The value of endothelin receptor type B promoter methylation as a biomarker for the risk assessment and diagnosis of prostate cancer: A meta-analysis

Previous researches have demonstrated that the methylation status of the EDNRB promoter was associated with the prostate cancer (PCa), but these conclusions remained controversial. Thus, the aim of this meta-analysis was to evaluate the association between EDNRB promoter methylation and the PCa. According to the PRISMA statement, the Web of Science, PubMed, EMBASE, and Cochrane Library databases were retrieved. The ORs and 95 % CIs were analyzed to evaluate the associations between EDNRB promoter methylation and the risk and clinical features of PCa. Heterogeneity among the included studies was estimated by I² statistic and Q test. Publication bias and sensitivity analysis were utilized to test the robustness of our outcomes. In addition, the pooled sensitivity and specificity were calculated to assess the diagnostic value of EDNRB methylation for PCa. Ultimately, 11 eligible studies were included. Under the random-effects model, the pooled OR shown that the frequency of EDNRB methylation was substantially higher in cases compared with controls (OR = 5.42, 95 % CI = 1.98–14.88, P = 0.001). The similar results were also found by the data from TCGA database. Subgroup analysis according to the methylation detection method showed that the heterogeneity in quantitative methylation-specific polymerase chain reaction (qMSP) group was insignificant (I² = 0.0 %, P = 0.669). Moreover, the pooled sensitivity for all-inclusive studies was 0.55 (95 % CI: 0.26-0.81), and the pooled specificity was 0.93 (95 % CI: 0.55-0.99). The methylation of EDNRB promoter might increase the risk of PCa. Meanwhile, EDNRB promoter methylation test combined with PSA testing and/or other biomarkers could be promising diagnostic biomarkers for more accurate detection of PCa.     

Attenuated familial adenomatous polyposis manifests as autosomal dominant late-onset colorectal cancer

Colorectal cancer (CRC) risk is well defined for families of patients with classical familial adenomatous polyposis (FAP). However, the risk for those with an attenuated form of FAP is less well characterised. In this study, we estimated CRC risks for carriers of a novel germline mutation in the APC gene that causes attenuated FAP (AFAP). We performed genetic testing on 53 individuals from seven AFAP families harbouring an identical APC:c.288T>A mutation. Using a modified segregation analysis, we estimated relative and absolute CRC risks for mutation carriers. Twenty-three individuals harboured the disease causing mutation. CRC occurred in 28 individuals (mean 61.7 years, range 32–80 years). The estimated CRC relative risks for mutation carriers aged 60–69 and ≥70 years were 19 (95% CI: 1.77–204.08) and 45 (95% CI: 11.32–180.10), respectively, while the absolute CRC lifetime risk for men was 94% (95% CI: 67.5–99.9%), and for women, 84% (95% CI: 50.9–99.0%). This study shows that AFAP can manifest as autosomal dominant late-onset CRC. These findings highlight a subgroup of inherited CRCs that require new criteria for identification and surveillance.     

Methionine synthase A2756G polymorphism and cancer risk: a meta-analysis

Polymorphisms in methionine synthase (MTR) gene may be involved in carcinogenesis by affecting DNA methylation. However, association studies on MTR A2756G polymorphism in cancers have reported conflicting results. Therefore we performed a meta-analysis to better assess the associations. A total of 24 896 cancer patients and 33 862 controls from 52 articles for MTR A2756G were investigated. Overall, individuals carrying MTR 2756GG genotype had a subtly reduced cancer risk under a recessive genetic model (odds ratio (OR), 0.92; P=0.053; 95% confidence interval (95% CI), 0.84–1.00; I²=0.0% P_{heterogeneity}=0.61). In the subgroup analyses by ethnicity, 2756GG was associated with a significantly reduced cancer risk in European populations (OR, 0.83; P=0.001; 95% CI, 0.74–0.93; I²=0.0% P_{heterogeneity}=0.99). However, in Asian populations, a significantly elevated association between 2756GG genotype and cancer risk was observed (OR, 1.33; P=0.012; 95% CI, 1.06–1.65; I²=0.0% P_{heterogeneity}=0.50). In studies stratified by tumor site, there was a significantly reduced risk of acute lymphoblastic leukemia (ALL) (OR, 0.54; P=0.049; 95% CI, 0.29–1.00; I²=10.7% P_{heterogeneity}=0.33) and colorectal cancer (OR, 0.63; P=0.004; 95% CI, 0.47–0.87; I²=0.0% P_{heterogeneity}=0.73) in European populations. Our study indicates that MTR A2756G polymorphism is a candidate gene polymorphism for cancer susceptibility regardless of environmental factors. Large-scale, well-designed, and population-based studies are required to further investigate gene–gene and gene–environment interactions on MTR A2756G polymorphism and tissue-specific cancer risk in an ethnicity-specific population.     

