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Background: While female survivors of Hodgkin lymphoma (HL) have an increased risk of breast cancer (BC), no BC risk prediction model is available. We developed such models incorporating mean radiation dose to the breast or breast quadrant-specific radiation doses., Methods: Relative risks and age-specific incidence for BC and competing events (mortality or other subsequent cancer) were estimated from 1194 Dutch five-year HL survivors, treated at ages 11-40 during 1965-2000. Predictors were doses to ten breast segments or mean breast radiation dose, BC family history, year of and age at HL diagnosis, ages at menopause and first live birth. Models were independently validated using U.S. Childhood Cancer Survivor Study cohort participants., Results: Predicted absolute BC risks 25 years after HL diagnosis ranged from 1.0% for survivors diagnosed at ages 20-24, with <10 Gy mean breast radiation dose and menopausal 5 years after HL diagnosis, to 22.0% for survivors 25-29 years at diagnosis, ≥25 Gy mean breast dose, and no menopause within 5 years. In external validation, the observed/expected BC case ratio was 1.19 (95% confidence interval 0.97 to 1.47) for the breast segment-specific doses model, and 1.29 (1.05 to 1.60) for the mean breast dose model. The areas under the receiver operating characteristic curve were 0.68 (0.63 to 0.74) and 0.68 (0.62 to 0.73), respectively., Conclusion: Breast segment-specific or mean breast radiation dose with personal and clinical characteristics predicted absolute BC risk in HL survivors with moderate discrimination but good calibration, rendering the models useful for clinical decision-making., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The use of ultra-high-field 7-Tesla (7T) MRI in multiple sclerosis (MS) research has grown significantly over the past two decades. With recent regulatory approvals of 7T scanners for clinical use in 2017 and 2020, the use of this technology for routine care is poised to continue to increase in the coming years. In this context, the North American Imaging in MS Cooperative (NAIMS) convened a workshop in February 2023 to review the previous and current use of 7T technology for MS research and potential future research and clinical applications. In this workshop, experts were tasked with reviewing the current literature and proposing a series of consensus statements, which were reviewed and approved by the NAIMS. In this review and consensus paper, we provide background on the use of 7T MRI in MS research, highlighting this technology's promise for identification and quantification of aspects of MS pathology that are more difficult to visualize with lower-field MRI, such as grey matter lesions, paramagnetic rim lesions, leptomeningeal enhancement and the central vein sign. We also review the promise of 7T MRI to study metabolic and functional changes to the brain in MS. The NAIMS provides a series of consensus statements regarding what is currently known about the use of 7T MRI in MS, and additional statements intended to provide guidance as to what work is necessary going forward to accelerate 7T MRI research in MS and translate this technology for use in clinical practice and clinical trials. This includes guidance on technical development, proposals for a universal acquisition protocol and suggestions for research geared towards assessing the utility of 7T MRI to improve MS diagnostics, prognostics and therapeutic efficacy monitoring. The NAIMS expects that this article will provide a roadmap for future use of 7T MRI in MS., Competing Interests: D.M.H. has received research funding from EMD-Serono and Roche-Genentech, consulting fees from Horizon Therapeutics, TG Therapeutics and EMD-Serono and royalties from Up To Date, Inc. F.B. has received speaker honoraria from EMD-Serono, Sanofi and Novartis and serves/ed as site PI of multi-centre studies sponsored by EMD-Serono and Novartis and on advisory boards for Sanofi, EMD-Serono and Biogen. S.N. has received research funding from Roche-Genentech and Immunotec, consulting fees from Sana Biotechnology and personal compensation from NeuroRx Research. S.G. has received research funding from Roche-Genentech. E.S.B. has received consulting fees from EMD-Serono. .J.Z. has received research support from Novartis, I-Mab Biopharma and the Race to Erase MS Foundation. R.B. has received speaking honoraria from EMD-Serono and research support from Bristol-Myers Squibb, EMD-Serono and Novartis. A.C. was supported by the ECTRIMS post-doctoral training fellowship (2022). A.C. has received speaker honoraria from Novartis. S.Y.H. has received research funding and consulting fees from Siemens Healthineers. The University Hospital Basel (USB), as the employer of C.G., has received the following fees which were used exclusively for research support: (i) advisory board and consultancy fees from Actelion, Genzyme-Sanofi, Novartis, GeNeuro and Roche; (ii) speaker fees from Genzyme-Sanofi, Novartis, GeNeuro and Roche; and (iii) research support from Siemens, GeNeuro and Roche. E.C.K. has received research funding from Abbvie, Biogen and Genentech and consulting fees from EMD-Serono, Genentech, INmune Bio, Myrobalan Therapeutics, OM1, Inc. and TG Therapeutics. C.M. has received research funding from Genentech-Roche. C.L., J.D., M.D., D.A.R. and P.B. have no disclosures to report., (Published by Oxford University Press on behalf of the Guarantors of Brain 2024.)

Chronic active lesions (CAL) are an important manifestation of chronic inflammation in multiple sclerosis and have implications for non-relapsing biological progression. In recent years, the discovery of innovative MRI and PET-derived biomarkers has made it possible to detect CAL, and to some extent quantify them, in the brain of persons with multiple sclerosis, in vivo. Paramagnetic rim lesions on susceptibility-sensitive MRI sequences, MRI-defined slowly expanding lesions on T1-weighted and T2-weighted scans, and 18-kDa translocator protein-positive lesions on PET are promising candidate biomarkers of CAL. While partially overlapping, these biomarkers do not have equivalent sensitivity and specificity to histopathological CAL. Standardization in the use of available imaging measures for CAL identification, quantification and monitoring is lacking. To fast-forward clinical translation of CAL, the North American Imaging in Multiple Sclerosis Cooperative developed a consensus statement, which provides guidance for the radiological definition and measurement of CAL. The proposed manuscript presents this consensus statement, summarizes the multistep process leading to it, and identifies the remaining major gaps in knowledge., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. Elements of this work were written by employees of the US Government.)

Ectopic pancreas (EP) is an uncommon, congenital focus of pancreatic tissue that is discontinuous with the principal pancreas. A 62-year-old female underwent multiple investigations for chronic epigastric pain. EP was identified intra-operatively. On retrospection, earlier imaging showed a thickened segment of jejunum with inflammation of the surrounding small bowel mesentery, suggestive of jejunal EP pancreatitis. Histology confirmed ectopic pancreatic tissue, with sections of the EP showing evidence of previous acute and chronic pancreatitis. When no cause for chronic abdominal pain is found, diagnostic laparoscopy should be considered, and the small bowel inspected, to further investigate for rare causes of abdominal pain, such as EP., Competing Interests: We have no conflicts of interests to declare. We have not received any financial support in the writing of this case report., (Published by Oxford University Press and JSCR Publishing Ltd. © The Author(s) 2024.)

Background: Early efforts at risk-adapted therapy for neuroblastoma are predicted to result in differential late effects; the magnitude of these differences has not been well described., Methods: Late mortality, subsequent malignant neoplasms (SMNs), and severe/life-threatening chronic health conditions (CHCs), graded according to CTCAE v4.03, were assessed among 5-year Childhood Cancer Survivor Study (CCSS) survivors of neuroblastoma diagnosed 1987-1999. Using age, stage at diagnosis, and treatment, survivors were classified into risk groups (low [n = 425]; intermediate [n = 252]; high [n = 245]). Standardized mortality ratios (SMRs) and standardized incidence ratios (SIRs) of SMNs were compared with matched population controls. Cox regression models estimated hazard ratios (HRs) and 95% confidence intervals for CHC compared with 1029 CCSS siblings., Results: Among survivors (49.8% male; median age = 21 years, range = 7-42; median follow-up = 19.3 years, range = 5-29.9), 80% with low-risk disease were treated with surgery alone, whereas 79.1% with high-risk disease received surgery, radiation, chemotherapy ± autologous stem cell transplant (ASCT). All-cause mortality was elevated across risk groups (SMRhigh = 27.7 [21.4-35.8]; SMRintermediate = 3.3 [1.7-6.5]; SMRlow = 2.8 [1.7-4.8]). SMN risk was increased among high- and intermediate-risk survivors (SIRhigh = 28.0 [18.5-42.3]; SIRintermediate = 3.7 [1.2-11.3]) but did not differ from the US population for survivors of low-risk disease. Compared with siblings, survivors had an increased risk of grade 3-5 CHCs, particularly among those with high-risk disease (HRhigh = 16.1 [11.2-23.2]; HRintermediate = 6.3 [3.8-10.5]; HRlow = 1.8 [1.1-3.1])., Conclusion: Survivors of high-risk disease treated in the early days of risk stratification carry a markedly elevated burden of late recurrence, SMN, and organ-related multimorbidity, whereas survivors of low/intermediate-risk disease have a modest risk of late adverse outcomes., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Applications of molecular phylogenetic approaches have uncovered evidence of hybridization across numerous clades of life, yet the environmental factors responsible for driving opportunities for hybridization remain obscure. Verbal models implicating geographic range shifts that brought species together during the Pleistocene have often been invoked, but quantitative tests using paleoclimatic data are needed to validate these models. Here, we produce a phylogeny for Heuchereae, a clade of 15 genera and 83 species in Saxifragaceae, with complete sampling of recognized species, using 277 nuclear loci and nearly complete chloroplast genomes. We then employ an improved framework with a coalescent simulation approach to test and confirm previous hybridization hypotheses and identify one new intergeneric hybridization event. Focusing on the North American distribution of Heuchereae, we introduce and implement a newly developed approach to reconstruct potential past distributions for ancestral lineages across all species in the clade and across a paleoclimatic record extending from the late Pliocene. Time calibration based on both nuclear and chloroplast trees recovers a mid- to late-Pleistocene date for most inferred hybridization events, a timeframe concomitant with repeated geographic range restriction into overlapping refugia. Our results indicate an important role for past episodes of climate change, and the contrasting responses of species with differing ecological strategies, in generating novel patterns of range contact among plant communities and therefore new opportunities for hybridization. The new ancestral niche method flexibly models the shape of niche while incorporating diverse sources of uncertainty and will be an important addition to the current comparative methods toolkit. [Ancestral niche reconstruction; hybridization; paleoclimate; pleistocene.]., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society of Systematic Biologists.)

