Resolution of non–small-cell lung cancer after withdrawal of anti-TNF therapy

We report the development of locally advanced non–small-cell lung cancer (tumor–node–metastasis [TNM] stage T4N2M0) in a 69-year-old woman with Crohn's colitis. Her condition had been diagnosed in 2000 and had required treatment with methotrexate (from 2003 to the present), together with anti–tumor necrosis factor (TNF) therapies — initially, episodic infliximab (from 2000 to 2004) and thereafter, maintenance adalimumab, until the tumor was diagnosed in June 2006. Remarkably, the tumor expressed TNF receptors and underwent regression and sustained remission on withdrawal of anti-TNF therapy, with no other therapeutic intervention

Implications from clean observables for the binned analysis of B -> K*ll at large recoil

We perform a frequentist analysis of q^2-dependent B-> K*(->Kpi)ll angular observables at large recoil, aiming at bridging the gap between current theoretical analyses and the actual experimental measurements. We focus on the most appropriate set of observables to measure and on the role of the q^2-binning. We highlight the importance of the observables P_i exhibiting a limited sensitivity to soft form factors for the search for New Physics contributions. We compute predictions for these binned observables in the Standard Model, and we compare them with their experimental determination extracted from recent LHCb data. Analyzing b->s and b->sll transitions within four different New Physics scenarios, we identify several New Physics benchmark points which can be discriminated through the measurement of P_i observables with a fine q^2-binning. We emphasise the importance (and risks) of using observables with (un)suppressed dependence on soft form factors for the search of New Physics, which we illustrate by the different size of hadronic uncertainties attached to two related observables (P_1 and S_3). We illustrate how the q^2-dependent angular observables measured in several bins can help to unravel New Physics contributions to B-> K*(->Kpi)ll, and show the extraordinary constraining power that the clean observables will have in the near future. We provide semi-numerical expressions for these observables as functions of the relevant Wilson coefficients at the low scale.Comment: 50 pages, 21 figures. Improved form factor analysis, conclusions unchanged. Plots with full resolution. Version published in JHE

Big data and data repurposing – using existing data to answer new questions in vascular dementia research

Introduction: Traditional approaches to clinical research have, as yet, failed to provide effective treatments for vascular dementia (VaD). Novel approaches to collation and synthesis of data may allow for time and cost efficient hypothesis generating and testing. These approaches may have particular utility in helping us understand and treat a complex condition such as VaD. Methods: We present an overview of new uses for existing data to progress VaD research. The overview is the result of consultation with various stakeholders, focused literature review and learning from the group’s experience of successful approaches to data repurposing. In particular, we benefitted from the expert discussion and input of delegates at the 9th International Congress on Vascular Dementia (Ljubljana, 16-18th October 2015). Results: We agreed on key areas that could be of relevance to VaD research: systematic review of existing studies; individual patient level analyses of existing trials and cohorts and linking electronic health record data to other datasets. We illustrated each theme with a case-study of an existing project that has utilised this approach. Conclusions: There are many opportunities for the VaD research community to make better use of existing data. The volume of potentially available data is increasing and the opportunities for using these resources to progress the VaD research agenda are exciting. Of course, these approaches come with inherent limitations and biases, as bigger datasets are not necessarily better datasets and maintaining rigour and critical analysis will be key to optimising data use

Deconstructing the DGAT1 enzyme: membrane interactions at substrate binding sites

Diacylglycerol acyltransferase 1 (DGAT1) is a key enzyme in the triacylglyceride synthesis pathway. Bovine DGAT1 is an endoplasmic reticulum membrane-bound protein associated with the regulation of fat content in milk and meat. The aim of this study was to evaluate the interaction of DGAT1 peptides corresponding to putative substrate binding sites with different types of model membranes. Whilst these peptides are predicted to be located in an extramembranous loop of the membrane-bound protein, their hydrophobic substrates are membrane-bound molecules. In this study, peptides corresponding to the binding sites of the two substrates involved in the reaction were examined in the presence of model membranes in order to probe potential interactions between them that might influence the subsequent binding of the substrates. Whilst the conformation of one of the peptides changed upon binding several types of micelles regardless of their surface charge, suggesting binding to hydrophobic domains, the other peptide bound strongly to negatively-charged model membranes. This binding was accompanied by a change in conformation, and produced leakage of the liposome-entrapped dye calcein. The different hydrophobic and electrostatic interactions observed suggest the peptides may be involved in the interactions of the enzyme with membrane surfaces, facilitating access of the catalytic histidine to the triacylglycerol substrates

