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The Annonaceae, the largest family in the early-divergent order Magnoliales, comprises 107 genera and c. 2,400 species. Previous molecular phylogenetic studies targeting different taxa have generated large quantities of partially overlapping DNA sequence data for many species, although a large-scale phylogeny based on the maximum number of representatives has never been reconstructed. We use a supermatrix of eight chloroplast markers (rbcL, matK, ndhF, psbA-trnH, trnL-F, atpB-rbcL, trnS-G and ycf1) to reconstruct the most comprehensive tree to date, including 705 species (29%) from 105 genera (98%). This provides novel insights into the relationships of five enigmatic genera (Bocagea, Boutiquea, Cardiopetalum, Duckeanthus and Phoenicanthus). Fifteen main clades are retrieved in subfamilies Annonoideae and Malmeoideae collectively, 14 of which correspond with currently recognised tribes. Phoenicanthus cannot be accommodated in any existing tribe, however: it is retrieved as sister to a clade comprising the tribes Dendrokingstonieae, Monocarpieae and Miliuseae, and we therefore validate a new tribe, Phoenicantheae. Our results provide strong support for many previously recognised groups, but also indicate non-monophyly of several genera (Desmopsis, Friesodielsia, Klarobelia, Oxandra, Piptostigma and Stenanona). The relationships of these non-monophyletic genera-and two other genera (Froesiodendron and Melodorum) not yet sampled-are discussed, with recommendations for future research.

Background: The Thoracic Revised Cardiac Index (ThRCRI) is a tool that differentiates patients who may proceed to lung resection (classes A or B) from those who should receive additional cardiac evaluation (classes C or D). This study aims to describe the ability of the ThRCRI to stratify patients based on major cardiac complication rates using a large multi-institutional dataset., Methods: Patients undergoing lobectomy or pneumonectomy were identified in the American College of Surgeons National Surgical Quality Improvement Program dataset from 2005 to 2012. Patients were grouped into 4 risk classes based on a summary score of preoperative risk factors: ischemic heart disease, cerebrovascular disease, renal comorbidity, and pneumonectomy. The primary outcome was the incidence of perioperative major cardiac complication in each of the 4 risk classes., Results: Of the 4,625 patients identified, the majority underwent surgery for malignant disease (78%) and had an open procedure (70%). Among ThRCRI risk factors, 9% of patients had ischemic heart disease, 7% had cerebrovascular disease, 2% had renal comorbidity, and 6% underwent pneumonectomy. Incidence of cardiac complication in all patients was 2%. Incidence of cardiac complication within risk classes A, B, C, and D were 1%, 3%, 9%, and 4%, respectively (p < 0.01)., Conclusions: Using a large multi-institutional dataset, the ThRCRI can differentiate patients at higher risk for cardiac complication following lung resection (classes C and D) and can be a useful preoperative instrument. The ThRCRI may allow for identifying patients who would benefit from additional cardiac evaluation., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Screening behavior depends on previous screening history and family members' behaviors, which can act as both confounders and intermediate variables on a causal pathway from screening to disease risk. Conventional analyses that adjust for these variables can lead to incorrect inferences about the causal effect of screening if high-risk individuals are more likely to be screened. Analyzing the data in a manner that treats screening as randomized conditional on covariates allows causal parameters to be estimated; inverse probability weighting based on propensity of exposure scores is one such method considered here. I simulated family data under plausible models for the underlying disease process and for screening behavior to assess the performance of alternative methods of analysis and whether a targeted screening approach based on individuals' risk factors would lead to a greater reduction in cancer incidence in the population than a uniform screening policy. Simulation results indicate that there can be a substantial underestimation of the effect of screening on subsequent cancer risk when using conventional analysis approaches, which is avoided by using inverse probability weighting. A large case-control study of colonoscopy and colorectal cancer from Germany shows a strong protective effect of screening, but inverse probability weighting makes this effect even stronger. Targeted screening approaches based on either fixed risk factors or family history yield somewhat greater reductions in cancer incidence with fewer screens needed to prevent one cancer than population-wide approaches, but the differences may not be large enough to justify the additional effort required. See video abstract at, http://links.lww.com/EDE/B207.

A geriatric ambulatory curriculum was created to improve internal medicine residents' care of geriatric patients. Second-year residents met for a 3-hour session weekly for 4 consecutive weeks during a block rotation with faculty geriatricians for a curriculum focused on dementia, falls, and urinary incontinence. After a 1-hour case-based didactic session, residents applied learned content and concepts to patient consultations. Consultative encounters were precepted by faculty and shared with the team. After completing our curriculum, residents reported knowledge acquired and enhanced evaluation and management skills of these three syndromes and were more likely to use all recommended screening tests in future practice. This article describes the process and strategies guiding development of a successful ambulatory geriatric curriculum model that can be embedded into preexisting internal medicine clinics to help future internists to better manage these and other common geriatric syndromes.

Evidence-based interventions to improve health care and medical education face multiple complex barriers to adoption and success. Implementation science focuses on the period following research dissemination, which is necessary but insufficient to address important gaps in clinician performance and patient outcomes. This article describes the forces on health care institutions, medical schools, physician clinicians, and trainees that have created the imperative to design educational interventions to address the gap between evidence and practice. These forces include accreditation, certification, licensure, and regulatory and research funding initiatives focused on improving the quality of health professions education and clinical practice. Medical educators must expand their focus on "what to change" to include "how to change" in order to prepare health care professionals and institutions to effectively adopt new evidence-based practices to improve patient, and ultimately population, outcomes.

Several evolutionary lineages in the early divergent angiosperm family Annonaceae possess flowers with a distinctive pollinator trapping mechanism, in which floral phenological events are very precisely timed in relation with pollinator activity patterns. This contrasts with previously described angiosperm pollinator traps, which predominantly function as pitfall traps. We assess the circadian rhythms of pollinators independently of their interactions with flowers, and correlate these data with detailed assessments of floral phenology. We reveal a close temporal alignment between patterns of pollinator activity and the floral phenology driving the trapping mechanism (termed 'circadian trapping' here). Non-trapping species with anthesis of standard duration (c. 48 h) cannot be pollinated effectively by pollinators with a morning-unimodal activity pattern; non-trapping species with abbreviated anthesis (23-27 h) face limitations in utilizing pollinators with a bimodal circadian activity; whereas species that trap pollinators (all with short anthesis) can utilize a broader range of potential pollinators, including those with both unimodal and bimodal circadian rhythms. In addition to broadening the range of potential pollinators based on their activity patterns, circadian trapping endows other selective advantages, including the possibility of an extended staminate phase to promote pollen deposition, and enhanced interfloral movement of pollinators. The relevance of the alignment of floral phenological changes with peaks in pollinator activity is furthermore evaluated for pitfall trap pollination systems.

