Clinical measurements versus patient-reported outcomes: analysis of the American Shoulder and Elbow Surgeons physician assessment in patients undergoing reverse total shoulder arthroplasty.

BackgroundThe American Shoulder and Elbow Surgeons (ASES) score is composed of a patient-reported portion and a physician assessment. Although the patient-reported score is frequently used to assess postoperative outcomes after shoulder arthroplasty, no previous studies have used the physician-assessment component. This study evaluated the relationship of the ASES physician-assessment measurements with patient-reported shoulder and general health outcomes.MethodsA retrospective review of a prospectively collected multicenter database was used to analyze patients who underwent primary reverse total shoulder arthroplasty (RTSA) from 2012 to 2015 with a minimum 2-year follow-up. ASES physician-assessment and patient-reported components and 12-Item Short Form Health Survey (SF-12) general health questionnaires were obtained preoperatively and 2 years postoperatively. The relationship between ASES physician measurements with ASES patient-reported outcome (PRO) scores and SF-12 Physical and Mental domain scores was assessed with Pearson correlation coefficients.ResultsIncluded were 74 patients (32 men; mean age, 69.2 years; body mass index, 29.4 kg/m2). Preoperative physician measurements and PRO scores were not significantly correlated. Postoperatively, only the ASES physician-measured active (R = 0.54, P < .01) and passive forward flexion (R = 0.53, P < .01) demonstrated moderate correlation with ASES patient scores. The remaining clinical measurements had no significant correlations with ASES patient or SF-12 scores. During the 2-year period, only improvements in active forward flexion correlated with improvements in ASES patient scores (R = 0.36, P < .01).ConclusionsLittle correlation exists between clinical measurements from the ASES physician component and PROs, including the ASES patient-reported and SF-12 general health surveys, in RTSA patients. Improvement in active forward flexion is the only clinical measurement correlated with PRO improvement at 2 years

Sociobiological Control of Plasmid copy number

Background:
All known mechanisms and genes responsible for the regulation of plasmid replication lie with the plasmid rather than the chromosome. It is possible therefore that there can be copy-up mutants. Copy-up mutants will have within host selective advantage. This would eventually result into instability of bacteria-plasmid association. In spite of this possibility low copy number plasmids appear to exist stably in host populations. We examined this paradox using a computer simulation model.

Model:
Our multilevel selection model assumes a wild type with tightly regulated replication to ensure low copy number. A mutant with slightly relaxed replication regulation can act as a “cheater” or “selfish” plasmid and can enjoy a greater within-host-fitness. However the host of a cheater plasmid has to pay a greater cost. As a result, in host level competition, host cell with low copy number plasmid has a greater fitness. Furthermore, another mutant that has lost the genes required for conjugation was introduced in the model. The non-conjugal mutant was assumed to undergo conjugal transfer in the presence of another conjugal plasmid in the host cell.

Results:
The simulatons showed that if the cost of carrying a plasmid was low, the copy-up mutant could drive the wild type to extinction or very low frequencies. Consequently, another mutant with a higher copy number could invade the first invader. This process could result into an increasing copy number. However above a certain copy number within-host selection was overcompensated by host level selection leading to a rock-paper-scissor (RPS) like situation. The RPS situation allowed the coexistence of high and low copy number plasmids. The non-conjugal “hypercheaters” could further arrest the copy numbers to a substantially lower level.

Conclusions:
These sociobiological interactions might explain the stability of copy numbers better than molecular mechanisms of replication regulation alone

Design and rationale of a multi-center, pragmatic, open-label randomized trial of antimicrobial therapy - the study of clinical efficacy of antimicrobial therapy strategy using pragmatic design in Idiopathic Pulmonary Fibrosis (CleanUP-IPF) clinical trial

