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BMC Cancer Nov 2016Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase responsible for regulating ribosomal biogenesis and protein synthesis. Dysregulation of mTOR... (Meta-Analysis)
Meta-Analysis Review
Clinicopathological and prognostic significance of mTOR and phosphorylated mTOR expression in patients with esophageal squamous cell carcinoma: a systematic review and meta-analysis.
BACKGROUND
Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase responsible for regulating ribosomal biogenesis and protein synthesis. Dysregulation of mTOR contributes to tumorigenesis, angiogenesis, cellular growth and metastasis but its roles in esophageal squamous cell carcinoma (ESCC) are controversial. Therefore, the objective of this study is to evaluate the prognostic and clinicopathological significance of mTOR/p-mTOR expression in ESCC.
METHODS
Literature retrieval was conducted by searching PubMed, EMBASE and the Web of Science for full-text papers that met our eligibility criteria. Odds ratio (OR) and hazard ratio (HR) with 95 % confidence interval (CI) served as the appropriate summarized statistics for assessments of clinicopathological and prognostic significance, respectively. Cochrane Q-test and I-statistic were adopted to estimate the heterogeneity level between studies. Potential publication bias was detected by Begg's test and Egger's test.
RESULTS
A total of 915 ESCC patients from nine original articles were included into this meta-analysis. The pooled analyses suggested that mTOR/p-mTOR expression was significantly correlated with the unfavorable outcomes of differentiation degree (OR: 2.63; 95 % CI: 1.71-4.05; P = 0.001), tumor invasion (OR: 1.48; 95 % CI: 1.02-2.13; P = 0.037), TNM stage (OR: 2.25; 95 % CI: 1.05-4.82; P = 0.037) and lymph node metastasis (OR: 1.82; 95 % CI: 1.06-3.11; P = 0.029), but had no significant relationship to the genders (OR: 0.81; 95 % CI: 0.50-1.32; P = 0.396). Moreover, mTOR/p-mTOR expression could independently predict the worse overall survival (HR: 2.04; 95 % CI: 1.58-2.62; P < 0.001), disease-free survival (HR: 2.39; 95 % CI: 1.64-3.49; P < 0.001) and cancer-specific survival (HR: 1.62; 95 % CI: 1.18-2.23; P = 0.003) of patients with ESCC. Such prognostic value of mTOR was not substantially altered by further subgroup analyses.
CONCLUSIONS
Positive expression of mTOR and p-mTOR was significantly associated with the unfavorable conditions on the depth of tumor invasion, TNM stage, differentiation degree and lymph node metastasis. mTOR and p-mTOR could serve as a valuable predictor for the poor prognosis of ESCC. More high-quality worldwide studies performing a multivariate analysis based on larger sample size are urgently required for further verifying and modifying our findings in the future.
Topics: Biomarkers, Tumor; Carcinoma, Squamous Cell; Esophageal Neoplasms; Humans; Lymphatic Metastasis; Neoplasm Invasiveness; Phosphoproteins; Phosphorylation; Prognosis; Protein Processing, Post-Translational; Survival Analysis; TOR Serine-Threonine Kinases
PubMed: 27835987
DOI: 10.1186/s12885-016-2940-7 -
Gastroenterology Jan 2017High-throughput sequencing analysis has accelerated searches for genes associated with risk for colorectal cancer (CRC); germline mutations in NTHL1, RPS20, FANCM, FAN1,... (Review)
Review
High-throughput sequencing analysis has accelerated searches for genes associated with risk for colorectal cancer (CRC); germline mutations in NTHL1, RPS20, FANCM, FAN1, TP53, BUB1, BUB3, LRP6, and PTPN12 have been recently proposed to increase CRC risk. We attempted to validate the association between variants in these genes and development of CRC in a systematic review of 11 publications, using sequence data from 863 familial CRC cases and 1604 individuals without CRC (controls). All cases were diagnosed at an age of 55 years or younger and did not carry mutations in an established CRC predisposition gene. We found sufficient evidence for NTHL1 to be considered a CRC predisposition gene-members of 3 unrelated Dutch families were homozygous for inactivating p.Gln90Ter mutations; a Canadian woman with polyposis, CRC, and multiple tumors was reported to be heterozygous for the inactivating NTHL1 p.Gln90Ter/c.709+1G>A mutations; and a man with polyposis was reported to carry p.Gln90Ter/p.Gln287Ter; whereas no inactivating homozygous or compound heterozygous mutations were detected in controls. Variants that disrupted RPS20 were detected in a Finnish family with early-onset CRC (p.Val50SerfsTer23), a 39-year old individual with metachronous CRC (p.Leu61GlufsTer11 mutation), and a 41-year-old individual with CRC (missense p.Val54Leu), but not in controls. We therefore found published evidence to support the association between variants in NTHL1 and RPS20 with CRC, but not of other recently reported CRC susceptibility variants. We urge the research community to adopt rigorous statistical and biological approaches coupled with independent replication before making claims of pathogenicity.
