A
bstract
Light pseudoscalars interacting pre-dominantly with Standard Model gauge bosons (so-called axion-like particles or ALPs) occur frequently in extensions of the Standard Model. In this work ...we review and update existing constraints on ALPs in the keV to GeV mass region from colliders, beam dump experiments and astrophysics. We furthermore provide a detailed calculation of the expected sensitivity of Belle II, which can search for visibly and invisibly decaying ALPs, as well as long-lived ALPs. The Belle II sensitivity is found to be substantially better than previously estimated, covering wide ranges of relevant parameter space. In particular, Belle II can explore an interesting class of dark matter models, in which ALPs mediate the interactions between the Standard Model and dark matter. In these models, the relic abundance can be set via resonant freeze-out, leading to a highly predictive scenario consistent with all existing constraints but testable with single-photon searches at Belle II in the near future.
Direct-to-consumer (DTC) genetic testing emerged in the early 2000s as a means of allowing consumers to access information on their genetics without the involvement of a physician. Although early ...models of DTC were popular with consumers, they were controversial in medical and regulatory circles. In this article, we trace the history of DTC genetic testing, discuss its regulatory implications, and describe the emergence of a new hybrid model we call DTC 2.0.
ABSTRACT
Cytomegalovirus (CMV) is a significant cause of morbidity and mortality among immunocompromised hosts, including transplant recipients. Antiviral prophylaxis or treatment is used to reduce ...the incidence of CMV disease in this patient population; however, there is concern about increasing antiviral resistance. Detection of antiviral resistance in CMV was traditionally accomplished using Sanger sequencing of
UL54
and
UL97
genes, in which specific mutations may result in reduced antiviral activity. In this study, a novel next-generation sequencing (NGS) method was developed and validated to detect mutations in
UL54
/
UL97
associated with antiviral resistance. Plasma samples (
n
= 27) submitted for antiviral resistance testing by Sanger sequencing were also analyzed using the NGS method. When compared to Sanger sequencing, the NGS assay demonstrated 100% (27/27) overall agreement for determining antiviral resistance/susceptibility and 88% (22/25) agreement at the level of resistance-associated mutations. The limit of detection of the NGS method was determined to be 500 IU/mL, and the lower threshold for detecting mutations associated with resistance was established at 15%. The NGS assay represents a novel laboratory tool that assists healthcare providers in treating patients who are infected with CMV harboring resistance-associated mutations and who may benefit from tailored antiviral therapy.
Background
Growing evidence suggests that maternal obesity may affect the intrauterine environment and increase a child's risk of developing asthma. We aim to investigate the relationship between ...prepregnancy obesity and childhood asthma risk.
Methods
Cohorts of children enrolled in Kaiser Permanente Northern California integrated healthcare system were followed from birth (2005–2014) to age 4 (n = 104,467), 6 (n = 63,084), or 8 (n = 31,006) using electronic medical records. Child's asthma was defined using ICD codes and asthma‐related prescription medication dispensing. Risk ratios (RR) and 95% confidence intervals (95% CIs) for child's asthma were estimated using Poisson regression with robust error variance for (1) prepregnancy BMI categories (underweight <18.5, normal 18.5–24.9, overweight 25–29.9, obese 1 30–34.9, and obese 2/3 ≥35) and (2) continuous prepregnancy BMI modeled using cubic splines with knots at BMI category boundaries. Models were adjusted for maternal age, education, race, asthma, allergies, smoking, gestational weight gain, child's birth year, parity, infant sex, gestational age, and child's BMI.
Results
Relative to normal BMI, RRs (95%CIs) for asthma at ages 4, 6, and 8 were 0.91 (0.75, 1.11), 0.95 (0.78, 1.16), and 0.97 (0.75, 1.27) for underweight, 1.06 (0.99, 1.14), 1.08 (1.01, 1.16), and 1.03 (0.94, 1.14) for overweight, 1.09 (1.00, 1.19), 1.12 (1.03, 1.23), 1.03 (0.91, 1.17) for obese 1, and 1.10 (0.99, 1.21), 1.13 (1.02, 1.25), 1.14 (0.99, 1.31) for obese 2/3. When continuous prepregnancy BMI was modeled with splines, child's asthma risk generally increased linearly with increasing prepregnancy BMI.
Conclusions
Higher prepregnancy BMI is associated with modestly increased childhood asthma risk.
This study investigated the relationship between maternal prepregnancy BMI and childhood asthma risk. Mothers were followed throughout their pregnancy, and children were followed up to age 4, 6, or 8 years using electronic medical records. Asthma was assessed at each follow‐up age. Higher prepregnancy BMI was associated with a modest increase in childhood asthma risk.Abbreviations: BMI, body mass index; EMR, electronic medical records; LMP, last menstrual period
Current clinical laboratory practice guidelines for next-generation sequencing (NGS) do not provide definitive guidance on confirming NGS variants. Sanger confirmation of NGS results can be ...inefficient, redundant, and expensive. We evaluated the accuracy of NGS-detected single-nucleotide variants (SNVs) and insertion/deletion variants (indels) and the necessity of NGS variant confirmation using four NGS target-capture gene panels covering 117 genes, 568 Kbp, and 77 patient DNA samples. Unique NGS-detected variants (1080 SNVs and 124 indels) underwent Sanger confirmation and/or were compared to data from the 1000 Genomes Project (1000G). Recurrent variants in unrelated samples resulted in 919 comparisons between NGS and Sanger, with 100% concordance. In a second comparison, 762 unique NGS results (736 SNVs, 26 indels) from seven 1000G samples were found to have 97.1% concordance with 1000G phase 1 data. Sanger sequencing and 1000G phase 3 data confirmed the accuracy of the NGS results for all 1000G phase 1 discrepancies. In all samples, the depth of coverage exceeded 100× in >99.7% of bases in the target regions. In conclusion, confirmatory analysis by Sanger sequencing of SNVs detected via capture-based NGS testing that meets appropriate quality thresholds is unnecessarily redundant. In contrast, Sanger sequencing for indels may be required for defining the correct genomic location, and Sanger may be used for quality-assurance purposes.