It has been postulated that during human fetal development, all cells of the lung epithelium derive from embryonic, endodermal, NK2 homeobox 1-expressing (NKX2-1+) precursor cells. However, this hypothesis has not been formally tested owing to an inability to purify or track these progenitors for detailed characterization. Here we have engineered and developmentally differentiated NKX2-1GFP reporter pluripotent stem cells (PSCs) in vitro to generate and isolate human primordial lung progenitors that express NKX2-1 but are initially devoid of differentiated lung lineage markers. After sorting to purity, these primordial lung progenitors exhibited lung epithelial maturation. In the absence of mesenchymal coculture support, this NKX2-1+ population was able to generate epithelial-only spheroids in defined 3D cultures. Alternatively, when recombined with fetal mouse lung mesenchyme, the cells recapitulated epithelial-mesenchymal developing lung interactions. We imaged these progenitors in real time and performed time-series global transcriptomic profiling and single-cell RNA sequencing as they moved through the earliest moments of lung lineage specification. The profiles indicated that evolutionarily conserved, stage-dependent gene signatures of early lung development are expressed in primordial human lung progenitors and revealed a CD47hiCD26lo cell surface phenotype that allows their prospective isolation from untargeted, patient-specific PSCs for further in vitro differentiation and future applications in regenerative medicine.

Effective derivation of functional airway organoids from induced pluripotent stem cells (iPSCs) would provide valuable models of lung disease and facilitate precision therapies for airway disorders such as cystic fibrosis. However, limited understanding of human airway patterning has made this goal challenging. Here, we show that cyclical modulation of the canonical Wnt signaling pathway enables rapid directed differentiation of human iPSCs via an NKX2-1 + progenitor intermediate into functional proximal airway organoids. We find that human NKX2-1 + progenitors have high levels of Wnt activation but respond intrinsically to decreases in Wnt signaling by rapidly patterning into proximal airway lineages at the expense of distal fates. Using this directed approach, we were able to generate cystic fibrosis patient-specific iPSC-derived airway organoids with a defect in forskolin-induced swelling that is rescued by gene editing to correct the disease mutation. Our approach has many potential applications in modeling and drug screening for airway diseases., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Importance: Adjuvant chemotherapy offers a survival benefit to a number of staging scenarios in non-small-cell lung cancer. Variable recovery from lung cancer surgery may delay a patient's ability to tolerate adjuvant chemotherapy, yet the urgency of chemotherapy initiation is unclear., Objective: To assess differences in survival according to the time interval between non-small-cell lung cancer resection and the initiation of postoperative chemotherapy to determine the association between adjuvant treatment timing and efficacy., Design, Setting, and Participants: This retrospective observational study examined treatment-naive patients with completely resected non-small-cell lung cancer who received postoperative multiagent chemotherapy between 18 and 127 days after resection between January 2004 and December 2012. The study population was limited to patients with lymph node metastases, tumors 4 cm or larger, or local extension. Patients were identified from the National Cancer Database, a hospital-based tumor registry that captures more than 70% of incident lung cancer cases in the United States. The association between time to initiation of adjuvant chemotherapy and survival was evaluated using Cox models with restricted cubic splines., Exposures: Adjuvant chemotherapy administered at different time points after surgery., Main Outcomes and Measures: Effectiveness of adjuvant chemotherapy according to time to initiation after surgery., Results: A total of 12 473 patients (median [interquartile range] age, 64 [57-70] years) were identified: 3073 patients (25%) with stage I disease; 5981 patients (48%), stage II; and 3419 patients (27%), stage III. A Cox model with restricted cubic splines identified the lowest mortality risk when chemotherapy was started 50 days postoperatively (95% CI, 39-56 days). Initiation of chemotherapy after this interval (57-127 days; ie, the later cohort) did not increase mortality (hazard ratio [HR], 1.037; 95% CI, 0.972-1.105; P = .27). Furthermore, in a Cox model of 3976 propensity-matched pairs, patients who received chemotherapy during the later interval had a lower mortality risk than those treated with surgery only (HR, 0.664; 95% CI, 0.623-0.707; P < .001)., Conclusions and Relevance: In the National Cancer Database, adjuvant chemotherapy remained efficacious when started 7 to 18 weeks after non-small-cell lung cancer resection. Patients who recover slowly from non-small-cell lung cancer surgery may still benefit from delayed adjuvant chemotherapy started up to 4 months after surgery.

With the aim of improving detection of novel single-nucleotide polymorphisms (SNPs) in genetic association studies, we propose a method of including prior biological information in a Bayesian shrinkage model that jointly estimates SNP effects. We assume that the SNP effects follow a normal distribution centered at zero with variance controlled by a shrinkage hyperparameter. We use biological information to define the amount of shrinkage applied on the SNP effects distribution, so that the effects of SNPs with more biological support are less shrunk toward zero, thus being more likely detected. The performance of the method was tested in a simulation study (1,000 datasets, 500 subjects with ∼200 SNPs in 10 linkage disequilibrium (LD) blocks) using a continuous and a binary outcome. It was further tested in an empirical example on body mass index (continuous) and overweight (binary) in a dataset of 1,829 subjects and 2,614 SNPs from 30 blocks. Biological knowledge was retrieved using the bioinformatics tool Dintor, which queried various databases. The joint Bayesian model with inclusion of prior information outperformed the standard analysis: in the simulation study, the mean ranking of the true LD block was 2.8 for the Bayesian model versus 3.6 for the standard analysis of individual SNPs; in the empirical example, the mean ranking of the six true blocks was 8.5 versus 9.3 in the standard analysis. These results suggest that our method is more powerful than the standard analysis. We expect its performance to improve further as more biological information about SNPs becomes available., (© 2017 WILEY PERIODICALS, INC.)

The phagocyte respiratory burst is crucial for innate immunity. The transfer of electrons to oxygen is mediated by a membrane-bound heterodimer, comprising gp91 phox and p22 phox subunits. Deficiency of either subunit leads to severe immunodeficiency. We describe Eros (essential for reactive oxygen species), a protein encoded by the previously undefined mouse gene bc017643 , and show that it is essential for host defense via the phagocyte NAPDH oxidase. Eros is required for expression of the NADPH oxidase components, gp91 phox and p22 phox Consequently, Eros -deficient mice quickly succumb to infection. Eros also contributes to the formation of neutrophil extracellular traps (NETS) and impacts on the immune response to melanoma metastases. Eros is an ortholog of the plant protein Ycf4, which is necessary for expression of proteins of the photosynthetic photosystem 1 complex, itself also an NADPH oxio-reductase. We thus describe the key role of the previously uncharacterized protein Eros in host defense., (© 2017 Thomas et al.)

The complexity of the human exposome-the totality of environmental exposures encountered from birth to death-motivates systematic, high-throughput approaches to discover new environmental determinants of disease. In this review, we describe the state of science in analyzing the human exposome and provide recommendations for the public health community to consider in dealing with analytic challenges of exposome-based biomedical research. We describe extant and novel analytic methods needed to associate the exposome with critical health outcomes and contextualize the data-centered challenges by drawing parallels to other research endeavors such as human genomics research. We discuss efforts for training scientists who can bridge public health, genomics, and biomedicine in informatics and statistics. If an exposome data ecosystem is brought to fruition, it will likely play a role as central as genomic science has had in molding the current and new generations of biomedical researchers, computational scientists, and public health research programs.