Topics: Adenomatous Polyposis Coli; Colorectal Neoplasms; Deoxyribonuclease (Pyrimidine Dimer); Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Ribosomal Proteins
PubMed: 27713038
DOI: 10.1053/j.gastro.2016.09.041 -
Genome Medicine May 2016The effects of probiotic supplementation on fecal microbiota composition in healthy adults have not been well established. We aimed to provide a systematic review of the... (Review)
Review
BACKGROUND
The effects of probiotic supplementation on fecal microbiota composition in healthy adults have not been well established. We aimed to provide a systematic review of the potential evidence for an effect of probiotic supplementation on the composition of human fecal microbiota as assessed by high-throughput molecular approaches in randomized controlled trials (RCTs) of healthy adults.
METHODS
The survey of peer-reviewed papers was performed on 17 August 2015 by a literature search through PubMed, SCOPUS, and ISI Web of Science. Additional papers were identified by checking references of relevant papers. Search terms included healthy adult, probiotic, bifidobacterium, lactobacillus, gut microbiota, fecal microbiota, intestinal microbiota, intervention, and (clinical) trial. RCTs of solely probiotic supplementation and placebo in healthy adults that examined alteration in composition of overall fecal microbiota structure assessed by shotgun metagenomic sequencing, 16S ribosomal RNA sequencing, or phylogenetic microarray methods were included. Independent collection and quality assessment of studies were performed by two authors using predefined criteria including methodological quality assessment of reports of the clinical trials based on revised tools from PRISMA/Cochrane and by the Jadad score.
RESULTS
Seven RCTs investigating the effect of probiotic supplementation on fecal microbiota in healthy adults were identified and included in the present systematic review. The quality of the studies was assessed as medium to high. Still, no effects were observed on the fecal microbiota composition in terms of α-diversity, richness, or evenness in any of the included studies when compared to placebo. Only one study found that probiotic supplementation significantly modified the overall structure of the fecal bacterial community in terms of β-diversity when compared to placebo.
CONCLUSIONS
This systematic review of the pertinent literature demonstrates a lack of evidence for an impact of probiotics on fecal microbiota composition in healthy adults. Future studies would benefit from pre-specifying the primary outcome and transparently reporting the results including effect sizes, confidence intervals, and P values as well as providing a clear distinction of between-group and within-group comparisons.
Topics: Adult; Bacteria; Feces; Healthy Volunteers; Humans; Microbiota; Phylogeny; Probiotics; Randomized Controlled Trials as Topic
PubMed: 27159972
DOI: 10.1186/s13073-016-0300-5 -
American Journal of Rhinology & Allergy 2016Our understanding of the resident microbiome of the paranasal sinuses has changed considerably in recent years. Once presumed to be sterile, healthy sinus cavities are... (Review)
Review
BACKGROUND
Our understanding of the resident microbiome of the paranasal sinuses has changed considerably in recent years. Once presumed to be sterile, healthy sinus cavities are now known to harbor a diverse assemblage of microorganisms, and, it is hypothesized that alterations in the kinds and quantities of these microbes may play a role in the pathogenesis of chronic rhinosinusitis (CRS).
OBJECTIVES
To review the current literature regarding the sinus microbiome and collate research findings from relevant studies published to date.
METHODS
A systematic literature review was performed on all molecular studies that investigated the microbial communities of the paranasal sinuses. Methods of detection, microbiome composition, and comparative profiling between patients with and without CRS were explored.
