Towards scalable parallel-in-time turbulent flow simulations

We present a reformulation of unsteady turbulent flow simulations. The initial condition is relaxed and information is allowed to propagate both forward and backward in time. Simulations of chaotic dynamical systems with this reformulation can be proven to be well-conditioned time domain boundary value problems. The reformulation can enable scalable parallel-in-time simulation of turbulent flows.United States. Air Force Office of Scientific Research. Small Business Technology Transfer Program (Contract FA9550-12-C-0065

Auxin efflux controls orderly nucellar degeneration and expansion of the female gametophyte in Arabidopsis

The nucellus tissue in flowering plants provides nutrition for the development of the female gametophyte (FG) and young embryo. The nucellus degenerates as the FG develops, but the mechanism controlling the coupled process of nucellar degeneration and FG expansion remains largely unknown. The degeneration process of the nucellus and spatiotemporal auxin distribution in the developing ovule before fertilization were investigated in Arabidopsis thaliana. Nucellar degeneration before fertilization occurs through vacuolar cell death and in an ordered degeneration fashion. This sequential nucellar degeneration is controlled by the signalling molecule auxin. Auxin efflux plays the core role in precisely controlling the spatiotemporal pattern of auxin distribution in the nucellus surrounding the FG. The auxin efflux carrier PIN1 transports maternal auxin into the nucellus while PIN3/PIN4/PIN7 further delivers auxin to degenerating nucellar cells and concurrently controls FG central vacuole expansion. Notably, auxin concentration and auxin efflux are controlled by the maternal tissues, acting as a key communication from maternal to filial tissue

Pathogenic Mutations in Cancer-Predisposing Genes: A Survey of 300 Patients with Whole-Genome Sequencing and Lifetime Electronic Health Records

Background: It is unclear whether and how whole-genome sequencing (WGS) data can be used to implement genomic medicine. Our objective is to retrospectively evaluate whether WGS can facilitate improving prevention and care for patients with susceptibility to cancer syndromes. Methods and Findings: We analyzed genetic mutations in 60 autosomal dominant cancer-predisposition genes in 300 deceased patients with WGS data and nearly complete long-term (over 30 years) medical records. To infer biological insights from massive amounts of WGS data and comprehensive clinical data in a short period of time, we developed an in-house analysis pipeline within the SeqHBase software framework to quickly identify pathogenic or likely pathogenic variants. The clinical data of the patients who carried pathogenic and/or likely pathogenic variants were further reviewed to assess their clinical conditions using their lifetime EHRs. Among the 300 participants, 5 (1.7%) carried pathogenic or likely pathogenic variants in 5 cancer-predisposing genes: one in APC, BRCA1, BRCA2, NF1, and TP53 each. When assessing the clinical data, each of the 5 patients had one or more different types of cancers, fully consistent with their genetic profiles. Among these 5 patients, 2 died due to cancer while the others had multiple disorders later in their lifetimes; however, they may have benefited from early diagnosis and treatment for healthier lives, had the patients had genetic testing in their earlier lifetimes. Conclusions: We demonstrated a case study where the discovery of pathogenic or likely pathogenic germline mutations from population-wide WGS correlates with clinical outcome. The use of WGS may have clinical impacts to improve healthcare delivery

Lymphovascular Invasion in Colorectal Cancer: An Interobserver Variability Study

Background: Lymphovascular invasion (LVI) in colorectal cancer (CRC) is considered a strong stage-independent prognostic factor and influences decisions regarding adjuvant chemotherapy in patients with Stage II tumors. However, the degree of interobserver agreement among pathologists for LVI in CRC is largely unknown. This study was undertaken to examine such interobserver variability, and we hypothesized that the use of immunohistochemical markers for vascular and lymphatic channels could improve interobserver agreement. Design: Fifty cases of AJCC stage II moderately differentiated CRC from 1990 to 2005 from the pathology archives were selected; mucinous, medullary, and other recognized special subtypes were excluded. Fifty H&E slides (one from each case) were circulated to 6 GI pathologists, who independently assessed small and large vessel invasion. No diagnostic guidelines were given to the participating pathologists; each was instructed to apply the criteria for LVI that he or she used in daily practice. Immunohistochemistry (IHC) for D2-40 and CD31 was performed on corresponding paraffin blocks. The IHC slides were randomized, recirculated, and rescored for LVI. Results were analyzed by kappa (κ)statistics, which correct for agreement by chance, and for percent agreement. Results: The average κ values were determined for the H&E slides (large and small vessel), CD31 (small vessel), and D2-40 (small vessel) (Figure 1). Agreement was fair for H&E small vessel invasion (κ = 0.28; 95%CI 0.22–0.34). The least agreement was seen in interpretation of H&E large vessel invasion (κ = 0.18; 95%CI 0.11–0.26). Agreement was not improved by use of immunohistochemical stains: CD31 (large vessel, κ = 0.42, 95%CI 0.20–0.63, small vessel, κ = 0.26, 95%CI 0.10–0.42) and D2-40 (κ = 0.32, 95%CI 0.21–0.42). Conclusions: Interobserver variability in diagnosis of LVI was substantial on H&E slides and did not improve upon use of IHC. Agreement in evaluation of large vessel invasion was only slightly higher than would be seen by chance alone. This study highlights the need for criteria in evaluation of lymphovascular invasion, as this assessment may impact patient prognosis and thus change the course of clinical treatment

