Morphological phylogenetics evaluated using novel evolutionary simulations

Evolutionary inferences require reliable phylogenies. Morphological data has traditionally been analysed using maximum parsimony, but recent simulation studies have suggested that Bayesian analyses yield more accurate trees. This debate is ongoing, in part, because of ambiguity over modes of morphological evolution and a lack of appropriate models. Here we investigate phylogenetic methods using two novel simulation models - one in which morphological characters evolve stochastically along lineages and another in which individuals undergo selection. Both models generate character data and lineage splitting simultaneously: the resulting trees are an emergent property, rather than a fixed parameter. Standard consensus methods for Bayesian searches (Mki) yield fewer incorrect nodes and quartets than the standard consensus trees recovered using equal weighting and implied weighting parsimony searches. Distances between the pool of derived trees (most parsimonious or posterior distribution) and the true trees - measured using Robinson-Foulds (RF), subtree prune and regraft (SPR), and tree bisection reconnection (TBR) metrics - demonstrate that this is related to the search strategy and consensus method of each technique. The amount and structure of homoplasy in character data differs between models. Morphological coherence, which has previously not been considered in this context, proves to be a more important factor for phylogenetic accuracy than homoplasy. Selection-based models exhibit relatively lower homoplasy, lower morphological coherence, and higher inaccuracy in inferred trees. Selection is a dominant driver of morphological evolution, but we demonstrate that it has a confounding effect on numerous character properties which are fundamental to phylogenetic inference. We suggest that the current debate should move beyond considerations of parsimony versus Bayesian, towards identifying modes of morphological evolution and using these to build models for probabilistic search methods

Ablation guided by STAR-mapping in addition to pulmonary vein isolation alone is superior to pulmonary vein isolation alone or in combination with CFAE/linear ablation for persistent AF

Introduction: The optimal ablation approach for persistent atrial fibrillation (AF) remains unclear. Methods and Results: Objective was to compare the long‐term rates of freedom from AF/AT in patients that underwent STAR mapping guided ablation against outcomes of patients undergoing conventional ablation procedures. Patients undergoing ablation for persistent AF as part of the Stochastic Trajectory Analysis of Ranked signals (STAR) mapping study were included. Outcomes following 'pulmonary vein isolation (PVI) plus STAR mapping guided ablation (STAR mapping cohort) were compared to patients undergoing PVI alone ablation during the same time period and also a propensity‐matched cohort undergoing PVI plus the addition of complex fractionated electrogram (CFAE) and/or linear ablation (“conventional ablation”). Rates of procedural AF termination and freedom from AF/AT during follow‐up were compared. Sixty‐five patients were included in both the STAR cohort and propensity matched conventional ablation cohort. AF termination rates were significantly higher in the STAR cohort (51/65, 78.5%) than conventional ablation cohort (10/65, 15.4%) and PVI alone ablation cohort (13/50, 26.0%; STAR cohort vs. other 2 cohorts both p < .001). There was no significant difference in procedure time between the three cohorts. During ≥20 months follow‐up a lower proportion of patients had AF/AT recurrence in the STAR cohort (20.0%) compared with the conventional ablation cohort (50.8%) or the PVI alone ablation cohort (50.0%; both p < .05 compared to STAR cohort). Conclusions: Outcomes of PVI plus STAR mapping guided ablation was superior to PVI alone or in combination with linear/CFAE ablation. A multicenter randomized controlled trial is planned to confirm these findings

Outcomes of preexisting diabetes mellitus in breast, colorectal, and prostate cancer.

This is the author accepted manuscript. The final version is available from Springer Verlag via the DOI in this record.PURPOSE: Preexisting diabetes is associated with increased morbidity and mortality in cancer. We examined the impact of incident cancer on the long-term outcomes of diabetes. METHODS: Using the United Kingdom Clinical Practice Research Datalink, we identified three cohorts of diabetes patients subsequently diagnosed with breast, colorectal, or prostate cancer, each matched to diabetic noncancer controls. Patients were required to have survived at least 1 year after cancer diagnosis (cases) or a matched index date (controls), and were followed up to 10 years for incident microvascular and macrovascular complications and mortality. Multivariate competing risks regression analyses were used to compare outcomes between cancer patients and controls. RESULTS: Overall, there were 3382 cancer patients and 11,135 controls with 59,431 person-years of follow-up. In adjusted analyses, there were no statistically significant (p ≤ 0.05) differences in diabetes complication rates between cancer patients and their controls in any of the three cancer cohorts. Combined, cancer patients were less likely (adjusted hazard ratio [HR] 0.88; 95% CI = 0.79-0.98) to develop retinopathy. Cancer patients were more likely to die of any cause (including cancer), but prostate cancer patients were less likely to die of causes associated with diabetes (HR 0.61; 95% CI = 0.43-0.88). CONCLUSIONS AND IMPLICATIONS: There is no evidence that incident cancer had an adverse impact on the long-term outcomes of preexisting diabetes. IMPLICATIONS FOR CANCER SURVIVORS: These findings are important for cancer survivors with preexisting diabetes because they suggest that substantial improvements in the relative survival of several of the most common types of cancer are not undermined by excess diabetes morbidity and mortality.This study was funded by the Population Research Committee, Cancer Research UK. Quality and Outcomes of Care for Chronic Conditions in Older Patients Diagnosed with Breast, Colorectal, or Prostate Cancer Compared to Non-Cancer Controls: An Observational Study Using the Clinical Practice Research Datalink (CPRD). Reference # 16609. 1 July 2013–29 February, 2016. In addition, Dr. Keating is supported by K24CA181510 from the US National Cancer Institute

Outcomes of preexisting diabetes mellitus in breast, colorectal, and prostate cancer.