Reanalysis of lattice QCD spectra leading to the Ds0*(2317) and Ds1*(2460)

We perform a reanalysis of the energy levels obtained in a recent lattice QCD simulation, from where the existence of bound states of KD and KD* are induced and identified with the narrow D-s0*(2317) and D-s1*(2460) resonances. The reanalysis is done in terms of an auxiliary potential, employing a single-channel basis KD(*()), and a two-channel basis KD(*()), eta D-s(()*()). By means of an extended Luscher method we determine poles of the continuum t-matrix, bound by about 40 MeV with respect to the KD and KD* thresholds, which we identify with the D-s0*(2317) and D-s1*(2460) resonances. Using a sum rule that reformulates Weinberg compositeness condition we can determine that the state D-s0*(2317) contains a KD component in an amount of about 70%, while the state D-s1*(2460) contains a similar amount of KD*. We argue that the present lattice simulation results do not still allow us to determine which are the missing channels in the bound state wave functions and we discuss the necessary information that can lead to answer this question

Probing the charged Higgs boson at the LHC in the CP-violating type-II 2HDM

We present a phenomenological study of a CP-violating two-Higgs-doublet Model with type-II Yukawa couplings at the Large Hadron Collider (LHC). In the light of recent LHC data, we focus on the parameter space that survives the current and past experimental constraints as well as theoretical bounds on the model. Once the phenomenological scenario is set, we analyse the scope of the LHC in exploring this model through the discovery of a charged Higgs boson produced in association with a W boson, with the former decaying into the lightest neutral Higgs and a second W state, altogether yielding a b\bar b W^+W^- signature, of which we exploit the W^+W^- semileptonic decays.Comment: 37 pages, 16 figures; v2 updated treatment of LHC constraint

Is tibial tuberosity-trochlear groove distance an appropriate measure for the identification of knees with patellar instability?

PURPOSE - Tibial tuberosity-trochlear groove distance (TT-TG) has been regarded as a useful tool for establishing therapeutic choices for patellar instability. Recently, it has been shown that TT-TG negatively correlated with the quadriceps angle, suggesting that if used individually, neither provide a valid measure of instability. This study aimed to compare TT-TG distance between both knees in patients with unilateral instability to assess whether this measurement is a decisive element in the management decisions for patellar instability. METHODS - Sixty-two patients (18 male and 44 female), reporting to a specialist patella clinic for recurrent unilateral patellar instability, were included in the study. Patients underwent bilateral long leg computed tomography scan to determine TT-TG distance in both knees. Tibial TT-TG in symptomatic and asymptomatic knees in the same individual was compared statistically. RESULTS - Mean TT-TG distance in the symptomatic knee was 16.9 (±4.9) mm, compared to 15.6 (±5.6) mm in the asymptomatic knee. Tibial TT-TG was not significantly different between stable and unstable knees (n.s.). CONCLUSIONS - The lack of difference in TT-TG distance between stable and unstable knees suggests that TT-TG distance alone may not be a decisive element in establishing therapeutic choices for patellar instability. It should, therefore, be interpreted with caution during clinical evaluations. LEVEL OF EVIDENCE: II

Is tibial tuberosity-trochlear groove distance an appropriate measure for the identification of knees with patellar instability?

PURPOSE - Tibial tuberosity-trochlear groove distance (TT-TG) has been regarded as a useful tool for establishing therapeutic choices for patellar instability. Recently, it has been shown that TT-TG negatively correlated with the quadriceps angle, suggesting that if used individually, neither provide a valid measure of instability. This study aimed to compare TT-TG distance between both knees in patients with unilateral instability to assess whether this measurement is a decisive element in the management decisions for patellar instability. METHODS - Sixty-two patients (18 male and 44 female), reporting to a specialist patella clinic for recurrent unilateral patellar instability, were included in the study. Patients underwent bilateral long leg computed tomography scan to determine TT-TG distance in both knees. Tibial TT-TG in symptomatic and asymptomatic knees in the same individual was compared statistically. RESULTS - Mean TT-TG distance in the symptomatic knee was 16.9 (±4.9) mm, compared to 15.6 (±5.6) mm in the asymptomatic knee. Tibial TT-TG was not significantly different between stable and unstable knees (n.s.). CONCLUSIONS - The lack of difference in TT-TG distance between stable and unstable knees suggests that TT-TG distance alone may not be a decisive element in establishing therapeutic choices for patellar instability. It should, therefore, be interpreted with caution during clinical evaluations. LEVEL OF EVIDENCE: II

