-
Neuropathology and Applied Neurobiology Jun 2022Codeletion of chromosomal arms 1p and 19q, in conjunction with a mutation in the isocitrate dehydrogenase 1 or 2 gene, is the molecular diagnostic criterion for... (Meta-Analysis)
Meta-Analysis Review
Codeletion of chromosomal arms 1p and 19q, in conjunction with a mutation in the isocitrate dehydrogenase 1 or 2 gene, is the molecular diagnostic criterion for oligodendroglioma, IDH mutant and 1p/19q codeleted. 1p/19q codeletion is a diagnostic marker and allows prognostication and prediction of the best drug response within IDH-mutant tumours. We performed a Cochrane review and simple economic analysis to establish the most sensitive, specific and cost-effective techniques for determining 1p/19q codeletion status. Fluorescent in situ hybridisation (FISH) and polymerase chain reaction (PCR)-based loss of heterozygosity (LOH) test methods were considered as reference standard. Most techniques (FISH, chromogenic in situ hybridisation [CISH], PCR, real-time PCR, multiplex ligation-dependent probe amplification [MLPA], single nucleotide polymorphism [SNP] array, comparative genomic hybridisation [CGH], array CGH, next-generation sequencing [NGS], mass spectrometry and NanoString) showed good sensitivity (few false negatives) for detection of 1p/19q codeletions in glioma, irrespective of whether FISH or PCR-based LOH was used as the reference standard. Both NGS and SNP array had a high specificity (fewer false positives) for 1p/19q codeletion when considered against FISH as the reference standard. Our findings suggest that G banding is not a suitable test for 1p/19q analysis. Within these limits, considering cost per diagnosis and using FISH as a reference, MLPA was marginally more cost-effective than other tests, although these economic analyses were limited by the range of available parameters, time horizon and data from multiple healthcare organisations.
Topics: Brain Neoplasms; Chromosome Aberrations; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 19; Glioma; Humans; Isocitrate Dehydrogenase; Mutation; Oligodendroglioma
PubMed: 34958131
DOI: 10.1111/nan.12790 -
Frontiers in Psychiatry 2021premutation is defined by 55-200 CGG repeats in the Fragile X Mental Retardation 1 () gene. premutation carriers are at risk of developing a neurodegenerative disease...
premutation is defined by 55-200 CGG repeats in the Fragile X Mental Retardation 1 () gene. premutation carriers are at risk of developing a neurodegenerative disease called fragile X-associated tremor/ataxia syndrome (FXTAS) and Fragile X-associated primary ovarian insufficiency (FXPOI) in adulthood. In the last years an increasingly board spectrum of clinical manifestations including psychiatric disorders have been described as occurring at a greater frequency among premutation carriers. Herein, we reviewed the neuroimaging findings reported in relation with psychiatric symptomatology in adult premutation carriers. A structured electronic literature search was conducted on premutation and neuroimaging yielding a total of 3,229 articles examined. Of these, 7 articles were analyzed and are included in this review. The results showed that the main radiological findings among adult premutation carriers presenting neuropsychiatric disorders were found on the amygdala and hippocampus, being the functional abnormalities more consistent and the volumetric changes more inconsistent among studies. From a molecular perspective, CGG repeat size, mRNA and FMRP levels have been investigated in relation with the neuroimaging findings. Based on the published results, FMRP might play a key role in the pathophysiology of the psychiatric symptoms described among premutation carriers. However, additional studies including further probes of brain function and a broader scope of psychiatric symptom measurement are required in order to obtain a comprehensive landscape of the neuropsychiatric phenotype associated with the premutation.
PubMed: 34721105
DOI: 10.3389/fpsyt.2021.728952 -
Briefings in Bioinformatics Jan 2022Since the first report of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, over 100 million people have been infected by COVID-19, millions...
Since the first report of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, over 100 million people have been infected by COVID-19, millions of whom have died. In the latest year, a large number of omics data have sprung up and helped researchers broadly study the sequence, chemical structure and function of SARS-CoV-2, as well as molecular abnormal mechanisms of COVID-19 patients. Though some successes have been achieved in these areas, it is necessary to analyze and mine omics data for comprehensively understanding SARS-CoV-2 and COVID-19. Hence, we reviewed the current advantages and limitations of the integration of omics data herein. Firstly, we sorted out the sequence resources and database resources of SARS-CoV-2, including protein chemical structure, potential drug information and research literature resources. Next, we collected omics data of the COVID-19 hosts, including genomics, transcriptomics, microbiology and potential drug information data. And subsequently, based on the integration of omics data, we summarized the existing data analysis methods and the related research results of COVID-19 multi-omics data in recent years. Finally, we put forward SARS-CoV-2 (COVID-19) multi-omics data integration research direction and gave a case study to mine deeper for the disease mechanisms of COVID-19.
