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PLoS Neglected Tropical Diseases Aug 2019Accurate and accessible diagnosis is key for the control of visceral leishmaniasis (VL). Yet, current diagnostic tests for VL have severe limitations: they are invasive...
BACKGROUND
Accurate and accessible diagnosis is key for the control of visceral leishmaniasis (VL). Yet, current diagnostic tests for VL have severe limitations: they are invasive or not suitable as point of care (POC) test or their performance is suboptimal in East Africa. We analysed the antigens in the VL serodiagnostics development pipeline to identify shortcomings and to propose strategies in the development of an alternative POC test for VL in East Africa.
OBJECTIVES
The objective of this study was to identify and to analyse all antigens for VL serodiagnosis that have been published before 2018 in order to identify candidates and gaps in the pipeline for a new POC test in East Africa.
METHODS
A systematic literature search was performed on PubMed for original research articles on Leishmania-specific antigens for antibody detection of VL in humans. From each article, the following information was extracted: the antigen name, test format and characteristics, its reported sensitivity and specificity and study cohort specifications.
RESULTS
One hundred and seven articles containing information about 96 tests based on 89 different antigens were included in this study. Eighty six of these tests, comprising 80 antigens, were evaluated in phase I and II studies only. Only 20 antigens, all of which are native, contain a carbohydrate and/or lipid moiety. Twenty-four antigens, of which 7 are non-native, are composed of antigen mixtures. Nineteen tests, comprising 18 antigens, have been evaluated on East African specimens, of which only 2 (rK28 based immunochromatographic test and intact promastigote based indirect fluorescent antibody technique) consistently showed sensitivities above 94 and specificities above 97% in a phase III study and one in a phase II study (dot blot with SLA). Only rK28 is a non-native mixture of antigens which we consider suitable for further evaluation and implementation.
CONCLUSIONS
The development pipeline for an alternative serodiagnostic test for VL is almost empty. Most antigens are not sufficiently evaluated. Non-protein antigens and antigen mixtures are being neglected. We propose to expand the evaluation of existing antigen candidates and to investigate the diagnostic potential of defined non-native carbohydrate and lipid antigens for VL serodiagnosis in East Africa.
Topics: Africa, Eastern; Antibodies, Protozoan; Antigens, Protozoan; Humans; Leishmania; Leishmaniasis, Visceral; Point-of-Care Systems; Sensitivity and Specificity; Serologic Tests
PubMed: 31415564
DOI: 10.1371/journal.pntd.0007658 -
Best Practice & Research. Clinical... Aug 2018The aim was to compare indirect immunofluorescence (IIF) and fluorescence enzyme immunoassay (FEIA) for initial screening of connective tissue diseases (CTDs) and to... (Meta-Analysis)
Meta-Analysis
A comparison of a fluorescence enzyme immunoassay versus indirect immunofluorescence for initial screening of connective tissue diseases: Systematic literature review and meta-analysis of diagnostic test accuracy studies.
The aim was to compare indirect immunofluorescence (IIF) and fluorescence enzyme immunoassay (FEIA) for initial screening of connective tissue diseases (CTDs) and to evaluate whether combining IIF with FEIA adds value. A comprehensive systematic literature review was conducted to identify fully paired, cross-sectional or case-control studies on ANA screening of CTD reporting results for IIF and FEIA. Study quality was assessed using the QUADAS-2 checklist. The reference standard was assessed against established classification criteria. The meta-analysis used hierarchical, bivariate and mixed-effects models to allow test results to vary within and across studies. Eighteen studies of good to fair quality were included in the review. IIF had a higher sensitivity than FEIA [cut-off 1:160, 7 studies, 3251 patients, 0.83 (95% CI 0.75-0.89) versus 0.73 (95% CI 0.64-0.80); cut-off 1:80, 7 studies, 12,311 patients, 0.89 (95% CI 0.84-0.93) versus 0.78 (95% CI 0.71-0.84)] but lower specificity [1:160, 0.81 (95% CI 0.73-0.87) versus 0.94 (95% CI 0.91-0.95); 1:80, 0.72 (95% CI 0.62-0.81) versus 0.94 (95% CI 0.90-0.96)]. A double-positive test had a higher likelihood ratio (LR) for CTD (26.2 (95% CI 23.0-29.9)) than a single positive test (14.4 (95% CI 13.1-15.9) FEIA+, 5.1 (95% CI 4.8-5.4) IIF+). A double-negative test result had more clinical value for ruling out CTD than a single negative test (LR 0.15 (95% CI 0.12-0.18) versus 0.21 (95% CI 0.18-0.25) IIF; 0.33 (95% CI 0.29-0.37) FEIA-). A FEIA+/IIF- discordant result had a higher LR than an IIF+/FEIA- discordant result (LR 2.4 (95% CI 1.7-3.4) versus 1.4 (95% CI 1.2-1.7)). Because of the comparatively higher specificity of FEIA and higher sensitivity of IIF, the combination of FEIA and IIF increases the diagnostic value. Clinicians should be acquainted with the clinical presentation of CTD and aware of the advantages and disadvantages of FEIA and IIF to avoid misinterpretation.
