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Background: We evaluated the temporal association between kidney function, assessed by estimated glomerular filtration rate (eGFR), and the risk of incident renal cell carcinoma (RCC). We also evaluated whether eGFR could improve RCC risk discrimination beyond established risk factors. Methods: We analyzed the UK Biobank cohort, including 463,178 participants of whom 1,447 were diagnosed with RCC during 5,696,963 person-years of follow-up. We evaluated the temporal association between eGFR and RCC risk using flexible parametric survival models, adjusted for C-reactive protein and RCC risk factors. eGFR was calculated from creatinine and cystatin C levels. Results: Lower eGFR, an indication of poor kidney function, was associated with higher RCC risk when measured up to 5 years prior to diagnosis. The RCC HR per SD decrease in eGFR when measured 1 year before diagnosis was 1.26 [95% confidence interval (95% CI), 1.16-1.37], and 1.11 (95% CI, 1.05-1.17) when measured 5 years before diagnosis. Adding eGFR to the RCC risk model provided a small improvement in risk discrimination 1 year before diagnosis with an AUC of 0.73 (95% CI, 0.67-0.84) compared with the published model (0.69; 95% CI, 0.63-0.79). Conclusions: This study demonstrated that kidney function markers are associated with RCC risk, but the nature of these associations are consistent with reversed causality. Markers of kidney function provided limited improvements in RCC risk discrimination beyond established risk factors. Impact: eGFR may be of potential use to identify individuals in the extremes of the risk distribution. [ABSTRACT FROM AUTHOR]

This review synthesized and appraised the evidence for an effect of inflammation on breast cancer risk. Systematic searches identified prospective cohort and Mendelian randomization studies relevant to this review. Meta-analysis of 13 biomarkers of inflammation were conducted to appraise the evidence for an effect breast cancer risk; we examined the dose-response of these associations. Risk of bias was evaluated using the ROBINS-E tool and the quality of evidence was appraised with Grading of Recommendations Assessment, Development, and Evaluation. Thirty-four observational studies and three Mendelian randomization studies were included. Meta-analysis suggested that women with the highest levels of C-reactive protein (CRP) had a higher risk of developing breast cancer [risk ratio (RR) = 1.13; 95% confidence interval (CI), 1.01-1.26] compared with women with the lowest levels. Women with highest levels of adipokines, particularly adiponectin (RR = 0.76; 95% CI, 0.61-0.91) had a reduced breast cancer risk, although this finding was not supported by Mendelian randomization analysis. There was little evidence of an effect of cytokines, including TNFa and IL6, on breast cancer risk. The quality of evidence for each biomarker ranged from very low to moderate. Beyond CRP, the published data do not clearly support the role of inflammation in the development of breast cancer. [ABSTRACT FROM AUTHOR]

The protective effect of physical activity on breast cancer incidence may partially be mediated by inflammation. Systematic searches of Medline, EMBASE, and SPORTDiscus were performed to identify intervention studies, Mendelian randomization studies, and prospective cohort studies that examined the effects of physical activity on circulating inflammatory biomarkers in adult women. Meta-analyses were performed to generate effect estimates. Risk of bias was assessed, and the Grading of Recommendations Assessment, Development, and Evaluation system was used to determine the overall quality of the evidence. Thirty-five intervention studies and one observational study met the criteria for inclusion. Meta-analyses of randomized controlled trials (RCT) indicated that, compared with control groups, exercise interventions reduced levels of C-reactive protein (CRP) [standardized mean difference (SMD) = -0.27, 95% confidence interval (CI) = -0.62 to 0.08), tumor necrosis factor alpha (TNFa, SMD = -0.63, 95% CI = -1.04 to -0.22), interleukin-6 (IL6, SMD = -0.55, 95% CI = -0.97 to -0.13) and leptin (SMD = -0.50, 95% CI = -1.10 to 0.09). Owing to heterogeneity in effect estimates and imprecision, evidence strength was graded as low (CRP, leptin) or moderate (TNFa and IL6). High-quality evidence indicated that exercise did not change adiponectin levels (SMD = 0.01, 95% CI = -0.14 to 0.17). These findings provide support for the biological plausibility of the first part of the physical activity--inflammation--breast cancer pathway. [ABSTRACT FROM AUTHOR]