Computing ancestral ranges via the Dispersion Extinction and Cladogensis (DEC) model of biogeography is characterized by an exponential number of states relative to the number of regions considered. This is because the DEC model requires computing a large matrix exponential, which typically accounts for up to 80% of overall runtime. Therefore, the kinds of biogeographical analyses that can be conducted under the DEC model are limited by the number of regions under consideration. In this work, we present a completely redesigned efficient version of the popular tool Lagrange which is up to 49 times faster with multithreading enabled, and is also 26 times faster when using only one thread. We call this new version Lagrange-NG (Lagrange-Next Generation). The increased computational efficiency allows Lagrange-NG to analyze datasets with a large number of regions in a reasonable amount of time, up to 12 regions in approximately 18 min. We achieve these speedups using a relatively new method of computing the matrix exponential based on Krylov subspaces. In order to validate the correctness of Lagrange-NG, we also introduce a novel metric on range distributions for trees so that researchers can assess the difference between any two range inferences. Finally, Lagrange-NG exhibits substantially higher adherence to coding quality standards. It improves a respective software quality indicator as implemented in the SoftWipe tool from average (5.5; Lagrange) to high (7.8; Lagrange-NG). Lagrange-NG is freely available under GPL2. [Biogeography; Phylogenetics; DEC Model.]., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society of Systematic Biologists.)

Phylogenetic analyses are increasingly being performed with data sets that incorporate hundreds of loci. Due to incomplete lineage sorting, hybridization, and horizontal gene transfer, the gene trees for these loci may often have topologies that differ from each other and from the species tree. The effect of these topological incongruences on divergence time estimation has not been fully investigated. Using a series of simulation experiments and empirical analyses, we demonstrate that when topological incongruence between gene trees and the species tree is not accounted for, the temporal duration of branches in regions of the species tree that are affected by incongruence is underestimated, whilst the duration of other branches is considerably overestimated. This effect becomes more pronounced with higher levels of topological incongruence. We show that this pattern results from the erroneous estimation of the number of substitutions along branches in the species tree, although the effect is modulated by the assumptions inherent to divergence time estimation, such as those relating to the fossil record or among-branch-substitution-rate variation. By only analyzing loci with gene trees that are topologically congruent with the species tree, or only taking into account the branches from each gene tree that are topologically congruent with the species tree, we demonstrate that the effects of topological incongruence can be ameliorated. Nonetheless, even when topologically congruent gene trees or topologically congruent branches are selected, error in divergence time estimates remains. This stems from temporal incongruences between divergence times in species trees and divergence times in gene trees, and more importantly, the difficulty of incorporating necessary assumptions for divergence time estimation. [Divergence time estimation; gene trees; species tree; topological incongruence.]., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society of Systematic Biologists.)

Prevalence of seafood-borne gastroenteritis caused by the human pathogen Vibrio parahaemolyticus is increasing globally despite current preventative measures. The United States Centers for Disease Control have designated V. parahaemolyticus as a reportable emerging human pathogen. The Eastern oyster (Crassostrea virginica) is a natural reservoir of the bacterium in marine environments, but little is actually known regarding interactions between oysters and V. parahaemolyticus. Therefore, a laboratory-scale Biosafety Level-2 (BSL2) inoculation system was developed wherein Chesapeake Bay region oysters harvested during summer or winter months, were exposed to the clinical RIMD2210633 strain carrying a chloramphenicol-selective marker (VP RIMDmC). Homogenized whole oyster tissues were spread on selective and differential agar medium to measure viable VP RIMDmC levels. Endogenous Vibrio spp. cell numbers were significantly reduced followed chloramphenicol treatment and this likely contributed to higher VP RIMDmC oyster-associated levels, especially using winter-harvested animals. Summer-harvested oysters had significantly higher existing Vibrio levels and a lower level of artificial oyster-associated VP RIMDmC. Thus, the pre-existing microbiome appears to afford some protection from an external V. parahaemolyticus challenge. Overall, this system successfully enabled controlled manipulation of parameters influencing V. parahaemolyticus-oyster interactions and will be useful in safely testing additional pertinent environmental variables and potential mitigation strategies., (© The Author(s) 2022. Published by Oxford University Press on behalf of FEMS.)