Topics: Connective Tissue Diseases; Cross-Sectional Studies; Diagnostic Tests, Routine; Fluorescent Antibody Technique, Indirect; Humans; Immunoenzyme Techniques
PubMed: 31174821
DOI: 10.1016/j.berh.2019.03.005 -
Scientific Reports May 2019The dried blood spot (DBS) is increasingly used for the hepatitis C virus (HCV) screening. Our objective was to perform a meta-analysis of the methodology for HCV... (Meta-Analysis)
Meta-Analysis
The dried blood spot (DBS) is increasingly used for the hepatitis C virus (HCV) screening. Our objective was to perform a meta-analysis of the methodology for HCV screening in DBS samples, particularly in the type of diagnostic assay used. We performed a meta-analysis of all eligible studies published to date (March 2018). The literature search revealed 26 studies: 21 for detection of anti-HCV antibodies and 10 for detection of HCV-RNA. Statistical analyses were performed using Meta-DiSc and STATA (MIDAS module). For detection of HCV antibodies, pooled diagnostic accuracy measures were as follows: sensitivity 96.1%, specificity 99.2%, positive likelihood ratio (PLR) 105, negative likelihood ratio (NLR) 0.04, diagnostic odds ratio (DOR) 2692.9, and summary receiver operating characteristic (SROC) 0.997 ± 0.001. For detection of HCV-RNA, the pooled diagnostic accuracy measures were as follows: sensitivity 97.8%, specificity 99.2%, PLR 44.8, NLR 0.04, DOR 1966.9, and SROC 0.996 ± 0.013. Similar values of pooled diagnostic accuracy measures were found according to the type of anti-HCV antibody detection assay (enzyme-linked immunosorbent assay, rapid diagnostic test, and chemiluminescence assays) and HCV-RNA detection assay (real-time polymerase chain reaction and transcription-mediated amplification). The analysis of external validity showed a high negative predicted value (NPV) for both approaches, but a low positive predicted value (PPV) when prevalence was < 10%, particularly in HCV-RNA tests. Finally, this meta-analysis is subject to limitations, especially publication bias and significant heterogeneity between studies. In conclusion, HCV screening in DBS samples has an outstanding diagnostic performance, with no relevant differences between the techniques used. However, external validity may be limited when the HCV prevalence is low.
Topics: Dried Blood Spot Testing; Enzyme-Linked Immunosorbent Assay; Hepacivirus; Hepatitis C; Hepatitis C Antibodies; Humans; Mass Screening; Predictive Value of Tests; RNA, Viral; ROC Curve; Viral Load
PubMed: 31086259
DOI: 10.1038/s41598-019-41139-8 -
PloS One 2019The presence of ≥3 oligoclonal bands (OCB) in the cerebrospinal fluid (CSF) without corresponding bands in serum represents a definite pathological pattern, whereas...
BACKGROUND
The presence of ≥3 oligoclonal bands (OCB) in the cerebrospinal fluid (CSF) without corresponding bands in serum represents a definite pathological pattern, whereas the clinical significance of 1-2 CSF bands (borderline pattern) is poorly investigated.
METHODS
We screened 1986 consecutive CSF and serum samples which were collected over a four-year time period and had results of isoelectric focusing (IEF) available. Of patients with borderline OCB we reviewed individual medical charts for assessment of clinical diagnoses. Where feasible, IEF was replicated and results of follow-up samples were obtained. IEF was performed using polyacrylamide gel followed by immunoblotting and IgG-specific antibody staining. Additionally, we performed a systematic literature review of the diagnostic specificity of OCB using different cut-offs for CSF-restricted bands.
RESULTS
Out of 253 patients with borderline OCB, 21.7% had an inflammatory neurological disease (IND) of the central nervous system, comprising 4% multiple sclerosis patients, and 14.2% had a peripheral IND, whereas the remaining 64.1% of patients showed non-inflammatory diseases. Frequency of one or two CSF bands without corresponding serum bands did not differ between the disease groups. In a subgroup of 100 patients IEF was repeated. Of those, 73% were OCB negative, while no sample was positive. In 26 patients IEF results were available of a follow-up sample collected after a median of 27 months. Of those, 4 (15.4%) turned positive. Systematic literature review revealed a diagnostic specificity of OCB of 97% and 92% using a cut-off ≥3 and ≥2 CSF bands in patients with mainly non-inflammatory neurological diseases.
