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Objective The aim of this study is to develop ddPCR based-assay for detecting alpha (0)-thalassemia (SEA) and beta-thalassemia (HbE and 41/42 (-CTTT) from cell-free fetal DNA (cffDNA) extracted form maternal plasma. Design Feasibility study using sample collected from prenatal clinic. Setting Thailand. Population 46 couples who were identified to be carriers of alpha or beta thalassemia. Method Cell-free DNA from 46 singleton pregnant women were isolated and quantified using ddPCR with specially designed probes for each target allele. Allelic copy number (CNV) calculation and likelihood ratio test were used to classify the most likely fetal genotypes. Classification performances were evaluated against ground truth fetal genotypes obtained from conventional amniocentesis. Main outcome measures Concordance with fetal genotyping results from invasive technique. Sensitivity and specificity of ddPCR-based assays. Results CNV analysis of SEA deletion accurately classify fetal genotypes in 20 out of 22 cases with an AUC of 0.98 (95% sensitivity and 91% specificity) for the prediction of Hb Bart’s hydrops fetalis. Application of sequential probability ratio tests to detect HbE and 41/42 correctly classified 12 out of 24 cases (10 out of 16 HbE and 2 out of 8 41/42) and provided inconclusive for 7 cases. Conclusion We showed that ddPCR-based analysis of maternal plasma is an accurate and effective NIPD for SEA deletion. Although the performance of ddPCR-based assay on HbE and 41/42 mutations is still not high enough for clinical application, our work should serve as a good foundation for future works in this field.

Varun Kaushik

and 2 more

Background: Pathogenic variants in the mismatch repair (MMR) genes are the drivers of Lynch Syndrome; optimal variant interpretation is required for the management of suspected and confirmed cases. Given the onerous nature of extracting information related to genetic variants, literature searching tools which harness artificial intelligence may aid in retrieving information to allow optimum variant classification. Methods: In this study, we described the nature of discordance in a sample of 80 variants from a list of variants requiring updating by InSiGHT for ClinGen by comparing their existing InSiGHT classifications on ClinVar. Variants were searched for using a traditional method (Google Scholar) and literature searching tool (Mastermind Genomenon) independently. Descriptive statistics were used to compare: the number of articles before and after screening for relevance and the number of relevant articles unique to either method. Results: 916 articles were returned by both methods. Mastermind averaged four relevant articles per search, Google Scholar, three. Of relevant Mastermind articles, 193/308 (62.7%) were unique to it, compared to 87/202, (43.0%) for Google Scholar. All 6/80 (20%) variants with pathogenic or likely pathogenic InSiGHT classifications have newer VUS assertions on ClinVar. Conclusion: Mastermind on average returned a more relevant literature search. Google Scholar still found unique information, suggesting that Mastermind could play a complementary role.