RESULTS
A complex consortium of microorganisms has been demonstrated in the sinuses of both patients with and without CRS. However, the latter generally have been characterized by reduced biodiversity compared with controls, with selective enrichment of particular microbes (e.g., Staphylococcus aureus). Such disruptions in the resident microbiome may contribute to disease pathogenesis by enhancing the virulence of potential pathogens and adversely modulating immune responses.
CONCLUSION
The advent of culture-independent molecular approaches has led to a greater appreciation of the intricate microbial ecology of the paranasal sinuses. Microbiota composition, distribution, and abundance impact mucosal health and influence pathogen growth and function. A deeper understanding of the host-microbiome relationship and its constituents may encourage development of new treatment paradigms for CRS, which target restoration of microbiome homeostasis and cultivation of optimal microbial communities.
Topics: Animals; Bacteria; Biodiversity; Chronic Disease; Homeostasis; Humans; Microbiota; Paranasal Sinuses; RNA, Ribosomal, 16S; Rhinitis, Allergic; Sinusitis
PubMed: 26867525
DOI: 10.2500/ajra.2016.30.4255 -
African Journal of Paediatric Surgery :... 2015This was a meta-analysis and systematic review to determine the global prevalence of the mitochondrially encoded 12S RNA (MT-RNR1) genetic mutation in order to assess... (Meta-Analysis)
Meta-Analysis Review
A meta-analysis and systematic review of the prevalence of mitochondrially encoded 12S RNA in the general population: Is there a role for screening neonates requiring aminoglycosides?
BACKGROUND
This was a meta-analysis and systematic review to determine the global prevalence of the mitochondrially encoded 12S RNA (MT-RNR1) genetic mutation in order to assess the need for neonatal screening prior to aminoglycoside therapy.
MATERIALS AND METHODS
A comprehensive search of MEDLINE, EMBASE, Ovid, Database of Abstracts of Reviews of Effect, Cochrane Library, Clinical Evidence and Cochrane Central Register of Trials was performed including cross-referencing independently by 2 assessors. Selections were restricted to human studies in English. Meta-analysis was done with MetaXL 2013.
RESULTS
Forty-five papers out of 295 met the criteria. Pooled prevalence in the general population for MT-RNR1 gene mutations (A1555G, C1494T, A7445G) was 2% (1-4%) at 99%.
CONCLUSION
Routine screening for MT-RNR1 mutations in the general population prior to treatment with aminoglycosides appear desirable but poorly supported by the weak level of evidence available in the literature. Routine screening in high-risk (Chinese and Spanish) populations appear justified.
Topics: Aminoglycosides; Genetic Testing; Humans; Infant, Newborn; Mitochondria; Mutation; Prevalence; RNA, Ribosomal
PubMed: 26168747
DOI: 10.4103/0189-6725.160342 -
PloS One 2015We aim to evaluate the accuracy of the 16S ribosomal ribonucleic acid (rRNA) gene polymerase chain reaction (PCR) test in the diagnosis of bloodstream infections through... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
We aim to evaluate the accuracy of the 16S ribosomal ribonucleic acid (rRNA) gene polymerase chain reaction (PCR) test in the diagnosis of bloodstream infections through a systematic review and meta-analysis.
METHODS
A computerized literature search was conducted to identify studies that assessed the diagnostic value of 16S rRNA gene PCR test for bloodstream infections. Study quality was assessed using the revised Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. We calculated the sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and their 95% confidence intervals (95% CI) for each study. Summary receiver operating characteristic (SROC) curve was used to summarize overall test performance. Statistical analysis was performed in Meta-DiSc 1.4 and Stata/SE 12.0 software.
RESULTS
Twenty-eight studies were included in our meta-analysis. Using random-effect model analysis, the pooled sensitivity, specificity, PLR, NLR, and DOR were 0.87 (95% CI, 0.85-0.89), 0.94 (95% CI, 0.93-0.95), 12.65 (95% CI, 8.04-19.90), 0.14 (95% CI, 0.08-0.24), and 116.76 (95% CI, 52.02-262.05), respectively. The SROC curve indicated that the area under the curve (AUC) was 0.9690 and the maximum joint sensitivity and specificity (Q*) was 0.9183. In addition, heterogeneity was statistically significant but was not caused by the threshold effect.
