Expert’s comment concerning Grand Rounds case entitled “Closing–Opening Wedge Osteotomy for Severe, Rigid Thoraco-Lumbar Post-tubercular Kyphosis” (by S. Rajasekaran, P. Rishimugesh Kanna and Ajoy Prasad Shetty)

Prevention or correction of severe kyphotic deformity in addition to eradication of the infective focus has become the modern standard of management of tuberculosis of the spine. Circumferential excision of the kyphus is now technically feasible with the development of rigid pedicle screw fixation system and intraoperative spinal cord monitoring in the past two decades

WMAP-Compliant Benchmark Surfaces for MSSM Higgs Bosons

We explore `benchmark surfaces' suitable for studying the phenomenology of Higgs bosons in the minimal supersymmetric extension of the Standard Model (MSSM), which are chosen so that the supersymmetric relic density is generally compatible with the range of cold dark matter density preferred by WMAP and other observations. These benchmark surfaces are specified assuming that gaugino masses m_{1/2}, soft trilinear supersymmetry-breaking parameters A_0 and the soft supersymmetry-breaking contributions m_0 to the squark and slepton masses are universal, but not those associated with the Higgs multiplets (the NUHM framework). The benchmark surfaces may be presented as M_A-tan_beta planes with fixed or systematically varying values of the other NUHM parameters, such as m_0, m_{1/2}, A_0 and the Higgs mixing parameter mu. We discuss the prospects for probing experimentally these benchmark surfaces at the Tevatron collider, the LHC, the ILC, in B physics and in direct dark-matter detection experiments. An Appendix documents developments in the FeynHiggs code that enable the user to explore for her/himself the WMAP-compliant benchmark surfaces.Comment: Minor corrections, references added. 43 pages, 10 figures. Version to appear in JHE

Disease-specific composite measures for psoriatic arthritis are highly responsive to a Janus kinase inhibitor treatment that targets multiple domains of disease

Background: The multiple disease domains affected in psoriatic arthritis (PsA) may make composite endpoints appropriate for assessing changes in disease activity over time. Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA. Data from two phase 3 studies of patients with PsA were used to evaluate the effect of tofacitinib on composite endpoints. Methods: Oral Psoriatic Arthritis triaL (OPAL) Broaden was a 12-month study of tumor necrosis factor inhibitor (TNFi)-naïve patients with an inadequate response to at least one conventional synthetic disease-modifying anti-rheumatic drug; OPAL Beyond was a 6-month study of patients with inadequate response to TNFi. Patients with active PsA received tofacitinib 5 or 10 mg doses twice daily (BID), adalimumab 40 mg subcutaneous injection once every 2 weeks (OPAL Broaden only), or placebo advancing at month 3 to tofacitinib 5 or 10 mg BID. The disease-specific composites were Psoriatic Arthritis Disease Activity Score (PASDAS), Disease Activity Index for Reactive Arthritis/Psoriatic Arthritis (DAPSA), and Composite Psoriatic Disease Activity Index (CPDAI). Change from baseline in composite endpoints was also assessed for minimal disease activity (MDA) responders versus non-responders. Results: Overall, 422 patients from OPAL Broaden and 394 patients from OPAL Beyond were treated. The mean changes from baseline to month 3 for tofacitinib 5 mg BID, tofacitinib 10 mg BID (standard error; effect size) were OPAL Broaden: PASDAS, −2.0 (0.14; 1.73), −2.4 (0.14; 2.4); DAPSA, −20.2 (1.72; 0.9), −24.4 (1.73; 1.23); and CPDAI, −2.9 (0.34; 1.03), −4.2 (0.36; 1.53); OPAL Beyond: PASDAS, −1.9 (0.14; 1.53), −2.1 (0.14; 1.84); DAPSA, −22.5 (1.67; 0.81), −21.0 (1.70; 0.84); and CPDAI, −3.3 (0.31; 1.41), −3.4 (0.31; 1.45). Greater changes from baseline to month 3 (P ≤0.05) were seen with both doses of tofacitinib versus placebo for all endpoints except CPDAI for tofacitinib 5 mg BID in OPAL Broaden. Effect sizes generally increased from 3 to 6 months. Mean changes from baseline were greater in MDA responders than MDA non-responders for all composite endpoints across all time points and treatments. Conclusions: This analysis suggests that disease-specific composite measures are appropriate for evaluating treatment efficacy on multiple disease domains in PsA. Trial registration: OPAL Broaden: ClinicalTrials.gov Identifier: NCT01877668, first posted June 12, 2013; OPAL Beyond: ClinicalTrials.gov Identifier: NCT01882439, first posted June 20, 2013

