Manifold learning of COPD

Analysis of CT scans for studying Chronic Obstructive Pulmonary Disease (COPD) is generally limited to mean scores of disease extent. However, the evolution of local pulmonary damage may vary between patients with discordant effects on lung physiology. This limits the explanatory power of mean values in clinical studies. We present local disease and deformation distributions to address this limitation. The disease distribution aims to quantify two aspects of parenchymal damage: locally diffuse/dense disease and global homogeneity/heterogeneity. The deformation distribution links parenchymal damage to local volume change. These distributions are exploited to quantify inter-patient differences. We used manifold learning to model variations of these distributions in 743 patients from the COPDGene study. We applied manifold fusion to combine distinct aspects of COPD into a single model. We demonstrated the utility of the distributions by comparing associations between learned embeddings and measures of severity. We also illustrated the potential to identify trajectories of disease progression in a manifold space of COPD

Pediatric Cardiac Xenotransplantation: Recommendations for the Ethical Design of Clinical Trials

For children with complex congenital heart problems, cardiac allotransplantation is sometimes the best therapeutic option. However, availability of hearts for pediatric patients is limited, resulting in a long and growing waitlist, and a high mortality rate while waiting. Cardiac xenotransplantation has been proposed as one therapeutic alternative for neonates and infants, either in lieu of allotransplantation or as a bridge until an allograft becomes available. Scientific and clinical developments in xenotransplantation appear likely to permit cardiac xenotransplantation clinical trials in adults in the coming years. The ethical issues around xenotransplantation of the heart and other organs and tissues have recently been examined, but to date, only limited literature is available on the ethical issues that are attendant with pediatric heart xenotransplantation. Here, we summarize the ethical issues, focusing on (i) whether cardiac xenotransplantation should proceed in adults or children first, (ii) pediatric recipient selection for initial xenotransplantation trials, (iii) special problems regarding informed consent in this context, and (iv) related psychosocial and public perception considerations. We conclude with specific recommendations regarding ethically informed design of pediatric heart xenotransplantation trials

Disease Progression Modelling in Chronic Obstructive Pulmonary Disease (COPD)

RATIONALE: The decades-long progression of Chronic Obstructive Pulmonary Disease (COPD) renders identifying different trajectories of disease progression challenging. OBJECTIVES: To identify subtypes of COPD patients with distinct longitudinal progression patterns using a novel machine-learning tool called "Subtype and Stage Inference (SuStaIn)", and to evaluate the utility of SuStaIn for patient stratification in COPD. METHODS: We applied SuStaIn to cross-sectional CT imaging markers in 3698 GOLD1-4 patients and 3479 controls from the COPDGene study to identify COPD patient subtypes. We confirmed the identified subtypes and progression patterns using ECLIPSE data. We assessed the utility of SuStaIn for patient stratification by comparing SuStaIn subtypes and stages at baseline with longitudinal follow-up data. MEASUREMENTS AND MAIN RESULTS: We identified two trajectories of disease progression in COPD: a "Tissue→Airway" subtype (n=2354, 70.4%) in which small airway dysfunction and emphysema precede large-airway wall abnormalities, and an "Airway→Tissue" subtype (n=988, 29.6%) in which large-airway wall abnormalities precede emphysema and small airway dysfunction. Subtypes were reproducible in ECLIPSE. Baseline stage in both subtypes correlated with future FEV1/FVC decline (r=-0.16 (p<0.001) in the Tissue→Airway group; r=-0.14 (p=0.011) in the Airway→Tissue group). SuStaIn placed 30% of smokers with normal lung function at non-baseline stages suggesting imaging changes consistent with early COPD. Individuals with early changes were 2.5 times more likely to meet COPD diagnostic criteria at follow-up. CONCLUSIONS: We demonstrate two distinct patterns of disease progression in COPD using SuStaIn, likely representing different endotypes. One-third of healthy smokers have detectable imaging changes, suggesting a new biomarker of 'early COPD'

Gene expression drives the evolution of dominance.