Background: Long-term patient-reported outcomes are needed to inform treatment decisions for localized prostate cancer. Methods: Patient-reported outcomes of 1643 randomly assigned participants in the ProtecT (Prostate Testing for Cancer and Treatment) trial were evaluated to assess the functional and quality-of-life impacts of prostatectomy, radiotherapy with neoadjuvant androgen deprivation, and active monitoring. This article focuses on the outcomes of the randomly assigned participants from 7 to 12 years using mixed effects linear and logistic models. Results: Response rates exceeded 80% for most measures. Among the randomized groups over 7 to 12 years, generic quality-of-life scores were similar. Among those in the prostatectomy group, urinary leakage requiring pads occurred in 18 to 24% of patients over 7 to 12 years, compared with 9 to 11% in the active monitoring group and 3 to 8% in the radiotherapy group. In the prostatectomy group, 18% reported erections sufficient for intercourse at 7 years, compared with 30% in the active monitoring and 27% in the radiotherapy groups; all converged to low levels of potency by year 12. Nocturia (voiding at least twice per night) occurred in 34% in the prostatectomy group compared with 48% in the radiotherapy group and 47% in the active monitoring group at 12 years. Fecal leakage affected 12% in the radiotherapy group compared with 6% in the other groups by year 12. The active monitoring group experienced gradual age-related declines in sexual and urinary function, avoiding radical treatment effects unless they changed management. Conclusions: ProtecT provides robust evidence about continued impacts of treatments in the long term. These data allow patients newly diagnosed with localized prostate cancer and their clinicians to assess the trade-offs between treatment harms and benefits and enable better informed and prudent treatment decisions. (Funded by the UK National Institute for Health and Care Research Health Technology Assessment Programme projects 96/20/06 and 96/20/99; ISRCTN number, ISRCTN20141297; ClinicalTrials.gov number, NCT02044172.) [ABSTRACT FROM AUTHOR]

Perturbation of the insulin/insulin-like growth factor (IGF) signaling system is often cited as a mechanism driving breast cancer risk. A systematic review identified prospective cohort studies and Mendelian randomization studies that examined the effects of insulin/IGF signaling (IGF, their binding proteins (IGFBP), and markers of insulin resistance] on breast cancer risk. Meta-analyses generated effect estimates; risk of bias was assessed and the Grading of Recommendations Assessment, Development and Evaluation system applied to evaluate the overall quality of the evidence. Four Mendelian randomization and 19 prospective cohort studies met our inclusion criteria. Meta-analysis of cohort studies confirmed that higher IGF-1 increased risk of breast cancer; this finding was supported by the Mendelian randomization studies. IGFBP-3 did not affect breast cancer. Meta analyses for connecting-peptide and fasting insulin showed small risk increases, but confidence intervals were wide and crossed the null. The quality of evidence obtained ranged from 'very low' to 'moderate'. There were insufficient studies to examine other markers of insulin/IGF signaling. These findings do not strongly support the biological plausibility of the second part of the physical activity--insulin/IGF signaling system--breast cancer pathway. Robust conclusions cannot be drawn due to the dearth of high quality studies. [ABSTRACT FROM AUTHOR]

Physical activity may reduce the risk of developing breast cancer via its effect on the insulin/insulin-like growth factor (IGF) signaling system. A systematic review searched for randomized controlled trials (RCT), Mendelian randomization and prospective cohort studies that examined the effects of physical activity on insulin/IGF signaling [IGFs, their binding proteins (IGFBP), and markers of insulin resistance] in adult women. Meta-analyses were performed to generate effect estimates. Risk of bias was assessed, and the Grading of Recommendations Assessment, Development, and Evaluation system used to determine the overall quality of the evidence. Fifty-eight RCTs met our inclusion criteria, no observational or Mendelian randomization studies met the criteria for inclusion. Meta-analyses indicated that physical activity interventions (vs. control) reduced fasting insulin, the Homeostatic Model Assessment for Insulin Resistance and fasting glucose. Physical activity increased IGF-1, but there was no clear effect on IGFBP-3 or the ratio of IGF-1:IGFBP-3. Strong evidence was only established for fasting insulin and insulin resistance. Further research is needed to examine the effect of physical activity on C-peptide and HBA1c in women. Reductions in fasting insulin and insulin resistance following exercise suggest some biological plausibility of the first part of the physical activity-insulin/IGF signaling-breast cancer pathway. [ABSTRACT FROM AUTHOR]