Mathematical model of a telomerase transcriptional regulatory network developed by cell-based screening: analysis of inhibitor effects and telomerase expression mechanisms

Cancer cells depend on transcription of telomerase reverse transcriptase (TERT). Many transcription factors affect TERT, though regulation occurs in context of a broader network. Network effects on telomerase regulation have not been investigated, though deeper understanding of TERT transcription requires a systems view. However, control over individual interactions in complex networks is not easily achievable. Mathematical modelling provides an attractive approach for analysis of complex systems and some models may prove useful in systems pharmacology approaches to drug discovery. In this report, we used transfection screening to test interactions among 14 TERT regulatory transcription factors and their respective promoters in ovarian cancer cells. The results were used to generate a network model of TERT transcription and to implement a dynamic Boolean model whose steady states were analysed. Modelled effects of signal transduction inhibitors successfully predicted TERT repression by Src-family inhibitor SU6656 and lack of repression by ERK inhibitor FR180204, results confirmed by RT-QPCR analysis of endogenous TERT expression in treated cells. Modelled effects of GSK3 inhibitor 6-bromoindirubin-3′-oxime (BIO) predicted unstable TERT repression dependent on noise and expression of JUN, corresponding with observations from a previous study. MYC expression is critical in TERT activation in the model, consistent with its well known function in endogenous TERT regulation. Loss of MYC caused complete TERT suppression in our model, substantially rescued only by co-suppression of AR. Interestingly expression was easily rescued under modelled Ets-factor gain of function, as occurs in TERT promoter mutation. RNAi targeting AR, JUN, MXD1, SP3, or TP53, showed that AR suppression does rescue endogenous TERT expression following MYC knockdown in these cells and SP3 or TP53 siRNA also cause partial recovery. The model therefore successfully predicted several aspects of TERT regulation including previously unknown mechanisms. An extrapolation suggests that a dominant stimulatory system may programme TERT for transcriptional stability

Team sports performance analysed through the lens of social network theory: implications for research and practice

This paper discusses how social network analyses and graph theory can be implemented in team sports performance analyses to evaluate individual (micro) and collective (macro) performance data, and how to use this information for designing practice tasks. Moreover, we briefly outline possible limitations of social network studies and provide suggestions for future research. Instead of cataloguing discrete events or player actions, it has been argued that researchers need to consider the synergistic interpersonal processes emerging between teammates in competitive performance environments. Theoretical assumptions on team coordination prompted the emergence of innovative, theoretically-driven methods for assessing collective team sport behaviours. Here, we contribute to this theoretical and practical debate by conceptualising sports teams as complex social networks. From this perspective, players are viewed as network nodes, connected through relevant information variables (e.g., a ball passing action), sustaining complex patterns of interaction between teammates (e.g., a ball passing network). Specialized tools and metrics related to graph theory could be applied to evaluate structural and topological properties of interpersonal interactions of teammates, complementing more traditional analysis methods. This innovative methodology moves beyond use of common notation analysis methods, providing a richer understanding of the complexity of interpersonal interactions sustaining collective team sports performance. The proposed approach provides practical applications for coaches, performance analysts, practitioners and researchers by establishing social network analyses as a useful approach for capturing the emergent properties of interactions between players in sports teams

Secondary school students’ epistemic insight into the relationships between science and religion – a preliminary enquiry

A number of previous studies have shown that there is a widespread view among young people that science and religion are opposed. In this paper, we suggest that it requires a significant level of what can be termed ‘epistemic insight’ to access the idea that some people see science and religion as compatible while others do not. To explore this further, we draw on previous work to devise a methodology to discover students’ thinking about apparent contradictions between scientific and religious explanations of the origins of the universe. In our discussion of the findings, we highlight that students’ epistemic insight in this context does seem in many cases to be limited and we outline some of the issues emerging from the study that seem to boost or limit students’ progress in this area