High consanguinity rates, poor access to accurate diagnostic tests, and costly therapies are the main causes of increased burden of lysosomal storage disorders (LSDs) in developing countries. Therefore, there is a major unmet need for accurate and economical diagnostic tests to facilitate diagnosis and consideration of therapies before irreversible complications occur. In cross-country study, we utilized dried blood spots (DBS) of 1,033 patients clinically suspected to harbor LSDs for enzymatic diagnosis using modified fluorometric assays from March 2013 through May 2015. Results were validated by demonstrating reproducibility, testing in different sample types (leukocytes/plasma/skin fibroblast), mutation study, or measuring specific biomarkers. Thirty percent (307/1,033) were confirmed to have one of the LSDs tested. Reference intervals established unambiguously identified affected patients. Correlation of DBS results with other biological samples (n = 172) and mutation studies (n = 74) demonstrated 100% concordance in Gaucher, Fabry, Tay Sachs, Sandhoff, Niemann-Pick, GM1, Neuronal ceroid lipofuscinosis (NCL), Fucosidosis, Mannosidosis, Mucopolysaccharidosis (MPS) II, IIIb, IVa, VI, VII, and I-Cell diseases, and 91.4% and 88% concordance in Pompe and MPS-I, respectively. Gaucher and Pompe are the most common LSDs in India and Pakistan, followed by MPS-I in both India and Sri Lanka. Study demonstrates utility of DBS for reliable diagnosis of LSDs. Diagnostic accuracy (97.6%) confirms veracity of enzyme assays. Adoption of DBS will overcome significant hurdles in blood sample transportation from remote regions. DBS enzymatic and molecular diagnosis should become the standard of care for LSDs to make timely diagnosis, develop personalized treatment/monitoring plan, and facilitate genetic counseling.

Background: A proportion of patients with clinical stage I small cell lung cancer (SCLC) will be upstaged following surgical resection. The existing data regarding the management of upstaged SCLC patients and guidelines for their treatment remains sparse. The primary objective was to describe the impact of pathologic upstaging following surgical resection., Methods: The National Cancer Database was queried for patients with clinical stage I SCLC (cT1-2a,N0,M0) who underwent resection with curative intent followed by adjuvant therapy, excluding patients who underwent surgery alone. Clinical and pathologic T, N, and M staging were compared to identify patients that were upstaged., Results: Four-hundred and seventy-seven patients were identified with clinical stage I SCLC. Pathologic upstaging occurred in 25% (117). Of those upstaged, 30% (35) were due to a higher pathologic T descriptor and 81% (95) were due to the presence of nodal disease. Overall 5-year survival was significantly worse for upstaged patients compared with those patients who remained a pathologically stage I (36% vs 52%, p<0.001). Among patients with positive lymph node involvement, adjuvant chemotherapy and radiation therapy was associated a significantly improved 5-year survival compared to adjuvant chemotherapy alone (20% vs 55%, respectively, p<0.01). The use of adjuvant chemotherapy and radiation therapy in patients with nodal disease after surgical resection was an independent predictor of improved survival (HR 0.36, 95% CI 0.18-0.73, p<0.01)., Conclusions: Pathologic upstaging is common after surgical resection of stage I SCLC, and is associated with significantly inferior survival. These data provide evidence that recommend the use of adjuvant chemotherapy and radiation therapy in the setting of nodal upstaging after resection of clinical stage I SCLC patients., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: To determine the diagnostic accuracy of preeclampsia (PE) screening test offered in early pregnancy for the prediction of the risks for early-onset (requiring delivery <32 weeks gestation) and late-onset (requiring delivery ≥32 weeks gestation) disease., Methods: In a retrospective study of 615 women with singleton pregnancy, the risk for PE was calculated by the combined effect of multiple variables: serum placental growth factor (PLGF) and pregnancy-associated plasma protein-A (PAPP-A), maternal age, parity, ethnicity, mean arterial pressure (MAP), body mass index (BMI), uterine artery-pulsatility index, and previous history of PE or hypertension (HT). The results of the screening test in three different groups of women were validated by pregnancy outcome: (i) control group - without any history of PE/HT; (ii) history of PE without HT; and (iii) history of HT without PE. The performance of the screening test was evaluated for early- and late-onset PE., Results: The multivariate screening effectively identified cases of PE with >97% specificity. The detection rate (DR) was 93.8% for late-onset PE at a false positive rate (FPR) of 2.3% and 44.4% for early-onset PE at an FPR of 0.0%. The incidence of PE was 7% overall, with 1.52% and 5.43% for early- and late-onset PE, respectively., Conclusion: The study demonstrated 96.6% diagnostic accuracy of the multi-variable screening test to predict the risk of PE in the first trimester. The negative predictive value (>98%) reinforces the utility of cost-effective noninvasive screening test for the early detection of PE., Abbreviations: PLGF: Placental growth factor; PAPP-A: Pregnancy-associated plasma protein-A; free β-HCG: Free beta-human chorionic gonadotropin; BMI: Body mass index; MAP: Mean arterial blood pressure; Ut-PI: Mean uterine artery pressure (left and right uterine artery)-pulsatility index; MoM: Multiple of median; NICE: National Institute for Health and Clinical Excellence.

Background: Rapid Syllable Transitions (ReST) treatment uses pseudo-word targets with varying lexical stress to target simultaneously articulation, prosodic accuracy and coarticulatory transitions in childhood apraxia of speech (CAS). The treatment is efficacious for the acquisition of imitated pseudo-words, and generalization of skill to untreated pseudo-words and real words. Despite the growing popularity of telehealth as a method of service delivery, there is no research into the efficacy of telehealth treatments for CAS. Telehealth service delivery is associated with compromised audio and visual signal transmission that may affect the efficacy of treatment., Aims: To conduct a phase 1 efficacy study of telehealth delivery of ReST treatment for CAS, and to discuss the efficacy with reference to face-to-face ReST treatment., Methods & Procedures: Using a multiple baseline across participants design, five children aged 5-11 years with CAS received ReST treatment four times a week for 3 weeks via video conferencing with Adobe Connect. The children's ability to imitate new pseudo-words, generalize the skills to untreated pseudo-words and real word items, and maintain the skills following treatment were assessed. Both visual and statistical analyses were utilized., Outcomes & Results: All five children significantly improved with their production of the imitated treated pseudo-word items and significantly generalized to similar untreated pseudo-words and real words. Additionally, two of the children showed significant generalization to imitated phrases with the treatment items. Four of the children maintained their treatment gains up to 4 months post-treatment. Telehealth delivery produced similar acquisition of pseudo-words and generalization to untreated behaviours as face-to-face delivery; however, in the 4 months following treatment, the children showed stable rather than improving speech skills. The intra- and inter-judge reliability was similar in telehealth delivery for face-to-face delivery. Caregivers and clinicians were satisfied with the telehealth treatment., Conclusions & Implications: This phase 1 study provides promising indications of the efficacy of ReST treatment when delivered four times per week via telehealth, and warrants further large-scale investigation., (© 2016 Royal College of Speech and Language Therapists.)