CONCLUSION
The clinical significance of one or two CSF-restricted bands is moderate and, hence, indicates a possible but not reliable proof of intrathecal B-cell activity. Sample re-testing, introduction of an additional diagnostic category, e.g. "possible intrathecal IgG synthesis", and follow-up lumbar puncture might be possible options to address this scenario.
Topics: Cerebrospinal Fluid; Female; Humans; Isoelectric Focusing; Male; Nervous System Diseases; Retrospective Studies
PubMed: 30986255
DOI: 10.1371/journal.pone.0215410 -
Annals of Physical and Rehabilitation... Jul 2019The imputability of neutralizing antibodies (NABs) in secondary non-response (SnR) to botulinum toxin (BoNT) injections for limb spasticity is still debated.
BACKGROUND
The imputability of neutralizing antibodies (NABs) in secondary non-response (SnR) to botulinum toxin (BoNT) injections for limb spasticity is still debated.
OBJECTIVE
This systematic literature review aimed to determine the prevalence of NABs after BoNT injections for limb spasticity and analyze their determinants and their causal role in SnR.
METHODS
We searched MEDLINE via PubMed, Cochrane and Embase databases for articles published during 1990-2018. Two independent reviewers extracted the data and assessed the quality of studies with a specific scale (according to PRISMA and STROBE guidelines). Because the techniques used to detect NABs did not influence the results, we calculated the global (all studies) sensitivity and specificity of NAB positivity to reveal SnR.
RESULTS
We included 14 articles published from 2002 to 2018 (including an epublication) describing 5 randomized controlled trials and 5 interventional and 4 observational studies. The quality was satisfactory (mean score 18/28 arbitrary units). NAB detection was the primary criterion in 5 studies and a secondary criterion in 9. In total, 1234 serum samples for 1234 participants (91% with stroke) were tested after injection. NAB prevalence was about 1%, with no significant difference among formulations. NAB positivity seemed favoured by long-duration therapy with high doses and a short interval between injections. The identification of non-response by NAB positivity had poor global sensitivity (56%) but very high specificity (99.6%). No consensual criteria were used to diagnose non-response to BoNT injection.
CONCLUSIONS
NAB prevalence is much lower after BoNT treatment for limb spasticity than cervical dystonia. Consensual criteria must be defined to diagnose non-response to BoNT injection. Because immunogenicity is not the most common cause of non-response to BoNT injection, NABs should be sought in individuals with SnR with no other cause explaining the treatment inefficacy. A test with 100% specificity is recommended. In cases for which immunogenicity is the most likely cause of non-response to BoNT injections, some biological arguments suggest trying another BoNT, but no clinical evidence supports this strategy.
Topics: Animals; Biological Assay; Botulinum Toxins, Type A; Cerebral Palsy; Clinical Trials as Topic; Cross-Sectional Studies; Drug Compounding; Humans; Injections, Intramuscular; Longitudinal Studies; Meta-Analysis as Topic; Mice; Multicenter Studies as Topic; Muscle Spasticity; Neuromuscular Agents; Observational Studies as Topic; Stroke
PubMed: 30980953
DOI: 10.1016/j.rehab.2019.03.004 -
Clinical Pharmacokinetics Oct 2019Enzyme-mediated biotransformation of pharmacological agents is a crucial step in xenobiotic detoxification and drug disposition. Herein, we investigated the metabolism...
Physicochemical Properties, Biotransformation, and Transport Pathways of Established and Newly Approved Medications: A Systematic Review of the Top 200 Most Prescribed Drugs vs. the FDA-Approved Drugs Between 2005 and 2016.
BACKGROUND
Enzyme-mediated biotransformation of pharmacological agents is a crucial step in xenobiotic detoxification and drug disposition. Herein, we investigated the metabolism and physicochemical properties of the top 200 most prescribed drugs (established) as well as drugs approved by the US Food and Drug Administration (FDA) between 2005 and 2016 (newly approved).
OBJECTIVE
Our objective was to capture the changing trends in the routes of administration, physicochemical properties, and prodrug medications, as well as the contributions of drug-metabolizing enzymes and transporters to drug clearance.