CONCLUSION
Existing data suggest that 16S rRNA gene PCR test is a practical tool for the rapid screening of sepsis. Further prospective studies are needed to assess the diagnostic value of PCR amplification and DNA microarray hybridization of 16S rRNA gene in the future.
Topics: Bacteremia; Databases, Factual; Humans; Odds Ratio; Polymerase Chain Reaction; Publication Bias; RNA, Ribosomal, 16S; Reproducibility of Results; Sensitivity and Specificity; Sepsis
PubMed: 25996771
DOI: 10.1371/journal.pone.0127195 -
Health Technology Assessment... May 2015There is growing interest in the potential utility of real-time polymerase chain reaction (PCR) in diagnosing bloodstream infection by detecting pathogen... (Review)
Review
Rapid detection of health-care-associated bloodstream infection in critical care using multipathogen real-time polymerase chain reaction technology: a diagnostic accuracy study and systematic review.
BACKGROUND
There is growing interest in the potential utility of real-time polymerase chain reaction (PCR) in diagnosing bloodstream infection by detecting pathogen deoxyribonucleic acid (DNA) in blood samples within a few hours. SeptiFast (Roche Diagnostics GmBH, Mannheim, Germany) is a multipathogen probe-based system targeting ribosomal DNA sequences of bacteria and fungi. It detects and identifies the commonest pathogens causing bloodstream infection. As background to this study, we report a systematic review of Phase III diagnostic accuracy studies of SeptiFast, which reveals uncertainty about its likely clinical utility based on widespread evidence of deficiencies in study design and reporting with a high risk of bias.
OBJECTIVE
Determine the accuracy of SeptiFast real-time PCR for the detection of health-care-associated bloodstream infection, against standard microbiological culture.
DESIGN
Prospective multicentre Phase III clinical diagnostic accuracy study using the standards for the reporting of diagnostic accuracy studies criteria.
SETTING
Critical care departments within NHS hospitals in the north-west of England.
PARTICIPANTS
Adult patients requiring blood culture (BC) when developing new signs of systemic inflammation.
MAIN OUTCOME MEASURES
SeptiFast real-time PCR results at species/genus level compared with microbiological culture in association with independent adjudication of infection. Metrics of diagnostic accuracy were derived including sensitivity, specificity, likelihood ratios and predictive values, with their 95% confidence intervals (CIs). Latent class analysis was used to explore the diagnostic performance of culture as a reference standard.
RESULTS
Of 1006 new patient episodes of systemic inflammation in 853 patients, 922 (92%) met the inclusion criteria and provided sufficient information for analysis. Index test assay failure occurred on 69 (7%) occasions. Adult patients had been exposed to a median of 8 days (interquartile range 4-16 days) of hospital care, had high levels of organ support activities and recent antibiotic exposure. SeptiFast real-time PCR, when compared with culture-proven bloodstream infection at species/genus level, had better specificity (85.8%, 95% CI 83.3% to 88.1%) than sensitivity (50%, 95% CI 39.1% to 60.8%). When compared with pooled diagnostic metrics derived from our systematic review, our clinical study revealed lower test accuracy of SeptiFast real-time PCR, mainly as a result of low diagnostic sensitivity. There was a low prevalence of BC-proven pathogens in these patients (9.2%, 95% CI 7.4% to 11.2%) such that the post-test probabilities of both a positive (26.3%, 95% CI 19.8% to 33.7%) and a negative SeptiFast test (5.6%, 95% CI 4.1% to 7.4%) indicate the potential limitations of this technology in the diagnosis of bloodstream infection. However, latent class analysis indicates that BC has a low sensitivity, questioning its relevance as a reference test in this setting. Using this analysis approach, the sensitivity of the SeptiFast test was low but also appeared significantly better than BC. Blood samples identified as positive by either culture or SeptiFast real-time PCR were associated with a high probability (> 95%) of infection, indicating higher diagnostic rule-in utility than was apparent using conventional analyses of diagnostic accuracy.
