-
BMC Infectious Diseases May 2020The burden of drug resistant tuberculosis in Africa is largely driven by the emergence and spread of multidrug resistant (MDR) and extensively drug resistant (XDR)...
BACKGROUND
The burden of drug resistant tuberculosis in Africa is largely driven by the emergence and spread of multidrug resistant (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis strains. MDR-TB is defined as resistance to isoniazid and rifampicin, while XDR-TB is defined as MDR-TB with added resistance to any of the second line injectable drugs and any fluoroquinolone. The highest burden of drug resistant TB is seen in countries further experiencing an HIV epidemic. The molecular mechanisms of drug resistance as well as the evolution of drug resistant TB strains have been widely studied using various genotyping tools. The study aimed to analyse the drug resistant lineages in circulation and transmission dynamics of these lineages in Africa by describing outbreaks, nosocomial transmission and migration. Viewed as a whole, this can give a better insight into the transmission dynamics of drug resistant TB in Africa.
METHODS
A systematic review was performed on peer reviewed original research extracted from PubMed reporting on the lineages associated with drug resistant TB from African countries, and their association with outbreaks, nosocomial transmission and migration. The search terms "Tuberculosis AND drug resistance AND Africa AND (spoligotyping OR molecular epidemiology OR IS6110 OR MIRU OR DNA fingerprinting OR RFLP OR VNTR OR WGS)" were used to identify relevant articles reporting the molecular epidemiology of drug resistant TB in Africa.
RESULTS
Diverse genotypes are associated with drug resistant TB in Africa, with variations in strain predominance within the continent. Lineage 4 predominates across Africa demonstrating the ability of "modern strains" to adapt and spread easily. Most studies under review reported primary drug resistance as the predominant type of transmission. Drug resistant TB strains are associated with community and nosocomial outbreaks involving MDR- and XDR-TB strains. The under-use of molecular epidemiological tools is of concern, resulting in gaps in knowledge of the transmission dynamics of drug resistant TB on the continent.
CONCLUSIONS
Genetic diversity of M. tuberculosis strains has been demonstrated across Africa implying that diverse genotypes are driving the epidemiology of drug resistant TB across the continent.
Topics: Africa; Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Epidemics; Extensively Drug-Resistant Tuberculosis; Genotype; High-Throughput Nucleotide Sequencing; Humans; Molecular Epidemiology; Mycobacterium tuberculosis; Polymorphism, Restriction Fragment Length
PubMed: 32404119
DOI: 10.1186/s12879-020-05031-5 -
Parkinsonism & Related Disorders Apr 2021We propose a modern approach to assist clinicians to recognize and diagnose inborn errors of metabolism (IEMs) in adolescents and adults that present with a movement...
We propose a modern approach to assist clinicians to recognize and diagnose inborn errors of metabolism (IEMs) in adolescents and adults that present with a movement disorder. IEMs presenting in adults are still largely unexplored. These disorders receive little attention in neurological training and daily practice, and are considered complicated by many neurologists. Adult-onset presentations of IEMs differ from childhood-onset phenotypes, which may lead to considerable diagnostic delay. The identification of adult-onset phenotypes at the earliest stage of the disease is important, since early treatment may prevent or lessen further brain damage. Our approach is based on a systematic review of all papers that concerned movement disorders due to an IEM in patients of 16 years or older. Detailed clinical phenotyping is the diagnostic cornerstone of the approach. An underlying IEM should be suspected in particular in patients with more than one movement disorder, or in patients with additional neurological, psychiatric, or systemic manifestations. As IEMs are all genetic disorders, we recommend next-generation sequencing (NGS) as the first diagnostic approach to confirm an IEM. Biochemical tests remain the first choice in acute-onset or treatable IEMs that require rapid diagnosis, or to confirm the metabolic diagnosis after NGS results. With the use of careful and systematic clinical phenotyping combined with novel diagnostic approaches such as NGS, the diagnostic yield of late-onset IEMs will increase, in particular in patients with mild or unusual phenotypes.
Topics: Age of Onset; High-Throughput Nucleotide Sequencing; Humans; Metabolism, Inborn Errors; Movement Disorders
PubMed: 33745796
DOI: 10.1016/j.parkreldis.2021.02.029 -
Gynecologic Oncology Feb 2021Ovarian cancer is often diagnosed in an advanced stage and is associated with a high mortality rate. It is assumed that early detection of ovarian cancer could improve...
