Summary Background Present guidelines are conflicting for patients at high risk of both cardiovascular and gastrointestinal events who continue to require non-steroidal anti-inflammatory drugs ...(NSAIDs). We hypothesised that a cyclooxygenase-2-selective NSAID plus proton-pump inhibitor is superior to a non-selective NSAID plus proton-pump inhibitor for prevention of recurrent ulcer bleeding in concomitant users of aspirin with previous ulcer bleeding. Methods For this industry-independent, double-blind, double-dummy, randomised trial done in one academic hospital in Hong Kong, we screened patients with arthritis and cardiothrombotic diseases who were presenting with upper gastrointestinal bleeding, were on NSAIDs, and require concomitant aspirin. After ulcer healing, an independent staff member randomly assigned (1:1) patients who were negative for Helicobacter pylori with a computer-generated list of random numbers to receive oral administrations of either celecoxib 100 mg twice per day plus esomeprazole 20 mg once per day or naproxen 500 mg twice per day plus esomeprazole 20 mg once per day for 18 months. All patients resumed aspirin 80 mg once per day. Both patients and investigators were masked to their treatments. The primary endpoint was recurrent upper gastrointestinal bleeding within 18 months. The primary endpoint and secondary safety endpoints were analysed in the modified intention-to-treat population. This study was registered with ClinicalTrials.gov , number NCT00153660. Findings Between May 24, 2005, and Nov 28, 2012, we enrolled 514 patients, assigning 257 patients to each study group, all of whom were included in the intention-to-treat population. Recurrent upper gastrointestinal bleeding occurred in 14 patients in the celecoxib group (nine gastric ulcers and five duodenal ulcers) and 31 patients in the naproxen group (25 gastric ulcers, three duodenal ulcers, one gastric ulcer and duodenal ulcer, and two bleeding erosions). The cumulative incidence of recurrent bleeding in 18 months was 5·6% (95% CI 3·3–9·2) in the celecoxib group and 12·3% (8·8–17·1) in the naproxen group (p=0·008; crude hazard ratio 0·44, 95% CI 0·23–0·82; p=0·010). Excluding patients who reached study endpoints, 21 (8%) patients in the celecoxib group and 17 (7%) patients in the naproxen group had adverse events leading to discontinuation of treatment. No treatment-related deaths occurred during the study. Interpretation In patients at high risk of both cardiovascular and gastrointestinal events who require concomitant aspirin and NSAID, celecoxib plus proton-pump inhibitor is the preferred treatment to reduce the risk of recurrent upper gastrointestinal bleeding. Naproxen should be avoided despite its perceived cardiovascular safety. Funding The Research Grant Council of Hong Kong.
Recent genome-wide association studies (GWAS) identified more than 70 novel loci for type 2 diabetes (T2D), some of which have been widely replicated in Asian populations. In this study, we ...investigated their individual and combined effects on T2D in a Chinese population.
We selected 14 single nucleotide polymorphisms (SNPs) in T2D genes relating to beta-cell function validated in Asian populations and genotyped them in 5882 Chinese T2D patients and 2569 healthy controls. A combined genetic score (CGS) was calculated by summing up the number of risk alleles or weighted by the effect size for each SNP under an additive genetic model. We tested for associations by either logistic or linear regression analysis for T2D and quantitative traits, respectively. The contribution of the CGS for predicting T2D risk was evaluated by receiver operating characteristic (ROC) analysis and net reclassification improvement (NRI).
We observed consistent and significant associations of IGF2BP2, WFS1, CDKAL1, SLC30A8, CDKN2A/B, HHEX, TCF7L2 and KCNQ1 (8.5×10(-18)<P<8.5×10(-3)), as well as nominal associations of NOTCH2, JAZF1, KCNJ11 and HNF1B (0.05<P<0.1) with T2D risk, which yielded odds ratios ranging from 1.07 to 2.09. The 8 significant SNPs exhibited joint effect on increasing T2D risk, fasting plasma glucose and use of insulin therapy as well as reducing HOMA-β, BMI, waist circumference and younger age of diagnosis of T2D. The addition of CGS marginally increased AUC (2%) but significantly improved the predictive ability on T2D risk by 11.2% and 11.3% for unweighted and weighted CGS, respectively using the NRI approach (P<0.001).
In a Chinese population, the use of a CGS of 8 SNPs modestly but significantly improved its discriminative ability to predict T2D above and beyond that attributed to clinical risk factors (sex, age and BMI).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Post-stroke cognitive impairment (PSCI) occurs in approximately half of people in the first year after stroke. Infarct location is a potential determinant of PSCI, but a comprehensive map of ...strategic infarct locations predictive of PSCI is unavailable. We aimed to identify infarct locations most strongly predictive of PSCI after acute ischaemic stroke and use this information to develop a prediction model.