Gene tree conflict is common and finding methods to analyze and alleviate the negative effects that conflict has on species tree analysis is a crucial part of phylogenomics. This study aims to expand the discussion of inferring species trees and molecular branch lengths when conflict is present. Conflict is typically examined in two ways: inferring its prevalence and inferring the influence of the individual genes (how strongly one gene supports any given topology compared to an alternative topology). Here, we examine a procedure for incorporating both conflict and the influence of genes in order to infer evolutionary relationships. All supported relationships in the gene trees are analyzed and the likelihood of the genes constrained to these relationships is summed to provide a likelihood for the relationship. Consensus tree assembly is conducted based on the sum of likelihoods for a given relationship and choosing relationships based on the most likely relationship assuming it does not conflict with a relationship that has a higher likelihood score. If it is not possible for all most likely relationships to be combined into a single bifurcating tree then multiple trees are produced and a consensus tree with a polytomy is created. This procedure allows for more influential genes to have a greater influence on an inferred relationship, does not assume conflict has arisen from any one source and does not force the data set to produce a single bifurcating tree. Using this approach, on three empirical data sets, we examine and discuss the relationship between influence and prevalence of gene tree conflict. We find that in one of the data sets, assembling a bifurcating consensus tree solely composed of the most likely relationships is impossible. To account for conflict in molecular rate analysis we also introduce a concordance-based approach to the summary and estimation of branch lengths suitable for downstream comparative analyses. We demonstrate through simulation that even under high levels of stochastic conflict, the mean and median of the concordant rates recapitulate the true molecular rate better than using a supermatrix approach. Using a large phylogenomic data set, we examine rate heterogeneity across concordant genes with a focus on the branch subtending crown angiosperms. Notably, we find highly variable rates of evolution along the branch subtending crown angiosperms. The approaches outlined here have several limitations, but they also represent some alternative methods for harnessing the complexity of phylogenomic data sets and enrich our inferences of both species relationships and evolutionary processes.[Branch length estimation; consensus tree; gene tree conflict; gene tree filtering; phylogenetics; phylogenomics.]., (© The Author(s) 2021. Published by Oxford University Press, on behalf of the Society of Systematic Biologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Evidence is mounting that cigarette smoking contributes to second primary contralateral breast cancer (CBC) risk. Whether radiation therapy (RT) interacts with smoking to modify this risk is unknown. In this multicenter, individually matched, case-control study, we examined the association between RT, smoking, and CBC risk. The study included 1521 CBC cases and 2212 controls with unilateral breast cancer, all diagnosed with first invasive breast cancer between 1985 and 2008 aged younger than 55 years. Absorbed radiation doses to contralateral breast regions were estimated with thermoluminescent dosimeters in tissue-equivalent anthropomorphic phantoms, and smoking history was collected by interview. Rate ratios (RRs) and 95% confidence intervals (CIs) for CBC risk were estimated by multivariable conditional logistic regression. There was no interaction between any measure of smoking with RT to increase CBC risk (eg, the interaction of continuous RT dose with smoking at first breast cancer diagnosis [ever/never]: RR = 1.00, 95% CI = 0.89 to 1.14; continuous RT dose with years smoked: RR = 1.00, 95% CI = 0.99 to 1.01; and continuous RT dose with lifetime pack-years: RR = 1.00, 95% CI = 0.99 to 1.01). There was no evidence that RT further increased CBC risk in young women with first primary breast cancer who were current smokers or had smoking history., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: Prediction of right heart failure (RHF) after left ventricular assist device (LVAD) implant remains a challenge. The EUROMACS right-sided heart failure (EUROMACS-RHF) risk score was proposed as a prediction tool for post-LVAD RHF but lacks from large external validation. The aim of our study was to externally validate the score., Methods and Results: From January 2007 to December 2017, 878 continuous-flow LVADs were implanted at three tertiary centres. We calculated the EUROMACS-RHF score in 662 patients with complete data. We evaluated its predictive performance for early RHF defined as either (i) need for short- or long-term right-sided circulatory support, (ii) continuous inotropic support for ≥14 days, or (iii) nitric oxide for ≥48 h post-operatively. Right heart failure occurred in 211 patients (32%). When compared with non-RHF patients, pre-operatively they had higher creatinine, bilirubin, right atrial pressure, and lower INTERMACS class (P < 0.05); length of stay and in-hospital mortality were higher. Area under the ROC curve for RHF prediction of the EUROMACS-RHF score was 0.64 [95% confidence interval (CI) 0.60-0.68]. Reclassification of patients with RHF was significantly better when applying the EUROMACS-RHF risk score on top of previous published scores. Patients in the high-risk category had significantly higher in-hospital and 2-year mortality [hazard ratio: 1.64 (95% CI 1.16-2.32) P = 0.005]., Conclusion: In an external cohort, the EUROMACS-RHF had limited discrimination predicting RHF. The clinical utility of this score remains to be determined., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Genome-scale data have the potential to clarify phylogenetic relationships across the tree of life but have also revealed extensive gene tree conflict. This seeming paradox, whereby larger data sets both increase statistical confidence and uncover significant discordance, suggests that understanding sources of conflict is important for accurate reconstruction of evolutionary history. We explore this paradox in squamate reptiles, the vertebrate clade comprising lizards, snakes, and amphisbaenians. We collected an average of 5103 loci for 91 species of squamates that span higher-level diversity within the clade, which we augmented with publicly available sequences for an additional 17 taxa. Using a locus-by-locus approach, we evaluated support for alternative topologies at 17 contentious nodes in the phylogeny. We identified shared properties of conflicting loci, finding that rate and compositional heterogeneity drives discordance between gene trees and species tree and that conflicting loci rarely overlap across contentious nodes. Finally, by comparing our tests of nodal conflict to previous phylogenomic studies, we confidently resolve 9 of the 17 problematic nodes. We suggest this locus-by-locus and node-by-node approach can build consensus on which topological resolutions remain uncertain in phylogenomic studies of other contentious groups. [Anchored hybrid enrichment (AHE); gene tree conflict; molecular evolution; phylogenomic concordance; target capture; ultraconserved elements (UCE).]., (© The Author(s) 2020. Published by Oxford University Press, on behalf of the Society of Systematic Biologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Gene tree discordance in large genomic data sets can be caused by evolutionary processes such as incomplete lineage sorting and hybridization, as well as model violation, and errors in data processing, orthology inference, and gene tree estimation. Species tree methods that identify and accommodate all sources of conflict are not available, but a combination of multiple approaches can help tease apart alternative sources of conflict. Here, using a phylotranscriptomic analysis in combination with reference genomes, we test a hypothesis of ancient hybridization events within the plant family Amaranthaceae s.l. that was previously supported by morphological, ecological, and Sanger-based molecular data. The data set included seven genomes and 88 transcriptomes, 17 generated for this study. We examined gene-tree discordance using coalescent-based species trees and network inference, gene tree discordance analyses, site pattern tests of introgression, topology tests, synteny analyses, and simulations. We found that a combination of processes might have generated the high levels of gene tree discordance in the backbone of Amaranthaceae s.l. Furthermore, we found evidence that three consecutive short internal branches produce anomalous trees contributing to the discordance. Overall, our results suggest that Amaranthaceae s.l. might be a product of an ancient and rapid lineage diversification, and remains, and probably will remain, unresolved. This work highlights the potential problems of identifiability associated with the sources of gene tree discordance including, in particular, phylogenetic network methods. Our results also demonstrate the importance of thoroughly testing for multiple sources of conflict in phylogenomic analyses, especially in the context of ancient, rapid radiations. We provide several recommendations for exploring conflicting signals in such situations. [Amaranthaceae; gene tree discordance; hybridization; incomplete lineage sorting; phylogenomics; species network; species tree; transcriptomics.]., (© The Author(s) 2020. Published by Oxford University Press, on behalf of the Society of Systematic Biologists.)

