A comparison of three clustering methods for finding subgroups in MRI, SMS or clinical data: SPSS TwoStep Cluster analysis, Latent Gold and SNOB

Background: There are various methodological approaches to identifying clinically important subgroups and one method is to identify clusters of characteristics that differentiate people in cross-sectional and/or longitudinal data using Cluster Analysis (CA) or Latent Class Analysis (LCA). There is a scarcity of head-to-head comparisons that can inform the choice of which clustering method might be suitable for particular clinical datasets and research questions. Therefore, the aim of this study was to perform a head-to-head comparison of three commonly available methods (SPSS TwoStep CA, Latent Gold LCA and SNOB LCA). Methods. The performance of these three methods was compared: (i) quantitatively using the number of subgroups detected, the classification probability of individuals into subgroups, the reproducibility of results, and (ii) qualitatively using subjective judgments about each program's ease of use and interpretability of the presentation of results.We analysed five real datasets of varying complexity in a secondary analysis of data from other research projects. Three datasets contained only MRI findings (n = 2,060 to 20,810 vertebral disc levels), one dataset contained only pain intensity data collected for 52 weeks by text (SMS) messaging (n = 1,121 people), and the last dataset contained a range of clinical variables measured in low back pain patients (n = 543 people). Four artificial datasets (n = 1,000 each) containing subgroups of varying complexity were also analysed testing the ability of these clustering methods to detect subgroups and correctly classify individuals when subgroup membership was known. Results: The results from the real clinical datasets indicated that the number of subgroups detected varied, the certainty of classifying individuals into those subgroups varied, the findings had perfect reproducibility, some programs were easier to use and the interpretability of the presentation of their findings also varied. The results from the artificial datasets indicated that all three clustering methods showed a near-perfect ability to detect known subgroups and correctly classify individuals into those subgroups. Conclusions: Our subjective judgement was that Latent Gold offered the best balance of sensitivity to subgroups, ease of use and presentation of results with these datasets but we recognise that different clustering methods may suit other types of data and clinical research questions

Cosmic Flows on 100 Mpc/h Scales: Standardized Minimum Variance Bulk Flow, Shear and Octupole Moments

The low order moments, such as the bulk flow and shear, of the large scale peculiar velocity field are sensitive probes of the matter density fluctuations on very large scales. In practice, however, peculiar velocity surveys are usually sparse and noisy, which can lead to the aliasing of small scale power into what is meant to be a probe of the largest scales. Previously, we developed an optimal ``minimum variance'' (MV) weighting scheme, designed to overcome this problem by minimizing the difference between the measured bulk flow (BF) and that which would be measured by an ideal survey. Here we extend this MV analysis to include the shear and octupole moments, which are designed to have almost no correlations between them so that they are virtually orthogonal. We apply this MV analysis to a compilation of all major peculiar velocity surveys, consisting of 4536 measurements. Our estimate of the BF on scales of ~ 100 Mpc/h has a magnitude of |v|= 416 +/- 78 km/s towards Galactic l = 282 degree +/- 11 degree and b = 6 degree +/- 6 degree. This result is in disagreement with LCDM with WMAP5 cosmological parameters at a high confidence level, but is in good agreement with our previous MV result without an orthogonality constraint, showing that the shear and octupole moments did not contaminate the previous BF measurement. The shear and octupole moments are consistent with WMAP5 power spectrum, although the measurement noise is larger for these moments than for the BF. The relatively low shear moments suggest that the sources responsible for the BF are at large distances.Comment: 13 Pages, 7 figures, 4 tables. Some changes to reflect the published versio

A trematode parasite derived growth factor binds and exerts influences on host immune functions via host cytokine receptor complexes