Background: Trained medical interpreters are instrumental to patient satisfaction and quality of care. They are especially important in student-run clinics, where many patients have limited English proficiency. Because student-run clinics have ties to their medical schools, they have access to bilingual students who may volunteer to interpret, but are not necessarily formally trained., Methods: To study the feasibility and efficacy of leveraging medical student volunteers to improve interpretation services, we performed a pilot study at the student-run clinic at the Icahn School of Medicine at Mount Sinai. In each fall semester in 2012-2015, we implemented a 6-h course providing didactic and interactive training on medical Spanish interpreting techniques and language skills to bilingual students. We then assessed the impact of the course on interpreter abilities., Results: Participants' comfort levels, understanding of their roles, and understanding of terminology significantly increased after the course (p < 0.05), and these gains remained several months later (p < 0.05) and were repeated in an independent cohort. Patients and student clinicians also rated participants highly (averages above 4.5 out of 5) on these measures in real clinical encounters., Conclusions: These findings suggest that a formal interpreter training course tailored for medical students in the setting of a student-run clinic is feasible and effective. This program for training qualified student interpreters can serve as a model for other settings where medical students serve as interpreters.

Introduction: Young patients with lung cancer represent a distinct subset of patients with this disease. The National Cancer Data Base includes patients of all ages and contains detailed staging, treatment, and survival information. The objective of this study was to examine treatment patterns and outcomes in young patients with non-small cell lung cancer (NSCLC)., Methods: The National Cancer Data Base was queried for NSCLC cases from 2003 to 2009. Younger patients were defined as those aged 20 to 46 years. Older patients were defined as those aged 47 to 89 years. Patient demographics, tumor characteristics, treatment, and survival were analyzed. The primary outcomes were 5-year overall and relative survival., Results: The study included 173,856 patients; 5657 were 20 to 46 years of age. Younger patients were treated differently and received more aggressive therapy at each stage. At stage I, 64% of younger patients received surgery only versus 55% of the older patients (p < 0.0001). Younger patients had improved survival at all stages. This effect was more pronounced at earlier stages (the hazard ratios for the older group were 1.84, 1.62, 1.18, and 1.14 for stages I through IV, respectively [all p < 0.0001]). The absolute differences in 5-year overall survival between the younger and older groups were 25% for stages I and II but only 9% and 2% for stages III and IV, respectively., Conclusions: Overall and relative survival in younger patients with NSCLC is better than in older patients, with greater benefit seen in earlier stages. Despite having fewer comorbidities and undergoing more aggressive treatment, younger patients with advanced-stage NSCLC have only marginally better overall and relative survival than older patients., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: Adjuvant chemotherapy after surgical resection of non-small cell lung cancer is associated with a survival advantage in several staging scenarios. T3 tumors associated with a separate tumor nodule in the same lobe (formerly "satellite nodules") have a significant risk for systemic failure, yet the efficacy of adjuvant chemotherapy in this setting is unknown. The survival of patients with T3 tumors and additional tumor nodules in the same lobe treated with and without postoperative chemotherapy was evaluated to understand the role of adjuvant chemotherapy in this setting., Methods: The National Cancer Data Base was queried for patients with T3 tumors with additional tumor nodules in the same lobe between 2010 and 2012. Primary outcomes were 3-year overall and relative survival (a surrogate of cancer-specific survival)., Results: A total of 1013 patients with T3 tumors and additional tumor nodules in the same lobe were identified; 56% received multiagent postoperative chemotherapy and 44% were treated with surgical resection only. The use of adjuvant chemotherapy versus resection alone was associated with improved 3-year overall survival (70% versus 59%, p < 0.001). A Cox model adjusting for patient, tumor, and treatment factors demonstrated that adjuvant chemotherapy was associated with a survival advantage compared with resection alone (hazard ratio = 0.544, p < 0.0001). Relative 3-year survival was also improved in the adjuvant chemotherapy subgroup (74% versus 64% for the surgery-only subgroup)., Conclusions: Adjuvant chemotherapy is associated with increased overall survival among patients with T3 tumors with additional pulmonary nodules. Further study is warranted to clarify the role of adjuvant chemotherapy in this setting., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

An estimated 73870 people will be diagnosed with melanoma in the United States in 2015, resulting in 9940 deaths. The majority of patients with cutaneous melanomas are cured with wide local excision. However, current evidence supports the use of sentinel lymph node biopsy (SLNB) given the 15%-20% of patients who harbor regional node metastasis. More importantly, the presence or absence of nodal micrometastases has been found to be the most important prognostic factor in early-stage melanoma, particularly in intermediate thickness melanoma. This review examines the development of SLNB for melanoma as a means to determine a patient's nodal status, the efficacy of SLNB in patients with melanoma, and the biology of melanoma metastatic to sentinel lymph nodes. Prospective randomized trials have guided the development of practice guidelines for use of SLNB for melanoma and have shown the prognostic value of SLNB. Given the rapidly advancing molecular and surgical technologies, the technical aspects of diagnosis, identification, and management of regional lymph nodes in melanoma continues to evolve and to improve. Additionally, there is ongoing research examining both the role of SLNB for specific clinical scenarios and the ways to identify patients who may benefit from completion lymphadenectomy for a positive SLN. Until further data provides sufficient evidence to alter national consensus-based guidelines, SLNB with completion lymphadenectomy remains the standard of care for clinically node-negative patients found to have a positive SLN.

Background: For the last decade the conceptual framework of the Genome-Wide Association Study (GWAS) has dominated the investigation of human disease and other complex traits. While GWAS have been successful in identifying a large number of variants associated with various phenotypes, the overall amount of heritability explained by these variants remains small. This raises the question of how best to follow up on a GWAS, localize causal variants accounting for GWAS hits, and as a consequence explain more of the so-called "missing" heritability. Advances in high throughput sequencing technologies now allow for the efficient and cost-effective collection of vast amounts of fine-scale genomic data to complement GWAS., Results: We investigate these issues using a colon cancer dataset. After QC, our data consisted of 1993 cases, 899 controls. Using marginal tests of associations, we identify 10 variants distributed among six targeted regions that are significantly associated with colorectal cancer, with eight of the variants being novel to this study. Additionally, we perform so-called 'SNP-set' tests of association and identify two sets of variants that implicate both common and rare variants in the etiology of colorectal cancer., Conclusions: Here we present a large-scale targeted re-sequencing resource focusing on genomic regions implicated in colorectal cancer susceptibility previously identified in several GWAS, which aims to 1) provide fine-scale targeted sequencing data for fine-mapping and 2) provide data resources to address methodological questions regarding the design of sequencing-based follow-up studies to GWAS. Additionally, we show that this strategy successfully identifies novel variants associated with colorectal cancer susceptibility and can implicate both common and rare variants.

