Sodium-glucose co-transporter-2 inhibitors and susceptibility to COVID-19: A population-based retrospective cohort study.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors are widely prescribed in people with type 2 diabetes. We aimed to investigate whether SGLT2 inhibitor prescription is associated with COVID-19, when compared with an active comparator. We performed a propensity-score-matched cohort study with active comparators and a negative control outcome in a large UK-based primary care dataset. Participants prescribed SGLT2 inhibitors (n = 9948) and a comparator group prescribed dipeptidyl peptidase-4 (DPP-4) inhibitors (n = 14 917) were followed up from January 30 to July 27, 2020. The primary outcome was confirmed or clinically suspected COVID-19. The incidence rate of COVID-19 was 19.7/1000 person-years among users of SGLT2 inhibitors and 24.7/1000 person-years among propensity-score-matched users of DPP-4 inhibitors. The adjusted hazard ratio was 0.92 (95% confidence interval 0.66 to 1.29), and there was no evidence of residual confounding in the negative control analysis. We did not observe an increased risk of COVID-19 in primary care amongst those prescribed SGLT2 inhibitors compared to DPP-4 inhibitors, suggesting that clinicians may safely use these agents in the everyday care of people with type 2 diabetes during the COVID-19 pandemic.

Fruit consumption and the risk of bladder cancer: A pooled analysis by the Bladder Cancer Epidemiology and Nutritional Determinants Study.

While the association between fruit consumption and bladder cancer risk has been extensively reported, studies have had inadequate statistical power to investigate associations between types of fruit and bladder cancer risk satisfactorily. Fruit consumption in relation to bladder cancer risk was investigated by pooling individual data from 13 cohort studies. Cox regression models with attained age as time scale were used to estimate hazard ratios (HRs) for intakes of total fruit and citrus fruits, soft fruits, stone fruits, tropical fruits, pome fruits and fruit products. Analyses were stratified by sex, smoking status and bladder cancer subtype. During on average 11.2 years of follow-up, 2836 individuals developed incident bladder cancer. Increasing fruit consumption (by 100 g/day) was inversely associated with the risk of bladder cancer in women (HR = 0.92; 95% CI 0.85-0.99). Although in women the association with fruit consumption was most evident for higher-risk nonmuscle invasive bladder cancer (NMIBC; HR = 0.72; 95% CI 0.56-0.92), the test for heterogeneity by bladder cancer subtype was nonsignificant (P-heterogeneity = .14). Increasing fruit consumption (by 100 g/day) was not associated with bladder cancer risk in men (HR = 0.99; 95% CI 0.94-1.03), never smokers (HR = 0.96; 95% CI 0.88-1.05), former smokers (HR = 0.98; 95% CI 0.92-1.05) or current smokers (HR = 0.95; 95% CI 0.89-1.01). The consumption of any type of fruit was not found to be associated with bladder cancer risk (P values > .05). Our study supports no evidence that the consumption of specific types of fruit reduces the risk of bladder cancer. However, increasing total fruit consumption may reduce bladder cancer risk in women.

Smoking is associated with lower age, higher grade, higher stage, and larger size of malignant bladder tumors at diagnosis.

Smoking is a strong risk factor of bladder cancer (BC), but it is currently unclear whether smoking is also associated with severity of BC at diagnosis. We performed a large hospital-based case-comparison study, examining the relation between smoking and clinical characteristics of BC at diagnosis. A total of 1,544 cases from participating hospitals in the West Midlands were recruited between 19 December 2005 and 21 April 2011. Eligible cases were adult BC patients without a previous history of this disease. At time of diagnosis, semi-structured face-to-face interviews were conducted by trained research nurses to collect smoking information. Clinical characteristics were obtained from medical records. Linear mixed models were performed to calculate predicted means in clinical outcomes for a variety of smoking behaviors. A p < 0.05 was considered statistically significant. After adjustment for age and gender, current smokers were on average 4.0 years younger at diagnosis (95% CI: -5.9 to -2.0), had larger tumors (mean difference: 0.48 cm, 95% CI: 0.04-0.91), a higher T stage (mean difference: 0.25, 95% CI: 0.08-0.41), and a borderline significantly higher grade than never smokers (mean difference: 0.15, 95% CI: 0.00-0.30). Our results suggest that smoking could be associated with a more malignant phenotype of BC at diagnosis. More research is needed on the relation between smoking and prognosis, but our results could strengthen the message about the potential risks of smoking to these patients.