Dominance is a fundamental concept in molecular genetics and has implications for understanding patterns of genetic variation, evolution, and complex traits. However, despite its importance, the degree of dominance in natural populations is poorly quantified. Here, we leverage multiple mating systems in natural populations of Arabidopsis to co-estimate the distribution of fitness effects and dominance coefficients of new amino acid changing mutations. We find that more deleterious mutations are more likely to be recessive than less deleterious mutations. Further, this pattern holds across gene categories, but varies with the connectivity and expression patterns of genes. Our work argues that dominance arises as a consequence of the functional importance of genes and their optimal expression levels

Radiological Decision Aid to determine suitability for medial unicompartmental knee arthroplasty: development and preliminary validation

Aims: An evidence-based radiographic Decision Aid for meniscal-bearing unicompartmental knee arthroplasty (UKA) has been developed and this study investigates its performance at an independent centre. Patients: and Methods Pre-operative radiographs, including stress views, from a consecutive cohort of 550 knees undergoing arthroplasty (UKA or total knee arthroplasty; TKA) by a single-surgeon were assessed. Suitability for UKA was determined using the Decision Aid, with the assessor blinded to treatment received, and compared with actual treatment received, which was determined by an experienced UKA surgeon based on history, examination, radiographic assessment including stress radiographs, and intra-operative assessment in line with the recommended indications as described in the literature. Results: The sensitivity and specificity of the Decision Aid was 92% and 88%, respectively. Excluding knees where a clear pre-operative plan was made to perform TKA, i.e. patient request, the sensitivity was 93% and specificity 96%. The false-positive rate was low (2.4%) with all affected patients readily identifiable during joint inspection at surgery. In patients meeting Decision Aid criteria and receiving UKA, the five-year survival was 99% (95% confidence intervals (CI) 97 to 100). The false negatives (3.5%), who received UKA but did not meet the criteria, had significantly worse functional outcomes (flexion p < 0.001, American Knee Society Score - Functional p < 0.001, University of California Los Angeles score p = 0.04), and lower implant survival of 93.1% (95% CI 77.6 to 100). Conclusion: The radiographic Decision Aid safely and reliably identifies appropriate patients for meniscal-bearing UKA and achieves good results in this population. The widespread use of the Decision Aid should improve the results of UKA

Intergenomic Arms Races: Detection of a Nuclear Rescue Gene of Male-Killing in a Ladybird

Many species of arthropod are infected by deleterious inherited micro-organisms. Typically these micro-organisms are inherited maternally. Consequently, some, particularly bacteria of the genus Wolbachia, employ a variety of strategies that favour female over male hosts. These strategies include feminisation, induction of parthenogenesis and male-killing. These strategies result in female biased sex ratios in host populations, which lead to selection for host factors that promote male production. In addition, the intra-genomic conflict produced by the difference in transmission of these cytoplasmic endosymbionts and nuclear factors will impose a pressure favouring nuclear factors that suppress the effects of the symbiont. During investigations of the diversity of male-killing bacteria in ladybirds (Coccinellidae), unexpected patterns of vertical transmission of a newly discovered male-killing taxon were observed in the ladybird Cheilomenes sexmaculata. Initial analysis suggested that the expression of the bacterial male-killing trait varies according to the male(s) a female has mated with. By swapping males between females, a male influence on the expression of the male-killing trait was confirmed. Experiments were then performed to determine the nature of the interaction. These studies showed that a single dominant allele, which rescues male progeny of infected females from the pathological effect of the male-killer, exists in this species. The gene shows typical Mendelian autosomal inheritance and is expressed irrespective of the parent from which it is inherited. Presence of the rescue gene in either parent does not significantly affect the inheritance of the symbiont. We conclude that C. sexmaculata is host to a male-killing γ-proteobacterium. Further, this beetle is polymorphic for a nuclear gene, the dominant allele of which rescues infected males from the pathogenic effects of the male-killing agent. These findings represent the first reported case of a nuclear suppressor of male-killing in a ladybird. They are considered in regard to sex ratio and intra-genomic conflict theories, and models of the evolutionary dynamics and distribution of inherited symbionts

Variable Incidence of Spiroplasma Infections in Natural Populations of Drosophila Species