The skewness of the first time derivative of a pressure waveform, or derivative skewness, has been used previously to describe the presence of shock-like content in jet and rocket noise. Despite its use, a quantitative understanding of derivative skewness values has been lacking. In this paper, the derivative skewness for nonlinearly propagating waves is investigated using analytical, numerical, and experimental methods. Analytical expressions for the derivative skewness of an initially sinusoidal plane wave are developed and, along with numerical data, are used to describe its behavior in the preshock, sawtooth, and old-age regions. Analyses of common measurement issues show that the derivative skewness is relatively sensitive to the effects of a smaller sampling rate, but less sensitive to the presence of additive noise. In addition, the derivative skewness of nonlinearly propagating noise is found to reach greater values over a shorter length scale relative to sinusoidal signals. A minimum sampling rate is recommended for sinusoidal signals to accurately estimate derivative skewness values up to five, which serves as an approximate threshold indicating significant shock formation.

Taxonomic delimitation of Disepalum (Annonaceae) is contentious, with some researchers favoring a narrow circumscription following segregation of the genus Enicosanthellum. We reconstruct the phylogeny of Disepalum and related taxa based on four chloroplast and two nuclear DNA regions as a framework for clarifying taxonomic delimitation and assessing evolutionary transitions in key morphological characters. Maximum parsimony, maximum likelihood and Bayesian methods resulted in a consistent, well-resolved and strongly supported topology. Disepalum s.l. is monophyletic and strongly supported, with Disepalum s.str. and Enicosanthellum retrieved as sister groups. Although this topology is consistent with both taxonomic delimitations, the distribution of morphological synapomorphies provides greater support for the inclusion of Enicosanthellum within Disepalum s.l. We propose a novel infrageneric classification with two subgenera. Subgen. Disepalum (= Disepalum s.str.) is supported by numerous synapomorphies, including the reduction of the calyx to two sepals and connation of petals. Subgen. Enicosanthellum lacks obvious morphological synapomorphies, but possesses several diagnostic characters (symplesiomorphies), including a trimerous calyx and free petals in two whorls. We evaluate changes in petal morphology in relation to hypotheses of the genetic control of floral development and suggest that the compression of two petal whorls into one and the associated fusion of contiguous petals may be associated with the loss of the pollination chamber, which in turn may be associated with a shift in primary pollinator. We also suggest that the formation of pollen octads may be selectively advantageous when pollinator visits are infrequent, although this would only be applicable if multiple ovules could be fertilized by each octad; since the flowers are apocarpous, this would require an extragynoecial compitum to enable intercarpellary growth of pollen tubes. We furthermore infer that the monocarp fruit stalks are likely to have evolved independently from those in other Annonaceae genera and may facilitate effective dispersal by providing a color contrast within the fruit.

Purpose: To elicit residents' perspectives on rewards and challenges of caring for ambulatory patients with chronic illness and ways to improve their education in caring for these patients., Method: The authors conducted a qualitative study with internal medicine residents during ambulatory medicine block rotations at three academic health centers from October 2011 through February 2012. Focus group questions covered rewards and challenges of caring for patients with chronic illness and strengths and weaknesses of residency education therein, and the Chronic Care Model provided a framework for interpretation. Qualitative analysis was used to identify themes., Results: Five focus groups were conducted with 28 residents. Discussions yielded 224 comments, which were categorized into 5 domains and 36 themes. Twelve themes related to perceptions of challenges in providing care, and 3 themes related to perceptions of rewards in providing care. Eight themes focused on strategies to improve the patient experience. Strengths of the residency program were identified in 7 themes. Six themes related to ways for improving learning about caring for patients with chronic disease in the ambulatory setting., Conclusions: Residents perceived rewards, challenges, and barriers in caring for patients with chronic illness in the ambulatory setting, from providers' and patients' perspectives. They have developed strategies to provide effective patient care. Residents identified best practices in their residency for resident education and patient care and also made suggestions for improvement. Findings have significant implications for residency education and practice redesign in the 21st century for care of patients with chronic illness.

A phylogenetic study of the genus Goniothalamus (Annonaceae) is presented using maximum parsimony, maximum likelihood and Bayesian approaches, with 65 species sampled (48.5% of the genus) based on sequences of nine chloroplast DNA regions (11,214 aligned positions). The resultant phylogeny clearly indicates that Goniothalamus is monophyletic. Preliminary research initially focused on identifying synapomorphies and estimating the phylogenetic signal of selected morphological characters based on parsimony and likelihood ancestral character state reconstructions. This prescreening of characters enabled 40 to be selected for further study, and of these 15 are shown here to demonstrate significant phylogenetic signal and to provide clear synapomorphies for several infrageneric clades. Although floral structure in Goniothalamus is comparatively uniform, suggesting a common basic pattern of pollination ecology, fruit and seed morphology in the genus is very diverse and is presumably associated with different patterns of frugivory. The present study assesses correlations amongst fruit and seed characters which are putatively of functional importance with regard to frugivory and dispersal. One-way phylogenetic ANOVA indicates significant phylogenetically independent correlation between the following fruit and seed characters: fruits borne on older branches and/or on the main trunk have larger monocarps than fruits borne on young branches; and monocarps that contain seeds with a hairy testa are larger than those with glabrous seeds. We discuss fruit morphologies and potential explanations for the inferred correlations, and suggest that they may be the result of adaptation to different frugivores (birds, larger non-volant animal and primate seed dispersers, respectively)., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To offer accurate prenatal diagnosis of lysosomal storage disorders in early pregnancy., Method: Prenatal enzymatic diagnoses of Gaucher, Fabry, Pompe, Niemann Pick A/B, Tay Sach, Sandoff, GM1, mucoplysaccharidoses, Wolman, Krabbe, Metachromatic leukodystrophy and Batten diseases were made in uncultured chorionic villi samples by fluorometric/spectrophotometric methods., Results: Of 331 prenatal enzymatic diagnosis, 207 fetuses (67%) were normal and 124 (37%) were affected. The interpretation of affected, normal and carrier fetuses was done using their respective reference ranges as well as % enzyme activity of normal mean. The prenatal molecular confirmation was feasible in 43 biochemically diagnosed fetuses. Of the 207 normal reported fetuses, post natal enzymatic confirmation was done in 23 babies, clinical status of another 165 babies was assessed as unaffected via questionnaire on telephone and 19 were lost to follow-up. In affected pregnancies, 123 opted for termination of which 44 were confirmed enzymatically after abortion. A single false positive was determined to be a carrier by prenatal mutation analysis and carried to term., Conclusion: We recommend uncultured chorionic villi for reliable prenatal enzymatic diagnosis of various lysosomal storage disorders on account of the low rate of false positive (0.5%) and false negative (2.2%) results., (© 2015 John Wiley & Sons, Ltd.)