The Efficacy of Emamectin Benzoate against Infestations of Lepeophtheirus salmonis on Farmed Atlantic Salmon (Salmo salar L) in Scotland, 2002–2006

Infestations of the parasitic copepod Lepeophtheirus salmonis, commonly referred to as sea lice, represent a major challenge to commercial salmon aquaculture. Dependence on a limited number of theraputants to control such infestations has led to concerns of reduced sensitivity in some sea lice populations. This study investigates trends in the efficacy of the in-feed treatment emamectin benzoate in Scotland, the active ingredient most widely used across all salmon producing regions. Study data were drawn from over 50 commercial Atlantic salmon farms on the west coast of Scotland between 2002 and 2006. An epi-informatics approach was adopted whereby available farm records, descriptive epidemiological summaries and statistical linear modelling methods were used to identify factors that significantly affect sea lice abundance following treatment with emamectin benzoate (SLICEH, Schering Plough Animal Health). The results show that although sea lice infestations are reduced following the application of emamectin benzoate, not all treatments are effective. Specifically there is evidence of variation across geographical regions and a reduction in efficacy over time. Reduced sensitivity and potential resistance to currently available medicines are constant threats to maintaining control of sea lice populations on Atlantic salmon farms. There is a need for on-going monitoring of emamectin benzoate treatment efficacy together with reasons for any apparent reduction in performance. In addition, strategic rotation of medicines should be encouraged and empirical evidence for the benefit of such strategies more fully evaluated

Assessment of heterogeneity between European Populations: a Baltic and Danish replication case-control study of SNPs from a recent European ulcerative colitis genome wide association study

<p>Abstract</p> <p>Background</p> <p>Differences in the genetic architecture of inflammatory bowel disease between different European countries and ethnicities have previously been reported. In the present study, we wanted to assess the role of 11 newly identified UC risk variants, derived from a recent European UC genome wide association study (GWAS) (Franke <it>et al</it>., 2010), for 1) association with UC in the Nordic countries, 2) for population heterogeneity between the Nordic countries and the rest of Europe, and, 3) eventually, to drive some of the previous findings towards overall genome-wide significance.</p> <p>Methods</p> <p>Eleven SNPs were replicated in a Danish sample consisting of 560 UC patients and 796 controls and nine missing SNPs of the German GWAS study were successfully genotyped in the Baltic sample comprising 441 UC cases and 1156 controls. The independent replication data was then jointly analysed with the original data and systematic comparisons of the findings between ethnicities were made. Pearson's χ², Breslow-Day (BD) and Cochran-Mantel-Haenszel (CMH) tests were used for association analyses and heterogeneity testing.</p> <p>Results</p> <p>The rs5771069 (<it>IL17REL</it>) SNP was not associated with UC in the Danish panel. The rs5771069 (<it>IL17REL</it>) SNP was significantly associated with UC in the combined Baltic, Danish and Norwegian UC study sample driven by the Norwegian panel (OR = 0.89, 95% CI: 0.79-0.98, P = 0.02). No association was found between rs7809799 <it>(SMURF1/KPNA7) </it>and UC (OR = 1.20, 95% CI: 0.95-1.52, P = 0.10) or between UC and all other remaining SNPs. We had 94% chance of detecting an association for rs7809799 <it>(SMURF1/KPNA7) </it>in the combined replication sample, whereas the power were 55% or lower for the remaining SNPs.</p> <p>Statistically significant P_BDwas found for OR heterogeneity between the combined Baltic, Danish, and Norwegian panel versus the combined German, British, Belgian, and Greek panel (rs7520292 (P = 0.001), rs12518307 (P = 0.007), and rs2395609 (TCP11) (P = 0.01), respectively).</p> <p>No SNP reached genome-wide significance in the combined analyses of all the panels.</p> <p>Conclusions</p> <p>This replication study supports an important role for the studied rs5771069 (<it>IL17REL</it>) SNP, but not for rs7809799 (<it>SMURF1</it>/<it>KPNA7</it>), in UC etiology in the Danish, Baltic, and Norwegian populations. Significant genetic heterogeneity was suggested for rs7520292, rs12518307, and rs2395609 (<it>TCP11</it>) in UC etiology between the Nordic and the other European populations.</p