A framework for the detection of de novo mutations in family-based sequencing data

Germline mutation detection from human DNA sequence data is challenging due to the rarity of such events relative to the intrinsic error rates of sequencing technologies and the uneven coverage across the genome. We developed PhaseByTransmission (PBT) to identify de novo single nucleotide variants and short insertions and deletions (indels) from sequence data collected in parent-offspring trios. We compute the joint probability of the data given the genotype likelihoods in the individual family members, the known familial relationships and a prior probability for the mutation rate. Candidate de novo mutations (DNMs) are reported along with their posterior probability, providing a systematic way to prioritize them for validation. Our tool is integrated in the Genome Analysis Toolkit and can be used together with the ReadBackedPhasing module to infer the parental origin of DNMs based on phase-informative reads. Using simulated data, we show that PBT outperforms existing tools, especially in low coverage data and on the X chromosome. We further show that PBT displays high validation rates on empirical parent-offspring sequencing data for whole-exome data from 104 trios and X-chromosome data from 249 parent-offspring families. Finally, we demonstrate an association between father's age at conception and the number of DNMs in female offspring's X chromosome, consistent with previous literature reports

Suitability of the use of low-molecular-weight heparins in the prevention of venous thromboembolism

Objetivo: Conocer la prevalencia de prescripción de heparinas de bajo peso molecular (HBPM) en la profilaxis de la enfermedad tromboembólica venosa en un hospital general, así como la adecuación a las recomendaciones de las guías de práctica clínica. Método: Estudio observacional, descriptivo, de corte transversal, tipo indicación-prescripción, con pacientes ingresados en servicios médicos y quirúrgicos. Resultados: Se incluyeron 345 pacientes. La prevalencia de prescripción de HBPM fue del 44,6% (intervalo de confianza [IC] del 95%, 39,3-50,1). Según el nivel de riesgo tromboembólico se encontró adecuación en la decisión de tratar profilácticamente (o no) en 261 casos (75,7%; IC del 95%, 70,7-80,1), en el resto la pauta de actuación no fue la adecuada, destacando 55 pacientes (15,9%; IC del 95%, 12,2-20,2) con riesgo alto a los que no se había prescrito profilaxis (infrautilización), y 29 pacientes (8,4%; IC del 95%, 5,7- 11,8) con riesgo bajo que estaban con profilaxis (sobreutilización). En los pacientes médicos la prevalencia de prescripción fue de 22,6% (IC del 95%, 16,9-29,1) y sólo el 33,3% de los de riesgo tomboembólico alto-moderado recibió profilaxis. La prevalencia de prescripción en cirugía general fue del 84,2% y en traumatología del 91,3%. Conclusiones: En pacientes quirúrgicos el nivel de profilaxis alcanzado es adecuado, pero hay un porcentaje importante de pacientes médicos con riesgo tromboembólico medio-alto, que sigue sin recibir la adecuada profilaxis (infrautilización), a pesar de las recomendaciones de consenso con amplio respaldo científico y profesional.Objective: To investigate the prevalence of low-molecular-weight heparin (LMWH) prescription in venous thromboembolism prophylaxis in a general hospital and the suitability of the recommendations from the clinical practice guidelines. Method: A descriptive, observational and cross-sectional study of the indication-prescription type, carried out on patients admitted to medical departments and for surgery. Results: 345 patients were included. The prevalence of HBPM use was 44.6% (95% CI, 39.3-50.1). Depending on the risk of thromboembolism, the decision to treat prophylactically (or not) was appropriate in 261 cases (75.7%; 95% CI, 70.7-80.1), and the action guidelines were not suitable for the remainder of patients. 55 patients (15.9%; 95% CI, 12.2-20.2) presented a high risk and were not prescribed prophylactically (underuse); and 29 patients (8.4%; 95% CI, 5.7-11.8) at low risk were treated prophylactically (overuse). There was a relationship between the appropriateness of the prescription and the type of patient (p<0.01). In the group of medical patients theprevalence of prescription was 22.6% (95% CI, 16.9-29.1) and only 33.3% of patients with a high to moderate risk of thromboembolism received prophylaxis. The prevalence of prescription in general surgery was 84.2% and 91.3% in traumatology. Conclusions: The degree of prophylaxis is adequate in surgical patients, but there was a significant percentage of medical patients with a high to moderate risk who did not receive suitable prophylaxis (underuse), despite recommendations with scientific and professional backing.Consejería de Salud de la Junta de AndalucíaInstituto de Salud Carlos II