Arsenic toxicokinetics are important for disease risks in exposed populations, but genetic determinants are not fully understood. We examined urine arsenic species patterns measured by HPLC-ICPMS among 2189 Strong Heart Study participants 18 years of age and older with data on ~400 genome-wide microsatellite markers spaced ~10 cM and arsenic speciation (683 participants from Arizona, 684 from Oklahoma, and 822 from North and South Dakota). We logit-transformed % arsenic species (% inorganic arsenic, %MMA, and %DMA) and also conducted principal component analyses of the logit % arsenic species. We used inverse-normalized residuals from multivariable-adjusted polygenic heritability analysis for multipoint variance components linkage analysis. We also examined the contribution of polymorphisms in the arsenic metabolism gene AS3MT via conditional linkage analysis. We localized a quantitative trait locus (QTL) on chromosome 10 (LOD 4.12 for %MMA, 4.65 for %DMA, and 4.84 for the first principal component of logit % arsenic species). This peak was partially but not fully explained by measured AS3MT variants. We also localized a QTL for the second principal component of logit % arsenic species on chromosome 5 (LOD 4.21) that was not evident from considering % arsenic species individually. Some other loci were suggestive or significant for 1 geographical area but not overall across all areas, indicating possible locus heterogeneity. This genome-wide linkage scan suggests genetic determinants of arsenic toxicokinetics to be identified by future fine-mapping, and illustrates the utility of principal component analysis as a novel approach that considers % arsenic species jointly., (© The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Unintended consequences of secondary prevention include potential introduction of bias into epidemiologic studies estimating genotype-disease associations. To better understand such bias, we simulated a family-based study of colorectal cancer (CRC), which can be prevented by resecting screen-detected polyps. We simulated genes related to CRC development through risk of polyps (G1), risk of CRC but not polyps (G2), and progression from polyp to CRC (G3). Then, we examined 4 analytical strategies for studying diseases subject to secondary prevention, comparing the following: 1) CRC cases with all controls, without adjusting for polyp history; 2) CRC cases with controls, adjusting for polyp history; 3) CRC cases with only polyp-free controls; and 4) cases with either CRC or polyps with controls having neither. Strategy 1 yielded estimates of association between CRC and each G that were not substantially biased. Strategies 2-4 yielded biased estimates varying in direction according to analysis strategy and gene type. Type I errors were correct, but strategy 1 provided greater power for estimating associations with G2 and G3. We also applied each strategy to case-control data from the Colon Cancer Family Registry (1997-2007). Generally, the best analytical option balancing bias and power is to compare all CRC cases with all controls, ignoring polyps., (© The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The Society for Academic Continuing Medical Education commissioned a study to clarify and, if possible, to standardize the terminology for a set of important educational interventions. In the form of a guideline, this article describes one such intervention, interprofessional education (IPE), which is a common intervention in health professions education. IPE is an opportunity for individuals of multiple professions to interact to learn together, to break down professional silos, and to achieve interprofessional learning outcomes in the service of high-value patient care. Based on a review of recent evidence and a facilitated discussion with US and Canadian experts, we describe IPE, its terminology, and other important information about the intervention. We encourage leaders and researchers to consider and to build on this guideline as they plan, implement, evaluate, and report IPE efforts. Clear and consistent use of terminology is imperative, along with complete and accurate descriptions of interventions, to improve the use and study of IPE.

The Society for Academic Continuing Medical Education commissioned a study to clarify and, if possible, to standardize the terminology for a set of important educational interventions. In the form of a guideline, this article describes one such intervention, educational meetings, which is a common intervention in health professions' education. An educational meeting is an opportunity for clinicians to assemble to discuss and apply important information relevant to patient care. Based on a review of recent evidence and a facilitated discussion with US and Canadian experts, we describe proper educational meeting terminology and other important information about the intervention. We encourage leaders and researchers to consider and to build on this guideline as they plan, implement, evaluate, and report educational meeting efforts. Clear and consistent use of terminology is imperative, along with complete and accurate descriptions of interventions, to improve the use and study of educational meetings.

The Society for Academic Continuing Medical Education commissioned a study to clarify and, if possible, to standardize the terminology for a set of important educational interventions. In the form of a guideline, this article describes one such intervention, performance measurement and feedback, which is a common intervention in health professions education. In the form of a summary report, performance measurement and feedback is an opportunity for clinicians to view data about the care they provide compared with some standard and often with peer and benchmark comparisons. Based on a review of recent evidence and a facilitated discussion with the US and Canadian experts, we describe proper terminology for performance measurement and feedback and other important information about the intervention. We encourage leaders and researchers to consider and build on this guideline as they plan, implement, evaluate, and report efforts with performance measurement and feedback. Clear and consistent use of terminology is imperative, along with complete and accurate descriptions of interventions, to improve the use and study of performance measurement and feedback.

The Society for Academic Continuing Medical Education commissioned a study to clarify and, if possible, standardize the terminology for a set of important educational interventions. In the form of a guideline, this article describes one such intervention, practice facilitation, which is a common strategy in primary care to help practices develop capacity and infrastructure to support their ability to improve patient care. Based on a review of recent evidence and a facilitated discussion with US and Canadian experts, we describe practice facilitation, its terminology, and other important information about the intervention. We encourage leaders and researchers to consider and build on this guideline as they plan, implement, evaluate, and report practice facilitation efforts. Clear and consistent use of terminology is imperative, along with complete and accurate descriptions of interventions, to improve the use and study of practice facilitation.

Tropical mountains are hot spots of biodiversity and endemism, but the evolutionary origins of their unique biotas are poorly understood. In varying degrees, local and regional extinction, long-distance colonization, and local recruitment may all contribute to the exceptional character of these communities. Also, it is debated whether mountain endemics mostly originate from local lowland taxa, or from lineages that reach the mountain by long-range dispersal from cool localities elsewhere. Here we investigate the evolutionary routes to endemism by sampling an entire tropical mountain biota on the 4,095-metre-high Mount Kinabalu in Sabah, East Malaysia. We discover that most of its unique biodiversity is younger than the mountain itself (6 million years), and comprises a mix of immigrant pre-adapted lineages and descendants from local lowland ancestors, although substantial shifts from lower to higher vegetation zones in this latter group were rare. These insights could improve forecasts of the likelihood of extinction and 'evolutionary rescue' in montane biodiversity hot spots under climate change scenarios.