Ovarian cancer is often diagnosed in an advanced stage and is associated with a high mortality rate. It is assumed that early detection of ovarian cancer could improve patient outcomes. Unfortunately, effective screening methods for early diagnosis of ovarian cancer are still lacking. Extracellular RNAs circulating in human biofluids can reliably be measured and are emerging as potential biomarkers in cancer. In this systematic review, we present 75 RNA biomarkers detectable in human biofluids that have been studied for early diagnosis of ovarian cancer. The majority of these markers are microRNAs identified using RT-qPCR or microarrays in blood-based fluids. A handful of studies used RNA-sequencing and explored alternative fluids, such as urine and ascites. Candidate RNA biomarkers that were more abundant in biofluids of ovarian cancer patients compared to controls in at least two independent studies include miR-21, the miR-200 family, miR-205, miR-10a and miR-346. Amongst the markers confirmed to be lower in at least two studies are miR-122, miR-193a, miR-223, miR-126 and miR-106b. While these biomarkers show promising diagnostic potential, further validation is required before implementation in routine clinical care. Challenges related to biomarker validation and reflections on future perspectives to accelerate progress in this field are discussed.
Topics: Ascitic Fluid; Biomarkers, Tumor; Carcinoma, Ovarian Epithelial; Early Detection of Cancer; Female; Humans; Liquid Biopsy; MicroRNAs; Ovarian Neoplasms; RNA-Seq
PubMed: 33257015
DOI: 10.1016/j.ygyno.2020.11.018 -
Frontiers in Genetics 2019Recent advances in high-throughput experimentation have put the exploration of genome sequences at the forefront of precision medicine. In an effort to interpret the...
Recent advances in high-throughput experimentation have put the exploration of genome sequences at the forefront of precision medicine. In an effort to interpret the sequencing data, numerous computational methods have been developed for evaluating the effects of genome variants. Interestingly, despite the fact that every person has as many synonymous (sSNV) as non-synonymous single nucleotide variants, our ability to predict their effects is limited. The paucity of experimentally tested sSNV effects appears to be the limiting factor in development of such methods. Here, we summarize the details and evaluate the performance of nine existing computational methods capable of predicting sSNV effects. We used a set of and artificially variants to approximate large scale performance expectations of these tools. We note that the distribution of these variants across amino acid and codon types suggests purifying evolutionary selection retaining variants out of the set; i.e., we expect the set to be enriched for deleterious variants. Closer inspection of the relationship between the variant frequencies and the associated prediction scores identifies predictor-specific scoring thresholds of reliable effect predictions. Notably, across all predictors, the variants scoring above these thresholds were significantly more often than . which confirms our assumption that the set is enriched for deleterious variants. Finally, we find that while the methods differ in their ability to identify severe sSNV effects, no predictor appears capable of definitively recognizing subtle effects of such variants on a large scale.
PubMed: 31649718
DOI: 10.3389/fgene.2019.00914 -
BMC Infectious Diseases Jan 2024Detecting pathogens in pediatric central nervous system infection (CNSI) is still a major challenge in medicine. In addition to conventional diagnostic patterns,... (Meta-Analysis)
Meta-Analysis
Diagnostic performance of metagenomic next-generation sequencing for the detection of pathogens in cerebrospinal fluid in pediatric patients with central nervous system infection: a systematic review and meta-analysis.
BACKGROUND
Detecting pathogens in pediatric central nervous system infection (CNSI) is still a major challenge in medicine. In addition to conventional diagnostic patterns, metagenomic next-generation sequencing (mNGS) shows great potential in pathogen detection. Therefore, we systematically evaluated the diagnostic performance of mNGS in cerebrospinal fluid (CSF) in pediatric patients with CNSI.
METHODS
Related literature was searched in the Web of Science, PubMed, Embase, and Cochrane Library. We screened the literature and extracted the data according to the selection criteria. The quality of included studies was assessed by the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool and the certainty of the evidence was measured by the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) score system. Then, the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odd's ratio (DOR), and area under the curve (AUC) of the summary receiver operating characteristic curve (sROC) were estimated in Stata Software and MetaDisc. Subgroup analyses were performed to investigate the potential factors that influence the diagnostic performance.
RESULTS
A total of 10 studies were included in the meta-analysis. The combined sensitivity was 0.68 (95% confidence interval [CI]: 0.59 to 0.76, I = 66.77%, p < 0.001), and the combined specificity was 0.89 (95% CI: 0.80 to 0.95, I = 83.37%, p < 0.001). The AUC of sROC was 0.85 (95% CI, 0.81 to 0.87). The quality level of evidence elevated by the GRADE score system was low.
CONCLUSIONS
Current evidence shows that mNGS presents a good diagnostic performance in pediatric CNSI. Due to the limited quality and quantity of the included studies, more high-quality studies are needed to verify the above conclusion.
Topics: Humans; Child; ROC Curve; Central Nervous System Infections; High-Throughput Nucleotide Sequencing
PubMed: 38238719
DOI: 10.1186/s12879-024-09010-y -
PloS One 2020Tuberculous meningitis (TBM) is a severe form of extrapulmonary tuberculosis and its early diagnosis is very difficult leading to present with severe disability or die.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Tuberculous meningitis (TBM) is a severe form of extrapulmonary tuberculosis and its early diagnosis is very difficult leading to present with severe disability or die. The current study aimed to assess the accuracy of metagenomic next generation sequencing (mNGS) for TBM, and to identify a new test for the early diagnosis of TBM.