The effect of physical activity on breast cancer risk may be partly mediated by sex steroid hormones. This review synthesized and appraised the evidence for an effect of physical activity on sex steroid hormones. Systematic searches were performed using MEDLINE (Ovid), EMBASE (Ovid), and SPORTDiscus to identify experimental studies and prospective cohort studies that examined physical activity and estrogens, progestins, and/or androgens, as well as sex hormone binding globulin (SHBG) and glucocorticoids in pre- and postmenopausal women. Meta-analyses were performed to generate effect estimates. Risk of bias was assessed, and the GRADE system was used to appraise quality of the evidence. Twenty-eight randomized controlled trials (RCT), 81 nonrandomized interventions, and six observational studies were included. Estrogens, progesterone, and androgens mostly decreased, and SHBG increased, in response to physical activity. Effect sizes were small, and evidence quality was graded moderate or high for each outcome. Reductions in select sex steroid hormones following exercise supports the biological plausibility of the first part of the physical activity-sex hormone-breast cancer pathway. The confirmed effect of physical activity on decreasing circulating sex steroid hormones supports its causal role in preventing breast cancer. [ABSTRACT FROM AUTHOR]

We undertook a systematic review and appraised the evidence for an effect of circulating sex steroid hormones and sex hormone-binding globulin (SHBG) on breast cancer risk in pre- and postmenopausal women. Systematic searches identified prospective studies relevant to this review. Meta-analyses estimated breast cancer risk for women with the highest compared with the lowest level of sex hormones, and the DRMETA Stata package was used to graphically represent the shape of these associations. The ROBINS-E tool assessed risk of bias, and the GRADE system appraised the strength of evidence. In premenopausal women, there was little evidence that estrogens, progesterone, or SHBG were associated with breast cancer risk, whereas androgens showed a positive association. In postmenopausal women, higher estrogens and androgens were associated with an increase in breast cancer risk, whereas higher SHBG was inversely associated with risk. The strength of the evidence quality ranged from low to high for each hormone. Dose-response relationships between sex steroid hormone concentrations and breast cancer risk were most notable for postmenopausal women. These data support the plausibility of a role for sex steroid hormones in mediating the causal relationship between physical activity and the risk of breast cancer. [ABSTRACT FROM AUTHOR]

Epidemiologic research suggests that physical activity is associated with a reduced risk of breast cancer, but the causal nature of this link is not clear. Investigating mechanistic pathways can provide evidence of biological plausibility and improve causal inference. This project will examine three putative pathways (sex steroid hormones, insulin signaling, and inflammation) in a series of two-stage systematic reviews. Stage 1 used Text Mining for Mechanism Prioritisation (TeMMPo) to identify and prioritize relevant biological intermediates. Stage 2 will systematically review the findings from studies of (i) physical activity and intermediates and (ii) intermediates and breast cancer. Ovid MEDLINE, EMBASE, and SPORTDiscus will be searched using a combination of subject headings and free-text terms. Human intervention and prospective, observational studies will be eligible for inclusion. Meta-analysis will be performed where possible. Risk of bias will be assessed using the Cochrane Collaboration tool, or the ROBINS-I or ROBINS-E tool, depending on study type. Strength of evidence will be assessed using the GRADE system. In addition to synthesizing the mechanistic evidence that links physical activity with breast cancer risk, this project may also identify priority areas for future research and help inform the design and implementation of physical activity interventions. [ABSTRACT FROM AUTHOR]

Background: Epidemiologic studies evaluating associations between sex steroid hormones and colorectal cancer risk have yielded inconsistent results. To elucidate the role of circulating levels of testosterone, and sex hormone-binding globulin (SHBG) in colorectal cancer risk, we conducted observational and Mendelian randomization (MR) analyses. Methods: The observational analyses included 333,530 participants enrolled in the UK Biobank with testosterone and SHBG measured. HRs and 95% confidence intervals (CI) were estimated using multivariable Cox proportional hazards models. For MR analyses, genetic variants robustly associated with hormone levels were identified and their association with colorectal cancer (42,866 cases/42,752 controls) was examined using two-sample MR. Results: In the observational analysis, there was little evidence that circulating levels of total testosterone were associated with colorectal cancer risk; the MR analyses showed a greater risk for women (OR per 1-SD = 1.09; 95% CI, 1.01-1.17), although pleiotropy may have biased this result. Higher SHBG concentrations were associated with greater colorectal cancer risk for women (HR per 1-SD = 1.16; 95% CI, 1.05-1.29), but was unsupported by the MR analysis. There was little evidence of associations between free testosterone and colorectal cancer in observational and MR analyses. Conclusions: Circulating concentrations of sex hormones are unlikely to be causally associated with colorectal cancer. Additional experimental studies are required to better understand the possible role of androgens in colorectal cancer development. Impact: Our results from large-scale analyses provide little evidence for sex hormone pathways playing a causal role in colorectal cancer development. [ABSTRACT FROM AUTHOR]