Aims: Impaired physical function is common in patients undergoing transcatheter aortic valve replacement (TAVR) and associated with worse outcomes. Participation in centre-based cardiac rehabilitation (CR) after cardiovascular procedures is sub-optimal. We aimed to test a home-based mobile health exercise intervention as an alternative or complementary approach., Methods and Results: At five centres, after a run-in period, eligible individuals treated with TAVR were randomized 1:1 at their 1-month post-TAVR visit to an intervention group [activity monitor (AM) with personalized daily step goal and resistance exercises] or a control group for 6 weeks. Among 50 participants, average age was 76 years, 34% were female, average STS score was 2.91.8, and 40% had Short Physical Performance Battery (SPPB) 9. Daily compliance with wearing the AM and performing exercises averaged 8590%. In the intention to treat population, there was no evidence that the intervention improved the co-primary endpoints: daily steps +769 (95% CI 244 to +1783); SPPB +0.68 (0.27 to 1.53); and Kansas City Cardiomyopathy Questionnaire 1.7 (9.1 to 7.1). The intervention did improve secondary physical activity parameters, including moderate-to-intense daily active minutes ( P <0.05). In a pre-specified analysis including participants who did not participate in CR ( n =30), the intervention improved several measures of physical activity: +1730 (1003360) daily steps; +66 (28105) daily active minutes; +53 (2780) moderate-to-intense active minutes; and 157 (265 to 50) sedentary minutes., Conclusion: Among selected participants treated with TAVR, this study did not provide evidence that a pragmatic home-based mobile health exercise intervention improved daily steps, physical performance or QoL for the overall cohort. However, the intervention did improve several measures of daily activity, particularly among individuals not participating in CR., Trial Registry: Clinicaltrials.gov NCT03270124., (The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Taste perception has been reported to vary with changes in affective state. Distortions of taste perception, including blunted recognition thresholds, intensity, and hedonic ratings have been identified in those suffering from depressive disorders. Serotonin is a key neurotransmitter implicated in the etiology of anxiety and depression; systemic and peripheral manipulations of serotonin signaling have previously been shown to modulate taste detection. However, the specific effects of central serotonin function on taste processing have not been widely investigated. Here, in a double-blind placebo-controlled study, acute tryptophan depletion was used to investigate the effect of reduced central serotonin function on taste perception. Twenty-five female participants aged 18-28 attended the laboratory on two occasions at least 1 week apart. On one visit, they received a tryptophan depleting drink and on the other, a control drink was administered. Approximately, 6 h after drink consumption, they completed a taste perception task which measured detection thresholds and supra-threshold perceptions of the intensity and pleasantness of four basic tastes (sweet, sour, bitter, and salt). While acutely reducing central levels of serotonin had no effect on the detection thresholds of sweet, bitter, or sour tastes, it significantly enhanced detection of salt. For supra-threshold stimuli, acutely reduced serotonin levels significantly enhanced the perceived intensity of both bitter and sour tastes and blunted pleasantness ratings of bitter quinine. These findings show manipulation of central serotonin levels can modulate taste perception and are consistent with previous reports that depletion of central serotonin levels enhances neural and behavioral responsiveness to aversive signals., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Most phylogenetic analyses assume that a single evolutionary history underlies one gene. However, both biological processes and errors can cause intragenic conflict. The extent to which this conflict is present in empirical data sets is not well documented, but if common, could have far-reaching implications for phylogenetic analyses. We examined several large phylogenomic data sets from diverse taxa using a fast and simple method to identify well-supported intragenic conflict. We found conflict to be highly variable between data sets, from 1% to >92% of genes investigated. We analyzed four exemplar genes in detail and analyzed simulated data under several scenarios. Our results suggest that alignment error may be one major source of conflict, but other conflicts remain unexplained and may represent biological signal or other errors. Whether as part of data analysis pipelines or to explore biologically processes, analyses of within-gene phylogenetic signal should become common., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Schmidingerella arcuata is an ecologically important tintinnid ciliate that has long served as a model species in plankton trophic ecology. We present a partial micronuclear genome and macronuclear transcriptome resource for S. arcuata, acquired using single-cell techniques, and we report on pilot analyses including functional annotation and genome architecture. Our analysis shows major fragmentation, elimination, and scrambling in the micronuclear genome of S. arcuata. This work introduces a new nonmodel genome resource for the study of ciliate ecology and genomic biology and provides a detailed functional counterpart to ecological research on S. arcuata., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Background: Childhood cancer survivors exposed to abdominal radiation (abdRT) are at increased risk for diabetes mellitus, but the association between risk and radiation dose and volume is unclear., Methods: Participants included 20 762 5-year survivors of childhood cancer (4568 exposed to abdRT) and 4853 siblings. For abdRT, we estimated maximum dose to abdomen; mean doses for whole pancreas, pancreatic head, body, tail; and percent pancreas volume receiving no less than 10, 20, and 30 Gy. Relative risks (RRs) were estimated with a Poisson model using generalized estimating equations, adjusted for attained age. All statistical tests were two-sided., Results: Survivors exposed to abdRT (median age = 31.6 years, range = 10.2-58.3 years) were 2.92-fold more likely than siblings (95% confidence interval [CI] = 2.02 to 4.23) and 1.60-times more likely than survivors not exposed to abdRT (95%CI = 1.24 to 2.05) to develop diabetes. Among survivors treated with abdRT, greater attained age (RRper 10 years = 2.11, 95% CI = 1.70 to 2.62), higher body mass index (RRBMI 30+ = 5.00, 95% CI = 3.19 to 7.83 with referenceBMI 18.5-24.9), and increasing pancreatic tail dose were associated with increased diabetes risk in a multivariable model; an interaction was identified between younger age at cancer diagnosis and pancreatic tail dose with much higher diabetes risk associated with increasing pancreatic tail dose among those diagnosed at the youngest ages (P < .001). Radiation dose and volume to other regions of the pancreas were not statistically significantly associated with risk., Conclusions: Among survivors treated with abdRT, diabetes risk was associated with higher pancreatic tail dose, especially at younger ages. Targeted interventions are needed to improve cardiometabolic health among those at highest risk., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Studies have demonstrated that pervasive gene tree conflict underlies several important phylogenetic relationships where different species tree methods produce conflicting results. Here, we present a means of dissecting the phylogenetic signal for alternative resolutions within a data set in order to resolve recalcitrant relationships and, importantly, identify what the data set is unable to resolve. These procedures extend upon methods for isolating conflict and concordance involving specific candidate relationships and can be used to identify systematic error and disambiguate sources of conflict among species tree inference methods. We demonstrate these on a large phylogenomic plant data set. Our results support the placement of Amborella as sister to the remaining extant angiosperms, Gnetales as sister to pines, and the monophyly of extant gymnosperms. Several other contentious relationships, including the resolution of relationships within the bryophytes and the eudicots, remain uncertain given the low number of supporting gene trees. To address whether concatenation of filtered genes amplified phylogenetic signal for relationships, we implemented a combinatorial heuristic to test combinability of genes. We found that nested conflicts limited the ability of data filtering methods to fully ameliorate conflicting signal amongst gene trees. These analyses confirmed that the underlying conflicting signal does not support broad concatenation of genes. Our approach provides a means of dissecting a specific data set to address deep phylogenetic relationships while also identifying the inferential boundaries of the data set. [Angiosperms; coalescent; gene-tree conflict; genomics; phylogenetics; phylogenomics.]., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society of Systematic Biologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Context: Data on hypothalamic-pituitary (HP) disorders in systematically evaluated childhood cancer survivors are limited., Objective: To describe prevalence, risk factors, and associated adverse health outcomes of deficiencies in GH deficiency (GHD), TSH deficiency (TSHD), LH/FSH deficiency (LH/FSHD), and ACTH deficiency (ACTHD), and central precocious puberty (CPP)., Design: Retrospective with cross-sectional health outcomes analysis., Setting: Established cohort; tertiary care center., Patients: Participants (N = 3141; median age, 31.7 years) were followed for a median 24.1 years., Main Outcome Measure: Multivariable logistic regression was used to calculate ORs and 95% CIs for associations among HP disorders, tumor- and treatment-related risk factors, and health outcomes., Results: The estimated prevalence was 40.2% for GHD, 11.1% for TSHD, 10.6% for LH/FSHD, 3.2% for ACTHD, and 0.9% for CPP among participants treated with HP radiotherapy (n = 1089), and 6.2% for GHD, and <1% for other HP disorders without HP radiotherapy. Clinical factors independently associated with HP disorders included HP radiotherapy (at any dose for GHD, TSHD, LH/FSHD, >30 Gy for ACTHD), alkylating agents (GHD, LH/FSHD), intrathecal chemotherapy (GHD), hydrocephalus with shunt placement (GHD, LH/FSHD), seizures (TSHD, ACTHD), and stroke (GHD, TSHD, LH/FSHD, ACTHD). Adverse health outcomes independently associated with HP disorders included short stature (GHD, TSHD), severe bone mineral density deficit (GHD, LH/FSHD), obesity (LH/FSHD), frailty (GHD), impaired physical health-related quality of life (TSHD), sexual dysfunction (LH/FSHD), impaired memory, and processing speed (GHD, TSHD)., Conclusion: HP radiotherapy, central nervous system injury, and, to a lesser extent, chemotherapy are associated with HP disorders, which are associated with adverse health outcomes., (Copyright © 2019 Endocrine Society.)

Spinal cord lesions detected on MRI hold important diagnostic and prognostic value for multiple sclerosis. Previous attempts to correlate lesion burden with clinical status have had limited success, however, suggesting that lesion location may be a contributor. Our aim was to explore the spatial distribution of multiple sclerosis lesions in the cervical spinal cord, with respect to clinical status. We included 642 suspected or confirmed multiple sclerosis patients (31 clinically isolated syndrome, and 416 relapsing-remitting, 84 secondary progressive, and 73 primary progressive multiple sclerosis) from 13 clinical sites. Cervical spine lesions were manually delineated on T2- and T2*-weighted axial and sagittal MRI scans acquired at 3 or 7 T. With an automatic publicly-available analysis pipeline we produced voxelwise lesion frequency maps to identify predilection sites in various patient groups characterized by clinical subtype, Expanded Disability Status Scale score and disease duration. We also measured absolute and normalized lesion volumes in several regions of interest using an atlas-based approach, and evaluated differences within and between groups. The lateral funiculi were more frequently affected by lesions in progressive subtypes than in relapsing in voxelwise analysis (P < 0.001), which was further confirmed by absolute and normalized lesion volumes (P < 0.01). The central cord area was more often affected by lesions in primary progressive than relapse-remitting patients (P < 0.001). Between white and grey matter, the absolute lesion volume in the white matter was greater than in the grey matter in all phenotypes (P < 0.001); however when normalizing by each region, normalized lesion volumes were comparable between white and grey matter in primary progressive patients. Lesions appearing in the lateral funiculi and central cord area were significantly correlated with Expanded Disability Status Scale score (P < 0.001). High lesion frequencies were observed in patients with a more aggressive disease course, rather than long disease duration. Lesions located in the lateral funiculi and central cord area of the cervical spine may influence clinical status in multiple sclerosis. This work shows the added value of cervical spine lesions, and provides an avenue for evaluating the distribution of spinal cord lesions in various patient groups., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Several plant lineages have evolved adaptations that allow survival in extreme and harsh environments including many families within the plant clade Portulacineae (Caryophyllales) such as the Cactaceae, Didiereaceae, and Montiaceae. Here, using newly generated transcriptomic data, we reconstructed the phylogeny of Portulacineae and examined potential correlates between molecular evolution and adaptation to harsh environments. Our phylogenetic results were largely congruent with previous analyses, but we identified several early diverging nodes characterized by extensive gene tree conflict. For particularly contentious nodes, we present detailed information about the phylogenetic signal for alternative relationships. We also analyzed the frequency of gene duplications, confirmed previously identified whole genome duplications (WGD), and proposed a previously unidentified WGD event within the Didiereaceae. We found that the WGD events were typically associated with shifts in climatic niche but did not find a direct association with WGDs and diversification rate shifts. Diversification shifts occurred within the Portulacaceae, Cactaceae, and Anacampserotaceae, and whereas these did not experience WGDs, the Cactaceae experienced extensive gene duplications. We examined gene family expansion and molecular evolutionary patterns with a focus on genes associated with environmental stress responses and found evidence for significant gene family expansion in genes with stress adaptation and clades found in extreme environments. These results provide important directions for further and deeper examination of the potential links between molecular evolutionary patterns and adaptation to harsh environments.