This is the author accepted manuscript. The final version is available from Springer Verlag via the DOI in this record.PURPOSE: Preexisting diabetes is associated with increased morbidity and mortality in cancer. We examined the impact of incident cancer on the long-term outcomes of diabetes. METHODS: Using the United Kingdom Clinical Practice Research Datalink, we identified three cohorts of diabetes patients subsequently diagnosed with breast, colorectal, or prostate cancer, each matched to diabetic noncancer controls. Patients were required to have survived at least 1 year after cancer diagnosis (cases) or a matched index date (controls), and were followed up to 10 years for incident microvascular and macrovascular complications and mortality. Multivariate competing risks regression analyses were used to compare outcomes between cancer patients and controls. RESULTS: Overall, there were 3382 cancer patients and 11,135 controls with 59,431 person-years of follow-up. In adjusted analyses, there were no statistically significant (p ≤ 0.05) differences in diabetes complication rates between cancer patients and their controls in any of the three cancer cohorts. Combined, cancer patients were less likely (adjusted hazard ratio [HR] 0.88; 95% CI = 0.79-0.98) to develop retinopathy. Cancer patients were more likely to die of any cause (including cancer), but prostate cancer patients were less likely to die of causes associated with diabetes (HR 0.61; 95% CI = 0.43-0.88). CONCLUSIONS AND IMPLICATIONS: There is no evidence that incident cancer had an adverse impact on the long-term outcomes of preexisting diabetes. IMPLICATIONS FOR CANCER SURVIVORS: These findings are important for cancer survivors with preexisting diabetes because they suggest that substantial improvements in the relative survival of several of the most common types of cancer are not undermined by excess diabetes morbidity and mortality.This study was funded by the Population Research Committee, Cancer Research UK. Quality and Outcomes of Care for Chronic Conditions in Older Patients Diagnosed with Breast, Colorectal, or Prostate Cancer Compared to Non-Cancer Controls: An Observational Study Using the Clinical Practice Research Datalink (CPRD). Reference # 16609. 1 July 2013–29 February, 2016. In addition, Dr. Keating is supported by K24CA181510 from the US National Cancer Institute

Quality of diabetes care in breast, colorectal, and prostate cancer

This is the final version. Available on open access from Springer via the DOI in this recordPURPOSE: Overlooking other medical conditions during cancer treatment and follow-up could result in excess morbidity and mortality, thereby undermining gains associated with early detection and improved treatment of cancer. We compared the quality of care for diabetes patients subsequently diagnosed with breast, colorectal, or prostate cancer to matched, diabetic non-cancer controls. METHODS: Longitudinal cohort study using primary care records from the Clinical Practice Research Datalink, United Kingdom. Patients with pre-existing diabetes were followed for up to 5 years after cancer diagnosis, or after an assigned index date (non-cancer controls). Quality of diabetes care was estimated based on Quality and Outcomes Framework indicators. Mixed effects logistic regression analyses were used to compare the unadjusted and adjusted odds of meeting quality measures between cancer patients and controls, overall and stratified by type of cancer. RESULTS: 3382 cancer patients and 11,135 controls contributed 44,507 person-years of follow-up. In adjusted analyses, cancer patients were less likely to meet five of 14 quality measures, including: total cholesterol ≤ 5 mmol/L (odds ratio [OR] = 0.82; 95% confidence interval [CI], 0.75-0.90); glycosylated hemoglobin ≤ 59 mmol/mol (adjusted OR = 0.77; 95% CI, 0.70-0.85); and albumin creatinine ratio testing (adjusted OR = 0.83; 95% CI, 0.75-0.91). However, cancer patients were as likely as their matched controls to meet quality measures for other diabetes services, including retinal screening, foot examination, and dietary review. CONCLUSIONS: Although in the short-term, cancer patients were less likely to achieve target thresholds for cholesterol and HbA1c, they continued to receive high-quality diabetes primary care throughout 5 years post diagnosis. IMPLICATIONS FOR CANCER SURVIVORS: These findings are important for cancer survivors with pre-existing diabetes because they indicate that high-quality diabetes care is maintained throughout the continuum of cancer diagnosis, treatment, and follow-up.This study was funded by the Population Research Committee, Cancer Research UK. Quality and Outcomes of Care for Chronic Conditions in Older Patients Diagnosed with Breast, Colorectal, or Prostate Cancer Compared to Non-Cancer Controls: An Observational Study Using the Clinical Practice Research Datalink (CPRD). Reference # 16609. 1 July 2013–29 February, 2016. In addition, Dr. Keating is supported by K24CA181510 from the US National Cancer Institute