Background: Hypertension in midlife is associated with increased risk of Alzheimer disease and vascular dementia late in life. In addition, some antihypertensive drugs have been proposed to have cognitive benefits, independent of their effect on hypertension. Consequently, there is potential to repurpose antihypertensive drugs for the prevention of dementia. This study systematically compared seven antihypertensive drug classes for this purpose, using the Clinical Practice Research Datalink.Methods: We assessed treatments for hypertension in an instrumental variable analysis to address potential confounding and reverse causation. We used physicians' prescribing preference as an ordinal instrument, defined by the physicians' last seven prescriptions. Participants considered were new antihypertensive users between 1996 and 2016, aged 40 and over.Results: We analyzed 849,378 patients, with total follow up of 5,497,266 patient-years. We estimated that β-adrenoceptor blockers and vasodilator antihypertensives conferred small protective effects-for example, β-adrenoceptor blockers were associated with 13 (95% confidence interval = 6, 20) fewer cases of any dementia per 1000 treated compared with other antihypertensives.Conclusions: We estimated small differences in the effects of antihypertensive drug classes on dementia outcomes. We also show that the magnitude of the differences between drug classes is smaller than that previously reported. Future research should look to implement other causal analysis methods to address biases in conventional observational research, with the ultimate aim of triangulating the evidence concerning this hypothesis. [ABSTRACT FROM AUTHOR]

Background: A polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening. Methods: United Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score =7, stage T3-T4, PSA =10, or nodal/distant metastases). Using HRs estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age, when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-year-standard risk), was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups. Results: The expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-year-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age. Conclusions: PHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS. [ABSTRACT FROM AUTHOR]

Background: The 5-year mortality rate for pancreatic cancer is among the highest of all cancers. Greater understanding of underlying causes could inform population-wide intervention strategies for prevention. Summary genetic data from genome-wide association studies (GWAS) have become available for thousands of phenotypes. These data can be exploited in Mendelian randomization (MR) phenome-wide association studies (PheWAS) to efficiently screen the phenome for potential determinants of disease risk. Methods: We conducted an MR-PheWAS of pancreatic cancer using 486 phenotypes, proxied by 9,124 genetic variants, and summary genetic data from a GWAS of pancreatic cancer (7,110 cancer cases, 7,264 controls). ORs and 95% confidence intervals per 1 SD increase in each phenotype were generated. Results: We found evidence that previously reported risk factors of body mass index (BMI; 1.46; 1.20-1.78) and hip circumference (1.42; 1.21-1.67) were associated with pancreatic cancer. We also found evidence of novel associations with metabolites that have not previously been implicated in pancreatic cancer: ADpSGEGDFXAEGGGVR*, a fibrinogen-cleavage peptide (1.60; 1.31-1.95), and O-sulfo-l-tyrosine (0.58; 0.46-0.74). An inverse association was also observed with lung adenocarcinoma (0.63; 0.54-0.74). Conclusions: Markers of adiposity (BMI and hip circumference) are potential intervention targets for pancreatic cancer prevention. Further clarification of the causal relevance of the fibrinogen-cleavage peptides and O-sulfo-l-tyrosine in pancreatic cancer etiology is required, as is the basis of our observed association with lung adenocarcinoma. Impact: For pancreatic cancer, MR-PheWAS can augment existing risk factor knowledge and generate novel hypotheses to investigate. [ABSTRACT FROM AUTHOR]