Topics: Antiviral Agents; COVID-19; Genomics; Humans; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 34718395
DOI: 10.1093/bib/bbab446 -
Gene Therapy Sep 2022Spinal muscular atrophy (SMA) is a severe childhood neuromuscular disease for which two genetic therapies, Nusinersen (Spinraza, an antisense oligonucleotide), and... (Meta-Analysis)
Meta-Analysis
Spinal muscular atrophy (SMA) is a severe childhood neuromuscular disease for which two genetic therapies, Nusinersen (Spinraza, an antisense oligonucleotide), and AVXS-101 (Zolgensma, an adeno-associated viral vector of serotype 9 AAV9), have recently been approved. We investigated the pre-clinical development of SMA genetic therapies in rodent models and whether this can predict clinical efficacy. We have performed a systematic review of relevant publications and extracted median survival and details of experimental design. A random effects meta-analysis was used to estimate and compare efficacy. We stratified by experimental design (type of genetic therapy, mouse model, route and time of administration) and sought any evidence of publication bias. 51 publications were identified containing 155 individual comparisons, comprising 2573 animals in total. Genetic therapies prolonged survival in SMA mouse models by 3.23-fold (95% CI 2.75-3.79) compared to controls. Study design characteristics accounted for significant heterogeneity between studies and greatly affected observed median survival ratios. Some evidence of publication bias was found. These data are consistent with the extended average lifespan of Spinraza- and Zolgensma-treated children in the clinic. Together, these results support that SMA has been particularly amenable to genetic therapy approaches and highlight SMA as a trailblazer for therapeutic development.
Topics: Animals; Disease Models, Animal; Genetic Therapy; Mice; Muscular Atrophy, Spinal; Oligonucleotides, Antisense; Rodentia; Treatment Outcome
PubMed: 34611322
DOI: 10.1038/s41434-021-00292-4 -
International Journal of Microbiology 2021Currently, a novel coronavirus found in 2019 known as SARS-CoV-2 is the etiological agent of the COVID-19 pandemic. Various parameters including clinical manifestations... (Review)
Review
BACKGROUND
Currently, a novel coronavirus found in 2019 known as SARS-CoV-2 is the etiological agent of the COVID-19 pandemic. Various parameters including clinical manifestations and molecular evaluation can affect the accuracy of diagnosis. This review aims to discuss the various clinical symptoms and molecular evaluation results in COVID-19 patients, to point out the importance of onset symptoms, type, and timing of the sampling, besides the methods that are used for detection of SARS-CoV-2.
METHODS
A systematic literature review of current articles in the Web of Science, PubMed, Scopus, and EMBASE was conducted according to the PRISMA guideline.
RESULTS
Of the 12946 patients evaluated in this investigation, 7643 were confirmed to be COVID-19 positive by molecular techniques, particularly the RT-PCR/qPCR combined technique (qRT-PCR). In most of the studies, all of the enrolled cases had 100% positive results for molecular evaluation. Among the COVID-19 patients who were identified as such by positive PCR results, most of them showed fever or cough as the primary clinical signs. Less common symptoms observed in clinically confirmed cases were hemoptysis, bloody sputum, mental disorders, and nasal congestion. The most common clinical samples for PCR-confirmed COVID-19 patients were obtained from throat, oropharyngeal, and nasopharyngeal swabs, while tears and conjunctival secretions seem to be the least common clinical samples for COVID-19 diagnosis among studies. Also, different conserved SARS-CoV-2 gene sequences could be targeted for qRT-PCR detection. The suggested molecular assay being used by most laboratories for the detection of SARS-CoV-2 is qRT-PCR.
CONCLUSION
There is a worldwide concern on the COVID-19 pandemic and a lack of well-managed global control. Hence, it is crucial to update the molecular diagnostics protocols for handling the situation. This is possible by understanding the available advances in assays for the detection of the SARS-CoV-2 infection. Good sampling procedure and using samples with enough viral loads, also considering the onset symptoms, may reduce the qRT-PCR false-negative results in symptomatic COVID-19 patients. Selection of the most efficient primer-probe for target genes and samples containing enough viral loads to search for the existence of SARS-CoV-2 helps detecting the virus on time using qRT-PCR.