Recent studies have demonstrated that conflict is common among gene trees in phylogenomic studies, and that less than one percent of genes may ultimately drive species tree inference in supermatrix analyses. Herein, we examined two data sets where supermatrix and coalescent-based species trees conflict. We identified two highly influential "outlier" genes in each data set. When removed from each data set, the inferred supermatrix trees matched the topologies obtained from coalescent analyses. We also demonstrate that, while the outlier genes in the vertebrate data set have been shown in a previous study to be the result of errors in orthology detection, the outlier genes from a plant data set did not exhibit any obvious systematic error, and therefore, may be the result of some biological process yet to be determined. While topological comparisons among a small set of alternate topologies can be helpful in discovering outlier genes, they can be limited in several ways, such as assuming all genes share the same topology. Coalescent species tree methods relax this assumption but do not explicitly facilitate the examination of specific edges. Coalescent methods often also assume that conflict is the result of incomplete lineage sorting. Herein, we explored a framework that allows for quickly examining alternative edges and support for large phylogenomic data sets that does not assume a single topology for all genes. For both data sets, these analyses provided detailed results confirming the support for coalescent-based topologies. This framework suggests that we can improve our understanding of the underlying signal in phylogenomic data sets by asking more targeted edge-based questions.

Patients with multiple sclerosis present with focal lesions throughout the spinal cord. There is a clinical need for non-invasive measurements of spinal cord activity and functional organization in multiple sclerosis, given the cord's critical role in the disease. Recent reports of spontaneous blood oxygenation level-dependent fluctuations in the spinal cord using functional MRI suggest that, like the brain, cord activity at rest is organized into distinct, synchronized functional networks among grey matter regions, likely related to motor and sensory systems. Previous studies looking at stimulus-evoked activity in the spinal cord of patients with multiple sclerosis have demonstrated increased levels of activation as well as a more bilateral distribution of activity compared to controls. Functional connectivity studies of brain networks in multiple sclerosis have revealed widespread alterations, which may take on a dynamic trajectory over the course of the disease, with compensatory increases in connectivity followed by decreases associated with structural damage. We build upon this literature by examining functional connectivity in the spinal cord of patients with multiple sclerosis. Using ultra-high field 7 T imaging along with processing strategies for robust spinal cord functional MRI and lesion identification, the present study assessed functional connectivity within cervical cord grey matter of patients with relapsing-remitting multiple sclerosis (n = 22) compared to a large sample of healthy controls (n = 56). Patient anatomical images were rated for lesions by three independent raters, with consensus ratings revealing 19 of 22 patients presented with lesions somewhere in the imaged volume. Linear mixed models were used to assess effects of lesion location on functional connectivity. Analysis in control subjects demonstrated a robust pattern of connectivity among ventral grey matter regions as well as a distinct network among dorsal regions. A gender effect was also observed in controls whereby females demonstrated higher ventral network connectivity. Wilcoxon rank-sum tests detected no differences in average connectivity or power of low frequency fluctuations in patients compared to controls. The presence of lesions was, however, associated with local alterations in connectivity with differential effects depending on columnar location. The patient results suggest that spinal cord functional networks are generally intact in relapsing-remitting multiple sclerosis but that lesions are associated with focal abnormalities in intrinsic connectivity. These findings are discussed in light of the current literature on spinal cord functional MRI and the potential neurological underpinnings.

Understanding plant evolution and diversity in a phylogenomic context is an enormous challenge due, in part, to limited availability of genome-scale data across phylodiverse species. The 10KP (10,000 Plants) Genome Sequencing Project will sequence and characterize representative genomes from every major clade of embryophytes, green algae, and protists (excluding fungi) within the next 5 years. By implementing and continuously improving leading-edge sequencing technologies and bioinformatics tools, 10KP will catalogue the genome content of plant and protist diversity and make these data freely available as an enduring foundation for future scientific discoveries and applications. 10KP is structured as an international consortium, open to the global community, including botanical gardens, plant research institutes, universities, and private industry. Our immediate goal is to establish a policy framework for this endeavor, the principles of which are outlined here.

Divergence time estimation-the calibration of a phylogeny to geological time-is an integral first step in modeling the tempo of biological evolution (traits and lineages). However, despite increasingly sophisticated methods to infer divergence times from molecular genetic sequences, the estimated age of many nodes across the tree of life contrast significantly and consistently with timeframes conveyed by the fossil record. This is perhaps best exemplified by crown angiosperms, where molecular clock (Triassic) estimates predate the oldest (Early Cretaceous) undisputed angiosperm fossils by tens of millions of years or more. While the incompleteness of the fossil record is a common concern, issues of data limitation and model inadequacy are viable (if underexplored) alternative explanations. In this vein, Beaulieu et al. (2015) convincingly demonstrated how methods of divergence time inference can be misled by both (i) extreme state-dependent molecular substitution rate heterogeneity and (ii) biased sampling of representative major lineages. These results demonstrate the impact of (potentially common) model violations. Here, we suggest another potential challenge: that the configuration of the statistical inference problem (i.e., the parameters, their relationships, and associated priors) alone may preclude the reconstruction of the paleontological timeframe for the crown age of angiosperms. We demonstrate, through sampling from the joint prior (formed by combining the tree (diversification) prior with the calibration densities specified for fossil-calibrated nodes) that with no data present at all, that an Early Cretaceous crown angiosperms is rejected (i.e., has essentially zero probability). More worrisome, however, is that for the 24 nodes calibrated by fossils, almost all have indistinguishable marginal prior and posterior age distributions when employing routine lognormal fossil calibration priors. These results indicate that there is inadequate information in the data to over-rule the joint prior. Given that these calibrated nodes are strategically placed in disparate regions of the tree, they act to anchor the tree scaffold, and so the posterior inference for the tree as a whole is largely determined by the pseudodata present in the (often arbitrary) calibration densities. We recommend, as for any Bayesian analysis, that marginal prior and posterior distributions be carefully compared to determine whether signal is coming from the data or prior belief, especially for parameters of direct interest. This recommendation is not novel. However, given how rarely such checks are carried out in evolutionary biology, it bears repeating. Our results demonstrate the fundamental importance of prior/posterior comparisons in any Bayesian analysis, and we hope that they further encourage both researchers and journals to consistently adopt this crucial step as standard practice. Finally, we note that the results presented here do not refute the biological modeling concerns identified by Beaulieu et al. (2015). Both sets of issues remain apposite to the goals of accurate divergence time estimation, and only by considering them in tandem can we move forward more confidently.

Background: Childhood cancer survivors treated with chest-directed radiotherapy have substantially elevated risk for developing breast cancer. Although genetic susceptibility to breast cancer in the general population is well studied, large-scale evaluation of breast cancer susceptibility after chest-directed radiotherapy for childhood cancer is lacking., Methods: We conducted a genome-wide association study of breast cancer in female survivors of childhood cancer, pooling two cohorts with detailed treatment data and systematic, long-term follow-up: the Childhood Cancer Survivor Study and St. Jude Lifetime Cohort. The study population comprised 207 survivors who developed breast cancer and 2774 who had not developed any subsequent neoplasm as of last follow-up. Genotyping and subsequent imputation yielded 16 958 466 high-quality variants for analysis. We tested associations in the overall population and in subgroups stratified by receipt of lower than 10 and 10 or higher gray breast radiation exposure. We report P values and pooled per-allele risk estimates from Cox proportional hazards regression models. All statistical tests were two-sided., Results: Among survivors who received 10 or higher gray breast radiation exposure, a locus on 1q41 was associated with subsequent breast cancer risk (rs4342822, nearest gene PROX1 , risk allele frequency in control subjects [RAF controls ] = 0.46, hazard ratio = 1.92, 95% confidence interval = 1.49 to 2.44, P = 7.09 × 10 -9 ). Two rare variants also showed potentially promising associations (breast radiation ≥10 gray: rs74949440, 11q23, TAGLN , RAF controls = 0.02, P = 5.84 × 10 -8 ; <10 gray: rs17020562, 1q32.3, RPS6KC1 , RAF controls = 0.0005, P = 6.68 × 10 -8 ). Associations were restricted to these dose subgroups, with consistent findings in the two survivor cohorts., Conclusions: Our study provides strong evidence that germline genetics outside high-risk syndromes could modify the effect of radiation exposure on breast cancer risk after childhood cancer., (Published by Oxford University Press 2017. This work is written by US Government employees and is in the public domain in the US.)