Common variants modify the age of onset for basal cell carcinomas in Gorlin syndrome

Gorlin syndrome is an autosomal dominant disorder, characterized by multiple early-onset basal cell carcinomas (BCCs) and jaw keratocysts. Through association studies in cohorts of sporadic BCC, nine genetic variants have previously been identified to increase the risk of BCC. The nine SNPs were genotyped by Taqman allelic discrimination in 125 individuals with Gorlin syndrome. Kaplan–Meier survival curves and Cox proportional-Hazard regression analysis were applied to determine the association between genotypes and age of first BCC in individuals with Gorlin syndrome. The p.(Arg151Cys) variant in MC1R (rs1805007) was associated with an earlier median age of onset of BCC of 27 years (95% CI: 20–34) compared with 34 years (95% CI: 30–40) for wild-type individuals (hazard ratio (HR)=1.64, 95% CI: 1.04–2.58, P=0.034). The risk allele of the variant at the chromosome 5p15 locus encompassing TERT-CLPTM1L (rs401681) was also associated with an earlier median onset of BCC, 31 years (95% CI: 28–37) compared with 41 years (95% CI: 32–48, HR=1.44, 95% CI: 1.08–1.93, P=0.014). In individuals with a risk allele at either rs1805007 or rs401681 the median time to BCC was 31 years of age (95% CI: 28–34) compared with 44 years of age (95% CI: 38–53) in wild-type individuals (HR=2.48, 95% CI: 1.47–4.17, P=0.0002). Our findings may have implications for future personalized risk estimates and BCC screening strategies in individuals with Gorlin syndrome.     

Relationship between low-density lipoprotein cholesterol,lipid-lowering agents and risk of stroke: a meta-analysis of observational studies (n = 355,591) and randomized controlled trials (n = 165,988)

IntroductionThe impact of low-density lipoprotein cholesterol (LDL-C) on the risk of different types of strokes is unclear. Therefore, we systematically evaluated the impact of LDL-C levels (cohort studies) and lipid-lowering agents (LLAs) (randomized controlled trials) on the different types of stroke.Material and methodsPubMed, SCOPUS, Web of Science and Google Scholar were searched up to 1^st September 2019. The DerSimonian-Laird method and generic inverse variance methods were used for quantitative data synthesis. The leave-one-out method was performed as sensitivity analysis. Trial sequential analysis (TSA) was used to evaluate the optimal sample size to detect a 35% reduction in outcomes after administration of LLAs.ResultsParticipants in the highest category of LDL-C had a lower risk of hemorrhagic stroke (RR = 0.91, 95% CI: 0.85–0.98, I² = 0%) compared with the lowest category of LDL-C. Subjects with the highest category of LDL-C had a higher risk of ischemic stroke (RR = 1.11, 95% CI: 1.07–1.14, I² = 0%) compared to the lowest LDL-C category. LLAs decreased the risk of all types of strokes for those who achieved LDL-C < 1.8 mmol/l (< 70 mg/dl; RR = 0.88, 95% CI: 0.80–0.96, absolute risk reduction (ARR): 0.7%, number needed to treat (NNT): 143, I² = 53%, n = 13). Statin therapy decreased the risk of all strokes (RR = 0.88, 95% CI: 0.80–0.97, ARR = 0.6%, NNT = 167, I² = 56%). With regard to ischemic stroke only, LLAs decreased the risk of ischemic stroke for those who achieved LDL-C < 1.8 mmol/l (< 70 mg/dl; RR = 0.75, 95% CI: 0.67–0.83, ARR = 1.3%, NNT = 77, I² = 0%); the same was observed for statins (RR = 0.76, 95% CI: 0.69–0.84, ARR = 1.3%, NNT = 77, I² = 32%). TSA indicated that both benefit boundaries and optimal sample size were reached. There was no significant effect of LLAs regardless of the achieved level of LDL-C on the risk of hemorrhagic stroke; however, TSA indicated that further studies are needed to settle the question and most of the effects were subject to high levels of heterogeneity.ConclusionsOur study sheds light on the debatable association between low LDL-C and different type of strokes. This information can help determine the optimal LDL-C range for stroke prevention, and help plan future LLA studies.     