Background: The advancements in laboratory technology and knowledge of the mechanisms behind metabolic disorders have facilitated accurate and reliable laboratory testing in screening, diagnosis and treatment of inherited metabolic disorders. Therefore, quality assurance and improvement in diagnostic proficiency have become essential in this area. In most developing countries, standard practices for quality assurance in testing of enzymes, hormones and metabolites involved in these genetic disorders have not been fully implemented. We highlight the benefits of quality assurance and aim to create awareness for greater compliance with the criteria established for quality control to ensure accuracy in biochemical genetic testing., Methods: Establishing the limit of detection and testing range for each analyte and enzyme are useful as a reference while setting up new assays. To minimize error, %CV should be monitored regularly. Evaluation of proficiency testing performance provides scope to the laboratory for improving testing quality., Results: Low precision seen in lysosomal enzyme assays does not undermine their diagnostic efficacy as differentiation between patients and normal subjects is possible by setting % coefficient of variation cutoffs., Conclusions: The study will facilitate the collaboration with other screening and diagnostic systems and help in development of new laboratory standards., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Data is presented in support of a phylogenetic reconstruction of the species-rich early-divergent angiosperm genus Goniothalamus (Annonaceae) (Tang et al., Mol. Phylogenetic Evol., 2015) [1], inferred using chloroplast DNA (cpDNA) sequences. The data includes a list of primers for amplification and sequencing for nine cpDNA regions: atpB-rbcL, matK, ndhF, psbA-trnH, psbM-trnD, rbcL, trnL-F, trnS-G, and ycf1, the voucher information and molecular data (GenBank accession numbers) of 67 ingroup Goniothalamus accessions and 14 outgroup accessions selected from across the tribe Annoneae, and aligned data matrices for each gene region. We also present our Bayesian phylogenetic reconstructions for Goniothalamus, with information on previous infrageneric classifications superimposed to enable an evaluation of monophyly, together with a taxon-character data matrix (with 15 morphological characters scored for 66 Goniothalamus species and seven other species from the tribe Annoneae that are shown to be phylogenetically correlated).

Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P<5.0E-08. These findings provide additional insight into the underlying biological mechanisms of colorectal cancer and demonstrate the scientific value of large consortia-based genetic epidemiology studies.

Background & Aims: Risk for colorectal cancer (CRC) can be greatly reduced through screening. To aid in the development of screening strategies, we refined models designed to determine risk of CRC by incorporating information from common genetic susceptibility loci., Methods: By using data collected from more than 12,000 participants in 6 studies performed from 1990 through 2011 in the United States and Germany, we developed risk determination models based on sex, age, family history, genetic risk score (number of risk alleles carried at 27 validated common CRC susceptibility loci), and history of endoscopic examinations. The model was validated using data collected from approximately 1800 participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, conducted from 1993 through 2001 in the United States., Results: We identified a CRC genetic risk score that independently predicted which patients in the training set would develop CRC. Compared with determination of risk based only on family history, adding the genetic risk score increased the discriminatory accuracy from 0.51 to 0.59 (P = .0028) for men and from 0.52 to 0.56 (P = .14) for women. We calculated age- and sex-specific 10-year CRC absolute risk estimates based on the number of risk alleles, family history, and history of endoscopic examinations. A model that included a genetic risk score better determined the recommended starting age for screening in subjects with and without family histories of CRC. The starting age for high-risk men (family history of CRC and genetic risk score, 90%) was 42 years, and for low-risk men (no family history of CRC and genetic risk score, 10%) was 52 years. For men with no family history and a high genetic risk score (90%), the starting age would be 47 years; this is an intermediate value that is 5 years earlier than it would be for men with a genetic risk score of 10%. Similar trends were observed in women., Conclusions: By incorporating information on CRC risk alleles, we created a model to determine the risk for CRC more accurately. This model might be used to develop screening and prevention strategies., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

An alternative pressure-sensor based method for estimating the acoustic intensity, the phase and amplitude gradient estimation (PAGE) method, is presented. This method uses the same hardware as the standard finite-difference method, but does not suffer from the frequency-dependent bias inherent to the finite-difference method. A detailed derivation of the PAGE method and the finite-difference method is presented. Both methods are then compared using simple acoustic fields. The ability to unwrap the phase component of the PAGE method is discussed, which leads to accurate intensity estimates above previous frequency limits. The uncertainties associated with both methods of estimation are presented. It is shown that the PAGE method provides more accurate intensity estimates over a larger frequency bandwidth.

Autophagy functions to degrade and recycle intracellular proteins and damaged organelles, maintaining the normal cellular function. Autophagy has been shown to play an important role in regulating normal function of pancreatic β cells and insulin-target tissues, such as skeletal muscle, liver, and adipose tissue. Enhanced autophagy also acts as a protective mechanism against oxidative stress in these tissues. Altered autophagic activity has been implicated in the progression of obesity to type 2 diabetes through impaired β-cell function and development of insulin resistance. In this review, we outline the normal regulation of autophagy in β cells and insulin target tissues and explore the dysregulation of autophagy in diabetic animal models and human subjects with type 2 diabetes. Furthermore, we highlight the role of impaired autophagy in the pathophysiology of diabetic complications, including nephropathy and cardiomyopathy. Finally, we summarize how autophagy might be targeted as a therapeutic option in type 2 diabetes.

Difficulties arise in attempting to discern the effects of nonlinearity in near-field jet-noise measurements due to the complicated source structure of high-velocity jets. This article describes a measure that may be used to help quantify the effects of nonlinearity on waveform propagation. This measure, called the average steepening factor (ASF), is the ratio of the average positive slope in a time waveform to the average negative slope. The ASF is the inverse of the wave steepening factor defined originally by Gallagher [AIAA Paper No. 82-0416 (1982)]. An analytical description of the ASF evolution is given for benchmark cases-initially sinusoidal plane waves propagating through lossless and thermoviscous media. The effects of finite sampling rates and measurement noise on ASF estimation from measured waveforms are discussed. The evolution of initially broadband Gaussian noise and signals propagating in media with realistic absorption are described using numerical and experimental methods. The ASF is found to be relatively sensitive to measurement noise but is a relatively robust measure for limited sampling rates. The ASF is found to increase more slowly for initially Gaussian noise signals than for initially sinusoidal signals of the same level, indicating the average distortion within noise waveforms occur more slowly.

Frequent turnover of staff in medical clinics creates challenges in the maintenance of clinical protocols, workflows, and information management. Care coordination between providers in such a setting can be complex; disruptions in communication may lead to poorer health outcomes and patient satisfaction. Furthermore, protocols change frequently in response to new guidelines, which demands rapid updates to maintain compliance. To address these challenges, we developed an intuitive, end-user editable web-based knowledge management system optimized for use on mobile devices. The resulting system served as a point of care information storage and retrieval tool that providers can reference quickly for operational tasks. Since launch, the platform has allowed our clinic to consolidate knowledge banks, standardize staff training, and streamline information flow during clinic, and is now used extensively by clinic staff. During a one-year period, 175 new pages have been created and 1686 edits have been submitted by users. We posit that a mobile platform for clinical information flow management has significant potential to improve information maintenance and facilitate transfer of up-to-date clinical protocols to new personnel.