Authorship Trends in the Journal of Orthopaedic Research: A Bibliometric Analysis

Publications are an important tool to measure one's success and achievement in academia. They can help propel a career forward and move one into a position of leadership. The overall purpose of this study was to investigate changes in bibliometric variables, authorship, and collaboration trends in the Journal of Orthopaedic Research (JOR®), since its inception in 1983. A bibliometric analysis was completed for all manuscripts meeting the inclusion criteria (638), which were published throughout the inaugural year plus one representative year of each decade. Several parameters were investigated including numbers of manuscripts, authors, collaborating institutions/countries, references, pages, and citations; region of origin and gender of authors over time and by region were main focuses. Significant increases over time were observed in all bibliometric variables analyzed except in the number of pages and citations. There was an approximate 27 percentage point increase for both female first and corresponding authors from 1983 to 2015. While this is most likely due to the increase in the number of women that have entered the field over time, similar increases in the percentage of women holding positions on the JOR editorial board or in leadership positions within in the field may have also contributed to improvements in gender parity. Understanding changes in publishing characteristics over time, by region, and by gender are critical, especially with the rising demands of publishing in academia. JOR has seen increase in most variables analyzed, including improvements in authorship by women in the field of orthopaedic research

Changing indications and socio-demographic determinants of (adeno)tonsillectomy among children in England--are they linked? A retrospective analysis of hospital data.

OBJECTIVE: To assess whether increased awareness and diagnosis of obstructive sleep apnoea syndrome (OSAS) and national guidance on tonsillectomy for recurrent tonsillitis have influenced the socio-demographic profile of children who underwent tonsillectomy over the last decade. METHOD: Retrospective time-trends study of Hospital Episodes Statistics data. We examined the age, sex and deprivation level, alongside OSAS diagnoses, among children aged <16 years who underwent (adeno)tonsillectomy in England between 2001/2 and 2011/12. RESULTS: Among children aged <16 years, there were 29,697 and 27,732 (adeno)tonsillectomies performed in 2001/2 and 2011/12, respectively. The median age at (adeno)tonsillectomy decreased from 7 (IQR: 5-11) to 5 (IQR: 4-9) years over the decade. (Adeno)tonsillectomy rates among children aged 4-15 years decreased by 14% from 350 (95%CI: 346-354) in 2001/2 to 300 (95%CI: 296-303) per 100,000 children in 2011/12. However, (adeno)tonsillectomy rates among children aged <4 years increased by 58% from 135 (95%CI: 131-140) to 213 (95%CI 208-219) per 100,000 children in 2001/2 and 2011/2, respectively. OSAS diagnoses among children aged <4 years who underwent surgery increased from 18% to 39% between these study years and the proportion of children aged <4 years with OSAS from the most deprived areas increased from 5% to 12%, respectively. CONCLUSIONS: (Adeno)tonsillectomy rates declined among children aged 4-15 years, which reflects national guidelines recommending the restriction of the operation to children with more severe recurrent throat infections. However, (adeno)tonsillectomy rates among pre-school children substantially increased over the past decade and one in five children undergoing the operation was aged <4 years in 2011/12.The increase in surgery rates in younger children is likely to have been driven by increased awareness and detection of OSAS, particularly among children from the most deprived areas

A Multi-Institutional Analysis of Adjuvant Chemotherapy and Radiation Sequence in Women With Stage IIIC Endometrial Cancer

PURPOSE: Our purpose was to evaluate the effect of sequence and type of adjuvant therapy for patients with stage IIIC endometrial carcinoma (EC) on outcomes. METHODS AND MATERIALS: In a multi-institutional retrospective cohort study, patients with stage IIIC EC who had surgical staging and received both adjuvant chemotherapy and radiation therapy (RT) were included. Adjuvant treatment regimens were classified as adjuvant chemotherapy followed by sequential RT (upfront chemo), which was predominant sequence; RT with concurrent chemotherapy followed by chemotherapy (concurrent); systemic chemotherapy before and after RT (sandwich); adjuvant RT followed by chemotherapy (upfront RT); or chemotherapy concurrent with vaginal cuff brachytherapy alone (chemo-brachy). Overall survival (OS) and recurrence-free survival (RFS) rates were estimated by the Kaplan-Meier method. RESULTS: A total of 686 eligible patients were included with a median follow-up of 45.3 months. The estimated 5-year OS and RFS rates were 74% and 66%, respectively. The sequence and type of adjuvant therapy were not correlated with OS or RFS (adjusted P = .68 and .84, respectively). On multivariate analysis, black race, nonendometrioid histology, grade 3 tumor, stage IIIC2, and presence of adnexal and cervical involvement were associated with worse OS and RFS (all P \u3c .05). Regardless of the sequence of treatment, the most common site of first recurrence was distant metastasis (20.1%). Vaginal only, pelvic only, and paraortic lymph node (PALN) recurrences occurred in 11 (1.6%),15 (2.2 %), and 43 (6.3 %) patients, respectively. Brachytherapy alone was associated with a higher rate of PALN recurrence (15%) compared with external beam radiation therapy (5%) P \u3c .0001. CONCLUSIONS: The sequence and type of combined adjuvant therapy did not affect OS or RFS rates. Brachytherapy alone was associated with a higher rate of PALN recurrence, emphasizing the role of nodal radiation for stage IIIC EC. The vast proportion of recurrences were distant despite systemic chemotherapy, highlighting the need for novel regimens