The trematode Fasciola hepatica is responsible for chronic zoonotic infection globally. Despite causing a potent T-helper 2 response, it is believed that potent immunomodulation is responsible for rendering this host reactive non-protective host response thereby allow- ing the parasite to remain long-lived. We have previously identified a growth factor, FhTLM, belonging to the TGF superfamily can have developmental effects on the parasite. Herein we demonstrate that FhTLM can exert influence over host immune functions in a host receptor specific fashion. FhTLM can bind to receptor members of the Transforming Growth Factor (TGF) superfamily, with a greater affinity for TGF-β RII. Upon ligation FhTLM initiates the Smad2/3 pathway resulting in phenotypic changes in both fibroblasts and macrophages. The formation of fibroblast CFUs is reduced when cells are cultured with FhTLM, as a result of TGF-β RI kinase activity. In parallel the wound closure response of fibroblasts is also delayed in the presence of FhTLM. When stimulated with FhTLM blood monocyte derived macrophages adopt an alternative or regulatory phenotype. They express high levels interleukin (IL)-10 and arginase-1 while displaying low levels of IL-12 and nitric oxide. Moreover they also undergo significant upregulation of the inhibitory recep- tor PD-L1 and the mannose receptor. Use of RNAi demonstrates that this effect is depen- dent on TGF-β RII and mRNA knock-down leads to a loss of IL-10 and PD-L1. Finally, we demonstrate that FhTLM aids newly excysted juveniles (NEJs) in their evasion of antibody- dependent cell cytotoxicity (ADCC) by reducing the NO response of macrophages—again dependent on TGF-β RI kinase. FhTLM displays restricted expression to the F. hepatica gut resident NEJ stages. The altered fibroblast responses would suggest a role for damp- ened tissue repair responses in facilitating parasite migration. Furthermore, the adoption of a regulatory macrophage phenotype would allow for a reduced effector response targetingjuvenile parasites which we demonstrate extends to an abrogation of the ADCC response. Thus suggesting that FhTLM is a stage specific evasion molecule that utilises host cytokine receptors. These findings are the first to clearly demonstrate the interaction of a helminth cytokine with a host receptor complex resulting in immune modifications that facilitate the non-protective chronic immune response which is characteristic of F. hepatica infection

Voltage Gated Calcium Channels Negatively Regulate Protective Immunity to Mycobacterium tuberculosis

Mycobacterium tuberculosis modulates levels and activity of key intracellular second messengers to evade protective immune responses. Calcium release from voltage gated calcium channels (VGCC) regulates immune responses to pathogens. In this study, we investigated the roles of VGCC in regulating protective immunity to mycobacteria in vitro and in vivo. Inhibiting L-type or R-type VGCC in dendritic cells (DCs) either using antibodies or by siRNA increased calcium influx in an inositol 1,4,5-phosphate and calcium release calcium activated channel dependent mechanism that resulted in increased expression of genes favoring pro-inflammatory responses. Further, VGCC-blocked DCs activated T cells that in turn mediated killing of M. tuberculosis inside macrophages. Likewise, inhibiting VGCC in infected macrophages and PBMCs induced calcium influx, upregulated the expression of pro-inflammatory genes and resulted in enhanced killing of intracellular M. tuberculosis. Importantly, compared to healthy controls, PBMCs of tuberculosis patients expressed higher levels of both VGCC, which were significantly reduced following chemotherapy. Finally, blocking VGCC in vivo in M. tuberculosis infected mice using specific antibodies increased intracellular calcium and significantly reduced bacterial loads. These results indicate that L-type and R-type VGCC play a negative role in M. tuberculosis infection by regulating calcium mobilization in cells that determine protective immunity

A Systems Approach for Tumor Pharmacokinetics

Recent advances in genome inspired target discovery, small molecule screens, development of biological and nanotechnology have led to the introduction of a myriad of new differently sized agents into the clinic. The differences in small and large molecule delivery are becoming increasingly important in combination therapies as well as the use of drugs that modify the physiology of tumors such as anti-angiogenic treatment. The complexity of targeting has led to the development of mathematical models to facilitate understanding, but unfortunately, these studies are often only applicable to a particular molecule, making pharmacokinetic comparisons difficult. Here we develop and describe a framework for categorizing primary pharmacokinetics of drugs in tumors. For modeling purposes, we define drugs not by their mechanism of action but rather their rate-limiting step of delivery. Our simulations account for variations in perfusion, vascularization, interstitial transport, and non-linear local binding and metabolism. Based on a comparison of the fundamental rates determining uptake, drugs were classified into four categories depending on whether uptake is limited by blood flow, extravasation, interstitial diffusion, or local binding and metabolism. Simulations comparing small molecule versus macromolecular drugs show a sharp difference in distribution, which has implications for multi-drug therapies. The tissue-level distribution differs widely in tumors for small molecules versus macromolecular biologic drugs, and this should be considered in the design of agents and treatments. An example using antibodies in mouse xenografts illustrates the different in vivo behavior. This type of transport analysis can be used to aid in model development, experimental data analysis, and imaging and therapeutic agent design.National Institutes of Health (U.S.) (grant T32 CA079443

Ensuring competency in end-of-life care: controlling symptoms

BACKGROUND: Palliative medicine is assuming an increasingly important role in patient care. The Education for Physicians in End-of-life Care (EPEC) Project is an ambitious program to increase core palliative care skills for all physicians. It is not intended to transmit specialty level competencies in palliative care. METHOD: The EPEC Curriculum was developed to be a comprehensive syllabus including trainer notes, multiple approaches to teaching the material, slides, and videos of clinical encounters to trigger discussion are provided. The content was developed through a combination of expert opinion, participant feedback and selected literature review. Content development was guided by the goal of teaching core competencies not included in the training of generalist and non-palliative medicine specialist physicians. RESULTS: Whole patient assessment forms the basis for good symptom control. Approaches to the medical management of pain, depression, anxiety, breathlessness (dyspnea), nausea/vomiting, constipation, fatigue/weakness and the symptoms common during the last hours of life are described. CONCLUSION: While some physicians will have specialist palliative care services upon which to call, most in the world will need to provide the initial approaches to symptom control at the end-of-life