Compelling data have linked disease progression in patients with idiopathic pulmonary fibrosis (IPF) with lung dysbiosis and the resulting dysregulated local and systemic immune response. Moreover, prior therapeutic trials have suggested improved outcomes in these patients treated with either sulfamethoxazole/ trimethoprim or doxycycline. These trials have been limited by methodological concerns. This trial addresses the primary hypothesis that long-term treatment with antimicrobial therapy increases the time-to-event endpoint of respiratory hospitalization or all-cause mortality compared to usual care treatment in patients with IPF. We invoke numerous innovative features to achieve this goal, including: 1) utilizing a pragmatic randomized trial design; 2) collecting targeted biological samples to allow future exploration of 'personalized' therapy; and 3) developing a strong partnership between the NHLBI, a broad range of investigators, industry, and philanthropic organizations. The trial will randomize approximately 500 individuals in a 1:1 ratio to either antimicrobial therapy or usual care. The site principal investigator will declare their preferred initial antimicrobial treatment strategy (trimethoprim 160 mg/ sulfamethoxazole 800 mg twice a day plus folic acid 5 mg daily or doxycycline 100 mg once daily if body weight is < 50 kg or 100 mg twice daily if ≥50 kg) for the participant prior to randomization. Participants randomized to antimicrobial therapy will receive a voucher to help cover the additional prescription drug costs. Additionally, those participants will have 4-5 scheduled blood draws over the initial 24 months of therapy for safety monitoring. Blood sampling for DNA sequencing and genome wide transcriptomics will be collected before therapy. Blood sampling for transcriptomics and oral and fecal swabs for determination of the microbiome communities will be collected before and after study completion. As a pragmatic study, participants in both treatment arms will have limited in-person visits with the enrolling clinical center. Visits are limited to assessments of lung function and other clinical parameters at time points prior to randomization and at months 12, 24, and 36. All participants will be followed until the study completion for the assessment of clinical endpoints related to hospitalization and mortality events. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02759120

Robust Detection of Hierarchical Communities from Escherichia coli Gene Expression Data

Determining the functional structure of biological networks is a central goal of systems biology. One approach is to analyze gene expression data to infer a network of gene interactions on the basis of their correlated responses to environmental and genetic perturbations. The inferred network can then be analyzed to identify functional communities. However, commonly used algorithms can yield unreliable results due to experimental noise, algorithmic stochasticity, and the influence of arbitrarily chosen parameter values. Furthermore, the results obtained typically provide only a simplistic view of the network partitioned into disjoint communities and provide no information of the relationship between communities. Here, we present methods to robustly detect coregulated and functionally enriched gene communities and demonstrate their application and validity for Escherichia coli gene expression data. Applying a recently developed community detection algorithm to the network of interactions identified with the context likelihood of relatedness (CLR) method, we show that a hierarchy of network communities can be identified. These communities significantly enrich for gene ontology (GO) terms, consistent with them representing biologically meaningful groups. Further, analysis of the most significantly enriched communities identified several candidate new regulatory interactions. The robustness of our methods is demonstrated by showing that a core set of functional communities is reliably found when artificial noise, modeling experimental noise, is added to the data. We find that noise mainly acts conservatively, increasing the relatedness required for a network link to be reliably assigned and decreasing the size of the core communities, rather than causing association of genes into new communities.Comment: Due to appear in PLoS Computational Biology. Supplementary Figure S1 was not uploaded but is available by contacting the author. 27 pages, 5 figures, 15 supplementary file

How predation and landscape fragmentation affect vole population dynamics

Background: Microtine species in Fennoscandia display a distinct north-south gradient from regular cycles to stable populations. The gradient has often been attributed to changes in the interactions between microtines and their predators. Although the spatial structure of the environment is known to influence predator-prey dynamics of a wide range of species, it has scarcely been considered in relation to the Fennoscandian gradient. Furthermore, the length of microtine breeding season also displays a north-south gradient. However, little consideration has been given to its role in shaping or generating population cycles. Because these factors covary along the gradient it is difficult to distinguish their effects experimentally in the field. The distinction is here attempted using realistic agent-based modelling. Methodology/Principal Findings: By using a spatially explicit computer simulation model based on behavioural and ecological data from the field vole (Microtus agrestis), we generated a number of repeated time series of vole densities whose mean population size and amplitude were measured. Subsequently, these time series were subjected to statistical autoregressive modelling, to investigate the effects on vole population dynamics of making predators more specialised, of altering the breeding season, and increasing the level of habitat fragmentation. We found that fragmentation as well as the presence of specialist predators are necessary for the occurrence of population cycles. Habitat fragmentation and predator assembly jointly determined cycle length and amplitude. Length of vole breeding season had little impact on the oscillations. Significance: There is good agreement between our results and the experimental work from Fennoscandia, but our results allow distinction of causation that is hard to unravel in field experiments. We hope our results will help understand the reasons for cycle gradients observed in other areas. Our results clearly demonstrate the importance of landscape fragmentation for population cycling and we recommend that the degree of fragmentation be more fully considered in future analyses of vole dynamics