Life-course origins of social inequalities in adult immune cell markers of inflammation in a developing southern Chinese population: the Guangzhou Biobank Cohort Study.

BACKGROUND: Socioeconomic position (SEP) throughout life is associated with cardiovascular disease, though the mechanisms linking these two are unclear. It is also unclear whether there are critical periods in the life course when exposure to better socioeconomic conditions confers advantages or whether SEP exposures accumulate across the whole life course. Inflammation may be a mechanism linking socioeconomic position (SEP) with cardiovascular disease. In a large sample of older residents of Guangzhou, in southern China, we examined the association of life course SEP with inflammation. METHODS: In baseline data on 9,981 adults (≥ 50 years old) from the Guangzhou Biobank Cohort Study (2006-08), we used multivariable linear regression and model fit to assess the associations of life course SEP at four stages (childhood, early adult, late adult and current) with white blood, granulocyte and lymphocyte cell counts. RESULTS: A model including SEP at all four life stages best explained the association of life course SEP with white blood and granulocyte cell count for men and women, with early adult SEP (education) making the largest contribution. A critical period model best explained the association of life course SEP with lymphocyte count, with sex-specific associations. Early adult SEP was negatively associated with lymphocytes for women. CONCLUSIONS: Low SEP throughout life may negatively impact late adult immune-inflammatory status. However, some aspects of immune-inflammatory status may be sensitive to earlier exposures, with sex-specific associations. The findings were compatible with the hypothesis that in a developing population, upregulation of the gonadotropic axis with economic development may obscure the normally protective effects of social advantage for men.

Relationship Between Weight Status and Health-Related Quality of Life in School-age Children in China.

Background: Some studies from high-income countries suggest that overweight and/or obesity in children are negatively associated with health-related quality of life (HRQOL). However, the relationship between weight status and HRQOL is not well established in China, where obesity trends follow a different pattern compared with high-income countries. The risk of obesity is greater in children from higher socioeconomic backgrounds and higher in boys compared with girls. Objective: The aim of this study was to examine the relationship between weight status and HRQOL in children between 6 and 7 years old in this unique country context. Methods: Baseline HRQOL and demographic data were collected from children recruited to the CHIRPY DRAGON obesity prevention trial in China. HRQOL was measured using the Chinese version of the Child Health Utility-9D (CHU-9D-CHN) and the Pediatric Quality of Life Inventory™ (PedsQL™) instruments. CHU-9D-CHN utility scores were generated using 2 scoring algorithms (UK and Chinese tariffs). Height and weight measures were taken at school by trained researchers using standardized methods, and BMI z scores were calculated using the World Health Organization 2007 growth charts. The relationship between HRQOL and weight status was examined using multivariable analyses, adjusting for age, gender, and socioeconomic status. Results: Full data were available for 1539 children (mean age, 6 years). In both unadjusted and adjusted analyses, HRQOL, using both the CHU-9D-CHN and the PedsQL™, was marginally higher in children who were overweight or living with obesity compared with children with healthy weight, although this difference did not reach statistical significance. Separate analyses and models by gender showed that the relationship between weight status and HRQOL scores was similar in boys and girls. Conclusions: Our results suggest no statistically significant difference in HRQOL between children with overweight/obesity compared with those with healthy weight. These results have implications for the methods of economic evaluation for obesity treatment and prevention interventions within this population cohort and country setting, as there appears to be no discernible consequences on children's HRQOL from living with overweight and obesity.

Genome-wide Meta-analysis Identifies Novel Genes Associated with Recurrence and Progression in Non-muscle-invasive Bladder Cancer.

