Anthropometric and reproductive factors have been reported as being established risk factors for breast cancer (BC). This study explores the contribution of anthropometric and reproductive factors in ...UK females developing BC in a large longitudinal cohort.
Data from the UK Biobank prospective study of 273,467 UK females were analyzed. Relative risks (RRs) and 95% confidence intervals (CIs) for each factor were adjusted for age, family history of BC and deprivation score. The analyses were stratified by the menopausal status.
Over the 9 years of follow up the total number of BC cases were 14,231 with 3,378 (23.7%) incident cases with an incidence rate of 2.09 per 1000 person-years. In pre-menopausal, increase in age, height, having low BMI, low waist to hip ratio, first degree family history of BC, early menarche age, nulliparous, late age at first live birth, high reproductive interval index, and long contraceptive use duration were all significantly associated with an increased BC risk. In post-menopausal, getting older, being taller, having high BMI, first degree BC family history, nulliparous, late age at first live birth, and high reproductive interval index were all significantly associated with an increased risk of BC. The population attributable fraction (PAF) suggested that an early first live birth, lower reproductive interval index and increased number of children can contribute to BC risk reduction up to 50%.
This study utilizes the UK Biobank study to confirm associations between anthropometric and reproductive factors and the risk of breast cancer development. Result of attributable fraction of risk contributed by each risk factor suggested that lifetime risk of BC can be reduced by controlling weight, reassessing individual approaches to the timing of childbirth and options for contraception and considering early screening for women with family history in the first degree relative.
This study was designed to investigate the relationship between a systematic inflammatory biomarker measure, concurrent and later cognitive performance, and future dementia risk. The literature has ...reported the potential involvement of inflammation in cognitive performance as well as Alzheimer's Disease, but not consistently. We used a population-based cohort of 500,000 people in the UK and assessed the association between a composite inflammatory biomarker and cognitive performance measures across five domains measured concurrently and 4-13 years later, taking advantage of the large sample size. We also assessed the same biomarker's association with dementia diagnosis 3-11 years later in the initially dementia-free sample. We report small but significant associations between elevated biomarker levels and worsened cognitive performance at baseline for four cognitive tasks (OR = 1.204, p<0.001 for Prospective memory, β = -0.366, p<0.001 for Fluid intelligence, β = 8.819, p<0.001 for Reaction time, and β = -0.224, p<0.001 for Numeric memory), comparing the highest quartile of the biomarker to the lowest. We also found that for one measure (Pairs matching) higher biomarker levels were associated with fewer errors, i.e. better performance (β = -0.096, p<0.001). We also report that the 4th quartiles of the baseline biomarker levels were significantly associated with cognitive task scores assessed years later on the p< = 0.002 level, except for the Pair matching test, for which none of the quartiles remained a significant predictor. Finally, the highest biomarker quartile was significantly associated with increased dementia risk compared to the lowest quartile (HR = 1.349, p<0.001). A case-only analysis to assess disease subtype heterogeneity suggested probable differences in the association with the highest biomarker quartile between vascular dementia and Alzheimer disease subtypes (OR = 1.483, p = 0.055). Our results indicate that systemic inflammation may play a small but significant part in dementia pathophysiology, especially in vascular dementia.
This two-sample Mendelian randomization (MR) study was conducted to investigate the causal associations between type 2 diabetes mellitus (T2DM) and the risk of pancreatic cancer (PaCa), as this ...causal relationship remains inconclusive in existing MR studies. The selection of instrumental variables for T2DM was based on two genome-wide association study (GWAS) meta-analyses from European cohorts. Summary-level data for PaCa were extracted from the FinnGen and UK Biobank databases. Inverse variance weighted (IVW) and four other robust methods were employed in our MR analysis. Various sensitivity analyses and multivariable MR approaches were also performed to enhance the robustness of our findings. In the IVW and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) analyses, the odds ratios (ORs) for each 1-unit increase in genetically predicted log odds of T2DM were approximately 1.13 for PaCa. The sensitivity tests and multivariable MR supported the causal link between T2DM and PaCa without pleiotropic effects. Therefore, our analyses suggest a causal relationship between T2DM and PaCa, shedding light on the potential pathophysiological mechanisms of T2DM's impact on PaCa. This finding underscores the importance of T2DM prevention as a strategy to reduce the risk of PaCa.