QUBIC: a qualitative biclustering algorithm for analyses of gene expression data

Biclustering extends the traditional clustering techniques by attempting to find (all) subgroups of genes with similar expression patterns under to-be-identified subsets of experimental conditions when applied to gene expression data. Still the real power of this clustering strategy is yet to be fully realized due to the lack of effective and efficient algorithms for reliably solving the general biclustering problem. We report a QUalitative BIClustering algorithm (QUBIC) that can solve the biclustering problem in a more general form, compared to existing algorithms, through employing a combination of qualitative (or semi-quantitative) measures of gene expression data and a combinatorial optimization technique. One key unique feature of the QUBIC algorithm is that it can identify all statistically significant biclusters including biclusters with the so-called ‘scaling patterns’, a problem considered to be rather challenging; another key unique feature is that the algorithm solves such general biclustering problems very efficiently, capable of solving biclustering problems with tens of thousands of genes under up to thousands of conditions in a few minutes of the CPU time on a desktop computer. We have demonstrated a considerably improved biclustering performance by our algorithm compared to the existing algorithms on various benchmark sets and data sets of our own. QUBIC was written in ANSI C and tested using GCC (version 4.1.2) on Linux. Its source code is available at: http://csbl.bmb.uga.edu/∼maqin/bicluster. A server version of QUBIC is also available upon request

Site Fidelity in Space Use by Spider Monkeys (Ateles geoffroyi) in the Yucatan Peninsula, Mexico

Animal home ranges may vary little in their size and location in the short term but nevertheless show more variability in the long term. We evaluated the degree of site fidelity of two groups of spider monkeys (Ateles geoffroyi) over a 10- and 13-year period, respectively, in the northeastern Yucatan peninsula, Mexico. We used the Local Convex Hull method to estimate yearly home ranges and core areas (defined as the 60% probability contour) for the two groups. Home ranges varied from 7.7 to 49.6 ha and core areas varied from 3.1 to 9.2 ha. We evaluated the degree of site fidelity by quantifying the number of years in which different areas were used as either home ranges or core areas. Large tracts were used only as home ranges and only for a few years, whereas small areas were used as either core area or home range for the duration of the study. The sum of the yearly core areas coincided partially with the yearly home ranges, indicating that home ranges contain areas used intermittently. Home ranges, and especially core areas, contained a higher proportion of mature forest than the larger study site as a whole. Across years and only in one group, the size of core areas was positively correlated with the proportion of adult males in the group, while the size of home ranges was positively correlated with both the proportion of males and the number of tree species included in the diet. Our findings suggest that spider monkey home ranges are the result of a combination of long-term site fidelity and year-to-year use variation to enable exploration of new resources

Mate-Finding as an Overlooked Critical Determinant of Dispersal Variation in Sexually-Reproducing Animals

Dispersal is a critically important process in ecology, but robust predictive models of animal dispersal remain elusive. We identify a potentially ubiquitous component of variation in animal dispersal that has been largely overlooked until now: the influence of mate encounters on settlement probability. We use an individual-based model to simulate dispersal in sexually-reproducing organisms that follow a simple set of movement rules based on conspecific encounters, within an environment lacking spatial habitat heterogeneity. We show that dispersal distances vary dramatically with fluctuations in population density in such a model, even in the absence of variation in dispersive traits between individuals. In a simple random-walk model with promiscuous mating, dispersal distributions become increasingly ‘fat-tailed’ at low population densities due to the increasing scarcity of mates. Similar variation arises in models incorporating territoriality. In a model with polygynous mating, we show that patterns of sex-biased dispersal can even be reversed across a gradient of population density, despite underlying dispersal mechanisms remaining unchanged. We show that some widespread dispersal patterns found in nature (e.g. fat tailed distributions) can arise as a result of demographic variability in the absence of heterogeneity in dispersive traits across the population. This implies that models in which individual dispersal distances are considered to be fixed traits might be unrealistic, as dispersal distances vary widely under a single dispersal mechanism when settlement is influenced by mate encounters. Mechanistic models offer a promising means of advancing our understanding of dispersal in sexually-reproducing organisms