METHODS
We searched for articles published in Embase, PubMed, Cochrane Library, China National Knowledge Infrastructure, and Wanfang Data up to June 30, 2020 for studies that assessed the efficacy of mNGS for the diagnosis of TBM. Then, the accuracy between mNGS and a composite reference standard (CRS) in these articles was compared using the meta-analysis approach.
RESULTS
Four independent studies with 342 samples comparing mNGS and a CRS were included in this study. The sensitivity of mNGS for TBM diagnosis ranged from 27% to 84%. The combined sensitivity of mNGS was 61%, and the I2 value was 92%. Moreover, the specificity of mNGS for TBM diagnosis ranged from 96% to 100%. The combined specificity of mNGS was 98%, and the I2 value was 74%. The heterogeneity between studies in terms of sensitivity and specificity was significant. The area under the curve (AUC) of the summary receiver operating characteristic curve (SROC) of mNGS for TBM was 0.98.
CONCLUSIONS
The sensitivity of mNGS for TBM diagnosis was moderate. Furthermore, the specificity was extremely high, and the AUC of the SROC indicated a very good diagnostic efficacy. mNGS could be used as an early diagnostic method for TBM, however, the results should be treated with caution for the heterogeneity between studies was extremely significant.
SYSTEMATIC REVIEW REGISTRATION
INPLASY202070100.
Topics: China; Early Diagnosis; High-Throughput Nucleotide Sequencing; Humans; Metagenome; Metagenomics; Mycobacterium tuberculosis; ROC Curve; Reference Standards; Sensitivity and Specificity; Tuberculosis, Meningeal
PubMed: 33259541
DOI: 10.1371/journal.pone.0243161 -
BMC Cancer Oct 2019Sarcomatoid carcinoma of unknown primary (SCUP) is a rare entity of either poorly differentiated carcinoma with sarcoma-like differentiation or a true mixed lineage...
BACKGROUND
Sarcomatoid carcinoma of unknown primary (SCUP) is a rare entity of either poorly differentiated carcinoma with sarcoma-like differentiation or a true mixed lineage neoplasm. Limited data regarding clinicopathological profile and management exists.
METHODS
We retrospectively reviewed the MD Anderson Cancer of Unknown Primary database and tumor registry to identify 48 SCUP patients between 2001 and 2017. Patient characteristics, pathology, molecular diagnostics, treatments, and outcomes were obtained. Kaplan-Meier method was used to estimate overall survival (OS) and compared using log rank test.
RESULTS
Median age at diagnosis was 59 years (range 27-86). Majority of patients were female (58%) and presented with ≥3 metastatic sites (52%), commonly lymph node (50%), bone (42%), lung (27%), and liver (21%). First line treatment included chemotherapy (35%), surgery (27%), and radiation (24%). Gemcitabine and docetaxel (18%) was the most common chemotherapy regimen. Median OS for entire cohort was 11 months (95% CI: 5.6 to 16.4). Poor performance status (PS), > 1 metastatic site, elevated lactate dehydrogenase (LDH), and high neutrophil-to-lymphocyte ratio (NLR) were significantly associated with worse OS on univariate analyses. On multivariate analyses, poor PS (HR 8.7; 95%CI: 3.0-25.0; p < 0.001) and high NLR (HR 3.4; 95%CI: 1.3-8.8; p = 0.011) emerged as independent prognostic factors for OS.
CONCLUSIONS
SCUP is a rare presentation with an aggressive clinical course and limited survival. Diagnosis is difficult to make and requires careful review and synthesis of histology, immunohistochemistry, and molecular diagnostics. Chemotherapy resistance remains a challenge. Early mutational profiling is warranted, and clinical trial participation should be encouraged for this subset.
Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinosarcoma; Combined Modality Therapy; Drug Resistance, Neoplasm; Female; Follow-Up Studies; High-Throughput Nucleotide Sequencing; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Molecular Targeted Therapy; Neoplasms, Unknown Primary; Prognosis; Prospective Studies; Rare Diseases; Retrospective Studies; Survival Rate; Treatment Outcome
PubMed: 31623602
DOI: 10.1186/s12885-019-6155-6 -
BMC Endocrine Disorders Nov 2021Maturity Onset Diabetes of the Young (MODY) is an autosomal dominant type of diabetes. Pathogenic variants in fourteen genes are reported as causes of MODY. Its symptoms...