Background: Women with unilateral breast cancer (UBC) are at risk of developing a subsequent contralateral breast cancer (CBC). Common variants are associated with breast cancer risk. Whether these influence CBC risk is unknown., Methods: Participants were breast cancer cases from the population-based Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study. Sixty-seven established breast cancer risk loci were genotyped directly or by imputation in 1459 case subjects with CBC and 2126 UBC control subjects. An unweighted polygenic risk score (PRS) was created by summing the number of risk alleles for each directly genotyped single nucleotide polymorphism (SNP), or for imputed loci, the imputed dosage. A weighted PRS was calculated similarly, but where each SNP's contribution was weighted by the published per-allele log odds ratio. Unweighted and weighted polygenic risk scores and CBC risk were modeled using conditional logistic regression. Cumulative CBC risk was estimated and benchmarked using Surveillance, Epidemiology, and End Results population incidence rates., Results: Both unweighted and weighted PRS were statistically significantly associated with CBC risk. The adjusted risk ratio of CBC in women in the upper quartile of unweighted PRS compared with the lowest quartile was 1.63 (95% confidence interval [CI] = 1.33 to 2.00). The estimated 10-year cumulative risk for women in the upper quartile of the unweighted PRS was 7.4% (95% CI = 6.0% to 9.1%). For women in the upper quartile of the weighted PRS, the risk ratio for CBC was 1.75 (95% CI = 1.41 to 2.18) compared with women in the lowest quartile. There was no statistically significant heterogeneity by age, treatment (radiation therapy dose, tamoxifen, chemotherapy), estrogen receptor status of the first primary, histology of the first primary, length of at-risk period for CBC, or breast cancer family history., Conclusions: Common genomic variants associated with the development of first primary breast cancer are also associated with the development of CBC; the risk is strongest among those who carry more risk alleles., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Summary: The ease with which phylogenomic data can be generated has drastically escalated the computational burden for even routine phylogenetic investigations. To address this, we present phyx : a collection of programs written in C ++ to explore, manipulate, analyze and simulate phylogenetic objects (alignments, trees and MCMC logs). Modelled after Unix/GNU/Linux command line tools, individual programs perform a single task and operate on standard I/O streams that can be piped to quickly and easily form complex analytical pipelines. Because of the stream-centric paradigm, memory requirements are minimized (often only a single tree or sequence in memory at any instance), and hence phyx is capable of efficiently processing very large datasets., Availability and Implementation: phyx runs on POSIX-compliant operating systems. Source code, installation instructions, documentation and example files are freely available under the GNU General Public License at https://github.com/FePhyFoFum/phyx., Contact: eebsmith@umich.edu., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author 2017. Published by Oxford University Press.)

Sequence similarity tools like Basic Local Alignment Search Tool (BLAST) are essential components of many functional genetic, genomic, phylogenetic and bioinformatic studies. Many modern analysis pipelines use significant sequence similarity scores (p- or E-values) and the ranked order of BLAST matches to test a wide range of hypotheses concerning homology, orthology, the timing of de novo gene birth/death and gene family expansion/contraction. Despite significant contrary findings, many of these tests still implicitly assume that stronger or higher-ranked E-value scores imply closer phylogenetic relationships between sequences. Here, we demonstrate that even though a general relationship does exist between the phylogenetic distance of two sequences and their E-value, significant and misleading errors occur in both the completeness and the order of results under realistic evolutionary scenarios. These results provide additional details to past evidence showing that studies should avoid drawing direct inferences of evolutionary relatedness from measures of sequence similarity alone, and should instead, where possible, use more rigorous phylogeny-based methods., (© The Author 2016. Published by Oxford University Press.)

Objective: The Agency for Healthcare Research and Quality Hospital Survey on Patient Safety Culture (HSOPS) was designed to assess staff views on patient safety culture in hospital. This study examines psychometrics of the Italian translation of the HSOPS for use in territorial prevention facilities., Design: After minimal adjustments and pre-test of the Italian version, a qualitative cross-sectional study was carried out., Setting: Departments of Prevention (DPs) of four Local Health Authorities in Northern Italy., Participants: Census of medical and non-medical staff (n. 479)., Intervention: Web-based self-administered questionnaire., Main Outcome Measures: Descriptive statistics, internal reliability, Confirmatory Factor Analysis (CFA) and intercorrelations among survey composites., Results: Initial CFA of the 12 patient safety culture composites and 42 items included in the original version of the questionnaire revealed that two dimensions (Staffing and Overall Perception of Patient Safety) and nine individual items did not perform well among Italian territorial Prevention staff. After dropping those composites and items, psychometric properties were acceptable (comparative fit index = 0.94; root mean square error of approximation = 0.04; standardized root mean square residual = 0.04). Internal consistency for each remaining composite met or exceeded the criterion 0.70. Intercorrelations were all statistically significant., Conclusions: Psychometric analyses provided overall support for 10 of the 12 initial patient safety culture composites and 33 of the 42 initial composite items. Although the original instrument was intended for US Hospitals, the Italian translation of the HSOPS adapted for use in territorial prevention facilities performed adequately in Italian DPs., (© The Author 2017. Published by Oxford University Press in association with the International Society for Quality in Health Care. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Use prevalence of alternative tobacco products and marijuana has increased dramatically. Unfortunately, clinical guidelines have focused on traditional cigarettes with limited attention regarding these emerging public health issues. Thus, it is critical to understand how healthcare professionals view this issue and are responding to it. This qualitative study explored knowledge, beliefs and clinic-based practices regarding traditional and alternative tobacco products (cigar-like products, smokeless tobacco, hookah, e-cigarettes) and marijuana among rural and urban Georgia primary healthcare providers. The sample comprised 20 healthcare providers in primary care settings located in the Atlanta Metropolitan area and rural southern Georgia who participated in semi-structured interviews. Results indicated a lack of knowledge about these products, with some believing that some products were less harmful than traditional cigarettes or that they may be effective in promoting cessation or harm reduction. Few reported explicitly assessing use of these various products in clinic. In addition, healthcare providers reported a need for empirical evidence to inform their clinical practice. Healthcare providers must systematically assess use of the range of tobacco products and marijuana. Evidence-based recommendations or information sources are needed to inform clinical practice and help providers navigate conversations with patients using or inquiring about these products., (© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Developmental dyslexia (DD) is highly heritable and previous studies observed reduced cortical volume, white matter integrity, and functional alterations in left posterior brain regions in individuals with DD. The primary sulcal pattern has been hypothesized to relate to optimal organization and connections of cortical functional areas. It is determined during prenatal development and may reflect early, genetically influenced, brain development. We characterize the sulcal pattern using graph-based pattern analysis and investigate whether sulcal patterns in parieto-temporal and occipito-temporal regions are atypical in elementary school-age children with DD and pre-readers/beginning readers (preschoolers/kindergarteners) with a familial risk (elementary school-age children: n [males/females], age range = 17/11, 84-155 months; preschoolers/kindergarteners: 16/15, 59-84 months). The pattern of sulcal basin area in left parieto-temporal and occipito-temporal regions was significantly atypical (more sulcal basins of smaller size) in children with DD and further correlated with reduced reading performance on single- and nonword reading measures. A significantly atypical sulcal area pattern was also confirmed in younger preschoolers/kindergarteners with a familial risk of DD. Our results provide further support for atypical early brain development in DD and suggest that DD may originate from altered organization or connections of cortical areas in the left posterior regions., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Motivation: Phylogenetic estimates from published studies can be archived using general platforms like Dryad (Vision, 2010) or TreeBASE (Sanderson et al., 1994). Such services fulfill a crucial role in ensuring transparency and reproducibility in phylogenetic research. However, digital tree data files often require some editing (e.g. rerooting) to improve the accuracy and reusability of the phylogenetic statements. Furthermore, establishing the mapping between tip labels used in a tree and taxa in a single common taxonomy dramatically improves the ability of other researchers to reuse phylogenetic estimates. As the process of curating a published phylogenetic estimate is not error-free, retaining a full record of the provenance of edits to a tree is crucial for openness, allowing editors to receive credit for their work and making errors introduced during curation easier to correct., Results: Here, we report the development of software infrastructure to support the open curation of phylogenetic data by the community of biologists. The backend of the system provides an interface for the standard database operations of creating, reading, updating and deleting records by making commits to a git repository. The record of the history of edits to a tree is preserved by git's version control features. Hosting this data store on GitHub (http://github.com/) provides open access to the data store using tools familiar to many developers. We have deployed a server running the 'phylesystem-api', which wraps the interactions with git and GitHub. The Open Tree of Life project has also developed and deployed a JavaScript application that uses the phylesystem-api and other web services to enable input and curation of published phylogenetic statements., Availability and Implementation: Source code for the web service layer is available at https://github.com/OpenTreeOfLife/phylesystem-api. The data store can be cloned from: https://github.com/OpenTreeOfLife/phylesystem. A web application that uses the phylesystem web services is deployed at http://tree.opentreeoflife.org/curator. Code for that tool is available from https://github.com/OpenTreeOfLife/opentree., Contact: mtholder@gmail.com., (© The Author 2015. Published by Oxford University Press.)