In this large-scale multicohort lesion-symptom mapping study, we pooled and harmonised individual patient data from 12 cohorts through the Meta-analyses on Strategic Lesion Locations for Vascular Cognitive Impairment using Lesion-Symptom Mapping (Meta VCI Map) consortium. The identified cohorts (as of Jan 1, 2019) comprised patients with acute symptomatic infarcts on CT or MRI (with available infarct segmentations) and a cognitive assessment up to 15 months after acute ischaemic stroke onset. PSCI was defined as performance lower than the fifth percentile of local normative data, on at least one cognitive domain on a multidomain neuropsychological assessment or on the Montreal Cognitive Assessment. Voxel-based lesion-symptom mapping (VLSM) was used to calculate voxel-wise odds ratios (ORs) for PSCI that were mapped onto a three-dimensional brain template to visualise PSCI risk per location. For the prediction model of PSCI risk, a location impact score on a 5-point scale was derived from the VLSM results on the basis of the mean voxel-wise coefficient (lnOR) within each patient's infarct. We did combined internal–external validation by leave-one-cohort-out cross-validation for all 12 cohorts using logistic regression. Predictive performance of a univariable model with only the location impact score was compared with a multivariable model with addition of other clinical PSCI predictors (age, sex, education, time interval between stroke onset and cognitive assessment, history of stroke, and total infarct volume). Testing of visual ratings was done by three clinicians, and accuracy, inter-rater reliability, and intra-rater reliability were assessed with Cohen's weighted kappa.
In our sample of 2950 patients (mean age 66·8 years SD 11·6; 1157 39·2% women), 1286 (43·6%) had PSCI. We achieved high lesion coverage of the brain in our analyses (86·9%). Infarcts in the left frontotemporal lobes, left thalamus, and right parietal lobe were strongly associated with PSCI (after false discovery rate correction, q<0·01; voxel-wise ORs >20). On cross-validation, the location impact score showed good correspondence, based on visual assessment of goodness of fit, between predicted and observed risk of PSCI across cohorts after adjusting for cohort-specific PSCI occurrence. Cross-validations showed that the location impact score by itself had similar performance to the combined model with other PSCI predictors, while allowing for easy visual assessment. Therefore the univariable model with only the location impact score was selected as the final model. Correspondence between visual ratings and actual location impact score (Cohen's weighted kappa: range 0·88–0·92), inter-rater agreement (0·85–0·87), and intra-rater agreement (for a single rater, 0·95) were all high.
To the best of our knowledge, this study provides the first comprehensive map of strategic infarct locations associated with risk of PSCI. A location impact score was derived from this map that robustly predicted PSCI across cohorts. Furthermore, we developed a quick and reliable visual rating scale that might in the future be applied by clinicians to identify individual patients at risk of PSCI.
The Netherlands Organisation for Health Research and Development.
To compare the visual outcomes and complication profiles of primary scleral-fixated intraocular lens (SFIOL) versus primary anterior chamber intraocular lens (ACIOL) implantation in cataract ...surgeries complicated by inadequate capsular support.
Retrospective, interventional, comparative cases series.
Thirty-six eyes of 36 patients undergoing SFIOL implantation (group 1) and 46 eyes of 46 patients undergoing ACIOL implantation (group 2).
Retrospective analysis of medical records of a consecutive series of complicated cataract surgeries with primary SFIOL or ACIOL implantation.
Postoperative best-corrected visual acuity (BCVA), intraoperative and postoperative complications, if any, and postoperative corneal endothelial cell counts. A multiple linear regression model was constructed with postoperative BCVA as the dependent variable and with IOL group (SFIOL vs. ACIOL), preoperative BCVA, surgeon's operative experience, planned operation, and patient's age as independent variables.
Fifty-eight percent (group 1) and 37% (group 2) of patients underwent phacoemulsification, whereas the rest underwent extracapsular cataract extraction. The mean postoperative follow-up was 33.4+/-17.9 months (range, 6-61 months). Postoperative Snellen BCVA of 20/40 or better was achieved in 47.2% (group 1) and 71.7% (group 2) of patients (P = 0.038). Regression analysis showed that primary ACIOL implantation was associated with a significantly better postoperative BCVA of -0.157 on the logarithm of minimum angle of resolution scale (95% confidence interval, -0.306 to -0.007; P = 0.040), compared with primary SFIOL implantation. Although both the number of eyes with complications and the total number of complications were higher in the SFIOL group, the differences in early (P = 0.073) and late (P = 0.377) complications were not statistically significant.