Moments of inertia, nucleon axial-vector coupling, the {\bf 8}, {\bf 10}, 10ˉ\bar{\bf 10} and 273/2{\bf 27}_{3/2} mass spectrums and the higher SU(3)_f representation mass splittings in the Skyrme model

The broad importance of a recent experimental discovery of pentaquarks requires more theoretical insight into the structure of higher representation multiplets. The nucleon axial-vector coupling, moments of inertia, the {\bf 8}, {\bf 10}, $\bar{\bf 10}$, and ${\bf 27}_{3/2}$ absolute mass spectra and the higher SU(3)$_f$ representation mass splittings for the multiplets ${\bf 8}$, ${\bf 10}$, $\bar{\bf 10}$, ${\bf 27}$, ${\bf 35}$, $\bar{\bf 35}$, and $\bf 64$ are computed in the framework of the minimal ${\rm SU(3)_f}$ extended Skyrme model by using only one free parameter, i.e., the Skyrme charge $e$. The analysis presented in this paper represents simple and clear theoretical estimates, obtained without using any experimental results for higher ($\bar{\bf 10}$,...) multiplets. The obtained results are in good agreement with other chiral soliton model approaches that more extensively use experimental results as inputs.Comment: 22 pages, 12 figures, 9 tables, version accepted in JHE

The differential diagnosis of chronic daily headaches: an algorithm-based approach

Chronic daily headaches (CDHs) refers to primary headaches that happen on at least 15 days per month, for 4 or more hours per day, for at least three consecutive months. The differential diagnosis of CDHs is challenging and should proceed in an orderly fashion. The approach begins with a search for “red flags” that suggest the possibility of a secondary headache. If secondary headaches that mimic CDHs are excluded, either on clinical grounds or through investigation, the next step is to classify the headaches based on the duration of attacks. If the attacks last less than 4 hours per day, a trigeminal autonomic cephalalgia (TAC) is likely. TACs include episodic and chronic cluster headache, episodic and chronic paroxysmal hemicrania, SUNCT, and hypnic headache. If the duration is ≥4 h, a CDH is likely and the differential diagnosis encompasses chronic migraine, chronic tension-type headache, new daily persistent headache and hemicrania continua. The clinical approach to diagnosing CDH is the scope of this review

The tale of TILs in breast cancer : a report from The International Immuno-Oncology Biomarker Working Group

The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC

Dark matter and collider phenomenology of split-UED

We explicitly show that split-universal extra dimension (split-UED), a recently suggested extension of universal extra dimension (UED) model, can nicely explain recent anomalies in cosmic-ray positrons and electrons observed by PAMELA and ATIC/PPB-BETS. Kaluza-Klein (KK) dark matters mainly annihilate into leptons because the hadronic branching fraction is highly suppressed by large KK quark masses and the antiproton flux agrees very well with the observation where no excess is found . The flux of cosmic gamma-rays from pion decay is also highly suppressed and hardly detected in low energy region (E<20 GeV). Collider signatures of colored KK particles at the LHC, especially q_1 q_1 production, are studied in detail. Due to the large split in masses of KK quarks and other particles, hard p_T jets and missing E_T are generated, which make it possible to suppress the standard model background and discover the signals.Comment: 32 pages, 15 figure

The Development of a Conceptual Framework and Tools to Assess Undergraduates' Principled Use of Models in Cellular Biology