A mistake has been found in the numerical code used to reproduce the bounds from proton beam dump experiments from ref. 1 in figures 2 and 7 of ref. 2. Correcting this mistake leads to slightly ...stronger bounds as shown below. We note that this correction does not include recent improvements in the analysis of proton beam dump experiments 3. Additional recent bounds on GeV-scale ALPs can be found in refs. 4–8.
Significant barriers, such as lack of professional guidelines, specialized training for interpretation of pharmacogenomics (PGx) data, and insufficient evidence to support clinical utility, prevent ...preemptive PGx testing from being widely clinically implemented. The current study, as a pilot project for the Right Drug, Right Dose, Right Time-Using Genomic Data to Individualize Treatment Protocol, was designed to evaluate the impact of preemptive PGx and to optimize the workflow in the clinic setting. We used an 84-gene next-generation sequencing panel that included SLCO1B1, CYP2C19, CYP2C9, and VKORC1 together with a custom-designed CYP2D6 testing cascade to genotype the 1013 subjects in laboratories approved by the Clinical Laboratory Improvement Act. Actionable PGx variants were placed in patient's electronic medical records where integrated clinical decision support rules alert providers when a relevant medication is ordered. The fraction of this cohort carrying actionable PGx variant(s) in individual genes ranged from 30% (SLCO1B1) to 79% (CYP2D6). When considering all five genes together, 99% of the subjects carried an actionable PGx variant(s) in at least one gene. Our study provides evidence in favor of preemptive PGx testing by identifying the risk of a variant being present in the population we studied.
To evaluate the impact of technically challenging variants on the implementation, validation, and diagnostic yield of commonly used clinical genetic tests. Such variants include large indels, small ...copy-number variants (CNVs), complex alterations, and variants in low-complexity or segmentally duplicated regions.
An interlaboratory pilot study used synthetic specimens to assess detection of challenging variant types by various next-generation sequencing (NGS)-based workflows. One well-performing workflow was further validated and used in clinician-ordered testing of more than 450,000 patients.
In the interlaboratory study, only 2 of 13 challenging variants were detected by all 10 workflows, and just 3 workflows detected all 13. Limitations were also observed among 11 less-challenging indels. In clinical testing, 21.6% of patients carried one or more pathogenic variants, of which 13.8% (17,561) were classified as technically challenging. These variants were of diverse types, affecting 556 of 1,217 genes across hereditary cancer, cardiovascular, neurological, pediatric, reproductive carrier screening, and other indicated tests.
The analytic and clinical sensitivity of NGS workflows can vary considerably, particularly for prevalent, technically challenging variants. This can have important implications for the design and validation of tests (by laboratories) and the selection of tests (by clinicians) for a wide range of clinical indications.
...regions of low sequence complexity, known as pseudogenes, or highly related gene family members, like members of the CYP family of genes, can be challenging to detect a real pathogenic change from ...one that is in the nonexpressed copy, or accurately gauge the total number of active vs inactive copies of the gene. ...the electronic chip platform enables a much more high-throughput approach compared to current methods, thereby greatly increasing efficiency and speed of turn-around. ...it is anticipated that long reads produced by this technology will greatly enhance the ability to address the aforementioned challenging genomic scenarios like copy number variants (CNVs) and trinucleotide repeat expansions as well as provide haplotype information and identify alternatively spliced mRNAs. ...to optimize the speed of tag detection, the authors chose to develop a system that would monitor the blockade current of the tags while they were still attached to the nucleotides.
To describe the experience and outcome of performing whole-exome sequencing (WES) for resolution of patients on a diagnostic odyssey in the first 18 months of an individualized medicine clinic (IMC).
...The IMC offered WES to physicians of Mayo Clinic practice for patients with suspected genetic disease. DNA specimens of the proband and relatives were submitted to WES laboratories. We developed the Genomic Odyssey Board with multidisciplinary expertise to determine the appropriateness for IMC services, review WES reports, and make the final decision about whether the exome findings explain the disease. This study took place from September 30, 2012, to March 30, 2014.
In the first 18 consecutive months, the IMC received 82 consultation requests for patients on a diagnostic odyssey. The Genomic Odyssey Board deferred 7 cases and approved 75 cases to proceed with WES. Seventy-one patients met with an IMC genomic counselor. Fifty-one patients submitted specimens for WES testing, and the results have been received for all. There were 15 cases in which a diagnosis was made on the basis of WES findings; thus, the positive diagnostic yield of this practice was 29%. The mean cost per patient for this service was approximately $8000. Medicaid supported 27% of the patients, and 38% of patients received complete or partial insurance coverage.
The significant diagnostic yield, moderate cost, and notable health marketplace acceptance for WES compared with conventional genetic testing make the former method a rational diagnostic approach for patients on a diagnostic odyssey.
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