care data. The determined sample population, estimated at 105 471 patients, will be divided according to their prescribed medications. Data on treatments will be compared for each group against outcomes such as death and hospitalisation due to AD and related dementias. Potential confounders will be adjusted for in the regression model. Associations between the exposures and outcomes will be assessed through multivariable regression analyses; multivariable Cox regression analysis for assessing survival rate; and marginal structural models to control for treatment switching. Appropriate statistical analysis methods will also be applied to account for other biases, including: propensity score regression to minimise bias due to working with data from non‐randomised comparison of treatments; multiple imputation to account for missing data; and use of appropriate inclusion criteria to prevent collider bias. Result: We will present the results at a later time. Conclusion: This project will allow us to better understand the link between progression of neurological disorders and pharmacotherapy. [ABSTRACT FROM AUTHOR]

OBJECTIVE To determine associations of lower urinary tract symptoms (LUTS) with prostate-specific antigen (PSA) levels and screen-detected localized and advanced prostate cancer. SUBJECTS AND METHODS A case-control study nested within the UK population-based ProtecT (Prostate testing for cancer and Treatment) study. Men aged 50–69 years were invited for PSA testing and those with a PSA level of ≥3.0 ng/mL were invited for biopsy. We determined whether LUTS were associated with a PSA level of ≥3.0 ng/mL and prostate cancer using logistic regression models adjusted for age, family history of prostate cancer and PSA level as appropriate. Areas under receiver operating characteristic curves (AUC) were compared between models with and without symptoms. RESULTS In all, 65 871 men had a PSA test: 7251 had a PSA level of ≥3.0 ng/mL including 2467 subsequently diagnosed with prostate cancer (2119 localized, 348 advanced). LUTS were positively associated with a PSA level of ≥3.0 ng/mL: odds ratios (ORs) were 1.18 (95% confidence interval, CI 1.01–1.38), 1.69 (95% CI 1.32–2.16), and 1.60 (95% CI 1.33–1.93) for daytime urination frequency (hourly vs less frequent), urgency and hesitancy (most/all the time vs never), respectively. LUTS among men with a PSA level of ≥3 ng/mL were negatively associated with prostate cancer: ORs were 0.44 (95% CI 0.22–0.83), 0.74 (95% CI 0.63–0.87), and 0.83 (95% CI 0.73–0.94) for nocturia (4+ vs 0), leakage and hesitancy (occasionally/sometimes vs never), respectively. LUTS improved the prediction of a PSA level of ≥3.0 ng/mL (AUC 0.635 vs 0.606, P < 0.001) and prostate cancer (AUC 0.661 vs 0.638; P < 0.001). CONCLUSIONS A history of LUTS before PSA testing marginally improves the prediction of an individual’s risk for prostate cancer; men with a PSA level of ≥3 ng/mL and LUTS were more likely to be diagnosed with benign disease than prostate cancer. [ABSTRACT FROM AUTHOR]

Screening for early prostate cancer is frequently employed in the routine management of men with lower urinary tract symptoms (LUTS), but the evidence-base linking LUTS with prostate cancer is limited. We assessed the association of LUTS with a subsequent prostate cancer diagnosis in a prospective cohort study based on 21,159 Norwegian men who completed baseline questionnaires, including the International Prostate Symptom Score (IPSS) questionnaire, between 1995 and 2007 as part of the second Nord-Trøndelag Health Study (HUNT 2). Men were followed-up for prostate cancer incidence and mortality from the date of clinical examination to end 2005. During a mean of 9 years follow-up, 518 incident prostate cancers were diagnosed and 74 men died from prostate cancer. Men with severe LUTS (IPSS 20-35) had a 2.26-fold (95% CI: 1.49-3.42) increased risk of prostate cancer compared to men reporting no symptoms. A positive association was observed for localized (hazard ratio, HR: 4.61; 2.23-9.54), but not advanced (HR: 0.51; 0.15-1.75), cancers ( p for heterogeneity <0.001). There was no evidence that moderate/severe symptoms (IPSS 8-35) were associated with prostate cancer mortality (HR: 0.83; 0.42-1.64) vs. no symptoms. Amongst 518 men with prostate cancer, there was a 46% lower (10-68%) risk of death with moderate/severe symptoms vs. no symptoms. We conclude that LUTS are positively associated with localized, but not advanced or fatal, prostate cancer, suggesting that urinary symptoms are not caused by prostate cancer. Thus, screening for early cancers on the basis of LUTS may not be justified. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

