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European Heart Journal. Acute... Aug 2019We tested the hypothesis that a single high sensitivity troponin at limits of detection (LOD HSTnT) (<5 ng/l) combined with a presentation non-ischaemic... (Comparative Study)
Comparative Study
BACKGROUND
We tested the hypothesis that a single high sensitivity troponin at limits of detection (LOD HSTnT) (<5 ng/l) combined with a presentation non-ischaemic electrocardiogram is superior to low-risk Global Registry of Acute Coronary Events (GRACE) (<75), Thrombolysis in Myocardial Infarction (TIMI) (≤1) and History, ECG, Age, Risk factors and Troponin (HEART) score (≤3) as an aid to early, safe discharge for suspected acute coronary syndrome.
METHODS
In a prospective cohort study, risk scores were computed in consecutive patients with suspected acute coronary syndrome presenting to the Emergency Room of a large English hospital. Adjudication of myocardial infarction, as per third universal definition, involved a two-physician, blinded, independent review of all biomarker positive chest pain re-presentations to any national hospital. The primary and secondary outcome was a composite of type 1 myocardial infarction, unplanned coronary revascularisation and all cause death (MACE) at six weeks and one year.
RESULTS
Of 3054 consecutive presentations with chest pain 1642 had suspected acute coronary syndrome (52% male, median age 59 years, 14% diabetic, 20% previous myocardial infarction). Median time from chest pain to presentation was 9.7 h. Re-presentations occurred in eight hospitals with 100% follow-up achieved. Two hundred and eleven (12.9%) and 279 (17%) were adjudicated to suffer MACE at six weeks and one year respectively. Only HEART ≤3 (negative predictive value MACE 99.4%, sensitivity 97.6%, %discharge 53.4) and LOD HSTnT strategy (negative predictive value MACE 99.8%, sensitivity 99.5%, %discharge 36.9) achieved pre-specified negative predictive value of >99% for MACE at six weeks. For type 1 myocardial infarction alone the negative predictive values at six weeks and one year were identical, for both HEART ≤3 and LOD HSTnT at 99.8% and 99.5% respectively.
CONCLUSION
HEART ≤3 or LOD HSTnT strategy rules out short and medium term myocardial infarction with ≥99.5% certainty, and short-term MACE with >99% certainty, allowing for early discharge of 53.4% and 36.9% respectively of suspected acute coronary syndrome. Adoption of either strategy has the potential to greatly reduce Emergency Room pressures and minimise follow-up investigations. Very early presenters (<3 h), due to limited numbers, are excluded from these conclusions.
Topics: Acute Coronary Syndrome; Aged; Chest Pain; Coronary Disease; Electrocardiography; Emergency Service, Hospital; Female; Humans; Male; Middle Aged; Myocardial Infarction; Patient Discharge; Percutaneous Coronary Intervention; Predictive Value of Tests; Prospective Studies; Risk Factors; Sensitivity and Specificity; Thrombolytic Therapy; Time Factors; Troponin; United Kingdom
PubMed: 29480016
DOI: 10.1177/2048872618755369 -
G3 (Bethesda, Md.) Dec 2023Hop production utilizes exclusively female plants, whereas male plants only serve to generate novel variation within breeding programs through crossing. Currently, hop...
Hop production utilizes exclusively female plants, whereas male plants only serve to generate novel variation within breeding programs through crossing. Currently, hop lacks a rapid and accurate diagnostic marker to determine whether plants are male or female. Without a diagnostic marker, breeding programs may take 1-2 years to determine the sex of new seedlings. Previous research on sex-linked markers was restricted to specific populations or breeding programs and therefore had limited transferability or suffered from low scalability. A large collection of 765 hop genotypes with known sex phenotypes, genotyping-by-sequencing, and genome-wide association mapping revealed a highly significant marker on the sex chromosome (LOD score = 208.7) that predicted sex within our population with 96.2% accuracy. In this study, we developed a PCR allele competitive extension (PACE) assay for the diagnostic SNP and tested three quick DNA extraction methodologies for rapid, high-throughput genotyping. Additionally, the marker was validated in a separate population of 94 individuals from 15 families from the USDA-ARS hop breeding program in Prosser, WA with 96% accuracy. This diagnostic marker is located in a gene predicted to encode the basic helix-loop-helix transcription factor protein, a family of proteins that have been previously implicated in male sterility in a variety of plant species, which may indicate a role in determining hop sex. The marker is diagnostic, accurate, affordable, and highly scalable and has the potential to improve efficiency in hop breeding.
Topics: Humans; Genome-Wide Association Study; Plant Breeding; Chromosome Mapping; Phenotype; Genotype
PubMed: 37963231
DOI: 10.1093/g3journal/jkad216 -
Pakistan Journal of Pharmaceutical... Jan 2022Reported high performance liquid chromatographic (HPLC) methods for estimating metformin hydrochloride (MET) and sitagliptin phosphate monohydrate (SIT) are either...