The results indicate that satisfactory results are achieved with primary implantation of current open-loop ACIOLs during cataract surgery complicated by loss of posterior capsule integrity. Eyes with these IOLs fared better than a cohort of eyes undergoing SFIOL implantation in a similar situation, at intermediate-term follow-up. Further prospective clinical trials with longer follow-up may help to evaluate the long-term visual outcomes and complication profiles after primary implantation of these lenses.
Objective: Recent genome-wide association studies have identified multiple novel loci associated with obesity in Europeans. We hypothesized that these genetic variants may be associated with obesity ...and type 2 diabetes (T2D) in Chinese.
Research Design and Methods: We examined 14 associated single-nucleotide polymorphisms at 12 loci (NEGR1, SEC16B, TMEM18, ETV5/DGKG, GNPDA2, LIN7C/BDNF, MTCH2, BCDIN3D/FAIM2, SH2B1, FTO, MC4R, and KCTD15) in 605 healthy adults, 1087 healthy adolescents and 6013 T2D patients from Hong Kong.
Results: The European at-risk alleles at five loci including GNPDA2, BCDIN3D/FAIM2, SH2B1, FTO, and KCTD15 were significantly associated with increased body mass index (BMI), waist circumference (4.5 × 10−8 < P < 0.024), and/or obesity risk (odds ratio 1.14–1.22, 2.0 × 10−5 < P < 0.002) in our Chinese populations. The former four loci as well as LIN7C/BDNF were also modestly associated with T2D risk (odds ratio 1.09–1.22, 0.008 < P < 0.041), but the associations were lost after adjustment for BMI, suggesting their roles in T2D risk are mediated through modulation of adiposity. Joint effect analyses of the five adiposity loci revealed an increase of about 0.29 kg/m2 in BMI with each additional copy of at-risk allele (Ptrend = 4.2 × 10−12).
Conclusions: Our findings support the important contribution of GNPDA2, BCDIN3D/FAIM2, SH2B1, FTO, and KCTD15 in the regulation of adiposity, which in turn affects T2D risk in Chinese.
Genetic variants at GNPDA2, BCDIN3D/FAIM2, SH2B1, FTO, and KCTD15 loci are associated with adiposity in Chinese.
Patients with nonalcoholic fatty liver disease (NAFLD) and family history of colorectal cancer (CRC) are at higher risks but how they should be screened remains uncertain. Hence, we evaluated the ...cost‐effectiveness of CRC screening among patients with NAFLD and family history by different strategies. A hypothetical population of 100,000 subjects aged 40–75 years receive: (i) yearly fecal immunochemical test (FIT) at 50 years; (ii) flexible sigmoidoscopy (FS) every 5 years at 50 years; (iii) colonoscopy 10 yearly at 50 years; (iv) colonoscopy 10 yearly at 50 years among those with family history/NAFLD and yearly FIT at 50 years among those without; (v) colonoscopy 10 yearly at 40 years among those with family history/NAFLD and yearly FIT at 50 years among those without and (vi) colonoscopy 10 yearly at 40 years among those with family history/NAFLD and colonoscopy 10 yearly at 50 years among those without. The incremental cost‐effectiveness ratio (ICER) was studied by Markov modeling. It was found that colonoscopy, FS and FIT reduced incidence of CRC by 49.5, 26.3 and 23.6%, respectively. Using strategies 4, 5 and 6, the corresponding reduction in CRC incidence was 29.9, 30.9 and 69.3% for family history, and 33.2, 34.7 and 69.8% for NAFLD. Compared with no screening, strategies 4 (US$1,018/life‐year saved) and 5 (US$7,485) for family history offered the lowest ICER, whilst strategy 4 (US$5,877) for NAFLD was the most cost‐effective. These findings were robust when assessed with a wide range of deterministic sensitivity analyses around the base case. These indicated that screening patients with family history or NAFLD by colonoscopy at 50 years was economically favorable.
What's new?
Non‐alcoholic fatty liver disease (NAFLD) is associated with an increased risk of colorectal cancer (CRC), potentially warranting earlier colorectal screening for NAFLD patients. It remains unclear, however, which of the existing CRC screening options would most benefit this population. In the present evaluation of the cost‐effectiveness of different CRC screening strategies, colonoscopy performed once every 10 years starting at age 50 was determined to be economically superior for patients with NAFLD and for persons with a family history of CRC. Annual fecal immunochemical testing was the most cost‐effective approach for individuals without a family history of CRC.