Elisa Azura Azman

and 4 more

thollet fabien

and 6 more

The present dataset is related to the Arc-Isère long-term environmental research part of the Rhône Basin Long Term Environmental Research Observatory. This alpine watershed located in the French Alps is characterized by high Suspended Particulate Matter (SPM) in very anthropogenized valleys. Suspended Sediment Concentrations (SSC) naturally observed in the river are very high, ranging from a few tens of milligrams per litre at low flow to tens of grams per litre during major natural hydrological events (floods, debris flows) or river dam hydraulic flushes. One research objective related to this site aims at better understanding the SSC dynamics along the river using a system of nested watersheds (Arvan, Arc, and Isère) in order to access to both temporal and spatial dynamics. Studies using this dataset are on the quantification of fine sediment fluxes but also on the related morphological changes due to fine sediment deposition or resuspension. Additionally, the observatory database can support studies on contaminants (either dissolved or particulate contaminant). Six hydro sedimentary stations monitor SSC with high frequency via turbidity sensors associated to automatic samplers. Discharge is measured via classical water level measurements and a rating curve. The oldest station (Grenoble-campus) started recording data from 2006 while others hydro-sedimentary stations were built from 2009 to 2011. Data are available in an online data website called “Base de Données des Observatoires en Hydrologie” (Hydrological observatory database, https://bdoh.irstea.fr/ARC-ISERE/) with DOI references for each site. The hydrological and sediment transport time series are stored, managed and made available to a wide community in order to be used at their full extent. This database is used as a data exchange tool for both scientists and operational end-users and as an online tool to compute integrated fluxes.
Tuberculosis kills more people than any other single infectious disease globally. Despite decades of research, there is no vaccine to prevent TB transmission. Bacille Calmette-Guerin (BCG) vaccine developed a century ago has little effect on pulmonary TB and does not control transmission. Lack of an effective vaccine emanates from lack of knowledge on correlates of protective immunity on which to base vaccine design and development. However, some household contacts who are extensively exposed to Mtb infection remain persistently negative to tuberculin skin test and interferon-gamma assay. These individuals called “resisters” clear Mtb infection early before the development of acquired immunity. The immunological basis of early Mtb clearance is yet to be established, however, innate lymphocytes such as monocytes/macrophages, dendritic cells, neutrophils and natural killer cells, and innate like T cells such as mucosal associated invariant T cells, invariant natural killer T cells and gamma-delta (γδ) T cells have been implicated in this early protection. One of the cells that has attracted increasing attention in recent years, in protection against Mtb is the natural killer cell. Emerging data from animal and epidemiological studies indicate that NK cells may play a significant role in the fight against Mtb. NK cells express various surface markers to recognize and kill both Mtb and Mtb-infected cells. In this review, recent advances in our understanding of NK cells in the fight against Mtb early during infection, with emphasis on cohort studies, will be presented.
Objective The aim of this study is to develop ddPCR based-assay for detecting alpha (0)-thalassemia (SEA) and beta-thalassemia (HbE and 41/42 (-CTTT) from cell-free fetal DNA (cffDNA) extracted form maternal plasma. Design Feasibility study using sample collected from prenatal clinic. Setting Thailand. Population 46 couples who were identified to be carriers of alpha or beta thalassemia. Method Cell-free DNA from 46 singleton pregnant women were isolated and quantified using ddPCR with specially designed probes for each target allele. Allelic copy number (CNV) calculation and likelihood ratio test were used to classify the most likely fetal genotypes. Classification performances were evaluated against ground truth fetal genotypes obtained from conventional amniocentesis. Main outcome measures Concordance with fetal genotyping results from invasive technique. Sensitivity and specificity of ddPCR-based assays. Results CNV analysis of SEA deletion accurately classify fetal genotypes in 20 out of 22 cases with an AUC of 0.98 (95% sensitivity and 91% specificity) for the prediction of Hb Bart’s hydrops fetalis. Application of sequential probability ratio tests to detect HbE and 41/42 correctly classified 12 out of 24 cases (10 out of 16 HbE and 2 out of 8 41/42) and provided inconclusive for 7 cases. Conclusion We showed that ddPCR-based analysis of maternal plasma is an accurate and effective NIPD for SEA deletion. Although the performance of ddPCR-based assay on HbE and 41/42 mutations is still not high enough for clinical application, our work should serve as a good foundation for future works in this field.

Yu Yang

and 3 more

ABSTRACT: This study investigates the correlation between classroom seating choice and academic performance of college students. We examined this relationship using statistical analysis, and our sample consisted of 142 undergraduate students enrolled in the School of Software at the Nanchang Hangkong University. First, over the course of one semester, we collected data on students’ seating choice, their final exam results, and other data on student characteristics. Second, we constructed a seat calculation model and used the Pearson correlation coefficient method to quantitatively analyze the data. We then visually displayed the seat selection process using two types of figures, color gradation figures and box-plots. This allowed us to empirically examine the relationship between seat selection and academic performance, as well as the effect of seat change on academic performance and the characteristics of the trajectory of student seat change. The results show that student performance is correlated with seat location and changes in seat location. In general, students seated closer to the front row performed better academically, as did students who did not change seats very often. Finally, we plotted the students’ seat change trajectories to investigate their seating choice patterns. We also conducted follow-up interviews with instructors and students to obtain more information about why the observed patterns emerged. This study has important implications for university teachers interested in improving classroom management and student learning based on classroom seating choices.