Efficacy of early treatment with hydroxychloroquine in people with mild to moderate COVID-19: a systematic review and meta-analysis

IntroductionNo early treatment intervention for COVID-19 has proven effective to date. We systematically reviewed the efficacy of hydroxychloroquine as early treatment for COVID-19.Material and methodsRandomized controlled trials (RCTs) evaluating hydroxychloroquine for early treatment of COVID-19 were searched in five engines and preprint websites until September 14, 2021. Primary outcomes were hospitalization and all-cause mortality. Secondary outcomes included COVID-19 symptom resolution, viral clearance, and adverse events. Inverse variance random-effects meta-analyses were performed and quality of evidence (QoE) per outcome was assessed with GRADE methods.ResultsFive RCTs (n = 1848) were included. The comparator was placebo in four RCTs and usual care in one RCT. The RCTs used hydroxychloroquine total doses between 1,600 and 4,400 mg and had follow-up times between 14 and 90 days. Compared to the controls, early treatment with hydroxychloroquine did not reduce hospitalizations (RR = 0.80, 95% CI: 0.47–1.36, I² = 2%, 5 RCTs, low QoE), all-cause mortality (RR = 0.77, 95% CI: 0.16–3.68, I² = 0%, 5 RCTs, very low QoE), symptom resolution (RR = 0.94, 95% CI: 0.77–1.16, I² = 71%, 3 RCTs, low QoE) or viral clearance at 14 days (RR = 1.02, 95% CI: 0.82–1.27, I² = 65%, 2 RCTs, low QoE). There was a larger non-significant increase of adverse events with hydroxychloroquine vs. controls (RR = 2.17, 95% CI: 0.86–5.45, I² = 92%, 5 RCTs, very low QoE).ConclusionsHydroxychloroquine was not efficacious as early treatment for COVID-19 infections in RCTs with low to very low quality of evidence for all outcomes. More RCTs are needed to elucidate the efficacy of hydroxychloroquine as early treatment intervention.     

Loop-mediated isothermal amplification method targeting the TTS1 gene cluster for detection of Burkholderia pseudomallei and diagnosis of melioidosis

Melioidosis is a severe infection caused by Burkholderia pseudomallei. The timely implementation of effective antimicrobial treatment requires rapid diagnosis. Loop-mediated isothermal amplification (LAMP) targeting the TTS1 gene cluster was developed for the detection of B. pseudomallei. LAMP was sensitive and specific for the laboratory detection of this organism. The lower limit of detection was 38 genomic copies per reaction, and LAMP was positive for 10 clinical B. pseudomallei isolates but negative for 5 B. thailandensis and 5 B. mallei isolates. A clinical evaluation was conducted in northeast Thailand to compare LAMP to an established real-time PCR assay targeting the same TTS1 gene cluster. A total of 846 samples were obtained from 383 patients with suspected melioidosis, 77 of whom were subsequently diagnosed with culture-confirmed melioidosis. Of these 77 patients, a positive result was obtained from one or more specimens by PCR in 26 cases (sensitivity, 34%; 95% confidence interval [CI], 23.4 to 45.4%) and by LAMP in 34 cases (sensitivity, 44%; 95% CI, 32.8 to 55.9%) (P = 0.02). All samples from 306 patients that were culture negative for B. pseudomallei were negative by PCR (specificity, 100%; 95% CI, 98.8 to 100%), but 5 of 306 patients (1.6%) were positive by LAMP (specificity, 98.4%; 95% CI, 96.2 to 99.5%) (P = 0.03). The diagnostic accuracies of PCR and LAMP were 86.7% (95% CI, 82.9 to 89.9%) and 87.5% (95% CI, 83.7 to 90.6%), respectively (P = 0.47). Both assays were very insensitive when applied to blood samples; PCR and LAMP were positive for 0 and 1 of 44 positive blood cultures, respectively. The PCR and LAMP assays evaluated here are not sufficiently sensitive to replace culture in our clinical setting.     