High intake of whole grain food has been suggested as an important factor for reducing the risk of colon cancer, owing to the abundance of indigestible fibers. Our findings demonstrated that, among ...various rice bran phenolic compounds tested, cycloartenyl ferulate (CF) showed the most prominent in vitro growth inhibition on human colorectal adenocarcinoma SW480, but had low toxicity on normal colon CCD-18-Co cells. The anticancer activity of CF was further illustrated by its ability to induce significant regression of SW480 xenograft in nude mice. CF elevated the death receptors DR4 and DR5 and triggered both the death receptor and the mitochondrial apoptosis pathways. Depletion of anti-apoptotic Bcl-2 and up-regulation of pro-apoptotic Bak were observed, accompanied by dissipation of the mitochondrial membrane potential and release of cyto c and SMAC/DIABLO from mitochondria into the cytosol. Bid was found to be cleaved by caspase-8, so that the death receptor pathway might be exaggerated by the mitochondrial pathway. Strikingly, we showed for the first time that CF also sensitized the metastatic and resistant colon cancer SW620 to TRAIL-induced apoptosis and the mechanisms involved at least enhanced activation of caspase-8 and -3. This study provides a clear evidence that the health-beneficial properties of whole grain consumption are not only limited by the presence of dietary fibers but also other molecules that can either act as a chemopreventive agent to directly induce tumor regression or as a sensitizer to enhance TRAIL-induced apoptosis in metastatic cancer cells.
Objective: Variations at a large linkage disequilibrium (LD) block of transcription factor 7-like 2 gene (TCF7L2) were reported to be associated with type 2 diabetes (T2D) in Icelandic, Danish and ...European-American populations and further replicated in other populations of European, African, and Asian ancestries. However, data for Chinese and comprehensive survey of the whole gene are lacking.
Design: We attempted to examine 22 tagging single-nucleotide polymorphisms (SNPs) spanning across the TCF7L2 gene for association with T2D in Hong Kong Chinese. We first studied a case-control sample involving 433 hospital cases with familial early-onset T2D and 419 normal controls and further studied the associated SNPs in 450 members of 142 diabetic families.
Results: Two of the previously reported risk alleles at rs11196205 (C) and rs7903146 (T) were rare in Chinese (0.013 and 0.024, respectively, in controls). Rs11196205 was associated with T2D odds ratio (OR) 95% confidence interval (CI) = 2.11 (1.04–4.26), whereas the association for rs7903146 OR (95% CI) = 1.27 (0.71–2.29) was not significant in the case-control sample. Interestingly, another SNP (rs11196218 G allele) located in adjacent LD block conferred independent risk for T2D OR (95%CI) =1.43 (1.14–1.79) and contributed high-population attributable risk of 42%. The association finding of rs11196218 and its haplotype for T2D was also replicated in the family sample (P < 0.05).
Conclusions: Our results are consistent with others’ findings that variations at TCF7L2 contribute to T2D, including Chinese. The presence of association signals spanning several LD blocks warrants further examination of extended regions to reveal the causal variant(s) for this important T2D gene.
Type 2 diabetes and chronic kidney disease (CKD) may share common risk factors. Here we used a 3-stage procedure to discover novel predictors of CKD by repeatedly applying a stepwise selection based ...on the Akaike information criterion to subsamples of a prospective complete-case cohort of 2755 patients. This cohort encompassed 25 clinical variables and 36 genetic variants associated with type 2 diabetes, obesity, or fasting plasma glucose. We compared the performance of the clinical, genetic, and clinico-genomic models and used net reclassification improvement to evaluate the impact of top selected genetic variants to the clinico-genomic model. Associations of selected genetic variants with CKD were validated in 2 independent cohorts followed by meta-analyses. Among the top 6 single-nucleotide polymorphisms selected from clinico-genomic data, three (rs478333 of G6PC2, rs7754840 and rs7756992 of CDKAL1) contributed toward the improvement of prediction performance. The variant rs478333 was associated with rapid decline (over 4% per year) in estimated glomerular filtration rate. In a meta-analysis of 2 replication cohorts, the variants rs478333 and rs7754840 showed significant associations with CKD after adjustment for conventional risk factors. Thus, this novel 3-stage approach to a clinico-genomic data set identified 3 novel genetic predictors of CKD in type 2 diabetes. This method can be applied to similar data sets containing clinical and genetic variables to select predictors for clinical outcomes.
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