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Wahaj Munir

and 3 more

Background: Acute type A aortic dissection (ATAAD), is a surgical emergency often requiring intervention on the aortic root. There is much controversy regarding root management; aggressively pursuing a root replacement, versus more conservative approaches to preserve native structures. Methods: Electronic database search we performed through PubMed, Embase, SCOPUS, google scholar and Cochrane identifying studies that reported on outcomes of surgical repair of ATAAD through either root preservation or replacement. The identified articles focused on short- and long-term mortalities, and rates of re-operation on the aortic root. Results: There remains controversy on replacing or preserving aortic root in ATAAD. Current evidence supports practice of both trends following an extensive decision-making framework, with conflicting series suggesting favourable results with both procedures as the approach that best defines higher survival rates and lower perioperative complications. Yet, the decision to perform either approach remains surgeon decision and bound to the extent of the dissection and tear entries in strong correlation with status of the aortic valve and involvement of coronaries in the dissection. Conclusions: There exists much controversy regarding fate of the aortic root in ATAAD. There are conflicting studies for impact of root replacement on mortality, whilst some study’s report no significant results at all. There is strong evidence regarding risk of re-operation being greater when root is not replaced. Majority of these studies are limited by the single centred, retrospective nature of these small sample sized cohorts, further hindered by potential of treatment bias.

Matthew Sussman

and 9 more

The recognition of fibrinolysis phenotypes in trauma patients has led to a reevaluation of antifibrinolytic therapy (AF). Many cardiac patients also receive AF, however the distribution of fibrinolytic phenotypes in that population is unknown. The purpose of this study was to fill that gap. Methods: Data were retrospectively reviewed from 78 cardiac surgery patients. Phenotypes were defined as hypofibrinolytic (LY30 <0.8%), physiologic (LY30 0.8-3.0%) and hyperfibrinolytic (LY30 >3%). Continuous variables were expressed as M ± SD or median (interquartile range). Results: The study population was 65±10 yrs old, 74% male, average body mass index of 29±5 kg/m2. Fibrinolytic phenotypes were distributed as physiologic=45%, hypo=32% and hyper = 23%. There was no obvious effect of age, gender, race, or ethnicity on the distribution of fibrinolysis phenotypes; 47% received AF. The time with chest tube during post-operative recovery was longer in those who received AF (4[3,5] days) vs no AF (3[2,4] days), P=0.037). All cause morbidity occurred in 51% of patients who received AF vs 25% with no AF (p=0.017). However, with AF vs no AF, apparent differences in median chest tube output (1379 vs 820ml, p=0.075), hospital LOS (13 vs 10 days, P=0.873), estimated blood loss (1100 vs 775 ml, P=0.127), units of transfused RBCs (4 vs 2], P=0.152) or all-cause mortality (5.4% [2/37] vs 10% [4/41], P=0.518) were not statistically significant. Conclusion: This is the first description of three distinctly different fibrinolytic phenotypes in cardiac surgery patients. In this population, the use of AF was associated with increased morbidity.

Arushi Singh

and 6 more

Background: Ibrutinib is associated with atrial fibrillation (AF), though echocardiographic predictors of AF have not been studied in this population. We sought to determine whether left atrial (LA) strain on transthoracic echocardiography could identify patients at risk for developing ibrutinib-related atrial fibrillation (IRAF). Methods: We performed a retrospective review of 66 patients who had an echocardiogram prior to ibrutinib treatment. LA strain was measured with TOMTEC Imaging Systems, obtaining peak atrial longitudinal strain (PALS) and peak atrial contraction strain (PACS) on 4-chamber and 2-chamber views. Statistical analysis was performed with Chi-square analysis, T-test, or binomial regression analysis, with a p-value < 0.05 considered statistically significant. Results: Twenty-two patients developed IRAF (33%). Age at initiation of ibrutinib was significantly associated with IRAF (65.1 years vs. 74.1 years, p = 0.002). Mean ibrutinib dose was lower among patients who developed IRAF (388.2 ± 121.7 vs. 448.6 ± 88.4, p = 0.025). E/e’ was significantly higher among patients who developed IRAF (11.5 vs. 9.3, p = 0.04). PALS was significantly lower in patients who developed AF (30.3% vs. 36.3%, p = 0.01). On multivariate regression analysis, age, PALS and PACS were significantly associated with IRAF. On multivariate regression analysis, only PACS remained significantly associated with IRAF while accounting for age. Conclusions: Age, ibrutinib dose, E/e’, and PALS on pre-treatment echocardiogram were significantly associated with development of IRAF. On multivariate regression analyses, age, PALS and PACS remained significantly associated with IRAF. Impaired LA mechanics add to the assessment of patients at risk for IRAF