A global view of drug-therapy interactions

Network science is already making an impact on the study of complex systems and offers a promising variety of tools to understand their formation and evolution (1-4) in many disparate fields from large communication networks (5,6), transportation infrastructures (7) and social communities (8,9) to biological systems (1,10,11). Even though new highthroughput technologies have rapidly been generating large amounts of genomic data, drug design has not followed the same development, and it is still complicated and expensive to develop new single-target drugs. Nevertheless, recent approaches suggest that multi-target drug design combined with a network-dependent approach and large-scale systems-oriented strategies (12-14) create a promising framework to combat complex multigenetic disorders like cancer or diabetes. Here, we investigate the human network corresponding to the interactions between all US approved drugs and human therapies, defined by known drug-therapy relationships. Our results show that the key paths in this network are shorter than three steps, indicating that distant therapies are separated by a surprisingly low number of chemical compounds. We also identify a sub-network composed by drugs with high centrality measures (15), which represent the structural back-bone of the drug-therapy system and act as hubs routing information between distant parts of the network. These findings provide for the first time a global map of the largescale organization of all known drugs and associated therapies, bringing new insights on possible strategies for future drug development. Special attention should be given to drugs which combine the two properties of (a) having a high centrality value and (b) acting on multiple targets.Comment: 16 pages, 4 figures. It was submitted to peer review on August 15, 200

The Effect of Immune Selection on the Structure of the Meningococcal Opa Protein Repertoire

The opa genes of the Gram negative bacterium Neisseria meningitidis encode Opacity-associated outer membrane proteins whose role is to promote adhesion to the human host tissue during colonisation and invasion. Each meningococcus contains 3–4 opa loci, each of which may be occupied by one of a large number of alleles. We analysed the Opa repertoire structure in a large, well-characterised collection of asymptomatically carried meningococci. Our data show an association between Opa repertoire and meningococcal lineages similar to that observed previously for meningococci isolated from cases of invasive disease. Furthermore, these Opa repertoires exhibit discrete, non-overlapping structure at a population level, and yet low within-repertoire diversity. These data are consistent with the predictions of a mathematical model of strong immune selection upon a system where identical alleles may occupy different loci

Effect of Mouth Rinsing and Ingestion of Carbohydrate Solutions on Mood and Perceptual Responses During Exercise

Background: The aim of this study was to investigate whether mouth rinsing or ingesting carbohydrate (CHO) solutions impact on perceptual responses during exercise. Methods: Nine moderately trained male cyclists underwent a 90-min glycogen-reducing exercise, and consumed a low CHO meal, prior to completing an overnight fast. A 1-h cycle time trial was performed the following morning. Four trials, each separated by 7days, were conducted in a randomized, counterbalanced study design: 15% CHO mouth rinse (CHOR), 7.5% CHO ingestion (CHOI), placebo mouth rinse (PLAR) and placebo ingestion (PLAI). Solution volumes (1.5ml·g-1 ingestion trials and 0.33ml·kg-1 rinsing trials) were provided after every 12.5% of completed exercise. Perceptual scales were used to assess affective valence (feeling scale, FS), arousal (felt arousal scale, FAS), exertion (ratings of perceived exertion, RPE) and mood (profile of mood states, POMS) before, during and immediately after exercise. Results: There was no difference in RPE (CHOI, 14.0±9; CHOR, 14.2±.7; PLAI, 14.6±1.8; PLAR, 14.6±2.0; P=0.35), FS (CHOI, 0.0±1.7; CHOR, -0.2±1.5; PLAI, -0.8±1.4; PLAR, -0.8±1.6; P0.15), or FAS (CHOI, 3.6±1.1; CHOR, 3.5±1.0; PLAI, 3.4±1.4; PLAR, 3.3±1.3; P=725) scores between trials. While overall POMS score did not appear to differ between trials, the 'vigour' subscale indicated that CHOI may facilitate the maintenance of 'vigour' scores over time, in comparison to the steady decline witnessed in other trials (P=0.04). There was no difference in time trial performance between trials (CHOI, 65.3±4.8min; CHOR, 68.4±3.9min; PLAI, 68.7±5.3min; PLAR, 68.3±5.2min; P=0.21) but power output was higher in CHOI (231.0±33.2 W) relative to other trials (221-223.6 W; Plt0.01). Conclusions: In a CHO-reduced state, mouth rinsing with a CHO solution did not impact on perceptual responses during high-intensity exercise in trained cyclists and triathletes. On the other hand CHO ingestion improved perceived ratings of vigour and increased power output during exercise