Validation of a rapid and economical RP-HPLC method for simultaneous determination of metformin hydrochloride and sitagliptin phosphate monohydrate: Greenness evaluation using AGREE score.
Reported high performance liquid chromatographic (HPLC) methods for estimating metformin hydrochloride (MET) and sitagliptin phosphate monohydrate (SIT) are either laborious or contain higher proportions of organic solvents in mobile phase, thus presenting exorbitant procedures. So, a rapid, significantly more economical and eco-friendly HPLC method for synchronized analysis of both drugs was aimed to develop and validate in current study. Analytical evaluation was executed on Shimadzou⌖ C column (250mm × 4.6mm, 5μm) using acidified water and methanol 60:40 (v/v) as mobile phase at a flow of 1mL/min; while peaks were detected at 260nm at 25°C. Resultant values of accuracy, precision, linearity, limit of detection (LOD), limit of quantification (LOQ), robustness and specificity depicted that the method was validated in accordance with the ICH Guidelines. The approximate retention time for MET and SIT were 1.96 and 3.70 min, correspondingly. The greenness score of the developed method was evaluated using AGREE software and was found better (0.81) as compared with the methods reported (<0.8). Conclusively, the developed method was time saving, economical, rapid, robust, rugged, precise, accurate and found to be applicable for simultaneous determination of MET and SIT in commercial tablets.
Topics: Chromatography, High Pressure Liquid; Green Chemistry Technology; Hypoglycemic Agents; Limit of Detection; Metformin; Reproducibility of Results; Sitagliptin Phosphate; Software
PubMed: 35221267
DOI: No ID Found -
Addiction Neuroscience Dec 2022Impulsive behavior and impulsivity are heritable phenotypes that are strongly associated with risk for substance use disorders. Identifying the neurogenetic mechanisms...
Impulsive behavior and impulsivity are heritable phenotypes that are strongly associated with risk for substance use disorders. Identifying the neurogenetic mechanisms that influence impulsivity may also reveal novel biological insights into addiction vulnerability. Our past studies using the BXD and Collaborative Cross (CC) recombinant inbred mouse panels have revealed that behavioral indicators of impulsivity measured in a reversal-learning task are heritable and are genetically correlated with aspects of intravenous cocaine self-administration. Genome-wide linkage studies in the BXD panel revealed a quantitative trait locus (QTL) on chromosome 10, but we expect to identify additional QTL by testing in a population with more genetic diversity. To this end, we turned to Diversity Outbred (DO) mice; 392 DO mice (156 males, 236 females) were phenotyped using the same reversal learning test utilized previously. Our primary indicator of impulsive responding, a measure that isolates the relative difficulty mice have with reaching performance criteria under reversal conditions, revealed a genome-wide significant QTL on chromosome 7 (max LOD score = 8.73, genome-wide corrected p<0.05). A measure of premature responding akin to that implemented in the 5-choice serial reaction time task yielded a suggestive QTL on chromosome 17 (max LOD score = 9.14, genome-wide corrected <0.1). Candidate genes were prioritized ( based upon expression QTL data we collected in DO and CC mice and analyses using publicly available gene expression and phenotype databases. These findings may advance understanding of the genetics that drive impulsive behavior and enhance risk for substance use disorders.
PubMed: 36714272
DOI: 10.1016/j.addicn.2022.100045 -
European Journal of Pediatrics Sep 2020Steroid-sensitive nephrotic syndrome (SSNS) is the most common form of nephrotic syndrome in childhood. Cases with the familial occurrence of SSNS suggest that genetics...
Steroid-sensitive nephrotic syndrome (SSNS) is the most common form of nephrotic syndrome in childhood. Cases with the familial occurrence of SSNS suggest that genetics may play a role in the disease. Human leucocyte antigen (HLA) alleles have been associated with SSNS. We present genetic findings in nine families (44 participants), each with at least two affected siblings. A total of 19 patients were affected with familial SSNS. Six of nine families showed linkage to markers on chromosome 6p (27.29-33.97 Mbp) (Hg19), especially to markers D6S1629 and D6S1560 on HLA dense region in this location. Interestingly, we also found linkage of disease phenotype of familial SSNS on chromosome 15 (91.7-96.9 Mbp) (Hg19) with a logarithm of odds (LOD) score Z = 3.02.Conclusion: Our findings confirm the linkage of HLA markers on chromosome 6, which strengthens the association of HLA alleles in SSNS. What is Known: • Human leukocyte antigen (HLA) alleles have been associated with idiopathic steroid-sensitive nephrotic syndrome (SSNS). Only few studies have investigated the association between HLA alleles and familial SSNS. What is New: • We present evidence of linkage of familial SSNS to chromosome 6p (27.29-33.97 Mbp) (Hg19), especially to markers D6S1629 and D6S1560 on HLA dense region in this location. We also found linkage of the disease phenotype of familial SSNS on chromosome 15 (91.7-96.9 Mbp) (Hg19) with a logarithm of odds (LOD) score of Z = 3.02 following autosomal recessive inheritance pattern.