Many phylogenomic studies based on transcriptomes have been limited to "single-copy" genes due to methodological challenges in homology and orthology inferences. Only a relatively small number of studies have explored analyses beyond reconstructing species relationships. We sampled 69 transcriptomes in the hyperdiverse plant clade Caryophyllales and 27 outgroups from annotated genomes across eudicots. Using a combined similarity- and phylogenetic tree-based approach, we recovered 10,960 homolog groups, where each was represented by at least eight ingroup taxa. By decomposing these homolog trees, and taking gene duplications into account, we obtained 17,273 ortholog groups, where each was represented by at least ten ingroup taxa. We reconstructed the species phylogeny using a 1,122-gene data set with a gene occupancy of 92.1%. From the homolog trees, we found that both synonymous and nonsynonymous substitution rates in herbaceous lineages are up to three times as fast as in their woody relatives. This is the first time such a pattern has been shown across thousands of nuclear genes with dense taxon sampling. We also pinpointed regions of the Caryophyllales tree that were characterized by relatively high frequencies of gene duplication, including three previously unrecognized whole-genome duplications. By further combining information from homolog tree topology and synonymous distance between paralog pairs, phylogenetic locations for 13 putative genome duplication events were identified. Genes that experienced the greatest gene family expansion were concentrated among those involved in signal transduction and oxidoreduction, including a cytochrome P450 gene that encodes a key enzyme in the betalain synthesis pathway. Our approach demonstrates a new approach for functional phylogenomic analysis in nonmodel species that is based on homolog groups in addition to inferred ortholog groups., (© The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Background: The Patient Assessment of Chronic Illness Care (PACIC) survey is a widely used instrument to assess the patient experience with healthcare delivery., Purpose: This study aims to evaluate the factorial structure of PACIC from the patient perspective., Methods: A postal survey was mailed to 4,796 randomly selected adults with diabetes from 34 primary care clinics. Internal consistencies of PACIC subscales were assessed by Cronhach's α. Factorial structure was evaluated by confirmatory and exploratory factor analyses., Results: Based on responses of 2,055 patients (43% response rate), exploratory factor analysis discerned a 4-factor, not 5-factor, model dominated by patient evaluation of healthcare services (explaining 74% of the variance). The other 3 factors addressed patient involvement (goal setting, participating in the healthcare team) and social support for self-management., Conclusions: The underlying factorial structure of PACIC, which reflects the patient perspective, is dynamic, patient-centered, and differs from the original 5-factor model that was more aligned with views of healthcare delivery stakeholders.

Orthology inference is central to phylogenomic analyses. Phylogenomic data sets commonly include transcriptomes and low-coverage genomes that are incomplete and contain errors and isoforms. These properties can severely violate the underlying assumptions of orthology inference with existing heuristics. We present a procedure that uses phylogenies for both homology and orthology assignment. The procedure first uses similarity scores to infer putative homologs that are then aligned, constructed into phylogenies, and pruned of spurious branches caused by deep paralogs, misassembly, frameshifts, or recombination. These final homologs are then used to identify orthologs. We explore four alternative tree-based orthology inference approaches, of which two are new. These accommodate gene and genome duplications as well as gene tree discordance. We demonstrate these methods in three published data sets including the grape family, Hymenoptera, and millipedes with divergence times ranging from approximately 100 to over 400 Ma. The procedure significantly increased the completeness and accuracy of the inferred homologs and orthologs. We also found that data sets that are more recently diverged and/or include more high-coverage genomes had more complete sets of orthologs. To explicitly evaluate sources of conflicting phylogenetic signals, we applied serial jackknife analyses of gene regions keeping each locus intact. The methods described here can scale to over 100 taxa. They have been implemented in python with independent scripts for each step, making it easy to modify or incorporate them into existing pipelines. All scripts are available from https://bitbucket.org/yangya/phylogenomic&#95;dataset&#95;construction., (© The Author 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Summary: New sequence data useful for phylogenetic and evolutionary analyses continues to be added to public databases. The construction of multiple sequence alignments and inference of huge phylogenies comprising large taxonomic groups are expensive tasks, both in terms of man hours and computational resources. Therefore, maintaining comprehensive phylogenies, based on representative and up-to-date molecular sequences, is challenging. PUmPER is a framework that can perpetually construct multi-gene alignments (with PHLAWD) and phylogenetic trees (with ExaML or RAxML-Light) for a given NCBI taxonomic group. When sufficient numbers of new gene sequences for the selected taxonomic group have accumulated in GenBank, PUmPER automatically extends the alignment and infers extended phylogenetic trees by using previously inferred smaller trees as starting topologies. Using our framework, large phylogenetic trees can be perpetually updated without human intervention. Importantly, resulting phylogenies are not statistically significantly worse than trees inferred from scratch., Availability and Implementation: PUmPER can run in stand-alone mode on a single server, or offload the computationally expensive phylogenetic searches to a parallel computing cluster. Source code, documentation, and tutorials are available at https://github.com/fizquierdo/perpetually-updated-trees., Contact: Fernando.Izquierdo@h-its.org, Supplementary Information: Supplementary Material is available at Bioinformatics online.

Since the advent of molecular phylogenetics more than 25 years ago, a major goal of plant systematists has been to discern the root of the angiosperms. Although most studies indicate that Amborella trichopoda is sister to all remaining extant flowering plants, support for this position has varied with respect to both the sequence data sets and analyses employed. Recently, Goremykin et al. (2013) questioned the "Amborella-sister hypothesis" using a "noise-reduction" approach and reported a topology with Amborella + Nymphaeales (water lilies) sister to all remaining angiosperms. Through a series of analyses of both plastid genomes and mitochondrial genes, we continue to find mostly strong support for the Amborella-sister hypothesis and offer a rebuttal of Goremykin et al. (2013). The major tenet of Goremykin et al. is that the Amborella-sister position is determined by noisy data--that is, characters with high rates of change and lacking true phylogenetic signal. To investigate the signal in these noisy data further, we analyzed the discarded characters from their noise-reduced alignments. We recovered a tree identical to that of the currently accepted angiosperm framework, including the position of Amborella as sister to all other angiosperms, as well as all other major clades. Thus, the signal in the "noisy" data is consistent with that of our complete data sets--arguing against the use of their noise-reduction approach. We also determined that one of the alignments presented by Goremykin et al. yields results at odds with their central claim--their data set actually supports Amborella as sister to all other angiosperms, as do larger plastid data sets we present here that possess more complete taxon sampling both within the monocots and for angiosperms in general. Previous unpartitioned, multilocus analyses of mitochondrial DNA (mtDNA) data have provided the strongest support for Amborella + Nymphaeales as sister to other angiosperms. However, our analysis of third codon positions from mtDNA sequence data also supports the Amborella-sister hypothesis. Finally, we challenge the conclusion of Goremykin et al. that the first flowering plants were aquatic and herbaceous, reasserting that even if Amborella + water lilies, or water lilies alone, are sister to the rest of the angiosperms, the earliest angiosperms were not necessarily aquatic and/or herbaceous.