Omega-6 fatty acids and the risk of cardiovascular disease: insights from a systematic review and meta-analysis of randomized controlled trials and a Mendelian randomization study

IntroductionOmega-6 polyunsaturated fatty acids (PUFAs) represent almost 15% of the total energy intake in Western countries. Their effects on the cardiovascular (CV) risk factors are still controversial. Thus, we performed a systematic review and meta-analysis of randomized control trials (RCTs) as well as a Mendelian randomization (MR) analysis to evaluate the links and possible causality between supplementation or serum levels of omega-6 PUFA, CV disease (CVD) and cardiometabolic risk factors.Material and methodsSelected databases were searched until September 2019 to identify prospective studies investigating the effects of omega-6 PUFA supplementation on CVD events/mortality. Random-effects model meta-analysis was performed for quantitative data synthesis. Trial sequential analysis (TSA) was used to evaluate the optimal sample size to detect a 20% reduction in outcomes after administration of omega-6 PUFAs. The inverse variance weighted (IVW) method, weighted median-based method, MR-Egger and MR-Pleiotropy RESidual Sum and Outlier (PRESSO) were applied for MR.ResultsThe pooled estimate risk ratio (RR) of omega-6 PUFA supplementation was 0.94 for any CVD event (95% CI: 0.77–1.15, I² = 66.2%), 1.06 for CVD death (95% CI: 0.73–1.55, I² = 66.2%), 0.84 for coronary heart disease (CHD) events (95% CI: 0.61–1.16, I² = 79.4%), 0.87 for myocardial infarction (MI) (95% CI: 0.74–1.01, I² = 2.3%) and 1.36 for stroke (95% CI: 0.45–4.07, I² = 55.3%). In contrast, MR showed that individuals with higher serum omega-6 acid – adrenic acid (AA) levels had a greater risk for CHD events (IVW β = 0.526), MI (IVW β = 0.606) and large artery stroke (IVW β = 1.694), as well as increased levels of fasting blood glucose (FBG) (IVW β = 0.417), low-density lipoprotein cholesterol (LDL-C) (IVW β = 0.806), high-density lipoprotein cholesterol (HDL-C) (IVW β = 0.820), and lower levels of triglycerides (TG) (IVW β = –1.064) and total cholesterol (TC) (IVW β = –1.064).ConclusionsOmega-6 PUFA supplementation did not affect the risk for CVD morbidity and mortality. Additionally, based on MR analysis we found that higher AA levels might even significantly increase the risk of CHD, MI and large artery stroke, as well as the levels of FBG and LDL-C, whereas they were negatively associated with TC and TG. Since a considerable chance of heterogeneity was observed for some of the results, further research is needed to elucidate the effects of omega-6 PUFAs on cardiometabolic outcomes.     

Improved COVID-19 ICU admission and mortality outcomes following treatment with statins: a systematic review and meta-analysis

IntroductionApproximately 1% of the world population has now been infected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19). With cases still rising and vaccines just beginning to rollout, we are still several months away from seeing reductions in daily case numbers, hospitalisations, and mortality. Therefore, there is a still an urgent need to control the disease spread by repurposing existing therapeutics. Owing to antiviral, anti-inflammatory, immunomodulatory, and cardioprotective actions, statin therapy has been considered as a plausible approach to improve COVID-19 outcomes.Material and methodsWe carried out a meta-analysis to investigate the effect of statins on 3 COVID-19 outcomes: intensive care unit (ICU) admission, tracheal intubation, and death. We systematically searched the PubMed, Web of Science, Scopus, and ProQuest databases using keywords related to our aims up to November 2, 2020. All published observational studies and randomised clinical trials on COVID-19 and statins were retrieved. Statistical analysis with random effects modelling was performed using STATA16 software.ResultsThe final selected studies (n = 24 studies; 32,715 patients) showed significant reductions in ICU admission (OR = 0.78, 95% CI: 0.58–1.06; n = 10; I² = 58.5%) and death (OR = 0.70, 95% CI: 0.55–0.88; n = 21; I² = 82.5%) outcomes, with no significant effect on tracheal intubation (OR = 0.79; 95% CI: 0.57–1.11; n = 7; I²= 89.0%). Furthermore, subgroup analysis suggested that death was reduced further by in-hospital application of stains (OR = 0.40, 95% CI: 0.22–0.73, n = 3; I² = 82.5%), compared with pre-hospital use (OR = 0.77, 95% CI: 0.60–0.98, n = 18; I² = 81.8%).ConclusionsThese findings call attention to the need for systematic clinical studies to assess both pre- and in-hospital use of statins as a potential means of reducing COVID-19 disease severity, particularly in terms of reduction of ICU admission and total mortality reduction.     