Background: Circulating insulin-like growth factor binding protein 3 (IGFBP-3) has been associated with prostate cancer. Preclinical studies found that vitamin D regulates IGFBP-3 expression, although evidence from epidemiologic studies is conflicting. Methods: Mendelian randomization analyses (MR) were conducted to reassess associations between IGFBP-3 and prostate cancer risk and advanced prostate cancer using summary statistics from the PRACTICAL consortium (44,825 cases; 27,904 controls). Observational and MR analyses were conducted to assess the relationship between inactive vitamin D [25(OH)D] and IGFBP-3 using data from the ProtecT study (1,366 cases;1,071 controls) and summary statistics from the CHARGE consortium (n = 18,995). Results: The OR for prostate cancer per SD unit increase in circulating IGFBP-3 was 1.14 [95% confidence interval (CI), 1.02-1.28]. The OR for advanced prostate cancer per SD unit increase in IGFBP-3 was 1.22 (95% CI, 1.07-1.40). Observationally, a SD increase in 25(OH)D was associated with a 0.1SD (95% CI, 0.05-0.14) increase in IGFBP-3. MR analyses found little evidence for a causal relationship between circulating 25(OH)D and IGFBP-3 in the circulation. Conclusions: This study provided confirmatory evidence that IGFBP-3 is a risk factor for prostate cancer risk and progression. Observationally, there was evidence that 25(OH)D is associated with IGFBP-3, but MR analyses suggested that these findings were unlikely to be causal. Findings may be limited by the nature of instrumentation of 25(OH)D and IGFBP-3 and the utility of circulating measures. 25(OH)D appears unlikely to be causally related to IGFBP-3 in the circulation, however, our findings do not preclude causal associations at the tissue level. Impact: IGFBP-3 is a prostate cancer risk factor but 25(OH)D are unlikely to be causally related to IGFBP-3 in the circulation. [ABSTRACT FROM AUTHOR]

Observational epidemiologic studies are prone to confounding, measurement error, and reverse causation, undermining robust causal inference. Mendelian randomization (MR) uses genetic variants to proxy modifiable exposures to generate more reliable estimates of the causal effects of these exposures on diseases and their outcomes. MR has seen widespread adoption within cardio-metabolic epidemiology, but also holds much promise for identifying possible interventions for cancer prevention and treatment. However, some methodologic challenges in the implementation of MR are particularly pertinent when applying this method to cancer etiology and prognosis, including reverse causation arising from disease latency and selection bias in studies of cancer progression. These issues must be carefully considered to ensure appropriate design, analysis, and interpretation of such studies. In this review, we provide an overview of the key principles and assumptions of MR, focusing on applications of this method to the study of cancer etiology and prognosis. We summarize recent studies in the cancer literature that have adopted a MR framework to highlight strengths of this approach compared with conventional epidemiological studies. Finally, limitations of MR and recent methodologic developments to address them are discussed, along with the translational opportunities they present to inform public health and clinical interventions in cancer. [ABSTRACT FROM AUTHOR]

Background: Human, animal, and cell experimental studies; human biomarker studies; and genetic studies complement epidemiologic findings and can offer insights into biological plausibility and pathways between exposure and disease, but methods for synthesizing such studies are lacking. We, therefore, developed a methodology for identifying mechanisms and carrying out systematic reviews of mechanistic studies that underpin exposure-cancer associations. Methods: A multidisciplinary team with expertise in informatics, statistics, epidemiology, systematic reviews, cancer biology, and nutrition was assembled. Five 1-day workshops were held to brainstorm ideas; in the intervening periods we carried out searches and applied our methods to a case study to test our ideas. Results: We have developed a two-stage framework, the first stage of which is designed to identify mechanisms underpinning a specific exposure-disease relationship; the second stage is a targeted systematic review of studies on a specific mechanism. As part of the methodology, we also developed an online tool for text mining for mechanism prioritization (TeMMPo) and a new graph for displaying related but heterogeneous data from epidemiologic studies (the Albatross plot). Conclusions: We have developed novel tools for identifying mechanisms and carrying out systematic reviews of mechanistic studies of exposure-disease relationships. In doing so, we have outlined how we have overcome the challenges that we faced and provided researchers with practical guides for conducting mechanistic systematic reviews. Impact: The aforementioned methodology and tools will allow potential mechanisms to be identified and the strength of the evidence underlying a particular mechanism to be assessed. [ABSTRACT FROM AUTHOR]