BACKGROUND: Non-muscle-invasive bladder cancer (NMIBC) is characterized by frequent recurrences and a risk of progression in stage and grade. Increased knowledge of underlying biological mechanisms is needed. OBJECTIVE: To identify single nucleotide polymorphisms (SNPs) associated with recurrence-free (RFS) and progression-free (PFS) survival in NMIBC. DESIGN, SETTING, AND PARTICIPANTS: We analyzed outcome data from 3400 newly diagnosed NMIBC patients from the Netherlands, the UK, Canada, and Spain. We generated genome-wide germline SNP data using Illumina OmniExpress and Infinium Global Screening Array in combination with genotype imputation. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cohort-specific genome-wide association studies (GWASs) for RFS and PFS were performed using a Cox proportional hazard model. Results were combined in a fixed-effect inverse-variance weighted meta-analysis. Candidate genes for the identified SNP associations were prioritized using functional annotation, gene-based analysis, expression quantitative trait locus analysis, and transcription factor binding site databases. Tumor expression levels of prioritized genes were tested for association with RFS and PFS in an independent NMIBC cohort. RESULTS AND LIMITATIONS: This meta-analysis revealed a genome-wide significant locus for RFS on chromosome 14 (lead SNP rs12885353, hazard ratio [HR] C vs T allele 1.55, 95% confidence interval [CI] 1.33-1.82, p = 4.0 × 10-8), containing genes G2E3 and SCFD1. Higher expression of SCFD1 was associated with increased RFS (HR 0.70, 95% CI 0.59-0.84, pFDR = 0.003). Twelve other loci were suggestively associated with RFS (p < 10-5), pointing toward 18 additional candidate genes. For PFS, ten loci showed suggestive evidence of association, indicating 36 candidate genes. Expression levels of ten of these genes were statistically significantly associated with PFS, of which four (IFT140, UBE2I, FAHD1, and NME3) showed directional consistency with our meta-analysis results and published literature. CONCLUSIONS: In this first prognostic GWAS in NMIBC, we identified several novel candidate loci and five genes that showed convincing associations with recurrence or progression. PATIENT SUMMARY: In this study, we searched for inherited DNA changes that affect the outcome of non-muscle-invasive bladder cancer (NMIBC). We identified several genes that are associated with disease recurrence and progression. The roles and mechanisms of these genes in NMIBC prognosis should be investigated in future studies.

Gene-environment interaction with smoking for increased non-muscle-invasive bladder cancer tumor size.

BACKGROUND: Urinary bladder cancer (UBC) is one of few cancers with an established gene-environment interaction (GxE) with smoking. However, it is unknown whether the interaction with tobacco use is present non-muscle invasive bladder cancer (NMIBC) and characteristics of prognostic relevance. We aimed to investigate if smoking status and/or smoking intensity interact with the effect of discovered variants on key NMIBC characteristics of tumor grade, stage, size, and patient age within the Bladder Cancer Prognosis Programme (BCPP) cohort. METHODS: Analyzed sample consisted of 546 NMIBC patients with valid smoking data from the BCPP. In a previous genome-wide association study (GWAS), we have identified 61 single nucleotide polymorphisms (SNPs) potentially associated with the NMIBC characteristics of tumor stage, grade, size, and patient age. In the current analysis, we have tested these SNPs for GxE with smoking. RESULTS: Out of 61 SNPs, 10 have showed suggestion (statistical significance level of P<0.05) for GxE with NMIBC tumor size rs35225990, rs188958632, rs180910528, rs74603364, rs187040828, rs144383242, rs117587674, rs113705641, rs2937268, and chromosome 14:38247577. All SNPs were located across loci of 1p31.3, 3p26.1, 6q14.1, 14q21.1, and 13q14.13. In addition, two of the tested polymorphisms were suggestive for interaction with smoking intensity (chromosome 14:38247577 and rs2937268). CONCLUSIONS: Our study suggests interaction between genetic variance and smoking behavior for increased NMIBC tumor size at the time of diagnosis. Further replication is required to validate these findings.