Effects of acetaminophen and ibuprofen monotherapy in febrile children: a meta-analysis of randomized controlled trials

IntroductionWhen a child presents with fever in the clinical encounter, parents are usually concerned about alleviating the fever. However, the indications for selecting an appropriate drug from the most commonly used antipyretic drugs, acetaminophen and ibuprofen, remain unclear. The purpose of this study was to assess the efficacy and safety of acetaminophen and ibuprofen in febrile children through a systematic review with meta-analysis of randomized controlled trials (RCTs).Material and methodsCochrane, Embase, and PubMed databases were searched for the relevant RCTs. Two authors individually extracted information on trial design, demography, rate of fever resolution, body temperature, and overall adverse events. Data were pooled mainly using a random-effects model; however, because of some sparse data, Peto odds ratios (PORs) were used for outcomes of fever resolution and adverse event. 95% confidence intervals (CIs) were also presented.ResultsIn total, 26 RCTs (n = 4137) fulfilled eligibility criteria. Pooled estimates demonstrated that acetaminophen led to significantly lower fever resolution rates than ibuprofen did (POR = 0.91, 95% CI: 0.84–0.98; I ² = 0%) in the subgroup of trials with a mean age of < 2 years. However, the treatment–time interaction model for body temperature demonstrated that the fever resolution effect was mainly from the time factor based on the available data (effect size = –0.20; 95% CI: –0.30 to –0.11; I ² = 6.9%). Acetaminophen demonstrated lower overall adverse event rates than ibuprofen (POR = 0.71; 95% CI: 0.58–0.87; I ² = 0%).ConclusionsThe effects of ibuprofen are similar to acetaminophen even in children with mean age of approximately 5 years. Nevertheless, acetaminophen is safer than ibuprofen, particularly in children approximately 5 years old.     

Tag-SNP analysis of the GFI1-EVI5-RPL5-FAM69 risk locus for multiple sclerosis

A recent genome-wide association study conducted by the International Multiple Sclerosis Genetic Consortium (IMSGC) identified, among others, a number of putative multiple sclerosis (MS) susceptibility variants at position 1p22. Twenty-one SNPs positively associated with MS were located at the GFI-EVI5-RPL5-FAM69A locus. In this study, we performed an analysis and fine mapping of this locus, genotyping eight Tag-SNPs in 732 MS patients and 974 controls from Spain. We observed an association with MS in three of eight Tag-SNPs: rs11804321 (P=0.008, OR=1.29; 95% CI=1.08–1.54), rs11808092 (P=0.048, OR=1.19; 95% CI=1.03–1.39) and rs6680578 (P=0.0082, OR=1.23; 95% CI=1.07–1.41). After correcting for multiple comparisons and using logistic regression analysis to test the addition of each SNP to the most associated SNPs, we observed that rs11804321 alone was sufficient to model the association. This Tag-SNP captures two SNPs in complete linkage disequilibrium (r²=1), both located within the 17th intron of the EVI5 gene. Our findings agree with the corresponding data of the recent IMSGC study and present new genetic evidence that points to EVI5 as a factor of susceptibility to MS.     

Duplicated copy of CHRNA7 increases risk and worsens prognosis of COPD and lung cancer

Recent genome-wide association studies implicated that the nicotinic acetylcholine receptors (nAChRs) are common susceptible genes of two contextual diseases: chronic obstructive pulmonary disease (COPD) and lung cancer. We aimed to test whether the copy number variations (CNVs) in nAChRs have hereditary contributions to development of the two diseases. In two, two-stage, case–control studies of southern and eastern Chinese, a common CNV-3956 that duplicates the cholinergic receptor, nicotinic, α7 (CHRNA7) gene was genotyped in a total of 7880 subjects and its biological phenotype was assessed. The ≥4-copy of CNV-3956 increased COPD risk (≥4-copy vs 2/3-copy: OR=1.44, 95% CI=1.23–1.68) and caused poor lung function, and it similarly augmented risk (OR=1.49, 95% CI=1.29–1.73) and worsened prognosis (hazard ratio (HR)=1.25, 95% CI=1.07–1.45) of lung cancer. The ≥4-copy was estimated to account for 1.56% of COPD heritability and 1.87% of lung cancer heritability, respectively. Phenotypic analysis further showed that the ≥4-copy of CNV-3956 improved CHRNA7 expression in vivo and increased the carriers'' smoking amount. The CNV-3956 of CHRNA7 contributed to increased risks and poor prognoses of both COPD and lung cancer, and this may be a genetic biomarker of the two diseases.     