PubMed: 34545287
DOI: 10.1155/2021/5528786 -
Rheumatology (Oxford, England) Dec 2021To investigate the reliability of high frequency ultrasound (HFUS) in measuring skin fibrosis in SSc.
OBJECTIVES
To investigate the reliability of high frequency ultrasound (HFUS) in measuring skin fibrosis in SSc.
METHODS
First, a systematic review (according to PRISMA) was conducted to identify studies that documented HFUS' reliability in SSc as a primary outcome. Then, in an additional pilot study, the inter- and intra-rater reliability of two investigators performing HFUS for dermal thickness (DT) measurements in a standardized manner across all 17 areas of the modified Rodnan Skin Score was evaluated in a group of 59 SSc patients and descriptively in 44 healthy controls (HC). As an external validation, DT measurements by HFUS were performed in a separate group of 30 SSc patients by the same first and another third investigator.
RESULTS
The systematic review retained few (4/1719 unique records) small-scale studies, with mixed study populations (combining SSc and HC). The reported data herein are suggestive of the inter-/intra-rater reliability of HFUS (intra-class correlation coefficient [ICCs] ranging 0.65-0.94/0.55-0.96, respectively). Additionally, in our pilot study, inter-/intra-rater reliability was good-to-excellent in both SSc groups and HC (ICCs ranging 0.70-0.97/0.70-0.98 and 0.65-0.95/0.63-0.96, respectively).
CONCLUSION
The identified small-scale studies were not only combining data from SSc and HC, they were also heterogeneous in terms of technical aspects (probes and frequency), image acquisition methods ([number of] areas assessed) and definitions used for skin thickness, which prevents drawing unequivocal conclusions. Despite these limitations, our standardized pilot study corroborated the findings in literature, paving the way for the applicability of HFUS as a reliable (complementary) tool to quantify skin fibrosis in SSc.
Topics: Adult; Aged; Female; Fibrosis; Humans; Male; Middle Aged; Pilot Projects; Reproducibility of Results; Scleroderma, Systemic; Skin; Ultrasonography
PubMed: 34037710
DOI: 10.1093/rheumatology/keab462 -
Clinical Microbiology and Infection :... Dec 2021Acute pharyngitis is one of the most common conditions in outpatient settings and an important source of inappropriate antibiotic prescribing. Rapid antigen detection... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Acute pharyngitis is one of the most common conditions in outpatient settings and an important source of inappropriate antibiotic prescribing. Rapid antigen detection tests (RADTs) offer diagnosis of group A streptococcus at the point of care but have limited sensitivity. Rapid nucleic acid tests (RNATs) are now available; a systematic review of their accuracy is lacking.
OBJECTIVES
To evaluate the accuracy of RNATs in patients with pharyngitis; to explore test-level and study-level factors that could explain variability in accuracy; and to compare the accuracy of RNATs with that of RADTs.
DATA SOURCES
MEDLINE, Embase, Web of Science (1990-2020).
STUDY ELIGIBILITY CRITERIA
Cross-sectional studies and randomized trials.
PARTICIPANTS
Patients with pharyngitis.
INDEX TEST/S AND REFERENCE STANDARDS
RNAT commercial kits compared with throat culture.
METHODS
We assessed risk of bias and applicability using QUADAS-2. We performed meta-analysis of sensitivity and specificity using the bivariate random-effects model. Variability was explored by subgroup analyses and meta-regression.
RESULTS
We included 38 studies (46 test evaluations; 17 411 test results). RNATs were most often performed in a laboratory. The overall methodological quality of primary studies was uncertain because of incomplete reporting. RNATs had a summary sensitivity of 97.5% (95% CI 96.2%-98.3%) and a summary specificity of 95.1% (95% CI 93.6%-96.3%). There was low variability in estimates across studies. Variability in sensitivity and specificity was partially explained by test type (p < 0.05 for both). Sensitivity analyses limited to studies with low risk of bias showed robust accuracy estimates. RNATs were more sensitive than RADTs (13 studies; 96.8% versus 82.3%, p 0.004); there was no difference in specificity (p 0.92).
CONCLUSIONS
The high diagnostic accuracy of RNATs may allow their use as stand-alone tests to diagnose group A streptococcus pharyngitis. Based on direct comparisons, RNATs have greater sensitivity than RADTs and equal specificity. Further studies should evaluate RNATs in point-of-care settings.