To examine associations between the transcription factors CCCTC-binding factor (CTCF) and forkhead box protein A1 (FOXA1) and the androgen receptor (AR) and their association with components of the insulin-like growth factor (IGF)-pathway in a cohort of men with localized prostate cancer. Using prostate tissue samples collected during the Prostate cancer: Evidence of Exercise and Nutrition Trial (PrEvENT) trial (N = 70 to 92, depending on section availability), we assessed the abundance of CTCF, FOXA1, AR, IGFIR, p-mTOR, PTEN and IGFBP-2 proteins using a modified version of the Allred scoring system. Validation studies were performed using large, publicly available datasets (TCGA) (N = 489). We identified a strong correlation between CTCF and AR staining with benign prostate tissue. CTCF also strongly associated with the IGF IR, with PTEN and with phospho-mTOR. FOXA1 was also correlated with staining for the IGF-IR, with IGFBP-2 and with staining for activated phosphor-mTOR. The staining for the IGF-IR was strongly correlated with the AR. Our findings emphasise the close and complex links between the endocrine controls, well known to play an important role in prostate cancer, and the transcription factors implicated by the recent genetic evidence. • What is already known on this topic: CCCTC-binding factor, forkhead box protein A1 and the insulin-like growth factor axis are important in prostate cancer. • What this study adds: Novel links between endocrine controls, the IGF-axis and key transcription factors, such as FOXA1 and the AR. • How this study might affect research, practice, or policy: Optimising treatment strategies by identifyingrelevant molecular associations found in tissue from men with prostate cancer. [ABSTRACT FROM AUTHOR]

The article discusses a study which aims to determine adherence to the World Cancer Research Fund (WCRF) and the American Institute for Cancer Research (AICR) recommendation for dietary and lifestyle and association of a prostate cancer dietary index with prostate cancer risk. It presents recommendation for high intake of plant foods and tomato products to protect against prostrate cancer. It also mentions about the null effect of selenium supplementation on prostate cancer risk.

The article discusses study which examines the association of genetic variation in prostate-specific antigen with prostate cancer detection and the effect of control selection on genome-wide association studies (GWAS). Topics discussed include associations of single nucleotide polymorphisms (SNPs) with circulating prostate-specific antigen (PSA), selection of controls for GWAS below PSA threshold, and comparing prostate cancer cases with low PSA controls.

Objective: Instrumental variable analysis can estimate treatment effects in the presence of residual or unmeasured confounding. We compared ordinary least squares regression versus instrumental variable estimates of the effects of selective cyclooxygenase-2 inhibitors (COX-2s) relative to nonselective nonsteroidal anti-inflammatory drug (NSAID) prescriptions on incidence of upper gastrointestinal complications and myocardial infarction (MI).Methods: We sampled a cohort of 62,933 first-time users of COX-2s or nonselective NSAIDs older than 60 years in the Clinical Practice Research Datalink. The instruments were physicians' previous prescriptions of COX-2s or nonselective NSAIDs, which are surrogates for physician preferences. We estimated risk differences of incident upper gastrointestinal complications and MI within 180 days of first COX-2 versus nonselective NSAID prescription.Results: Using ordinary least squares regression, adjusted for baseline confounders, we observed little association of COX-2 prescriptions with incident upper gastrointestinal complications (risk difference = -0.08 [95% confidence interval = -0.20 to 0.04]) or MI (0.06 [-0.06 to 0.17]) per 100 patients treated. Our adjusted instrumental variable results suggested 0.46 per 100 (-0.15 to 1.07) fewer upper gastrointestinal complications and little difference in acute MIs (0.08 per 100 [-0.61 to 0.76]), within 180 days of being prescribed COX-2s. Estimates were more precise when we used 20 previous prescriptions; the instrumental variable analysis implied 0.74 (0.28 to 1.19) fewer MIs per 100 patients prescribed COX-2s.Conclusions: Using instrumental variable analysis, we found some evidence that COX-2 prescriptions reduced the risk of upper gastrointestinal complications, consistent with randomized controlled trials. Our results using multiple instruments suggest that COX-2s may have heterogeneous within-class effects on MI. [ABSTRACT FROM AUTHOR]

The article discusses the genetic factors associated with pigmentation traits affecting response to sunlight, and the evaluated relationship of lifecourse ultraviolet radiation (UVR) exposure with detected prostate cancer risk and plasma levels of vitamin D. Topics covered include how the subjects were screened for randomized controlled trial, the obtained exposure data and the statistical analysis used to assess the association of genetic scores with pigmentation and sun exposure variables.