Early goal-directed therapy reduces mortality in adult patients with severe sepsis and septic shock: Systematic review and meta-analysis

Introduction:

Survival sepsis campaign guidelines have promoted early goal-directed therapy (EGDT) as a means for reduction of mortality. On the other hand, there were conflicting results coming out of recently published meta-analyses on mortality benefits of EGDT in patients with severe sepsis and septic shock. On top of that, the findings of three recently done randomized clinical trials (RCTs) showed no survival benefit by employing EGDT compared to usual care. Therefore, we aimed to do a meta-analysis to evaluate the effect of EGDT on mortality in severe sepsis and septic shock patients.

Methodology:

We included RCTs that compared EGDT with usual care in our meta-analysis. We searched in Hinari, PubMed, EMBASE, and Cochrane central register of controlled trials electronic databases and other articles manually from lists of references of extracted articles. Our primary end point was overall mortality.

Results:

A total of nine trails comprising 4783 patients included in our analysis. We found that EGDT significantly reduced mortality in a random-effect model (RR, 0.86; 95% confidence interval [CI], 0.72–0.94; P = 0.008;   I² =50%). We also did subgroup analysis stratifying the studies by the socioeconomic status of the country where studies were conducted, risk of bias, the number of sites where the trials were conducted, setting of trials, publication year, and sample size. Accordingly, trials carried out in low to middle economic income countries (RR, 0.078; 95% CI, 0.67–0.91; P = 0.002; I² = 34%) significantly reduced mortality compared to those in higher income countries (RR, 0.93; 95% CI, 0.33–1.06; P = 0.28; I² = 29%). On the other hand, patients receiving EGDT had longer length of hospital stay compared to the usual care (mean difference, 0.49; 95% CI, –0.04–1.02; P = 0.07; I² = 0%).

Conclusion:

The result of our study showed that EGDT significantly reduced mortality in patients with severe sepsis and septic shock. Paradoxically, EGDT increased the length of hospital stay compared to usual routine care.     

Cutoff points of T1 rho/T2 mapping relaxation times distinguishing early-stage and advanced osteoarthritis

IntroductionThe histopathology grading system is the gold standard post-operative method to evaluate cartilage degeneration in knee osteoarthritis (OA). Magnetic resonance imaging (MRI) T1 rho/T2 mapping imaging can be used for preoperative detection. An association between histopathology and T1 rho/T2 mapping relaxation times was suggested in previous research. However, the cutoff point was not determined among different histopathology grades. Our study aimed to determine the cutoff point of T1 rho/T2 mapping.Material and methodsT1 rho/T2 mapping images were acquired from 80 samples before total knee replacements. Then the histopathology grading system was applied.ResultsThe mean T1 rho/T2 mapping relaxation times of 80 samples were 39.17 ms and 37.98 ms respectively. Significant differences were found in T1 rho/T2 mapping values between early-stage and advanced OA (p < 0.001). The cutoff point for T1 rho was 33 ms with a sensitivity of 94.12 (95% CI: 80–99.3) and a specificity of 91.30 (95% CI: 79.2–97.6). The cutoff point for T2 mapping was suggested as 35.04 ms with a sensitivity of 88.24 (95% CI: 72.5–96.7) and specificity of 97.83 (95% CI: 88.5–99.9). After bootstrap simulation, the 95% CI of the T1 rho/T2 mapping cutoff point was estimated as 29.36 to 36.32 ms and 34.8 to 35.04 ms respectively. The area under the PR curve of T1 rho/T2 mapping was 0.972 (95% CI: 0.925–0.992) and 0.949 (95% CI: 0.877–0.989) respectively.ConclusionsThe cutoff point of T1 rho relaxation times, which was suggested as 33 ms, could be used to distinguish early-stage and advanced OA.     

Impact of bariatric surgery on circulating PCSK9 levels as a marker of cardiovascular disease risk: a meta-analysis

IntroductionThis systematic review and meta-analysis focuses on PCSK9 changes in obese patients following bariatric surgery.MethodsA systematic literature search in four databases was performed. Comprehensive Meta-Analysis (CMA) V2 software used to conduct the meta-analysis. Studies were evaluated regarding heterogeneity in design, populations under investigation, and treatment duration using a random-effects model and the generic inverse variance weighting approach. A random-effect meta-regression approach was used to investigate the association with the estimated effect size.ResultsThe results of the meta-analysis on 4 trials including 260 individuals demonstrated a remarkable decline of PCSK9 after bariatric surgery (WMD = –57.34 ng/ml, 95% CI: –87.97, –26.71, p < 0.001; I² = 96.25%). Consistently, a significant decrease of LDL-C after bariatric surgery (WMD = –22.57 mg/dl, 95% CI: –27.5, –17.574, p < 0.001; I² = 86.35%) was observed.ConclusionsPCSK9 is reduced significantly after bariatric surgery. The decrease of PCSK9 might be utilized as an independent surrogate marker of improvement of atherosclerotic cardiovascular disease risk after bariatric surgery.     