The effect of smoking on the male excess of bladder cancer: a meta-analysis and geographical analyses.

Smoking is considered the primary risk factor for bladder cancer. Although smoking prevalence and bladder cancer incidence vary around the world, bladder cancer is on average 4 times more common in males than in females. This article describes the observed male-female incidence ratio of bladder cancer for 21 world regions in 2002 and 11 geographical areas during the time period 1970-1997. A meta-analysis, including 34 studies, was performed to ascertain the increased risk for bladder cancer in males and females when smoking. The summary odds ratios (SORs) calculated in the meta-analysis were used to estimate the male-female incidence ratio of bladder cancer that would be expected for hypothetical smoking prevalence scenarios. These expected male-female incidence ratios were compared with the observed ratios to evaluate the role of smoking on the male excess of bladder cancer. The male-female incidence ratio of bladder cancer was higher than expected worldwide and over time, based on a smoking prevalence of 75% in males, 10% in females and an increased risk (SOR) of bladder cancer associated with smoking of 4.23 for males and 1.35 for females, respectively. This implied that, at least in the Western world, smoking can only partially explain the difference in bladder cancer incidence. Consequently, other factors are responsible for the difference in bladder cancer incidence.

External Replication of Urinary Bladder Cancer Prognostic Polymorphisms in the UK Biobank.

Introduction: Multiple studies have reported genetic associations with prognostic outcomes of urinary bladder cancer. However, the lack of replication of these associations prohibits establishing further evidence-based research directions. Moreover, there is a lack of independent bladder cancer patient samples that contain prognostic measures, making genetic replication analyses even more challenging. Materials and Methods: We have identified 1,534 eligible patients and used data on Hospital Episode Statistics in the UK Biobank to model variables of otherwise non-collected events on bladder cancer recurrence and progression. Data on survival was extracted from the Death Registry. We have used SNPTEST software to replicate previously reported genetic associations with bladder cancer recurrence (N = 69), progression (N = 23), survival (N = 53), and age at the time of diagnosis (N = 20). Results: Using our algorithm, we have identified 618 recurrence and 58 UBC progression events. In total, there were 209 deaths (106 UBC-specific). In replication analyses, eight SNPs have reached nominal statistical significance (p < 0.05). Rs2042329 (CWC27) for UBC recurrence; rs804256, rs4639, and rs804276 (in/close to NEIL2) for NMIBC recurrence; rs2293347 (EGFR) for UBC OS; rs3756712 (PDCD6) for NMIBC OS; rs2344673 (RGS5) for MIBC OS, and rs2297518 (NOS2) for UBC progression. However, none have remained significant after adjustments for multiple comparisons. Discussion: External replication in genetic epidemiology is an essential step to identify credible findings. In our study, we identify potential genetic targets of higher interest for UBC prognosis. In addition, we propose an algorithm for identifying UBC recurrence and progression using routinely-collected data on patient interventions.

Systematic Review: Genetic Associations for Prognostic Factors of Urinary Bladder Cancer.

INTRODUCTION: Many germline associations have been reported for urinary bladder cancer (UBC) outcomes and prognostic characteristics. It is unclear whether there are overlapping genetic patterns for various prognostic endpoints. We aimed to review contemporary literature on genetic associations with UBC prognostic outcomes and to identify potential overlap in reported genes. METHODS: EMBASE, MEDLINE, and PubMed databases were queried for relevant articles in English language without date restrictions. The initial search identified 1346 articles. After exclusions, 112 studies have been summarized. Cumulatively, 316 single-nucleotide polymorphisms (SNPs) were reported across prognostic outcomes (recurrence, progression, death) and characteristics (tumor stage, grade, size, age, risk group). There were considerable differences between studied outcomes in the context of genetic associations. The most commonly reported SNPs were located in OGG1, TP53, and MDM2. For outcomes with the highest number of reported associations (ie, recurrence and death), functional enrichment annotation yields different terms, potentially indicating separate biological mechanisms. CONCLUSIONS: Our study suggests that all UBC prognostic outcomes may have different biological origins with limited overlap. Further validation of these observations is essential to target a phenotype that could best predict patient outcome and advance current management practices.