METHODS
The University of Washington Drug Interaction Database (DIDB) as well as other online resources (e.g., CenterWatch.com, Drugs.com, DrugBank.ca, and PubChem.ncbi.nlm.nih.gov) was used to collect and stratify the dataset required for exploring the above-mentioned trends.
RESULTS
Analyses revealed that ~ 90% of all drugs in the established and newly approved drug lists were administered systemically (oral or intravenous). Meanwhile, the portion of biologics (molecular weight > 1 kDa) was 15 times greater in the newly approved list than established drugs. Additionally, there was a 4.5-fold increase in the number of compounds with a high calculated partition coefficient (cLogP > 3) and a high total polar surface area (> 75 Å) in the newly approved drug vs. the established category. Further, prodrugs in established or newly approved lists were found to be converted to active compounds via hydrolysis, demethylases, and kinases. The contribution of cytochrome P450 (CYP) 3A4, as the major biotransformation pathway, has increased from 40% in the established drug list to 64% in the newly approved drug list. Moreover, the role of CYP1A2, CYP2C19, and CYP2D6 were decreased as major metabolizing enzymes among the newly approved medications. Among non-CYP major metabolizers, the contribution of alcohol dehydrogenases/aldehyde dehydrogenases (ADH/ALDH) and sulfotransferases decreased in the newly approved drugs compared with the established list. Furthermore, the highest contribution among uptake and efflux transporters was found for Organic Anion Transporting Polypeptide 1B1 (OATP1B1) and P-glycoprotein (P-gp), respectively.
CONCLUSIONS
The higher portion of biologics in the newly approved drugs compared with the established list confirmed the growing demands for protein- and antibody-based therapies. Moreover, the larger number of hydrophilic drugs found in the newly approved list suggests that the probability of toxicity is likely to decrease. With regard to CYP-mediated major metabolism, CYP3A5 showed an increased involvement owing to the identification of unique probe substrates to differentiate CYP3As. Furthermore, the contribution of OATP1B1 and P-gp did not show a significant shift in the newly approved drugs as compared to the established list because of their broad substrate specificity.
Topics: Animals; Biological Transport; Biotransformation; Drug Approval; Humans; Prescription Drugs; United States; United States Food and Drug Administration
PubMed: 30972694
DOI: 10.1007/s40262-019-00750-8 -
International Journal of Molecular... Feb 2019The role of autoantibodies in in vitro fertilization (IVF) has been discussed for almost three decades. Nonetheless, studies are still scarce and widely controversial....
The role of autoantibodies in in vitro fertilization (IVF) has been discussed for almost three decades. Nonetheless, studies are still scarce and widely controversial. The aim of this study is to provide a comprehensive systematic review on the possible complications associated to autoantibodies (AA) impeding the chances of a successful IVF cycle. An Embase, PubMed/Medline and Cochrane Central Database search was performed on 1 December 2018, from 2006 until that date. From the 598 articles yielded in the search only 44 relevant articles ultimately fulfilled the inclusion criteria and were qualitatively analyzed. Five subsets of results were identified, namely, thyroid related AA, anti-phospholipid antibodies, anti-nuclear antibodies, AA affecting the reproductive system and AA related to celiac disease. It may be implied that the majority of auto-antibodies exert a statistically significant effect on miscarriage rates, whereas the effects on clinical pregnancy and live birth rates differ according to the type of auto-antibodies. While significant research is performed in the field, the quality of evidence provided is still low. The conduction of well-designed prospective cohort studies is an absolute necessity in order to define the impact of the different types of autoantibodies on IVF outcome.