Folate-related polymorphisms in gastrointestinal stromal tumours: susceptibility and correlation with tumour characteristics and clinical outcome

The folate metabolism pathway has a crucial role in tumorigenesis as it supports numerous critical intracellular reactions, including DNA synthesis, repair, and methylation. Despite its importance, little is known about the influence of the folate pathway on gastrointestinal stromal tumour (GIST), a rare tumour with an incidence ranging between 6 and 19.6 cases per million worldwide. The importance of folate metabolism led us to investigate the influence of polymorphisms in the genes coding folate-metabolising enzymes on GIST susceptibility, tumour characteristics and clinical outcome. We investigated a panel of 13 polymorphisms in 8 genes in 60 cases and 153 controls. The TS 6-bp deletion allele (formerly rs34489327, delTInsTTAAAG) was associated with reduced risk of GIST (OR=0.20, 95% CI 0.05–0.67, P=0.0032). Selected polymorphisms in patients stratified by age, gender, and other main molecular and clinical characteristics showed that few genotypes may show a likely correlation. We also observed a significant association between the RFC AA/AG genotype and time to progression (HR=0.107, 95% CI 0.014–0.82; P=0.032). Furthermore, we observed a tendency towards an association between the SHMT1 variant allele (TT, rs1979277) and early death (HR=4.53, 95% CI 0.77–26.58, P=0.087). Aware of the strengths and limitations of the study, these results suggest that polymorphisms may modify the risk of GIST and clinical outcome, pointing to the necessity for further investigations with information on folate plasma levels and a larger study population.     

Accuracy of AccessBio Immunoglobulin M and Total Antibody Rapid Immunochromatographic Assays for the Diagnosis of Acute Scrub Typhus Infection

Using archived samples, we assessed the diagnostic capacity of a rapid immunochromatographic test (ICT) for the detection of Orientia tsutsugamushi IgM and total antibodies to aid with the diagnosis of acute scrub typhus infection in febrile patients in Laos. The sensitivity and the specificity of the ICT for the detection of IgM were 96.8% (121/125 samples; 95% confidence interval [CI], 92.1 to 99.1%) and 93.3% (98/105 samples; 95% CI, 86.7 to 97.3%), respectively. For the detection of total antibodies, the sensitivity was 97.6% (122/125 samples; 95% CI, 93.1 to 99.5%), but the specificity was much lower, at 71.4% (75/105 samples; 95% CI, 61.8 to 79.8%).Scrub typhus, caused by Orientia tsutsugamushi, is an important acute febrile illness in the Asia-Pacific region. As very few health facilities have accessible accurate diagnostic tests, the diagnosis of scrub fever must be based on clinical features. However, this is difficult because the clinical symptoms and signs are similar to those of many other febrile diseases, such as murine typhus, leptospirosis, and dengue virus infection. The diagnosis of scrub typhus infection has relied on the detection of O. tsutsugamushi antibodies during the acute phase of the disease, and the “gold standard” assay is the indirect immunofluorescence antibody assay (IFA) (9). The development of rapid, diagnostic tests by the use of immunochromatographic test (ICT) technologies has provided a mechanism for point-of-care serological testing. The objective of the study described here was to assess the diagnostic capacities of two commercial rapid ICTs for the detection of O. tsutsugamushi IgM and whole antibodies to aid with the diagnosis of acute scrub typhus infection by the use of stored, characterized sera collected from febrile patients in the tropical environment of the Lao People''s Democratic Republic (Laos) and Thailand where scrub typhus is endemic.     