Genome-wide Association Study for Tumour Stage, Grade, Size, and Age at Diagnosis of Non-muscle-invasive Bladder Cancer.

BACKGROUND: Non-muscle-invasive bladder cancer (NMIBC) causes a considerable health burden due to the high recurrence and progression rates. Past studies have identified multiple candidate loci associated with NMIBC prognosis, albeit lacking validation. Moreover, scarce reports exist on genetic susceptibility to independent prognostic predictors of NMIBC, such as stage or grade. OBJECTIVE: To investigate genetic associations with NMIBC tumour and patient characteristics at the time of diagnosis. DESIGN, SETTING, AND PARTICIPANTS: A sample of 653 NMIBC cases comes from the Bladder Cancer Prognosis Programme. Replication of the significant findings was conducted in the Nijmegen Bladder Cancer Study cohort (N=1470). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A genome-wide association study (GWAS) was carried out for outcomes of tumour size (as a continuous variable in centimetres), stage (Tis and T1 vs Ta), grade (G3 vs G2 and G1), and age (as continuous [years] and dichotomous [70.2 yr as a cut-off] variables). RESULTS AND LIMITATIONS: Significant (p<5E-08) associations (N=61) with tumour size, stage, grade, and age were identified in the GWAS discovery stage. None of the variants were independently significantly associated in the replication cohort. A meta-analysis of both cohorts suggests that rs180940944 (13q13.3 locus, NBEA) was associated with tumour size as a continuous variable (ß=0.9cm, p=2.92E-09). However, other single nucleotide polymorphisms in this region did not show evidence of association in the meta-analysis. CONCLUSIONS: Our study suggests that rs180940944 (NBEA) is associated with an increased NMIBC tumour size at the time of diagnosis. Given study limitations, further replication is essential to validate the finding. PATIENT SUMMARY: The current study reports on a genome-wide association study on non-muscle-invasive bladder cancer tumour and patient characteristics. We suggest that NBEA gene might be associated with increased tumour size at the time of diagnosis. The result must be replicated to establish validity.

Discriminatory performance of adiponectin and leptin in the identification of impaired glucose tolerance: The Guangzhou Biobank Cohort Study - Cardiovascular Disease Subcohort.

BACKGROUND: To evaluate the additional discriminatory performance of adiponectin, leptin, and their ratio in the identification of impaired glucose tolerance (IGT) in men and women without diabetes on top of conventional risk factors. METHODS & RESULTS: A total of 698 subjects underwent an oral glucose tolerance test (oGTT) and adipocytokine measurements. A comprehensive stepwise selection procedure was performed, followed by c-statistics and integrated discrimination improvement (IDI) analysis. In males, adiponectin levels were significantly lower in the IGT group compared to the non-IGT group (Whitney U test, p < 10-4), whereas leptin levels were significantly higher (p = 0.009) in IGT group. In females, adiponectin and leptin levels were not significantly different between groups (Mann-Whitney U test, p = 0.073 and p = 0.08, respectively). Adjusting for the most informative, sex-specific, clinical and biochemical factors, adiponectin, leptin and their ratio were not found to be significant predictors of the response to the glucose load, when modelled as continuous terms or tertiles. In males, the area-under-the-curve (AUC) for adiponectin was estimated at 0.620 (95% CI: 0.558-0.682) and the addition of adiponectin into the basic model provided a ΔAUC benefit of 0.004, showing no additional discriminatory benefit on top of conventional risk factors (IDI p-value: 0.27), nor did the addition of leptin or their ratio. The results were similar in females. CONCLUSIONS: In Chinese individuals without diabetes, no significant evidence for the potential discriminatory value of adiponectin, leptin or their ratio in the identification of IGT on top of conventional risk factors was observed.

Glycated Hemoglobin, Albuminuria and Surrogate Markers of Macrovascular Disease in Adults Without Diabetes: The Guangzhou Biobank Cohort Study, Cardiovascular Disease Subcohort.