Recent science education reform has been marked by a shift away from a focus on facts toward deep, rich, conceptual understanding. This requires assessment that also focuses on conceptual understanding rather than recall of facts. This study outlines our development of a new assessment framework and tool—a taxonomy— which, unlike existing frameworks and tools, is grounded firmly in a framework that considers the critical role that models play in science. It also provides instructors a resource for assessing students' ability to reason about models that are central to the organization of key scientific concepts. We describe preliminary data arising from the application of our tool to exam questions used by instructors of a large-enrollment cell and molecular biology course over a 5-yr period during which time our framework and the assessment tool were increasingly used. Students were increasingly able to describe and manipulate models of the processes and systems being studied in this course as measured by assessment items. However, their ability to apply these models in new contexts did not improve. Finally, we discuss the implications of our results and the future directions for our research

WGS-based telomere length analysis in Dutch family trios implicates stronger maternal inheritance and a role for RRM1 gene

Telomere length (TL) regulation is an important factor in ageing, reproduction and cancer development. Genetic, hereditary and environmental factors regulating TL are currently widely investigated, however, their relative contribution to TL variability is still understudied. We have used whole genome sequencing data of 250 family trios from the Genome of the Netherlands project to perform computational measurement of TL and a series of regression and genome-wide association analyses to reveal TL inheritance patterns and associated genetic factors. Our results confirm that TL is a largely heritable trait, primarily with mother’s, and, to a lesser extent, with father’s TL having the strongest influence on the offspring. In this cohort, mother’s, but not father’s age at conception was positively linked to offspring TL. Age-related TL attrition of 40 bp/year had relatively small influence on TL variability. Finally, we have identified TL-associated variations in ribonuclease reductase catalytic subunit M1 (RRM1 gene), which is known to regulate telomere maintenance in yeast. We also highlight the importance of multivariate approach and the limitations of existing tools for the analysis of TL as a polygenic heritable quantitative trait

Nontuberculous mycobacteria, Zambia

Clinical relevance of nontuberculous mycobacteria (NTM) isolated from 180 chronically ill patients and 385 healthy controls in Zambia was evaluated to examine the contribution of these isolates to tuberculosis (TB)-like disease. The proportion of NTM-positive sputum samples was significantly higher in the patient group than in controls; 11% and 6%, respectively (p<0.05). NTM-associated lung disease was diagnosed for 1 patient, and a probable diagnosis was made for 3 patients. NTM-positive patients and controls were more likely to report vomiting and diarrhea and were more frequently underweight than the NTM-negative patients and controls. Chest radiographs of NTM-positive patients showed deviations consistent with TB more frequently than those of controls. The most frequently isolated NTM was Mycobacterium avium complex. Multiple, not previously identified mycobacteria (55 of 171 NTM) were isolated from both groups. NTM probably play an important role in the etiology of TB-like diseases in Zambia

Exome sequencing of family trios from the National Birth Defects Prevention Study: Tapping into a rich resource of genetic and environmental data

Background: The National Birth Defects Prevention Study (NBDPS) is a multisite, population-based, case–control study of genetic and nongenetic risk factors for major structural birth defects. Eligible women had a pregnancy affected by a birth defect or a liveborn child without a birth defect between 1997 and 2011. They were invited to complete a telephone interview to collect pregnancy exposure data and were mailed buccal cell collection kits to collect specimens from themselves, their child (if living), and their child's father. Over 23,000 families representing more than 30 major structural birth defects provided DNA specimens. Methods: To evaluate their utility for exome sequencing (ES), specimens from 20 children with colonic atresia were studied. Evaluations were conducted on specimens collected using cytobrushes stored and transported in open versus closed packaging, on native genomic DNA (gDNA) versus whole genome amplified (WGA) products and on a library preparation protocol adapted to low amounts of DNA. Results: The DNA extracted from brushes in open packaging yielded higher quality sequence data than DNA from brushes in closed packaging. Quality metrics of sequenced gDNA were consistently higher than metrics from corresponding WGA products and were consistently high when using a low input protocol. Conclusions: This proof-of-principle study established conditions under which ES can be applied to NBDPS specimens. Successful sequencing of exomes from well-characterized NBDPS families indicated that this unique collection can be used to investigate the roles of genetic variation and gene–environment interaction effects in birth defect etiologies, providing a valuable resource for birth defect researchers