Clinical relevance of 8q23, 15q13 and 18q21 SNP genotyping to evaluate colorectal cancer risk

To determine if the at-risk single-nucleotide polymorphism (SNP) alleles for colorectal cancer (CRC) could contribute to clinical situations suggestive of an increased genetic risk for CRC, we performed a prospective national case–control study based on highly selected patients (CRC in two first-degree relatives, one before 61 years of age; or CRC diagnosed before 51 years of age; or multiple primary CRCs, the first before 61 years of age; exclusion of Lynch syndrome and polyposes) and controls without personal or familial history of CRC. SNPs were genotyped using SNaPshot, and statistical analyses were performed using Pearson''s χ² test, Cochran–Armitage test of trend and logistic regression. We included 1029 patients and 350 controls. We confirmed the association of CRC risk with four SNPs, with odds ratio (OR) higher than previously reported: rs16892766 on 8q23.3 (OR: 1.88, 95% confidence interval (CI): 1.30–2.72; P=0.0007); rs4779584 on 15q13.3 (OR: 1.42, CI: 1.11–1.83; P=0.0061) and rs4939827 and rs58920878/Novel 1 on 18q21.1 (OR: 1.49, CI: 1.13–1.98; P=0.007 and OR: 1.49, CI: 1.14–1.95; P=0.0035). We found a significant (P<0.0001) cumulative effect of the at-risk alleles or genotypes with OR at 1.62 (CI: 1.10–2.37), 2.09 (CI: 1.43–3.07), 2.87 (CI: 1.76–4.70) and 3.88 (CI: 1.72–8.76) for 1, 2, 3 and at least 4 at-risk alleles, respectively, and OR at 1.71 (CI: 1.18–2.46), 2.29 (CI: 1.55–3.38) and 6.21 (CI: 2.67–14.42) for 1, 2 and 3 at-risk genotypes, respectively. Combination of SNPs may therefore explain a fraction of clinical situations suggestive of an increased risk for CRC.     

Two British women studies replicated the association between the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) and BMI

The goal of this study is to investigate the relationship between the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) and body mass index (BMI) in two sizable and well-characterized populations of British women: the British Women''s Heart and Health Study (BWHHS) (age 60–79 years) and the mothers from the Avon Longitudinal Study of Parents and Children (age 16–44 years). We genotyped the Val66Met polymorphism (rs6265) in these two populations, and conducted a linear regression analysis to test for an association between this polymorphism and BMI. Both study populations indicated an association between BMI and the Val66Met polymorphism, with individuals carrying the Met–Met genotype having a lower mean BMI than those with the Val–Met or Val–Val genotypes (in the BWHHS): mean BMI difference=−0.911 kg/m², 95% confidence interval (CI): −1.70 to −0.12, P=0.023; in the mothers from the Avon Longitudinal Study of Parents and Children (ALSPAC): mean BMI difference=−0.57 kg/m², 95%CI: −1.08 to −0.054, P=0.03). In a pooled analysis of these two studies, together with one further published study that provided data in a suitable format for inclusion in our meta-analysis, we found a pooled difference of −0.76 (95% CI: −1.16, −0.036) for adult women; I²–test for heterogeneity=51%, P=0.13. Our study indicated an association between BDNF and BMI in two general population studies of women. The exact role of BDNF in weight regulation merits further investigation.     

Utility of real-time PCR for diagnosis of Legionnaires' disease in routine clinical practice

The main aim of our study was to determine the added value of PCR for the diagnosis of Legionnaires’ disease (LD) in routine clinical practice. The specimens were samples submitted for routine diagnosis of pneumonia from December 2002 to November 2005. Patients were evaluated if, in addition to PCR, the results of at least one of the following diagnostic tests were available: (i) culture for Legionella spp. on buffered charcoal yeast extract agar or (ii) detection of Legionella pneumophila antigen in urine specimens. Of the 151 evaluated patients, 37 (25%) fulfilled the European Working Group on Legionella Infections criteria for a confirmed case of LD (the “gold standard”). An estimated sensitivity, specificity, and overall percent agreement of 86% (32 of 37; 95% confidence interval [CI] = 72 to 95%), 95% (107 of 112; 95% CI = 90 to 98%), and 93% (139 of 149), respectively, were found for 16S rRNA-based PCR, and corresponding values of 92% (34 of 37; 95% CI = 78 to 98%), 98% (110 of 112; 95% CI = 93 to 100%), and 97% (144 of 149), respectively, were found for the mip gene-based PCR. A total of 35 patients were diagnosed by using the urinary antigen test, and 34 were diagnosed by the 16S rRNA-based PCR. With the mip gene PCR one more case of LD (n = 36; not significant) was detected. By combining urinary antigen test and the mip gene PCR, LD was diagnosed in an additional 4 (11%) patients versus the use of the urinary antigen test alone. The addition of a L. pneumophila-specific mip gene PCR to a urinary antigen test is useful in patients with suspected LD who produce sputum and might allow the early detection of a significant number of additional patients.