Topics: Humans; Nucleic Acid Amplification Techniques; Nucleic Acids; Pharyngitis; Point-of-Care Testing; Sensitivity and Specificity; Streptococcus pyogenes
PubMed: 33964409
DOI: 10.1016/j.cmi.2021.04.021 -
Frontiers in Aging Neuroscience 2021Alzheimer's disease (AD) is characterized by specific alterations of brain DNA methylation (DNAm) patterns. Age and sex, two major risk factors for AD, are also known to...
Alzheimer's disease (AD) is characterized by specific alterations of brain DNA methylation (DNAm) patterns. Age and sex, two major risk factors for AD, are also known to largely affect the epigenetic profiles in brain, but their contribution to AD-associated DNAm changes has been poorly investigated. In this study we considered publicly available DNAm datasets of four brain regions (temporal, frontal, entorhinal cortex, and cerebellum) from healthy adult subjects and AD patients, and performed a meta-analysis to identify sex-, age-, and AD-associated epigenetic profiles. In one of these datasets it was also possible to distinguish 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) profiles. We showed that DNAm differences between males and females tend to be shared between the four brain regions, while aging differently affects cortical regions compared to cerebellum. We found that the proportion of sex-dependent probes whose methylation is modified also during aging is higher than expected, but that differences between males and females tend to be maintained, with only a few probes showing age-by-sex interaction. We did not find significant overlaps between AD- and sex-associated probes, nor disease-by-sex interaction effects. On the contrary, we found that AD-related epigenetic modifications are significantly enriched in probes whose DNAm varies with age and that there is a high concordance between the direction of changes (hyper or hypo-methylation) in aging and AD, supporting accelerated epigenetic aging in the disease. In summary, our results suggest that age-associated DNAm patterns concur to the epigenetic deregulation observed in AD, providing new insights on how advanced age enables neurodegeneration.
PubMed: 33790779
DOI: 10.3389/fnagi.2021.639428 -
The Cochrane Database of Systematic... Mar 2021Tuberculosis is a leading cause of infectious disease-related death and is one of the top 10 causes of death worldwide. The World Health Organization (WHO) recommends... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Tuberculosis is a leading cause of infectious disease-related death and is one of the top 10 causes of death worldwide. The World Health Organization (WHO) recommends the use of specific rapid molecular tests, including Xpert MTB/RIF or Xpert Ultra, as initial diagnostic tests for the detection of tuberculosis and rifampicin resistance in people with signs and symptoms of tuberculosis. However, the WHO estimates that nearly one-third of all active tuberculosis cases go undiagnosed and unreported. We were interested in whether a single test, Xpert MTB/RIF or Xpert Ultra, could be useful as a screening test to close this diagnostic gap and improve tuberculosis case detection.
OBJECTIVES
To estimate the accuracy of Xpert MTB/RIF and Xpert Ultra for screening for pulmonary tuberculosis in adults, irrespective of signs or symptoms of pulmonary tuberculosis in high-risk groups and in the general population. Screening "irrespective of signs or symptoms" refers to screening of people who have not been assessed for the presence of tuberculosis symptoms (e.g. cough). To estimate the accuracy of Xpert MTB/RIF and Xpert Ultra for detecting rifampicin resistance in adults screened for tuberculosis, irrespective of signs and symptoms of pulmonary tuberculosis in high-risk groups and in the general population.
SEARCH METHODS
We searched 12 databases including the Cochrane Infectious Diseases Group Specialized Register, MEDLINE and Embase, on 19 March 2020 without language restrictions. We also reviewed reference lists of included articles and related Cochrane Reviews, and contacted researchers in the field to identify additional studies.
SELECTION CRITERIA
Cross-sectional and cohort studies in which adults (15 years and older) in high-risk groups (e.g. people living with HIV, household contacts of people with tuberculosis) or in the general population were screened for pulmonary tuberculosis using Xpert MTB/RIF or Xpert Ultra. For tuberculosis detection, the reference standard was culture. For rifampicin resistance detection, the reference standards were culture-based drug susceptibility testing and line probe assays.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data using a standardized form and assessed risk of bias and applicability using QUADAS-2. We used a bivariate random-effects model to estimate pooled sensitivity and specificity with 95% credible intervals (CrIs) separately for tuberculosis detection and rifampicin resistance detection. We estimated all models using a Bayesian approach. For tuberculosis detection, we first estimated screening accuracy in distinct high-risk groups, including people living with HIV, household contacts, people residing in prisons, and miners, and then in several high-risk groups combined.
