Yee Hui Yeo

Multiplex PCR System for Rapid Detection of Pathogens in Patients with Presumed Sepsis – A Systemic Review and Meta-Analysis

Background Blood culture is viewed as the golden standard for the diagnosis of sepsis but suffers from low sensitivity and long turnaround time. LightCycler SeptiFast (LC-SF) is a real-time multiplex polymerase chain reaction test able to detect 25 common pathogens responsible for bloodstream infections within hours. We aim to assess the accuracy of LC-SF by systematically reviewing the published studies. Method Related literature on Medline, Embase, and Cochrane databases was searched up to October 2012 for studies utilizing LC-SF to diagnose suspected sepsis and that provided sufficient data to construct two-by-two tables. Results A total of 34 studies enrolling 6012 patients of suspected sepsis were included. The overall sensitivity and specificity for LC-SF to detect bacteremia or fungemia was 0·75 (95% CI: 0·65–0·83) and 0·92 (95%CI:0·90–0·95), respectively. LC-SF had a high positive likelihood ratio (10·10) and a moderate negative likelihood ratio (0·27). Specifically, LC-SF had a sensitivity of 0·80 (95%CI: 0·70–0·88) and a specificity of 0·95(95%CI: 0·93–0·97) for the bacteremia outcome, and a sensitivity of 0·61 (95%CI: 0·48–0·72) and a specificity of 0·99 (95%CI: 0·99–0·99) for the fungemia outcome. High heterogeneity was found in the bacteremia outcome subgroup but not in the fungemia outcome subgroup. Conclusion LC-SF is of high rule-in value for early detection of septic patients. In a population with low pretest probability, LC-SF test can still provide valuable information for ruling out bacteremia or fungemia.

Liberal versus restricted fluid resuscitation strategies in trauma patients: a systematic review and meta-analysis of randomized controlled trials and observational studies*.

Objective:Hemorrhage is responsible for most deaths that occur during the first few hours after trauma. Animal models of trauma have shown that restricting fluid administration can reduce the risk of death; however, studies in patients are difficult to conduct due to logistical and ethical problems. To maximize the value of the existing evidence, we performed a meta-analysis to compare liberal versus restricted fluid resuscitation strategies in trauma patients. Data Sources:Medline and Embase were systemically searched from inception to February 2013. Study Selection:We selected randomized controlled trials and observational studies that compared different fluid administration strategies in trauma patients. There were no restrictions for language, population, or publication year. Data Extraction:Four randomized controlled trials and seven observational studies were identified from 1,106 references. One of the randomized controlled trials suffered from a high protocol violation rate and was excluded from the final analysis. Data Synthesis:The quantitative synthesis indicated that liberal fluid resuscitation strategies might be associated with higher mortality than restricted fluid strategies, both in randomized controlled trials (risk ratio, 1.25; 95% CI, 1.01–1.55; three trials; I2, 0) and observational studies (odds ratio, 1.14; 95% CI, 1.01–1.28; seven studies; I2, 21.4%). When only adjusted odds ratios were pooled for observational studies, odds for mortality with liberal fluid resuscitation strategies increased (odds ratio, 1.19; 95% CI, 1.02–1.38; six studies; I2, 26.3%). Conclusions:Current evidence indicates that initial liberal fluid resuscitation strategies may be associated with higher mortality in injured patients. However, available studies are subject to a high risk of selection bias and clinical heterogeneity. This result should be interpreted with great caution.

First-line Helicobacter pylori eradication therapies in countries with high and low clarithromycin resistance: a systematic review and network meta-analysis.

Objective To determine the optimal regimen of different first-line Helicobacter pylori eradication therapies according to the clarithromycin resistance rate. Design Electronic search for articles published between January 2005 and April 2016. Randomised, controlled trials that reported the effectiveness of first-line eradication therapies in treatment-naïve adults were included. Two independent reviewers performed articles screening and data extraction. Network and traditional meta-analyses were conducted using the random effect model. Subgroup analyses were performed to determine the ranking of regimens in countries with high (>15%) and low (<15%) clarithromycin resistance. Data including adverse events and therapeutic cure rate were also extracted and analysed. Results 117 trials (totally 32 852 patients) for 17 H. pylori eradication regimens were eligible for inclusion. Compared with 7-day clarithromycin-based triple therapy, sequential therapy (ST) for 14 days had the highest effectiveness (OR=3.74, 95% CrI 2.37 to 5.96). ST-14 (OR=6.53, 95% CrI 3.23 to 13.63) and hybrid therapy (HY) for 10 days or more (OR=2.85, 95% CrI 1.58 to 5.37) represented the most effective regimen in areas with high and low clarithromycin resistance, respectively. The effectiveness of standard triple therapy was below therapeutic eradication rate in most of the countries. Longer duration was associated with higher eradication rate, but with a higher risk of events that lead to discontinuation. Conclusions ST and HY appeared to be the most effective therapies in countries with high and low clarithromycin resistance, respectively. The clinical decision for optimal regimen can be supported by referring to the rank ordering of relative efficacies stratified by local eradication rates, antibiotic resistance and safety profile. Trial registration number CRD42015025445.

Adult with cerebellar anaplastic pilocytic astrocytoma associated with BRAF V600E mutation and p16 loss.