CONCLUSION
SeptiFast real-time PCR on blood samples may have rapid rule-in utility for the diagnosis of health-care-associated bloodstream infection but the lack of sensitivity is a significant limiting factor. Innovations aimed at improved diagnostic sensitivity of real-time PCR in this setting are urgently required. Future work recommendations include technology developments to improve the efficiency of pathogen DNA extraction and the capacity to detect a much broader range of pathogens and drug resistance genes and the application of new statistical approaches able to more reliably assess test performance in situation where the reference standard (e.g. blood culture in the setting of high antimicrobial use) is prone to error.
STUDY REGISTRATION
The systematic review is registered as PROSPERO CRD42011001289.
FUNDING
The National Institute for Health Research Health Technology Assessment programme. Professor Daniel McAuley and Professor Gavin D Perkins contributed to the systematic review through their funded roles as codirectors of the Intensive Care Foundation (UK).
Topics: Bacteremia; Critical Care; Cross Infection; England; False Negative Reactions; False Positive Reactions; Humans; Prospective Studies; Real-Time Polymerase Chain Reaction; Sensitivity and Specificity; State Medicine; Technology Assessment, Biomedical; Time Factors
PubMed: 25961752
DOI: 10.3310/hta19350 -
Journal of Neurology Sep 2014Neuropsychiatric systemic lupus erythematosus (NPSLE) is one of the most important manifestations of SLE, and includes a variety of clinical manifestations, classified... (Review)
Review
Neuropsychiatric systemic lupus erythematosus (NPSLE) is one of the most important manifestations of SLE, and includes a variety of clinical manifestations, classified by the American College of Rheumatology in 19 different neuropsychiatric syndromes. To date, more than 116 antibodies have been reported in SLE and at least 20 of them, including 11 brain-specific and 9 systemic antibodies, have been controversially associated with NPSLE. To systematically review the available evidence, to define the association between the above antibodies and NPSLE as a whole and with the 19 neuropsychiatric syndromes associated with SLE, by strictly applying the American College Rheumatology case definitions. Medline reports published between 1999 and 2013 investigating the association between antibodies and NPSLE were included. Whenever possible, associations between antibodies and both NPSLE as a whole and with the 19 syndromes were analysed. This systematic review is based on available data from more than 8,000 patients and controls from 42 studies analysing antibodies and NPSLE. Nineteen studies analysed the role of antiphospholipid antibodies (aPL), 11 focused on anti-ribosomal-P protein antibodies and 5 on anti-N-Methyl-D-Aspartate receptor antibodies. Two studies analysed, respectively, antibodies to aquaporin-4 and VH4-34 encoded antibodies. Given the multitude of clinical manifestations related to NPSLE, a single biomarker failed to be reliably associated with all neuropsychiatric events. Our findings provide evidence that aPL, mainly the lupus anticoagulant, and anti-ribosomal P antibodies are significantly associated with specific manifestations of neuropsychiatric disease attributed to SLE, namely, cerebrovascular events and psychosis, respectively.
Topics: Antibodies, Antiphospholipid; Aquaporin 4; Autoantibodies; Biomarkers; Humans; Lupus Coagulation Inhibitor; Lupus Vasculitis, Central Nervous System; Mental Disorders; Receptors, N-Methyl-D-Aspartate; Ribosomal Proteins
PubMed: 24952022
DOI: 10.1007/s00415-014-7406-8 -
Malaria Journal Sep 2012Confirmation of artemisinin-delayed parasite clearance in Plasmodium falciparum along the Thai-Myanmar border has inspired a global response to contain and monitor drug...
Molecular surveillance for drug-resistant Plasmodium falciparum in clinical and subclinical populations from three border regions of Burma/Myanmar: cross-sectional data and a systematic review of resistance studies.
BACKGROUND
Confirmation of artemisinin-delayed parasite clearance in Plasmodium falciparum along the Thai-Myanmar border has inspired a global response to contain and monitor drug resistance to avert the disastrous consequences of a potential spread to Africa. However, resistance data from Myanmar are sparse, particularly from high-risk areas where limited health services and decades of displacement create conditions for resistance to spread. Subclinical infections may represent an important reservoir for resistance genes that confer a fitness disadvantage relative to wild-type alleles. This study estimates the prevalence of resistance genotypes in three previously unstudied remote populations in Myanmar and tests the a priori hypothesis that resistance gene prevalence would be higher among isolates collected from subclinical infections than isolates collected from febrile clinical patients. A systematic review of resistance studies is provided for context.