Background: The number of patients starting renal replacement therapy (RRT) is increasing in England, as it is worldwide. Improvements in the management of chronic kidney disease (CKD) across communities to alter this trend are a public health priority. We have prospectively studied changes in the incidence and modality of treatment for end-stage renal disease following the introduction of a CKD management programme in the West Midlands region of England., Methods: Nephrology service to approximately 700 000 adult population of mixed ethnicity in urban and suburban areas, many with social deprivation. The programme was introduced in stages between 2003 and 2006 and comprised primary care education and financial incentives, personal clinical reports written directly to patients following every consultation, routine laboratory estimated glomerular filtration rate (eGFR) reporting, eGFR graph surveillance to identify and monitor patients at risk, multidisciplinary pre-RRT care and conservative care. Prevalent patients: 10 552 with CKD and 8509 without CKD with diabetes., Outcomes: access to nephrology care, trends in RRT incidence and starting modality, place of death without RRT. Incident count was adjusted for changes in the local adult population recorded in national censuses., Results: Ninety-one per cent of patients aged ≥75 years with incident CKD stage 5 were known to a nephrologist. The population-adjusted incident RRT rate peaked in 2005 and then declined; the proportion starting with transplant, peritoneal dialysis or haemodialysis by arterio-venous fistula increased to 63% by 2012 (P = 0.001 versus 2005). Fifty-two per cent of patients receiving planned conservative care without dialysis died out of hospital., Conclusions: Following the introduction of a community-wide systematic CKD management programme, the population-adjusted incidence of RRT reduced, modality of initiation of RRT improved and a majority of patients receiving planned conservative care without dialysis died out of hospital.

B cells originate from precursors in the bone marrow, and the first cells which migrate to the peripheral blood have been classified as 'transitional B cells'. Transitional B cells have been characterized in human blood with stage 1 (T1) and stage 2 (T2) subsets being proposed. In the present study, 27 normal human bone marrow samples were analysed for transitional B cell markers by eight-colour flow cytometry. T1 transitional B cells (CD45(+)CD19(+)CD10(+)IgM(+)IgD(lo)) and T2 transitional B cells (CD45(+)CD19(+)CD10(+)IgM(+)IgD(+)) were identified in normal bone marrow samples at a mean frequency of 3·2 and 3·1% of total B lineage cells, respectively. A majority of the bone marrow transitional B cells were CD24(hi)CD38(hi) , the phenotype of blood transitional B cells. Consistent with recent peripheral blood data, T2 B cells had a significantly higher CD21 expression compared with T1 B cells (72·4 versus 40·9%) in the bone marrow. These data raise the possibility that transitional B cells are capable of differentiating from T1 to T2 B cells within the bone marrow. Furthermore, transitional cells at either stages 1 or 2 might be capable of migrating out of the bone marrow., (© 2013 British Society for Immunology.)

The immunopathogenesis of severe dengue is poorly understood, but there is concern that induction of cross-reactive nonneutralizing antibodies by infection or vaccination may increase the likelihood of severe disease during a subsequent infection. We generated a total of 63 new human monoclonal antibodies to compare the B-cell response of subjects who received the National Institutes of Health live attenuated dengue vaccine rDEN1Δ30 to that of subjects following symptomatic primary infection with DENV1. Both infection and vaccination induced serum neutralizing antibodies and DENV1-reactive peripheral blood B cells, but the magnitude of induction was lower in vaccinated individuals. Serotype cross-reactive weakly neutralizing antibodies dominated the response in both vaccinated and naturally infected subjects. Antigen specificities were very similar, with a slightly greater percentage of antibodies targeting E protein domain I/II than domain III. These data shed light on the similarity of human B-cell response to live attenuated DENV vaccine or natural infection.

Unlabelled: Ever larger phylogenies are being constructed due to the explosion of genetic data and development of high-performance phylogenetic reconstruction algorithms. However, most methods for calculating divergence times are limited to datasets that are orders of magnitude smaller than recently published large phylogenies. Here, we present an algorithm and implementation of a divergence time method using penalized likelihood that can handle datasets of thousands of taxa. We implement a method that combines the standard derivative-based optimization with a stochastic simulated annealing approach to overcome optimization challenges. We compare this approach with existing software including r8s, PATHd8 and BEAST., Availability: Source code, example files, binaries and documentation for treePL are available at https://github.com/blackrim/treePL.

Background: Basal cell carcinoma (BCC) is the most common malignancy in the United States. Ionizing radiation is an established risk factor in certain populations, including cancer survivors. We quantified the association between ionizing radiation dose and the risk of BCC in childhood cancer survivors., Methods: Participants in the Childhood Cancer Survivor Study who reported a BCC (case subjects, n = 199) were matched on age and length of follow-up to three study participants who had not developed a BCC (control subjects, n = 597). The radiation-absorbed dose (in Gy) to the BCC location was calculated based on individual radiotherapy records using a custom-designed dosimetry program. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between demographic and treatment factors, therapeutic radiation dose, and surrogate markers of sun sensitivity (skin and hair color) and the risk of BCC. A linear dose-response model was fitted to evaluate the excess odds ratio per Gy of radiation dose., Results: Among case subjects, 83% developed BCC between the ages of 20 and 39 years. Radiation therapy, either alone or in combination with chemotherapy, was associated with an increased risk of BCC compared with no chemotherapy or radiation. The odds ratio for subjects who received 35 Gy or more to the skin site vs no radiation therapy was 39.8 (95% CI = 8.6 to 185). Results were consistent with a linear dose-response relationship, with an excess odds ratio per Gy of 1.09 (95% CI = 0.49 to 2.64). No other treatment variables were statistically significantly associated with an increased risk of BCC., Conclusions: Radiation doses to the skin of more than 1 Gy are associated with an increased risk of BCC.

Motivation: Due to advances in molecular sequencing and the increasingly rapid collection of molecular data, the field of phyloinformatics is transforming into a computational science. Therefore, new tools are required that can be deployed in supercomputing environments and that scale to hundreds or thousands of cores., Results: We describe RAxML-Light, a tool for large-scale phylogenetic inference on supercomputers under maximum likelihood. It implements a light-weight checkpointing mechanism, deploys 128-bit (SSE3) and 256-bit (AVX) vector intrinsics, offers two orthogonal memory saving techniques and provides a fine-grain production-level message passing interface parallelization of the likelihood function. To demonstrate scalability and robustness of the code, we inferred a phylogeny on a simulated DNA alignment (1481 taxa, 20 000 000 bp) using 672 cores. This dataset requires one terabyte of RAM to compute the likelihood score on a single tree. CODE AVAILABILITY: https://github.com/stamatak/RAxML-Light-1.0.5 DATA AVAILABILITY: http://www.exelixis-lab.org/onLineMaterial.tar.bz2, Contact: alexandros.stamatakis@h-its.org, Supplementary Information: Supplementary data are available at Bioinformatics online.

The patient portal is a web service which allows patients to view their electronic health record, communicate online with their care teams, and manage healthcare appointments and medications. Despite advantages of the patient portal, registrations for portal use have often been slow. Using a secure video system on our existing exam room electronic health record displays during regular office visits, the authors showed patients a video which promoted use of the patient portal. The authors compared portal registrations and portal use following the video to providing a paper instruction sheet and to a control (no additional portal promotion). From the 12,050 office appointments examined, portal registrations within 45 days of the appointment were 11.7%, 7.1%, and 2.5% for video, paper instructions, and control respectively (p<0.0001). Within 6 months following the interventions, 3.5% in the video cohort, 1.2% in the paper, and 0.75% of the control patients demonstrated portal use by initiating portal messages to their providers (p<0.0001).

The Lonicera clade Caprifolium contains approximately 25 species distributed around the Northern Hemisphere, including in the Mediterranean climates of California and Europe. We sequenced the second intron of LFY to help resolve relationships within the clade where the internal transcribed spacer and chloroplast markers had previously failed to do so. Divergence time estimation and biogeographic analyses over the posterior distribution of dated trees suggest that a widespread ancestor was distributed across the Northern Hemisphere some 7-17 million years ago. Asian species form a sister group to a clade in which the European species are sister to the North American species. We use climatic niche modeling and divergence time estimates to explore the evolution of climate variables in the group. Principal component analyses help to identify instances of convergence, especially between distantly related species in the Mediterranean basin and in the chaparral of California. We document several cases of significant divergence between sister species in eastern North America and western North America. Climatic models were projected from one continent into the others (e.g., North American species projected into Asia and Europe) to examine whether species living in these areas occupy similar climates. This study demonstrates the utility of combining niche modeling with historical biogeographic analyses and documents significant climatic niche evolution within a group of species distributed throughout the Northern Hemisphere. These results suggest a possible model for the origin of the Madrean-Tethyan disjunction pattern.