Previous studies have investigated the associations between exposure to ambient air pollution and biomarkers of physiological pathways, yet little has been done on the comparison across biomarkers of different pathways to establish the temporal pattern of biological response. In the current study, we aim to compare the relative temporal patterns in responses of candidate pathways to different pollutants. Four biomarkers of pulmonary inflammation and oxidative stress, five biomarkers of systemic inflammation and oxidative stress, ten parameters of autonomic function, and three biomarkers of hemostasis were repeatedly measured in 125 young adults, along with daily concentrations of ambient CO, PM2.5, NO2, SO2, EC, OC, and sulfate, before, during, and after the Beijing Olympics. We used a two-stage modeling approach, including Stage I models to estimate the association between each biomarker and pollutant over each of 7 lags, and Stage II mixed-effect models to describe temporal patterns in the associations when grouping the biomarkers into the four physiological pathways. Our results show that candidate pathway groupings of biomarkers explained a significant amount of variation in the associations for each pollutant, and the temporal patterns of the biomarker-pollutant-lag associations varied across candidate pathways (p<0.0001) and were not linear (from lag 0 to lag 3: p = 0.0629, from lag 3 to lag 6: p = 0.0005). These findings suggest that, among this healthy young adult population, the pulmonary inflammation and oxidative stress pathway is the first to respond to ambient air pollution exposure (within 24 hours) and the hemostasis pathway responds gradually over a 2-3 day period. The initial pulmonary response may contribute to the more gradual systemic changes that likely ultimately involve the cardiovascular system.

Unlabelled: This study investigated the effectiveness of twice-weekly Rapid Syllable Transitions (ReST) treatment for Childhood Apraxia of Speech (CAS). ReST is an effective treatment at a frequency of four sessions a week for three consecutive weeks. In this study we used a multiple-baselines across participants design to examine treatment efficacy for four children with CAS, aged four to eight years, who received ReST treatment twice a week for six weeks. The children's ability to acquire new skills, generalize these skills to untreated items and maintain the skills after treatment was examined. All four children improved their production of the target items. Two of the four children generalized the treatment effects to similar untreated pseudo words and all children generalized to untreated real words. During the maintenance phase, all four participants maintained their skills to four months post-treatment, with a stable rather than rising profile. This study shows that ReST treatment delivered twice-weekly results in significant retention of treatment effects to four months post-treatment and generalization to untrained but related speech behaviors. Compared to ReST therapy four times per week, the twice-weekly frequency produces similar treatment gains but no ongoing improvement after the cessation of treatment. This implies that there may be a small but significant benefit of four times weekly therapy compared with twice-weekly ReST therapy., Learning Outcomes: Readers will be able to define dose-frequency, and describe how this relates to overall intervention intensity. Readers will be able to explain the acquisition, generalization and maintenance effects in the study and describe how these compare to higher dose frequency treatments. Readers will recognize that the current findings give preliminary support for high dose-frequency CAS treatment., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Next-generation sequencing (NGS) studies are becoming commonplace, and the NGS field is continuing to develop rapidly. Analytic methods aimed at testing for the various roles that genetic susceptibility plays in disease are also rapidly being developed and optimized. Studies that incorporate large, complex pedigrees are of particular importance because they provide detailed information about inheritance patterns and can be analyzed in a variety of complementary ways. The nine contributions from our Genetic Analysis Workshop 18 working group on family-based tests of association for rare variants using simulated data examined analytic methods for testing genetic association using whole-genome sequencing data from 20 large pedigrees with 200 phenotype simulation replicates. What distinguishes the approaches explored is how the complexities of analyzing familial genetic data were handled. Here, we explore the methods that either harness inheritance patterns and transmission information or attempt to adjust for the correlation between family members in order to utilize computationally and conceptually simpler statistical testing procedures. Although directly comparing these two classes of approaches across contributions is difficult, we note that the two classes balance robustness to population stratification and computational complexity (the transmission-based approaches) with simplicity and increased power, assuming no population stratification or proper adjustment for it (decorrelation approaches)., (© 2014 WILEY PERIODICALS, INC.)

Tobacco smoking is a bladder cancer risk factor and a source of carcinogens that induce DNA damage to urothelial cells. Using data and samples from 988 cases and 1,004 controls enrolled in the Los Angeles County Bladder Cancer Study and the Shanghai Bladder Cancer Study, we investigated associations between bladder cancer risk and 632 tagSNPs that comprehensively capture genetic variation in 28 DNA repair genes from four DNA repair pathways: base excision repair (BER), nucleotide excision repair (NER), non-homologous end-joining (NHEJ) and homologous recombination repair (HHR). Odds ratios (ORs) and 95% confidence intervals (CIs) for each tagSNP were corrected for multiple testing for all SNPs within each gene using pACT and for genes within each pathway and across pathways with Bonferroni. Gene and pathway summary estimates were obtained using ARTP. We observed an association between bladder cancer and POLB rs7832529 (BER) (pACT = 0.003; ppathway = 0.021) among all, and SNPs in XPC (NER) and OGG1 (BER) among Chinese men and women, respectively. The NER pathway showed an overall association with risk among Chinese males (ARTP NER p = 0.034). The XRCC6 SNP rs2284082 (NHEJ), also in LD with SREBF2, showed an interaction with smoking (smoking status interaction pgene = 0.001, ppathway = 0.008, poverall = 0.034). Our findings support a role in bladder carcinogenesis for regions that map close to or within BER (POLB, OGG1) and NER genes (XPC). A SNP that tags both the XRCC6 and SREBF2 genes strongly modifies the association between bladder cancer risk and smoking., (© 2014 UICC.)

Transient waves, like all other acoustic waves, will diffract around solid objects, such as measurement instrumentation. A derivation of an impulse response function on the surface of a rigid sphere, based on linear, classical scattering theory, is presented. The theoretical impulse response function is validated using an experiment with blast noise. An application of the impulse response function to a rocket noise measurement is discussed. The impulse response function shows that the presence of the rigid sphere significantly affects the measurement and estimation of rocket-noise waveforms, power spectral densities, and statistical measures.

The cost of next-generation sequencing is now approaching that of the first generation of genome-wide single-nucleotide genotyping panels, but this is still out of reach for large-scale epidemiologic studies with tens of thousands of subjects. Furthermore, the anticipated yield of millions of rare variants poses serious challenges for distinguishing causal from noncausal variants for disease. We explore the merits of using family-based designs for sequencing substudies to identify novel variants and prioritize them for their likelihood of causality. While the sharing of variants within families means that family-based designs may be less efficient for discovery than sequencing of a comparable number of unrelated individuals, the ability to exploit cosegregation of variants with disease within families helps distinguish causal from noncausal ones. We introduce a score test criterion for prioritizing discovered variants in terms of their likelihood of being functional. We compare the relative statistical efficiency of 2-stage versus1-stage family-based designs by application to the Genetic Analysis Workshop 18 simulated sequence data.