The organisation and delivery of health improvement in general practice and primary care: a scoping study

Background This project examines the organisation and delivery of health improvement activities by and within general practice and the primary health-care team. The project was designed to examine who delivers these interventions, where they are located, what approaches are developed in practices, how individual practices and the primary health-care team organise such public health activities, and how these contribute to health improvement. Our focus was on health promotion and ill-health prevention activities. Aims The aim of this scoping exercise was to identify the current extent of knowledge about the health improvement activities in general practice and the wider primary health-care team. The key objectives were to provide an overview of the range and type of health improvement activities, identify gaps in knowledge and areas for further empirical research. Our specific research objectives were to map the range and type of health improvement activity undertaken by general practice staff and the primary health-care team based within general practice; to scope the literature on health improvement in general practice or undertaken by health-care staff based in general practice and identify gaps in the evidence base; to synthesise the literature and identify effective approaches to the delivery and organisation of health improvement interventions in a general practice setting; and to identify the priority areas for research as defined by those working in general practice. Methods We undertook a comprehensive search of the literature. We followed a staged selection process involving reviews of titles and abstracts. This resulted in the identification of 1140 papers for data extraction, with 658 of these papers selected for inclusion in the review, of which 347 were included in the evidence synthesis. We also undertook 45 individual and two group interviews with primary health-care staff. Findings Many of the research studies reviewed had some details about the type, process or location, or who provided the intervention. Generally, however, little attention is paid in the literature to examining the impact of the organisational context on the way services are delivered or how this affects the effectiveness of health improvement interventions in general practice. We found that the focus of attention is mainly on individual prevention approaches, with practices engaging in both primary and secondary prevention. The range of activities suggests that general practitioners do not take a population approach but focus on individual patients. However, it is clear that many general practitioners see health promotion as an integral part of practice, whether as individual approaches to primary or secondary health improvement or as a practice-based approach to improving the health of their patients. Our key conclusion is that there is currently insufficient good evidence to support many of the health improvement interventions undertaken in general practice and primary care more widely. Future Research Future research on health improvement in general practice and by the primary health-care team needs to move beyond clinical research to include delivery systems and be conducted in a primary care setting. More research needs to examine areas where there are chronic disease burdens – cancer, dementia and other disabilities of old age. Reviews should be commissioned that examine the whole prevention pathway for health problems that are managed within primary care drawing together research from general practice, pharmacy, community engagement, etc

Exome sequencing of pleuropulmonary blastoma reveals frequent biallelic loss of TP53 and two hits in DICER1 resulting in retention of 5p-derived miRNA hairpin loop sequences

Pleuropulmonary blastoma is a rare childhood malignancy of lung mesenchymal cells that can remain dormant as epithelial cysts or progress to high-grade sarcoma. Predisposing germline loss-of-function DICER1 variants have been described. We sought to uncover additional contributors through whole exome sequencing of 15 tumor/normal pairs, followed by targeted resequencing, miRNA analysis and immunohistochemical analysis of additional tumors. In addition to frequent biallelic loss of TP53 and mutations of NRAS or BRAF in some cases, each case had compound disruption of DICER1: a germline (12 cases) or somatic (3 cases) loss-of-function variant plus a somatic missense mutation in the RNase IIIb domain. 5p-Derived microRNA (miRNA) transcripts retained abnormal precursor miRNA loop sequences normally removed by DICER1. This work both defines a genetic interaction landscape with DICER1 mutation and provides evidence for alteration in miRNA transcripts as a consequence of DICER1 disruption in cancer