Topics: Alleles; HLA Antigens; Humans; Nephrotic Syndrome; Phenotype; Steroids
PubMed: 32198629
DOI: 10.1007/s00431-020-03634-3 -
Genetic Variation and Recurrent Haplotypes on Chromosome 6q23-25 Risk Locus in Familial Lung Cancer.Cancer Research Jun 2021Although lung cancer is known to be caused by environmental factors, it has also been shown to have genetic components, and the genetic etiology of lung cancer remains...
Although lung cancer is known to be caused by environmental factors, it has also been shown to have genetic components, and the genetic etiology of lung cancer remains understudied. We previously identified a lung cancer risk locus on 6q23-25 using microsatellite data in families with a history of lung cancer. To further elucidate that signal, we performed targeted sequencing on nine of our most strongly linked families. Two-point linkage analysis of the sequencing data revealed that the signal was heterogeneous and that different families likely had different risk variants. Three specific haplotypes were shared by some of the families: 6q25.3-26 in families 42 and 44, 6q25.2-25.3 in families 47 and 59, and 6q24.2-25.1 in families 30, 33, and 35. Region-based logarithm of the odds scores and expression data identified the likely candidate genes for each haplotype overlap: at 6q25.3, at 6q26, and (6q24.1) and (6q24.2). Further annotation was used to zero in on potential risk variants in those genes. All four genes are good candidate genes for lung cancer risk, having been linked to either lung cancer specifically or other cancers. However, this is the first time any of these genes has been implicated in germline risk. Functional analysis of these four genes is planned for future work. SIGNIFICANCE: This study identifies four genes associated with lung cancer risk, which could help guide future lung cancer prevention and treatment approaches.
Topics: Biomarkers, Tumor; Chromosome Mapping; Chromosomes, Human, Pair 6; Female; Genetic Linkage; Genetic Predisposition to Disease; Genetic Variation; Genome, Human; Haplotypes; Humans; Lod Score; Lung Neoplasms; Male; Pedigree; Prognosis
PubMed: 33853833
DOI: 10.1158/0008-5472.CAN-20-3196 -
Analytical and Bioanalytical Chemistry Apr 2023The blood levels of cancer antigen 125 (CA125) and human epididymal secretory protein 4 (HE4) are measured in the diagnosis and progression monitoring of ovarian cancer...
The blood levels of cancer antigen 125 (CA125) and human epididymal secretory protein 4 (HE4) are measured in the diagnosis and progression monitoring of ovarian cancer (OC), and the Risk of Ovarian Malignancy Algorithm (ROMA) score% values are calculated for cancer risk assessment. For the first time, disposable dual screen-printed carbon electrodes modified with reduced graphene oxide, polythionine, and gold nanoparticles were used to fabricate label-free electrochemical dual CA125-HE4 immunosensors for the sensitive, fast, and practical simultaneous determination of CA125 and HE4. DPV and SWV methods were used to simultaneously determine antigens in two different linear ranges (1-100 pg mL and 1-50 ng mL). High sensitivity, low LOD, and LOQ were obtained for two linear ranges with a correlation coefficient above 0.99. The application stability of the dual CA125-HE4 immunosensors was determined as 60 days, and the storage stability was determined as 16 weeks. The dual immunosensors exhibited high selectivity in eight different antigen mixtures. The reusability of the dual immunosensors has been tested up to 9 cycles. ROMA score% values for pre-menopausal and post-menopausal status were calculated using the concentration of CA125 and HE4 in the blood serum and assessing OC risk. The disposable dual immunosensors can be used in point-of-care tests for rapid and practical simultaneous determination of CA125 and HE4 with high selectivity, sensitivity, and repeatability.
Topics: Female; Humans; Biomarkers, Tumor; Biosensing Techniques; CA-125 Antigen; Early Detection of Cancer; Gold; Immunoassay; Metal Nanoparticles; Ovarian Neoplasms; Proteins; Electrochemical Techniques
PubMed: 36719438
DOI: 10.1007/s00216-023-04569-y -
PloS One 2019Hypotrichosis simplex (HS) with and without woolly hair (WH) comprises a group of rare, monogenic disorders of hair loss. Patients present with a diffuse loss of scalp...