OBJECTIVES: To explore the clinical utility of glycated hemoglobin (A1C) levels as an early marker of albuminuria, macrovascular disease and subclinical cardiovascular disease in comparison to fasting and postprandial glucose levels in a well-characterized Chinese population with no history of diabetes. METHODS: The study population consisted of 1223 individuals who were enrolled in the Guangzhou Biobank Cohort Study, Cardiovascular Disease Subcohort, and who had undergone oral glucose tolerance tests. The associations between each glycemic measure and albuminuria, carotid intima-media thickness (CIMT) and CIMT-based presence of carotid plaques and aortic arch calcification were assessed by chest radiographs. RESULTS: The overall prevalence of albuminuria, carotid plaque and any aortic arch calcification was 20.6%, 22.8% and 25.8%, respectively. All 3 glycemia indices were significantly associated with albuminuria, but only 1 (fasting glucose) was associated with carotid plaques. No significant difference was detected among them in the area under the curve for albuminuria (chi-square test; p=0.84), carotid plaques (p=0.28) or calcifications (p=0.29). In sensitivity analysis, adjusted for age and sex, the above findings remained unchanged. CONCLUSIONS: Although there was evidence suggesting differential associations, the performance of the glycemic indices was similar, and their association with macrovascular disease and albuminuria was modest.

Interleukin-17-positive mast cells influence outcomes from BCG for patients with CIS: Data from a comprehensive characterisation of the immune microenvironment of urothelial bladder cancer.

The tumour immune microenvironment is considered to influence cancer behaviour and outcome. Using a panel of markers for innate and adaptive immune cells we set out to characterise and understand the bladder tumour microenvironment of 114 patients from a prospective multicentre cohort of newly-diagnosed bladder cancer patients, followed-up for 4.33±1.71 years. We found IL-17-positive cells were significantly increased in primary and concomitant carcinoma in situ (CIS), p<0.0001, a highly malignant lesion which is the most significant single risk factor for disease progression. Further characterisation of the tumour immunophenotype identified IL-17+ cells as predominantly mast cells rather than T-cells, in contrast to most other tumour types. Expression of the IL-17-receptor in bladder tumours, and functional effects and gene expression changes induced by IL-17 in bladder tumour cells in vitro suggest a role in tumour behaviour. Finally, we assessed the effects of IL-17 in the context of patient outcome, following intravesical BCG immunotherapy which is the standard of care; higher numbers of IL-17+ cells were associated with improved event-free survival (p = 0.0449, HR 0.2918, 95% CI 0.08762-0.9721) in patients with primary and concomitant CIS (n = 41), we propose a model of IL-17+ Mast cells mechanism of action. Thus, in the context of bladder CIS, IL-17+ mast cells predict favourable outcome following BCG immunotherapy indicative of a novel mechanism of BCG immunotherapy in UBC and could form the basis of a stratified approach to treatment.

Incidence of cancers following orthotopic liver transplantation in a single center: comparison with national cancer incidence rates for England and Wales.

BACKGROUND: The incidence of de novo cancers is increased in liver allograft recipients but there are few data assessing the extent of the increased risk compared with a matched population. METHODS: A retrospective study of 1,778 adults transplanted between January 1982 and March 2004, followed for a median of 65 months. The observed cancer incidence was compared with age-, sex-, and calendar year-matched expected cancer rates in England and Wales population. RESULTS: In all, 141 (7.9%) developed a new cancer. There was an increase in the incidence of all tumors compared with that expected (Standardized Incidence Ratio (SIR) 207, 95% CI 174-244, P < 0.001); the greatest increase was seen in lymphoid tumors (SIR 1026, 95% CI 608-1621, P < 0.001), skin cancers (SIR 580, 95% CI 432-763, P < 0.001), and cancer of the large bowel (SIR 496, 95% CI 290-774, P < 0.001). Large bowel cancer was more common in those patients with ulcerative colitis than those without (SIR 2727 vs. 347) and in older patients. Females had a greater risk of lung cancer than males (SIR 336 vs. 56). CONCLUSIONS: There is an increased incidence of tumors following liver transplantation. Although the absolute risk of cancer is low, we found that the increase in risk is greater in the younger aged recipients than the older ones. Increased awareness of colon cancer is needed especially in older patients and those with ulcerative colitis. There should be awareness for the high lung cancer incidence in females. Increased surveillance for breast and cervical cancer is not necessary.