Identification of shared causal genes between dementia and its related clinical outcomes can help understand shared aetiology and multimorbidity surrounding dementia. We performed the HyPrColoc ...colocalization analysis to detect possible shared causal genes between dementia or Alzheimer's disease (AD) and 5 selected traits: stroke, diabetes, atherosclerosis, cholesterol level, and alcohol consumption within 601 dementia or AD associated genetic regions using summary results of the UK Biobank genome-wide association studies. Functional analysis was performed on the candidate causal genes to explore potential biological pathways. Rs150562240 in the LPIN3 gene was identified as a candidate shared causal variant across dementia, AD and atherosclerosis. Evidence for pairwise colocalization between dementia and stroke, dementia (or AD) and atherosclerosis, and dementia (or AD) and diabetes was found in 2, 6 and 2 genetic regions respectively. Colocalization signals between diabetes and the other 3 non-dementia/AD traits were detected in 5 regions. The colocalization evidence shown in our study suggested shared aetiology between dementia and related diseases such as stroke, atherosclerosis, and diabetes.
The immune response to infections could be largely driven by the individual's genes, especially in the major histocompatibility complex (MHC) region. Varicella-zoster virus (VZV) is a highly ...communicable pathogen. In addition to infection, the reactivations of VZV can be a potential causal factor for multiple traits. Identification of VZV immune response-related health conditions can therefore help elucidate the aetiology of certain diseases.
A phenome-wide Mendelian randomization (MR) study of anti-VZV immunoglobulin G (IgG) levels with 1370 traits was conducted to explore the potential causal role of VZV-specific immune response on multiple traits using the UK Biobank cohort. For the robustness of the results, we performed MR analyses using five different methods. To investigate the impact of the MHC region on MR results, the analyses were conducted using instrumental variables (IVs) inside (IV
) and outside (IV
) the MHC region or all together (IV
).
Forty-nine single nucleotide polymorphisms (IV
) were associated with anti-VZV IgG levels, of which five (IV
) were located in the MHC region and 44 (IV
) were not. Statistical evidence (false discovery rate < 0.05 in at least three of the five MR methods) for a causal effect of anti-VZV IgG levels was found on 22 traits using IV
, while no evidence was found when using IV
or IV
. The reactivations of VZV increased the risk of Dupuytren disease, mononeuropathies of the upper limb, sarcoidosis, coeliac disease, teeth problems and earlier onset of allergic rhinitis, which evidence was concordant with the literature. Suggestive causal evidence (P < 0.05 in at least three of five MR methods) using IV
, IV
and IV
was detected in 92, 194 and 56 traits, respectively. MR results from IV
correlated with those from IV
or IV
. However, the results between IV
and IV
were noticeably different, as evidenced by causal associations in opposite directions between anti-VZV IgG and ten traits.
In this exploratory study, anti-VZV IgG was causally associated with multiple traits. IVs in the MHC region might have a substantial impact on MR, and therefore, could be potentially considered in future MR studies.
Transcription factor mediated lineage reprogramming of human pancreatic exocrine tissue could conceivably provide an unlimited supply of islets for transplantation in the treatment of diabetes. ...Exocrine tissue can be efficiently reprogrammed to islet-like cells using a cocktail of transcription factors: Pdx1, Ngn3, MafA and Pax4 in combination with growth factors. We show here that overexpression of exogenous Pax4 in combination with suppression of the endogenous transcription factor ARX considerably enhances the production of functional insulin-secreting β-like cells with concomitant suppression of α-cells. The efficiency was further increased by culture on laminin-coated plates in media containing low glucose concentrations. Immunocytochemistry revealed that reprogrammed cultures were composed of ~45% islet-like clusters comprising >80% monohormonal insulin+ cells. The resultant β-like cells expressed insulin protein levels at ~15-30% of that in adult human islets, efficiently processed proinsulin and packaged insulin into secretory granules, exhibited glucose responsive insulin secretion, and had an immediate and prolonged effect in normalising blood glucose levels upon transplantation into diabetic mice. We estimate that approximately 3 billion of these cells would have an immediate therapeutic effect following engraftment in type 1 diabetes patients and that one pancreas would provide sufficient tissue for numerous transplants.
The causes that trigger the onset of dementia are still unknown. Recently there has been an increasing interest in the possible role of infectious agents in the brain in the pathogenesis of this ...condition. Amongst the viruses, members of the Herpesviridae family, namely herpes simplex virus-1 (HSV1), cytomegalovirus (CMV), human herpesvirus-6 (HHV6), human herpesvirus-7 (HHV7) and varicella zoster virus (VZV) have been suggested as potential causes of the disease. However, the relative importance of these and other viruses in contributing to dementia remains unclear. We evaluated the association between seropositivity status of all viruses available in a large, population-based dataset (the UK Biobank) and dementia risk in an unbiased way. Of the 15 viruses investigated, our results showed a statistically significant increase of dementia risk associated only with HSV1 seropositivity (OR 2.14, 95% C.I. 1.21-3.81). However, by combining the data we found that seropositivity for 4 viruses (HSV1, HHV6, HHV7 and VZV) also significantly increases the risk of dementia (OR = 2.37, 95% C.I. 1.43-3.92). These four viruses have been described previously as neurotropic viruses. Our results provide support for a role for neurotropic viruses in the pathology of dementia.