Initial fixation placement in face images is driven by top-down guidance

The eyes are often inspected first and for longer period during face exploration. To examine whether this saliency of the eye region at the early stage of face inspection is attributed to its local structure properties or to the knowledge of its essence in facial communication, in this study we investigated the pattern of eye movements produced by rhesus monkeys (Macaca mulatta) as they free viewed images of monkey faces. Eye positions were recorded accurately using implanted eye coils, while images of original faces, faces with scrambled eyes, and scrambled faces except for the eyes were presented on a computer screen. The eye region in the scrambled faces attracted the same proportion of viewing time and fixations as it did in the original faces, even the scrambled eyes attracted substantial proportion of viewing time and fixations. Furthermore, the monkeys often made the first saccade towards to the location of the eyes regardless of image content. Our results suggest that the initial fixation placement in faces is driven predominantly by ‘top-down’ or internal factors, such as the prior knowledge of the location of “eyes” within the context of a face

A Novel Mapping System for Panoramic Mapping of the Left Atrium: Application to Detect and Characterize Localized Sources Maintaining Atrial Fibrillation

Objectives This study sought to use a novel panoramic mapping system (CARTOFINDER) to detect and characterize drivers in persistent atrial fibrillation (AF). Background Mechanisms sustaining persistent AF remain uncertain. Methods Patients undergoing catheter ablation for persistent AF were included. A 64-pole basket catheter was used to acquire unipolar signals, which were processed by the mapping system to generate wavefront propagation maps. The system was used to identify and characterize potential drivers in AF pre- and post-pulmonary vein (PV) isolation. The effect of ablation on drivers identified post-PV isolation was assessed. Results Twenty patients were included in the study with 112 CARTOFINDER maps created. Potential drivers were mapped in 19 of 20 patients with AF (damage to the basket and noise on electrograms was present in 1 patient). Thirty potential drivers were identified all of which were transient but repetitive; 19 were rotational and 11 focal. Twenty-six drivers were ablated with a predefined response in 22 of 26 drivers: AF terminated with 12 and cycle length slowed (≥30 ms) with 10. Drivers with rotational activation were predominantly mapped to sites of low-voltage zones (81.8%). PV isolation had no remarkable impact on the cycle length at the driver sites (138.4 ± 14.3 ms pre-PV isolation vs. 137.2 ± 15.2 ms post-PV isolation) and drivers that had also been identified on pre-PV isolation maps were more commonly associated with AF termination. Conclusions Drivers were identified in almost all patients in the form of intermittent but repetitive focal or rotational activation patterns. The mechanistic importance of these phenomena was confirmed by the response to ablation

Correcting pervasive errors in RNA crystallography through enumerative structure prediction

Three-dimensional RNA models fitted into crystallographic density maps exhibit pervasive conformational ambiguities, geometric errors and steric clashes. To address these problems, we present enumerative real-space refinement assisted by electron density under Rosetta (ERRASER), coupled to Python-based hierarchical environment for integrated 'xtallography' (PHENIX) diffraction-based refinement. On 24 data sets, ERRASER automatically corrects the majority of MolProbity-assessed errors, improves the average Rfree factor, resolves functionally important discrepancies in noncanonical structure and refines low-resolution models to better match higher-resolution models

Automated detection of repetitive focal activations in persistent atrial fibrillation: Validation of a novel detection algorithm and application through panoramic and sequential mapping

INTRODUCTION: Identifying drivers in persistent atrial fibrillation (AF) remains challenging. We sought to validate an automated system for detection of focal activation using basket and PentaRay catheters in AF. METHODS: Patients having ablation for atrial tachycardia (AT) and persistent AF were mapped. Thirty-second unipolar basket and PentaRay recordings were analyzed using CARTOFINDER. Focal activation or "region of interest" (ROI) was defined as more than or equal to 2 consecutive focal activations with one electrode leading relative to its neighbors with QS morphology on the unipolar electrogram. ROI was validated in AT. AF patients were mapped to (1) look for evidence of focal activations on wavefront maps, (2) evaluate whether these were detected as ROI on basket recordings, and (3) whether these sites could be identified on sequential PentaRay recordings. RESULTS: ROIs were identified in five focal ATs but none of 16 reentrant ATs. Twenty-eight AF patients had 35 focal drivers identified from basket wavefront maps with an ablation response in all (16 cycle length slowing and 19 AF termination). Thirty focal activations were detected on basket ROI maps (86%). Twenty-three of 28 patients had sequential PentaRay mapping and 22 of 30 focal drivers in these patients (73%) were identified as ROI. These drivers had greater temporal stability (3.6 ± 0.6 vs 2.7 ± 0.6; P < 0.001), higher recurrence rate (12.4 ± 2.7 vs 7.2 ± 0.9; P < 0.001), and more frequently were associated with AF termination ( P < 0.001) compared with those not identified as ROI. CONCLUSIONS: Focal activations can be detected in AF using sequential recordings. The ablation response at focal sources suggests they may be viable therapeutic targets