Hypotrichosis simplex (HS) with and without woolly hair (WH) comprises a group of rare, monogenic disorders of hair loss. Patients present with a diffuse loss of scalp and/or body hair, which usually begins in early childhood and progresses into adulthood. Some of the patients also show hair that is tightly curled. Approximately 10 genes for autosomal recessive and autosomal dominant forms of HS have been identified in the last decade, among them five genes for the dominant form. We collected blood and buccal samples from 17 individuals of a large British family with HS and WH. After having sequenced all known dominant genes for HS in this family without the identification of any disease causing mutation, we performed a genome-wide scan, using the HumanLinkage-24 BeadChip, followed by a classical linkage analysis; and whole exome-sequencing (WES). Evidence for linkage was found for a region on chromosome 4q35.1-q35.2 with a maximum LOD score of 3.61. WES led to the identification of a mutation in the gene SORBS2, encoding sorbin and SH3 domain containing 2. Unfortunately, we could not find an additional mutation in any other patient/family with HS; and in cell culture, we could not observe any difference between cloned wildtype and mutant SORBS2 using western blotting and immunofluorescence analyses. Therefore, at present, SORBS2 cannot be considered a definite disease gene for this phenotype. However, the locus on chromosome 4q is a robust and novel finding for hypotrichosis with woolly hair. Further fine mapping and sequencing efforts are therefore warranted in order to confirm SORBS2 as a plausible HS disease gene.
Topics: Alleles; Chromosome Mapping; Chromosomes, Human, Pair 4; Female; Genes, Dominant; Genetic Association Studies; Genetic Linkage; Genetic Predisposition to Disease; Humans; Hypotrichosis; Male; Mutation; Pedigree; Phenotype; Quantitative Trait Loci; United Kingdom; Whole Genome Sequencing
PubMed: 31790498
DOI: 10.1371/journal.pone.0225943 -
Computational and Structural... 2022Although methodologies and software packages for bulked segregant analysis (BSA) are well established, it is difficult to detect extremely over-dominant and small-effect...
Although methodologies and software packages for bulked segregant analysis (BSA) are well established, it is difficult to detect extremely over-dominant and small-effect genes for quantitative traits in F population. To address this issue, we proposed a combinatorial strategy to identify all types of quantitative trait loci (QTLs) using extreme phenotype individuals in F. To popularize this strategy, we developed an R software package dQTG.seq v1.0.1. It has some features not found in other BSA software packages: 1) new (dQTG-seq1 and dQTG-seq2) and existing (G', deltaSNP, Euclidean distance (ED), and SmoothLOD) methods are available to identify all types of QTLs in bi-parental segregation populations, one data file with two BSA and three QTL-mapping data formats was inputted, and two *.csv files and one figure were outputted; 2) main smoothing methods (AIC, Window size, and Block) have been incorporated into each of the above-mentioned methods; 3) the threshold value of LOD score for significant QTLs is determined by permutation experiments. To save running time, vroom function was used to read the dataset, and parallel operation was used to estimate parameters. In real data analyses, users should select a suitable initial value of window size, depending on the species, and appropriate smoothing methods to obtain the best result. dQTG-seq2 detects more known loci and genes for rice grain number per panicle than composite interval mapping (CIM) and inclusive CIM, especially extremely over-dominant and small-effect genes. A handbook for our software package (https://cran.r-project.org/web/packages/dQTG.seq/index.html) has been provided in the supplemental materials for the users' convenience.
PubMed: 35615028
DOI: 10.1016/j.csbj.2022.05.009 -
Indian Journal of Ophthalmology Jun 2023This case-control study aims to examine possible associations of VSX1 exon3 gene variants with the development of keratoconus (KC) in Malaysian patients.
PURPOSE
This case-control study aims to examine possible associations of VSX1 exon3 gene variants with the development of keratoconus (KC) in Malaysian patients.
METHODS
A case-control study was done on 42 keratoconus cases, 127 family member controls, and 96 normal controls.
RESULTS
Three gene variants, p.A182A, p.P237P, and p.R217H showed significant associations with keratoconus (P < 0.05). While p.A182A and p.P227P were more prevalent than in the family and normal controls (OR 3.14-4.05), the reverse was observed with p.R217H (OR 0.086-1.59). With Haploview analysis, p.A182A and p.P237P were shown to be in linkage disequilibrium (LD) (LOD (logarithm of the odds score) score of 2.0, r2 of 0.957, and 95% confidence interval (CI) of 0.96-1.00).
CONCLUSION
The study results suggest that the p.A182A and p.P237P variants could have contributed to the development of keratoconus in some Malaysians and that these two variants are likely to be co-inherited. In contrast, the p.R217H variant appeared to confer some protection against the development of keratoconus.
Topics: Humans; Asian People; Case-Control Studies; Eye Proteins; Homeodomain Proteins; Keratoconus
PubMed: 37322657
DOI: 10.4103/IJO.IJO_2894_22