OBJECTIVE To aid the interpretation of the trends in prostate cancer mortality, which declined in the UK in the early 1990s for unknown reasons, by investigating prostate cancer death rates, incidence and treatments in England and Wales in 1975–2004. METHODS Join-point regression was used to assess secular trends in mortality and incidence (source: Office of National Statistics), radical prostatectomy and orchidectomy (source: Hospital Episode Statistics database) and androgen-suppression drugs (source: Intercontinental Medical Statistics). RESULTS Prostate cancer mortality declined from 1992 (95% confidence interval, CI, 1990–94). The relative decline in mortality to 2004 was greater and more sustained amongst men aged 55–74 years (annual percentage mortality reduction 2.75%; 95% CI 2.33–3.18%) than amongst those aged ≥75 years (0.71%, 0.26–1.15%). The use of radical prostatectomy increased between 1991 (89 operations) and 2004 (2788) amongst men aged 55–74 years. The prescribing of androgen suppression increased between 1987 (33 000 prescriptions) and 2004 (470 000). CONCLUSIONS The decrease in prostate cancer mortality was greater amongst men aged 55–74 years than in those aged ≥75 years, but pre-dated the substantial use of prostate-specific antigen screening and radical prostatectomy in the UK. An increase in radical therapy amongst younger groups with localized cancers and screen-detected low-volume locally advanced disease as a result of stage migration, as well as prolonged survival from increased medical androgen suppression therapy, might partly explain recent trends. [ABSTRACT FROM AUTHOR]

OBJECTIVE To investigate the morbidity and mortality after radical prostatectomy (RP) in relation to the numbers of RPs carried out at individual hospitals, as recent studies of complex surgery report worse outcomes in low-volume hospitals, and there has been a large increase in RPs for localized prostate cancer. METHODS We analysed hospital episode statistics data for all 18 027 RPs in English National Health Service hospitals between 1997 and 2004. RESULTS In multivariate analysis, there was a U–shaped association of hospital volume with mortality ( P for nonlinear trend, 0.004), but this finding was based on only 59 (0.3%) deaths. The mean length of stay was 6 days and decreased by 2.96% (95% confidence interval, CI, 1.98–3.92; P < 0.001) per quintile increase in hospital volume. In all, 16.1% of men had 30-day in-hospital complications; 20.3% were readmitted with complications within a year. The odds of 30-day in-hospital wound/bleeding complications decreased by 6% (95% CI 1–11; P = 0.02), and miscellaneous medical complications decreased by 10% (0–19; P = 0.04) per increase in hospital volume quintile. For re-admissions within a year, the hazard of vascular complications decreased by 15% (6–22; P = 0.001), wound/bleeding complications decreased by 8% (2–13; P = 0.01) and genitourinary complications decreased by 5% (2–8; P = 0.002), per increase in hospital volume quintile. CONCLUSION In men undergoing RP the length of hospital stay and rates of some short- and long-term postoperative complications afterward are lower in high-volume hospitals. The magnitudes of these effects on the outcomes studied may be too small and inconsistent to indicate a policy of selective referral to high-volume hospitals. Quality of life and oncological outcomes, however, could not be investigated in this dataset. [ABSTRACT FROM AUTHOR]

We conducted a systematic review of the association between HMG-CoA reductase inhibitor (statin) use and cancer risk. We searched MEDLINE, EMBASE, Web of Science, ISI Proceedings and BIOSIS Previews bibliographic databases, electronic trials registers and reference lists for potentially eligible randomized trials and observational studies. Thirty-eight individual studies (26 randomized trials involving 103,573 participants and 12 observational studies with 826,854 participants) were included. Median follow-up was 3.6 and 6.2 years for trials and observational studies, respectively. In metaanalyses of randomized trials, there was no evidence that statin therapy was associated with incidence of all-cancers (26 trials; pooled risk ratio = 1.00; 95% CI 0.95-1.05; I [ABSTRACT FROM AUTHOR]