Brokering Trust to Enhance Leadership: A Self-Monitoring Approach to Leadership Emergence

What kind of person is likely to emerge as an informal leader in the workplace? Experimental research shows that high self-monitors—who tend to adjust their attitudes and behaviors to the demands of different situations—emerge as informal leaders in temporary groups. By contrast, low self-monitors—who tend to be true to themselves in terms of consistency in attitudes and behaviors across different situations—are less likely to emerge as leaders. But this prior research does not address the criticism that the emergence of high self-monitors as leaders represents ephemeral impression management in the context of laboratory experiments. To address this issue, we collected and analyzed data from a 116-member high-technology firm. Our results show that self-monitoring is related not only to leadership emergence, but also to the provision of advice to co-workers. Further, people who occupied brokerage positions (being trusted by those who did not trust each other) tended to be seen as leaders if they were high rather than low self-monitors. From these results, we build a picture of the high self-monitoring emergent leader as someone who notices problems and ameliorates them through the provision of advice and the brokerage of relationships across social divides. The occupation of a structurally advantageous position may well be more advantageous for some (i.e., high self-monitors) relative to others (i.e., low self-monitors)

Combined dynamics of mercury and terrigenous organic matter following impoundment of Churchill Falls Hydroelectric Reservoir, Labrador

Sediments from two recently (40 years) flooded lakes (Gabbro lake and Sandgirt lake) and an unflooded lake (Atikonak lake) were sampled to investigate the effects of reservoir impoundment on mercury (Hg) and terrigenous organic matter (TOM) loading in the Churchill Falls Hydroelectric complex in Labrador, Canada. Lignin biomarkers in TOM, which exclusively derive from terrestrial vegetation, were used as biomarkers for the presence and source origin of TOM—and for Hg due to their close associations—in sediments. In the two flooded Gabbro and Sandgirt lakes, we observed drastic increases in total mercury concentrations, T-[Hg], in sediments, which temporally coincided with the time of reservoir impoundment as assessed by 210Pb age dating. In the natural Atikonak lake sediments, on the other hand, T-[Hg] showed no such step-increase but gradually and slowly increased until present. T-[Hg] increases in lake sediments after flooding were also associated with a change in the nature of TOM: biomarker signatures changed to typical signatures of TOM from vegetated terrestrial landscape surrounding the lakes, and indicate a change to TOM that was much less degraded and typical of forest soil organic horizons. We conclude that T-[Hg] increase in the sediments of the two flooded reservoirs was the result of flooding of surrounding forests, whereby mainly surface organic horizons and upper soil horizons were prone to erosion and subsequent re-sedimentation in the reservoirs. The fact that T-[Hg] was still enriched 40 years after reservoir impoundment indicates prolonged response time of lake Hg and sediment loadings after reservoir impoundments

Safety and immunogenicity of the candidate tuberculosis vaccine MVA85A in West Africa.

BACKGROUND: Vaccination with a recombinant modified vaccinia Ankara expressing antigen 85A from Mycobacterium tuberculosis, MVA85A, induces high levels of cellular immune responses in UK volunteers. We assessed the safety and immunogenicity of this new vaccine in West African volunteers. METHODS AND FINDINGS: We vaccinated 21 healthy adult male subjects (11 BCG scar negative and 10 BCG scar positive) with MVA85A after screening for evidence of prior exposure to mycobacteria. We monitored them over six months, observing for clinical, haematological and biochemical adverse events, together with assessment of the vaccine induced cellular immune response using ELISPOT and flow cytometry. MVA85A was well tolerated with no significant adverse events. Mild local and systemic adverse events were consistent with previous UK trials. Marked immunogenicity was found whether individuals had a previous BCG scar or not. There was not enhanced immunogenicity in those with a BCG scar, and induced T cell responses were better maintained in apparently BCG-naïve Gambians than previously studied BCG-naïve UK vaccinees. Although responses were predominantly attributable to CD4+ T cells, we also identified antigen specific CD8+ T cell responses, in subjects who were HLA B-35 and in whom enough blood was available for more detailed immunological analysis. CONCLUSIONS: These data on the safety and immunogenicity of MVA85A in West Africa support its accelerated development as a promising booster vaccine for tuberculosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00423839