Topics: Antibodies, Antinuclear; Antibodies, Antiphospholipid; Antibody Specificity; Autoantibodies; Autoimmune Diseases; Celiac Disease; Female; Fertilization in Vitro; Humans; Infertility; Pregnancy; Thyroid Gland; Treatment Outcome
PubMed: 30791371
DOI: 10.3390/ijms20040892 -
The Canadian Journal of Infectious... 2018IgM against may be detected by enzyme-linked immunosorbent assays (ELISAs) based on phenolic glycolipid I (PGL-I) or natural disaccharide octyl bovine serum albumin... (Review)
Review
IgM against may be detected by enzyme-linked immunosorbent assays (ELISAs) based on phenolic glycolipid I (PGL-I) or natural disaccharide octyl bovine serum albumin (ND-O-BSA) as antigens, and the IgG response can be detected by an ELISA based on lipid droplet protein 1 (LID-1). The titers of antibodies against these antigens vary with operational classification. The aim of this study was to compare the accuracy of ELISAs involving PGL-I and ND-O-BSA with that involving LID-1. We included studies that analyze multibacillary and paucibacillary leprosy cases and evaluate the diagnostic accuracy of ELISAs based on LID-1 and/or PGL-I or ND-O-BSA as antigens to measure antibody titers against . Studies were found via PubMed, the Virtual Health Library Regional Portal, Literatura Latino-Americana e do Caribe em Ciências da Saúde, Índice Bibliográfico Espanhol de Ciências de Saúde, the Brazilian Society of Dermatology, National Institute for Health and Clinical Excellence, Cochrane Library, Embase (the Elsevier database), and Cumulative Index to Nursing and Allied Health Literature. The Quality Assessment of Diagnostic Accuracy Studies served as a methodological validity tool. Quantitative data were extracted using the Standards for Reporting of Diagnostic Accuracy. Sensitivity, specificity, and a diagnostic odds ratio were calculated, and a hierarchical summary receiver-operating characteristic curve and forest plots were constructed. The protocol register code for this meta-analysis is PROSPERO 2017: CRD42017055983. Nineteen studies were included. ND-O-BSA showed better overall performance in terms of sensitivity, specificity, positive and negative likelihood ratios, and diagnostic odds ratio when compared with PGL-I and LID-1. The multibacillary group showed better performance on these parameters (than the paucibacillary group did), at 94%, 99%, 129, 0.05, and 2293, respectively. LID-1 did not provide any advantage regarding the overall estimate of sensitivity in comparison with PGL-I or ND-O-BSA.
PubMed: 30622658
DOI: 10.1155/2018/9828023 -
Brain and Behavior Oct 2018Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is the most commonly observed phenotype among chronic acquired demyelinating polyneuropathies and is... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is the most commonly observed phenotype among chronic acquired demyelinating polyneuropathies and is clinically variable. The aim of this meta-analysis was to evaluate the diagnostic value and characteristics of CIDP targeting neurofascin 155 (NF155).
METHODS
A systematic literature search was performed on March 2018, and two reviewers independently extracted data and assessed the risk of bias on MEDLINE, EMBASE, the Web of Science, and the Cochrane Library to identify relevant articles.
RESULTS
Ten articles for the NF155 protein test with 1,161 patients and 1,636 controls were identified. The results showed that the pooled sensitivity was 0.09 (95% CI: 0.06-015), and specificity was 1.00 (95% CI: 0.98-1.00) of the NF155 for CIDP. The meta-analysis revealed that the sensory ataxic occurrence rate (OR: 10.79, 95% CI: 5.24-22.22) and tremor occurrence rate (OR: 6.71, 95% CI: 3.37-13.39) were higher among patients positive for NF155 compared with NF155-negative CIDP patients. However, the rate of good treatment response to intravenous immunoglobulin (IVIg) (OR: 0.09, 95% CI: 0.02-0.42) was lower in NF155-positive CIDP patients.
CONCLUSIONS
NF155 is a specific protein marker for CIDP, but its diagnostic value has been questioned due to low sensitivity. However, as an antibody against paranodal antigens, NF155 seems more valuable in defining clinical subsets of CIDP.
Topics: Autoantibodies; Biomarkers; Cell Adhesion Molecules; Humans; Immunoglobulin G; Immunoglobulins, Intravenous; Nerve Growth Factors; Phenotype; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating
PubMed: 30240176
DOI: 10.1002/brb3.1115 -
Anais Da Academia Brasileira de Ciencias 2018The objective of the study was to conduct a systematic review to synthesize the current evidence on the accuracy of IgM and IgA to early diagnosis the dengue virus. The... (Meta-Analysis)
Meta-Analysis Review
The objective of the study was to conduct a systematic review to synthesize the current evidence on the accuracy of IgM and IgA to early diagnosis the dengue virus. The review protocol was registered at PROSPERO (CRD 42015024808). We searched for studies in the following electronic database from 1990 to January 2018. The search identified 3507 studies. Five studies were included for quantitative analysis. Three studies included evaluations of salivary IgM provided a sensitivity of 86% and specificity of 93%. Two studies included evaluating of IgA salivary showed a combined sensitivity of 69% and a combined specificity of 98%. Despite the results found and the low methodological quality of the studies included in the meta-analysis it is still soon to claim that IgA is better than IgM to diagnosis Dengue.
Topics: Antibodies, Viral; Antibody Specificity; Biomarkers; Dengue; Dengue Virus; Early Diagnosis; Humans; Immunoglobulin A, Secretory; Immunoglobulin M; Polymerase Chain Reaction; Risk Factors; Saliva; Sensitivity and Specificity
PubMed: 29947679
DOI: 10.1590/0001-3765201820170989