Spiroplasma is widespread as a heritable bacterial symbiont in insects and some other invertebrates, in which it sometimes acts as a male-killer and causes female-biased sex ratios in hosts. Besides Wolbachia, it is the only heritable bacterium known from Drosophila, having been found in 16 of over 200 Drosophila species screened, based on samples of one or few individuals per species. To assess the extent to which Spiroplasma infection varies within and among species of Drosophila, intensive sampling consisting of 50–281 individuals per species was conducted for natural populations of 19 Drosophila species. Infection rates varied among species and among populations of the same species, and 12 of 19 species tested negative for all individuals. Spiroplasma infection never was fixed, and the highest infection rates were 60% in certain populations of D. hydei and 85% in certain populations of D. mojavensis. In infected species, infection rates were similar for males and females, indicating that these Spiroplasma infections do not confer a strong male-killing effect. These findings suggest that Spiroplasma has other effects on hosts that allow it to persist, and that environmental or host variation affects transmission or persistence leading to differences among populations in infection frequencies

Perceptual Other-Race Training Reduces Implicit Racial Bias

Background: Implicit racial bias denotes socio-cognitive attitudes towards other-race groups that are exempt from conscious awareness. In parallel, other-race faces are more difficult to differentiate relative to own-race faces – the ‘‘Other-Race Effect.’ ’ To examine the relationship between these two biases, we trained Caucasian subjects to better individuate other-race faces and measured implicit racial bias for those faces both before and after training. Methodology/Principal Findings: Two groups of Caucasian subjects were exposed equally to the same African American faces in a training protocol run over 5 sessions. In the individuation condition, subjects learned to discriminate between African American faces. In the categorization condition, subjects learned to categorize faces as African American or not. For both conditions, both pre- and post-training we measured the Other-Race Effect using old-new recognition and implicit racial biases using a novel implicit social measure – the ‘‘Affective Lexical Priming Score’ ’ (ALPS). Subjects in the individuation condition, but not in the categorization condition, showed improved discrimination of African American faces with training. Concomitantly, subjects in the individuation condition, but not the categorization condition, showed a reduction in their ALPS. Critically, for the individuation condition only, the degree to which an individual subject’s ALPS decreased was significantly correlated with the degree of improvement that subject showed in their ability to differentiate African American faces

A transcriptional network of cell cycle dysregulation in noninvasive papillary urothelial carcinoma

Human cancers display a restricted set of expression profiles, despite diverse mutational drivers. This has led to the hypothesis that select sets of transcription factors act on similar target genes as an integrated network, buffering a tumor’s transcriptional state. Noninvasive papillary urothelial carcinoma (NIPUC) with higher cell cycle activity has higher risk of recurrence and progression. In this paper, we describe a transcriptional network of cell cycle dysregulation in NIPUC, which was delineated using the ARACNe algorithm applied to expression data from a new cohort (n = 81, RNA sequencing), and two previously published cohorts. The transcriptional network comprised 121 transcription factors, including the pluripotency factors SOX2 and SALL4, the sex hormone binding receptors ESR1 and PGR, and multiple homeobox factors. Of these 121 transcription factors, 65 and 56 were more active in tumors with greater and less cell cycle activity, respectively. When clustered by activity of these transcription factors, tumors divided into High Cell Cycle versus Low Cell Cycle groups. Tumors in the High Cell Cycle group demonstrated greater mutational burden and copy number instability. A putative mutational driver of cell cycle dysregulation, such as homozygous loss of CDKN2A, was found in only 50% of High Cell Cycle NIPUC, suggesting a prominent role of transcription factor activity in driving cell cycle dysregulation. Activity of the 121 transcription factors strongly associated with expression of EZH2 and other members of the PRC2 complex, suggesting regulation by this complex influences expression of the transcription factors in this network. Activity of transcription factors in this network also associated with signatures of pluripotency and epithelial-to-mesenchymal transition (EMT), suggesting they play a role in driving evolution to invasive carcinoma. Consistent with this, these transcription factors differed in activity between NIPUC and invasive urothelial carcinoma

Applying refinement to the use of mice and rats in rheumatoid arthritis research

Rheumatoid arthritis (RA) is a painful, chronic disorder and there is currently an unmet need for effective therapies that will benefit a wide range of patients. The research and development process for therapies and treatments currently involves in vivo studies, which have the potential to cause discomfort, pain or distress. This Working Group report focuses on identifying causes of suffering within commonly used mouse and rat ‘models’ of RA, describing practical refinements to help reduce suffering and improve welfare without compromising the scientific objectives. The report also discusses other, relevant topics including identifying and minimising sources of variation within in vivo RA studies, the potential to provide pain relief including analgesia, welfare assessment, humane endpoints, reporting standards and the potential to replace animals in RA research