NSAIDs and gastrointestinal cancer prevention.

Numerous studies report the relationship between aspirin and other nonsteroidal anti-inflammatories (NSAIDs) and cancer incidence, in particular for colorectal cancer. This paper systematically reviews the evidence of the effect of aspirin and other NSAIDs on the primary prevention of colorectal and other gastrointestinal cancers in the general population. In 25 investigations of NSAIDs and colorectal cancer, 23 observational studies reported a relative risk reduction but estimates vary widely. Cohort studies generally indicate lesser reductions than case-control studies suggesting possible biases in the latter. Clear evidence of a dose relationship generally appears lacking but data do not indicate useful effects of aspirin in cardioprophylactic doses. Differences have otherwise not been detected between aspirin and other NSAIDs, nor between non-aspirin NSAIDs. There is some evidence that the risk of colorectal cancer reduces with increased duration of NSAID use. The lower incidence of oesophageal and gastric cancers results in smaller numbers of cases in the studies reporting these cancers, particularly in the cohort studies. The trend is for a risk reduction for oesophageal and gastric cancers in people taking NSAIDs, which is more likely to be statistically significant in the case-control studies. A very small number of observational studies have reported the relationship between NSAIDs and the incidence of pancreatic, gallbladder and liver cancers. These show no consistent relationship. In view of the inadequate information about optimal dose and duration of NSAIDs for colorectal cancer reduction, and the adverse effects of NSAIDs, we are not yet in a position to recommend NSAIDs for the primary prevention of colorectal cancer in the general population.

Hyperglycaemia and vitamin D: a systematic overview.

Vitamin D plays a role in a range of functions that may impact on glycaemic control. In this study we systematically report on clinical studies evaluating the impact of vitamin D on aspects of hyperglycaemia in non-pregnant adults. A total of 1,294 articles, of which 417 were reviews, were identified. No well-designed randomised, controlled trials were identified that specifically investigated the effects of vitamin D supplementation on glucose and insulin concentrations. The majority of the studies that are available were poorly designed, having limited numbers, short study duration, or were conducted in volunteers with normal baseline, as measured by 25-hydroxyvitamin D (25(OH)D), concentrations or used inadequate doses of the supplements to normalise vitamin D concentrations, or used inappropriate analyses. Most studies did not observe improvements in glycaemia, with few exceptions. The results were more equivocal for aspects of insulin resistance. Most found no benefit on measures of insulin resistance, although some did. However, more studies described improved insulin release, although data from the studies to date are really inadequate to provide any reliable conclusions. Well-conducted randomised, controlled trials with adequate vitamin D doses are required to effectively assess whether this vitamin can reduce the incidence of diabetes.

A systematic review of lifestyle modification and glucose intolerance in the prevention of type 2 diabetes.

Diabetes is reaching epidemic proportions. High risk groups, such as those older individuals or with glucose intolerance have been shown to exhibit a high risk of developing diabetes. We aimed to systematically identify and evaluate those studies that have investigated the impact of lifestyle interventions on the prevention of the development of incident Type 2 diabetes in those with glucose intolerance. Non-pharmacological lifestyle interventions, including manipulation of dietary intakes and physical activity levels are the main approaches taken to reduce the onset of diabetes in high risk groups, such as those with glucose intolerance. Intensive use of each of these lifestyle interventions have been shown to halve the risk of incident diabetes, although less intensive interventions appear to be less effective. Lifestyle modification is a useful weapon in the armoury of preventing the onset of diabetes, which is essential to reduce the associated increased risk of morbidity and mortality that might otherwise overwhelm health care systems in both developed and developing countries.