MAIN RESULTS
We included a total of 21 studies: 18 studies (13,114 participants) evaluated Xpert MTB/RIF as a screening test for pulmonary tuberculosis and one study (571 participants) evaluated both Xpert MTB/RIF and Xpert Ultra. Three studies (159 participants) evaluated Xpert MTB/RIF for rifampicin resistance. Fifteen studies (75%) were conducted in high tuberculosis burden and 16 (80%) in high TB/HIV-burden countries. We judged most studies to have low risk of bias in all four QUADAS-2 domains and low concern for applicability. Xpert MTB/RIF and Xpert Ultra as screening tests for pulmonary tuberculosis In people living with HIV (12 studies), Xpert MTB/RIF pooled sensitivity and specificity (95% CrI) were 61.8% (53.6 to 69.9) (602 participants; moderate-certainty evidence) and 98.8% (98.0 to 99.4) (4173 participants; high-certainty evidence). Of 1000 people where 50 have tuberculosis on culture, 40 would be Xpert MTB/RIF-positive; of these, 9 (22%) would not have tuberculosis (false-positives); and 960 would be Xpert MTB/RIF-negative; of these, 19 (2%) would have tuberculosis (false-negatives). In people living with HIV (1 study), Xpert Ultra sensitivity and specificity (95% CI) were 69% (57 to 80) (68 participants; very low-certainty evidence) and 98% (97 to 99) (503 participants; moderate-certainty evidence). Of 1000 people where 50 have tuberculosis on culture, 53 would be Xpert Ultra-positive; of these, 19 (36%) would not have tuberculosis (false-positives); and 947 would be Xpert Ultra-negative; of these, 16 (2%) would have tuberculosis (false-negatives). In non-hospitalized people in high-risk groups (5 studies), Xpert MTB/RIF pooled sensitivity and specificity were 69.4% (47.7 to 86.2) (337 participants, low-certainty evidence) and 98.8% (97.2 to 99.5) (8619 participants, moderate-certainty evidence). Of 1000 people where 10 have tuberculosis on culture, 19 would be Xpert MTB/RIF-positive; of these, 12 (63%) would not have tuberculosis (false-positives); and 981 would be Xpert MTB/RIF-negative; of these, 3 (0%) would have tuberculosis (false-negatives). We did not identify any studies using Xpert MTB/RIF or Xpert Ultra for screening in the general population. Xpert MTB/RIF as a screening test for rifampicin resistance Xpert MTB/RIF sensitivity was 81% and 100% (2 studies, 20 participants; very low-certainty evidence), and specificity was 94% to 100%, (3 studies, 139 participants; moderate-certainty evidence).
AUTHORS' CONCLUSIONS
Of the high-risks groups evaluated, Xpert MTB/RIF applied as a screening test was accurate for tuberculosis in high tuberculosis burden settings. Sensitivity and specificity were similar in people living with HIV and non-hospitalized people in high-risk groups. In people living with HIV, Xpert Ultra sensitivity was slightly higher than that of Xpert MTB/RIF and specificity similar. As there was only one study of Xpert Ultra in this analysis, results should be interpreted with caution. There were no studies that evaluated the tests in people with diabetes mellitus and other groups considered at high-risk for tuberculosis, or in the general population.
Topics: Adult; Antibiotics, Antitubercular; Bacteriological Techniques; Bayes Theorem; Bias; Cohort Studies; Cross-Sectional Studies; Drug Resistance, Bacterial; False Negative Reactions; False Positive Reactions; HIV Infections; Humans; Mycobacterium tuberculosis; Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Pulmonary
PubMed: 33755189
DOI: 10.1002/14651858.CD013694.pub2 -
Molecular and Cellular Probes Feb 2021The newly emerged coronavirus (SARS-CoV-2) continues to infect humans, and no effective treatment has yet been found. Antibody therapy is one way to control infection...
The newly emerged coronavirus (SARS-CoV-2) continues to infect humans, and no effective treatment has yet been found. Antibody therapy is one way to control infection caused by COVID-19. However, the use of classical antibodies raises complex issues. Heavy chain antibodies (HCAbs) are single-domain antibodies derived from the Camelidae family. The variable part of these antibodies (Nanobodies or VHH) has interesting properties such as small size, cost-effective production, and good tissue permeability, causing VHH to be regarded as an antiviral therapeutics. However, the small size of nanobodies may lead to low antigen binding affinity and rapid renal clearance. In this systematic review, the application of nanobodies in the treatment of COVID-19 infection and other similar infections (MERS and SARS) was reviewed.
Topics: Antibodies, Neutralizing; COVID-19; COVID-19 Testing; Humans; SARS-CoV-2; Single-Domain Antibodies
PubMed: 33358936
DOI: 10.1016/j.mcp.2020.101692