METHODS
Community health workers in Karen and Kachin States and an area spanning the Indo-Myanmar border collected dried blood spots from 988 febrile clinical patients and 4,591 villagers with subclinical infection participating in routine prevalence surveys. Samples positive for P. falciparum 18 s ribosomal RNA by real-time PCR were genotyped for P. falciparum multidrug resistance protein (pfmdr1) copy number and the pfcrt K76T polymorphism using multiplex real-time PCR.
RESULTS
Pfmdr1 copy number increase and the pfcrt K76 polymorphism were determined for 173 and 269 isolates, respectively. Mean pfmdr1 copy number was 1.2 (range: 0.7 to 3.7). Pfmdr1 copy number increase was present in 17.5%, 9.6% and 11.1% of isolates from Karen and Kachin States and the Indo-Myanmar border, respectively. Pfmdr1 amplification was more prevalent in subclinical isolates (20.3%) than clinical isolates (6.4%, odds ratio 3.7, 95% confidence interval 1.1 - 12.5). Pfcrt K76T prevalence ranged from 90-100%.
CONCLUSIONS
Community health workers can contribute to molecular surveillance of drug resistance in remote areas of Myanmar. Marginal and displaced populations under-represented among previous resistance investigations can and should be included in resistance surveillance efforts, particularly once genetic markers of artemisinin-delayed parasite clearance are identified. Subclinical infections may contribute to the epidemiology of drug resistance, but determination of gene amplification from desiccated filter samples requires further validation when DNA concentration is low.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antimalarials; Asymptomatic Diseases; Child; Child, Preschool; DNA, Protozoan; Drug Resistance; Female; Genetic Variation; Genotype; Humans; Infant; Infant, Newborn; Malaria, Falciparum; Male; Membrane Transport Proteins; Middle Aged; Multidrug Resistance-Associated Proteins; Myanmar; Plasmodium falciparum; Polymerase Chain Reaction; Protozoan Proteins; Young Adult
PubMed: 22992214
DOI: 10.1186/1475-2875-11-333 -
The Indian Journal of Medical Research Sep 2011Diagnosis for Mycoplasma pneumoniae usually relies on serological tests. PCR technology has some advantages but also limitations. The optimal selection for these tests... (Comparative Study)
Comparative Study Meta-Analysis Review
BACKGROUND & OBJECTIVES
Diagnosis for Mycoplasma pneumoniae usually relies on serological tests. PCR technology has some advantages but also limitations. The optimal selection for these tests still needs discussion. This paper reviews the overall diagnostic accuracy of PCR versus serological assays for diagnosis of M. pneumoniae infections and to identify factors associated with heterogeneity of results.
METHODS
MEDLINE and Embase databases were searched. Articles meeting the selection criteria were retrieved for data collection and analysis. Studies were assessed for methodological quality using QUADAS. Hierarchial summary receiver operating characteristic (HSROC) model was used to estimate summary ROC curve.
RESULTS
Initial meta-analysis showed a summary estimate of sensitivity (SEN) 0.62 (95% CI, 0.45-0.76), and specificity (SPE) 0.96 (95% CI, 0.93-0.98). Subgroup analyses were performed to identify factors associated with heterogeneity. For different gene targets, reference standards, subjects (children or adults) and different PCR types, these aspects can generate results of heterogeneity. The 16s rDNA target and adult subjects and real-time PCR may have better test results for PCR.
INTERPRETATION & CONCLUSIONS
Commercial PCR tests generated consistent results with high specificity but a lower and more variable sensitivity. The findings suggest commercial PCR tests having superiorities in diagnosing M. pneumoniae infections but still cannot replace serology. PCR plus serology could be good screening tests for reliable and accurate diagnosis of M. pneumoniae.
Topics: Adult; Child; Humans; MEDLINE; Mycoplasma pneumoniae; Pneumonia, Mycoplasma; Polymerase Chain Reaction; RNA, Ribosomal, 16S; ROC Curve; Sensitivity and Specificity; Serology
PubMed: 21985809
DOI: No ID Found