BACKGROUND
Maturity Onset Diabetes of the Young (MODY) is an autosomal dominant type of diabetes. Pathogenic variants in fourteen genes are reported as causes of MODY. Its symptoms overlap with type 1 and type 2 diabetes. Reviews for clinical characteristics, diagnosis and treatments are available but a comprehensive list of genetic variants, is lacking. Therefore this study was designed to collect all the causal variants involved in MODY, reported to date.
METHODS
We searched PubMed from its date of inception to December 2019. The search terms we used included disease names and name of all the known genes involved. The ClinVar database was also searched for causal variants in the known 14 MODY genes.
RESULTS
The record revealed 1647 studies and among them, 326 studies were accessed for full-text. Finally, 239 studies were included, as per our inclusion criteria. A total of 1017 variants were identified through literature review and 74 unpublished variants from Clinvar database. The gene most commonly affected was GCK, followed by HNF1a. The traditional Sanger sequencing was used in 76 % of the cases and 65 % of the studies were conducted in last 10 years. Variants from countries like Jordan, Oman and Tunisia reported that the MODY types prevalent worldwide were not common in their countries.
CONCLUSIONS
We expect that this paper will help clinicians interpret MODY genetics results with greater confidence. Discrepancies in certain middle-eastern countries need to be investigated as other genes or factors, like consanguinity may be involved in developing diabetes.
Topics: Adaptor Proteins, Signal Transducing; Apoptosis Regulatory Proteins; Basic Helix-Loop-Helix Transcription Factors; Diabetes Mellitus, Type 2; Glucokinase; Hepatocyte Nuclear Factor 1-alpha; Hepatocyte Nuclear Factor 1-beta; Hepatocyte Nuclear Factor 4; High-Throughput Nucleotide Sequencing; Homeodomain Proteins; Humans; Insulin; Lipase; Paired Box Transcription Factors; Potassium Channels, Inwardly Rectifying; Repressor Proteins; Sequence Analysis, DNA; Sulfonylurea Receptors; Trans-Activators; src-Family Kinases
PubMed: 34763692
DOI: 10.1186/s12902-021-00891-7 -
Cancer Epidemiology, Biomarkers &... Aug 2020The application of next-generation sequencing (NGS) technologies in cancer research has accelerated the discovery of somatic mutations; however, progress in the...
The application of next-generation sequencing (NGS) technologies in cancer research has accelerated the discovery of somatic mutations; however, progress in the identification of germline variation associated with cancer risk is less clear. We conducted a systematic literature review of cancer genetic susceptibility studies that used NGS technologies at an exome/genome-wide scale to obtain a fuller understanding of the research landscape to date and to inform future studies. The variability across studies on methodologies and reporting was considerable. Most studies sequenced few high-risk (mainly European) families, used a candidate analysis approach, and identified potential cancer-related germline variants or genes in a small fraction of the sequenced cancer cases. This review highlights the importance of establishing consensus on standards for the application and reporting of variants filtering strategies. It also describes the progress in the identification of cancer-related germline variation to date. These findings point to the untapped potential in conducting studies with appropriately sized and racially diverse families and populations, combining results across studies and expanding beyond a candidate analysis approach to advance the discovery of genetic variation that accounts for the unexplained cancer heritability.
Topics: Exome; Genetic Predisposition to Disease; Genome-Wide Association Study; High-Throughput Nucleotide Sequencing; Humans
PubMed: 32467344
DOI: 10.1158/1055-9965.EPI-19-1551 -
Archives of Virology Nov 2021Human T-lymphotropic virus type 1 (HTLV-1) was the first human retrovirus described. The viral factors involved in the different clinical manifestations of infected...
Human T-lymphotropic virus type 1 (HTLV-1) was the first human retrovirus described. The viral factors involved in the different clinical manifestations of infected individuals are still unknown, and in this sense, sequencing technologies can support viral genome studies, contributing to a better understanding of infection outcome. Currently, several sequencing technologies are available with different approaches. To understand the methodological advances in the HTLV-1 field, it is necessary to organize a synthesis by a rigorous review. This systematic literature review describes different technologies used to generate HTLV-1 sequences. The review follows the PRISMA guidelines, and the search for articles was performed in PubMed, Lilacs, Embase, and SciELO databases. From the 574 articles found in search, 62 were selected. The articles showed that, even with the emergence of new sequencing technologies, the traditional Sanger method continues to be the most commonly used methodology for generating HTLV-1 genome sequences. There are many questions that remain unanswered in the field of HTLV-1 research, and this reflects on the small number of studies using next-generation sequencing technologies, which could help address these gaps. The data compiled and analyzed here can help research on HTLV-1, assisting in the choice of sequencing technologies.
Topics: Brazil; Genome, Viral; HTLV-I Infections; High-Throughput Nucleotide Sequencing; Human T-lymphotropic virus 1; Humans; Sequence Analysis, RNA
PubMed: 34415436
DOI: 10.1007/s00705-021-05204-w