Pilocytic astrocytoma (PA) is the most common pediatric tumor, with the vast majority being benign (WHO Grade I). Herein, we present a rare sporadic (not radiation- or NF1-associated) anaplastic PA arising from the cerebellum of an adult patient. The diagnosis was based on the coexistence of classic PA and more cellular foci, associated with both tumor necrosis and up to 27 mitoses per 10 high power fields. Based on these features, the tumor was felt to be equivalent in biological behavior to that of a WHO Grade III astrocytoma. Additional genetic studies revealed the presence of a BRAF V600E mutation. In comparison to the foci of classic PA, the malignant component showed increased p53 protein expression, decreased p16 protein expression, and hemizygous p16 gene deletion by FISH analysis. This case provides additional support for the concept of anaplastic transformation in PA and further elucidates the possible molecular pathways associated with malignant progression.

Matriptase autoactivation is tightly regulated by the cellular chemical environments.

The ability of cells to rapidly detect and react to alterations in their chemical environment, such as pH, ionic strength and redox potential, is essential for cell function and survival. We present here evidence that cells can respond to such environmental alterations by rapid induction of matriptase autoactivation. Specifically, we show that matriptase autoactivation can occur spontaneously at physiological pH, and is significantly enhanced by acidic pH, both in a cell-free system and in living cells. The acid-accelerated autoactivation can be attenuated by chloride, a property that may be part of a safety mechanism to prevent unregulated matriptase autoactivation. Additionally, the thio-redox balance of the environment also modulates matriptase autoactivation. Using the cell-free system, we show that matriptase autoactivation is suppressed by cytosolic reductive factors, with this cytosolic suppression being reverted by the addition of oxidizing agents. In living cells, we observed rapid induction of matriptase autoactivation upon exposure to toxic metal ions known to induce oxidative stress, including CoCl2 and CdCl2. The metal-induced matriptase autoactivation is suppressed by N-acetylcysteine, supporting the putative role of altered cellular redox state in metal induced matriptase autoactivation. Furthermore, matriptase knockdown rendered cells more susceptible to CdCl2-induced cell death compared to control cells. This observation implies that the metal-induced matriptase autoactivation confers cells with the ability to survive exposure to toxic metals and/or oxidative stress. Our results suggest that matriptase can act as a cellular sensor of the chemical environment of the cell that allows the cell to respond to and protect itself from changes in the chemical milieu.

Systematic review with meta‐analysis: effectiveness and tolerability of interferon‐free direct‐acting antiviral regimens for chronic hepatitis C genotype 1 in routine clinical practice in Asia

Direct‐acting antiviral (DAA) regimens have shown high efficacy and tolerability for patients with HCV genotype 1/1b (GT1/1b) in clinical trials. However, robust real‐world evidence of interferon (IFN)‐free DAA treatment for HCV GT1‐infected patients in Asia is still lacking.

Matriptase expression and zymogen activation in human pilosebaceous unit.

Studies of human genetic disorders and mouse models reveal the important roles of matriptase in hair growth. Here, we investigate matriptase expression and zymogen activation in hair follicles. We show: 1) layer-dependent distribution patterns, with much higher matriptase expression in cells of the outer root sheath and matrix cells of the hair bulb than in cells of the inner root sheath; 2) cycle-dependent expression patterns, with matriptase expressed in the anagen and catagen phases of the hair lifecycle, but not in the telogen phase; 3) reduced expression of the matriptase inhibitor, HAI-1, in the catagen phase, suggesting increased proteolytic activity in this phase; and 4) definitive matriptase zymogen activation patterns, with the highest matriptase activation observed in matrix cells and outer root sheath cells in the isthmus/bulge region. In sebaceous glands, matriptase is highly expressed in basal and ductal cells, with much lower expression in the differentiated, lipid-filled cells of the interior. We also show that matriptase potently activates hepatocyte growth factor (HGF) in vitro, and that the HGF receptor, c-Met, is co-expressed in those cells that express activated matriptase. Our observations suggest that the matriptase-HGF-c-MET pathway has the potential to be engaged, primarily in proliferative cells rather than terminally differentiated epithelial cells of the human pilosebaceous unit.

Higher mortality and hospital charges in patients with cirrhosis and acute respiratory illness: a population-based study

Both cirrhosis and acute respiratory illness (ARI) carry substantial disease and financial burden. To compare hospitalized patients with cirrhosis with ARI to cirrhotic patients without ARI, a retrospective cohort study was conducted using the California Office of Statewide Health Planning and Development database. To balance the groups, propensity score matching (PSM) was used. We identified a total of 46,192 cirrhotic patients during the three study periods (14,049, 15,699, and 16,444 patients, respectively). Among patients hospitalized with cirrhosis, the ARI prevalence was higher in older age groups (p < 0.001), the Asian population (p = 0.002), non-Hispanic population (p = 0.001), and among Medicare patients (p < 0.001). Compared to controls, patients with ARI had 53.8% higher adjusted hospital charge (

Individual surveillance using model-based hepatocellular carcinoma risk estimates in chronic hepatitis C patients after antiviral treatment

122,555 vs.

Systematic review and network meta-analysis: Comparative effectiveness of therapies for second-line Helicobacter pylori eradication: Second-line therapy for H. pylori infection

79,685 per patient per admission, p < 0.001) and 35.0% higher adjusted in-hospital mortality (p < 0.001). Older patients, patients with alcoholic liver disease or liver cancer were at particularly higher risk (adjusted hazard ratio = 2.94 (95% CI: 2.26–3.83), 1.22 (95% CI: 1.02–1.45), and 2.17 (95% CI: 1.76–2.68) respectively, p = 0.028 to <0.001). Mortality rates and hospital charges in hospitalized cirrhotic patients with ARI were higher than in cirrhotic controls without ARI. Preventive efforts such as influenza and pneumococcal vaccination, especially in older patients and those with liver cancer, or alcoholic liver disease, would be of value.