Background & Aims: Although observational studies have found regular aspirin use to be associated with a reduced risk of colorectal neoplasia, results from randomized trials using aspirin have been ...inconsistent. Dietary folate intake also has been found to be associated with a reduced risk of colorectal neoplasms in observational studies. Methods: A multicenter, randomized, double-blind trial of aspirin (300 mg/day) and folate supplements (0.5 mg/day) to prevent colorectal adenoma recurrence was performed using a 2 × 2 factorial design. All patients had an adenoma (≥0.5 cm) removed in the 6 months before recruitment and were followed-up at 4-month intervals with a second colonoscopy after approximately 3 years. The primary outcome measure was a colorectal adenoma diagnosed after baseline. Results: A total of 945 patients were recruited into the study, of whom 853 (90.3%) underwent a second colonoscopy. In total, 99 (22.8%) of 434 patients receiving aspirin had a recurrent adenoma compared with 121 (28.9%) of 419 patients receiving placebo (relative risk, 0.79; 95% confidence interval CI, 0.63–0.99). A total of 104 patients developed an advanced colorectal adenoma; 41 (9.4%) of these were in the aspirin group and 63 (15.0%) were in the placebo group (relative risk, 0.63; 95% CI, 0.43–0.91). Folate supplementation was found to have no effect on adenoma recurrence (relative risk, 1.07; 95% CI, 0.85–1.34). Conclusions: Aspirin (300 mg/day) but not folate (0.5 mg/day) use was found to reduce the risk of colorectal adenoma recurrence, with evidence that aspirin could have a significant role in preventing the development of advanced lesions.
ObjectiveTo identify risk prediction models for prostate cancer (PCa) that can be used in the primary care and community health settings.DesignSystematic review.Data sourcesMEDLINE and Embase ...databases combined from inception and up to the end of January 2019.EligibilityStudies were included based on satisfying all the following criteria: (i) presenting an evaluation of PCa risk at initial biopsy in patients with no history of PCa, (ii) studies not incorporating an invasive clinical assessment or expensive biomarker/genetic tests, (iii) inclusion of at least two variables with prostate-specific antigen (PSA) being one of them, and (iv) studies reporting a measure of predictive performance. The quality of the studies and risk of bias was assessed by using the Prediction model Risk Of Bias ASsessment Tool (PROBAST).Data extraction and synthesisRelevant information extracted for each model included: the year of publication, source of data, type of model, number of patients, country, age, PSA range, mean/median PSA, other variables included in the model, number of biopsy cores to assess outcomes, study endpoint(s), cancer detection, model validation and model performance.ResultsAn initial search yielded 109 potential studies, of which five met the set criteria. Four studies were cohort-based and one was a case-control study. PCa detection rate was between 20.6% and 55.8%. Area under the curve (AUC) was reported in four studies and ranged from 0.65 to 0.75. All models showed significant improvement in predicting PCa compared with being based on PSA alone. The difference in AUC between extended models and PSA alone was between 0.06 and 0.21.ConclusionOnly a few PCa risk prediction models have the potential to be readily used in the primary healthcare or community health setting. Further studies are needed to investigate other potential variables that could be integrated into models to improve their clinical utility for PCa testing in a community setting.
Abstract
Background
Dementia affects ability to remember, think, or make decisions that interfere with doing everyday activities. There is no cure, therefore any prevention or delay of the onset is ...of importance. This study aims to investigate the association between zoster and influenza vaccinations and the risk of developing dementia.
Methods
We conducted a retrospective population-based cohort study using electronic health records from 1469 general practices contributing to the Clinical Practice Research Datalink (CPRD)
Aurum
database with linked hospital episode statistics (HES) and Office for National Statistics (ONS) mortality records. We built two 'matched cohorts': zoster vaccine (854,745 exposed individuals) matched with 8.8 million comparators without a history of zoster vaccination, and influenza vaccine (742,487 exposed individuals) matched with 7.12 million comparators without a history of vaccination as another comparator group. The cohorts were then followed to assess the association of exposure (vaccine) with outcome (dementia diagnosis).
Results
Zoster vaccination was associated with a lower risk of dementia diagnosis (adjusted hazard ratio (HR) 0.78 with 95% CI: 0.77–0.79), Alzheimer’s diagnosis (adjusted HR 0.91 with 95% CI: 0.89–0.92 and other types of dementia (adjusted HR 0.71 with 95% CI: 0.69–0.72). Influenza vaccination also was associated with a slightly reduced hazard of dementia risk (adjusted HR 0.96 with 95% CI: 0.94–0.97).
Conclusion
Both zoster vaccine for prevention of shingles / herpes zoster and influenza vaccine to prevent influenza were associated with diminished risk of dementia, with the zoster association appearing more pronounced.
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