James Hummel

and 1 more

We thank Medina et al. for their interest in our recent work on QTc prolongation associated with treatment of COVID-19 patients with hydroxychloroquine and azithromycin. As they appropriately point out in their letter, genetic variation is likely a significant determinant of QT prolongation in the population at large and in COVID-19 patients specifically. While drugs causing acquired long QT syndrome and torsades de pointes are generally blockers of IKr, repolarization results from the aggregate of multiple inward and outward currents. Patients with sub-clinical defects in any of these ion channels can have normal or only slightly prolonged baseline QT intervals, but may possess decreased repolarization reserve leading to an exaggerated response to IKr blockade (1).  In our study, a baseline QTc of > 460 ms was associated with excessive QTc prolongation, and this likely represents a group of patients with sub-clinical cardiac ion channel mutations (so called “first hit”) (2). We also agree that many patients with latent mutations demonstrate a normal baseline QT, which gets prolonged with the addition of a drug or a change in the clinical condition “second hit” (3). The patients in our study who exhibited QTc prolongation were generally acutely ill, and displayed “multiple hits” that led to QTc prolongation and it is certainly plausible that many may have had sub-clinical cardiac ion mutations. We therefore wholeheartedly agree that pharmacogenetics should be considered in studies of drug-induced QT prolongation, however this information is rarely available to include for acutely ill patients. And while it makes sense to obtain genetic profiles prior to administration of QT-prolonging medications, that can only be performed in the elective outpatient setting, while taking into consideration medical, ethical and social issues related to asymptomatic genetic screening (e.g. cost, reimbursement, informed consent, etc…). There is significant interest in building genomic databases, and when this becomes a reality for the population at large we believe that genetic information should certainly be included in studies of QT prolongation.Roden DM Long QT syndrome: reduced repolarization reserve and the genetic link. J Intern Med. 2006 Jan; 259(1):59-69.Napolitano C, Schwartz PJ, Brown AM, et al. Evidence for a cardiac ion channel mutation underlying drug-induced QT prolongation and life-threatening arrhythmias. J Cardiovasc Electrophysiol. 2000;11:691–6Sauer AJ and Newton-Cheh C. Clinical and genetic determinants of torsade de pointes risk. Circulation. 2012;125:1684-94.

Norman Mukarati

and 10 more

Numerous unknown factors influence anthrax epidemiology in multi-host systems, especially at wildlife/livestock/human interfaces. Serology tests for anti-anthrax antibodies in carnivores are useful tools in identifying the presence or absence of Bacillus anthracis in a range. These were employed to ascertain if the disease pattern followed the recognized high and low risk anthrax zonation in Zimbabwe and also to establish if anthrax was absent from Hwange National Park in which there has been no reported outbreaks. African lions (Panthera leo) (n= 114) drawn from -free-range protected areas and captive game parks located in recognized high and low risk zones across Zimbabwe were tested for antibodies to anthrax PA antigen using the ELISA immunoassay. A random selection of 27 lion sera samples comprising 17 sero-positive and 10 sero-negative sera were further tested in the species-independent toxin neutralization assay (TNA) in order to validate the former as a surveillance tool for anthrax in African lions. Using the ELISA-PA immunoassay, 21.9% (25/114) of the lions tested positive for antibodies to anthrax. Seropositivity was recorded in all study areas and there was no significant difference (p= 0.852) in seropositivity between lions in high and low risk anthrax zones. Also, there was no significant difference (McNemar’s χ2 = 0.9, p = 0.343) in the proportion of lions testing positive to anti-PA anthrax antibodies on ELISA-PA immunoassay compared to the TNA, with fair agreement between the two tests [Kappa (K) statistic = 0.30; 0.08

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