The article presents a study which attempts to connect over a period of time lifestyle factors and anthropometric measures with prostate-specific antigen (PSA) growth in men with localized prostate cancer. The PSA measures of men aged 50-69 years undergoing active monitoring were examined. It was found that smoking and exercise are the lifestyle factors associated with PSA levels in men with prostate cancer.

The article presents a study on the roles of folate, vitamin B12, homocysteine and folate-pathway polymorphisms in determining prostate-specific antigen velocity (PSAV) in men diagnosed with localized prostate cancer. For the study, researchers examined 424 men in Great Britain with prostate cancer. They found that vitamin B12, holo-haptocorrin, holo-transcobalamin, total transcobalamin, and total homocysteine were not linked to postdiagnosis PSAV. They found little evidence on the link of higher folate with cancer progression.

The article presents a study presenting the evidence that genetic variants in the vitamin D receptor delays the advancement of prostate cancer in men. It also notes the participants in these cancer cases were chosen from the Prostate Testing for Cancer and Treatment Review. Genetic analysis and experimentation results from different men with prostate cancer are also presented.

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]

Purpose: There is continuing controversy over the most appropriate treatment for screen detected and clinically localized prostate cancer, and increasing interest in monitoring such men initially with radical treatment targeted at cancers showing signs of progressive potential but while they are still curable. Current evidence on monitoring protocols and biomarkers used to predict disease progression was systematically reviewed. Materials and Methods: The MEDLINE and Excerpta Medica (EMBASE) bibliographic databases were searched from 1988 to October 2004, supplemented by manual searches of reference lists, focusing on studies reporting monitoring of men with localized prostate cancer. Results: A total of 48 potentially eligible articles were found but only 5 studies, in which there was a total of 451 participants, restricted entry criteria to men with clinically localized (T1-T2) prostate cancer. Monitoring protocols varied with little consensus, although the majority used prostate specific antigen and digital rectal examination, while some added re-biopsy to assess progression. Actuarial probabilities of freedom from disease progression at 4 to 5 years of followup were 67% to 72%. However, up to 50% of men abandoned monitoring within 2 years, largely because of anxiety related to increasing prostate specific antigen rather than objective evidence of disease progression. There was no robust evidence to support prostate specific antigen doubling times or velocity to identify men in whom disease may progress. Studies were characterized by small sample size, short-term followup, observer bias and uncertain validity around variable definitions of progression. Conclusions: Current evidence suggests that some form of monitoring would be a suitable treatment option in men with localized prostate cancer but there is little consensus over what markers should be used in such a program or how progression should be properly defined. The search for a method that safely identifies men with prostate cancer who could avoid radical intervention must continue. [Copyright &y& Elsevier]

Background: A person's birth weight is inversely related to both their own and their parents' cardiovascular disease mortality risk, but mechanisms underlying such transgenerational associations are unclear. We investigated the influence of the childhood growth of the mother or father on the birth weight of their first-born offspring.Methods: We used data from the long-term follow up (in 1997-1998) of 4999 children from 1352 families who participated in the Boyd Orr Survey of Diet and Health in Pre-War Britain (1937-1939). Complete information on childhood height, potential confounding variables, and the birth weight of first-born offspring was available for 637 subjects.Results: Mother's height in childhood was positively associated with her offspring's birth weight. Leg length, but not trunk length, was the component of maternal height associated with offspring birth weight. For each unit increase in z-score for maternal childhood leg length, there was a 96-g (95% confidence interval = 6-186) increase in offspring birth weight after controlling for childhood socioeconomic variables and adult height. There were weaker positive associations of paternal height and leg length in childhood with offspring birth weight. Associations were not confounded by maternal birth weight or midgrandparental height.Conclusions: Our findings are consistent with the hypothesis that maternal growth during childhood influences offspring birth weight, independently of maternal birth weight, final attained height, or midgrandparental height. Because leg length is a sensitive marker of adverse nutritional and social exposures during childhood, these results suggest a key role for a mother's early environmental exposures as a determinant of her child's subsequent health. [ABSTRACT FROM AUTHOR]