Patterns and Predictors of Relapse Following Radical Chemoradiation Therapy Delivered Using Intensity Modulated Radiation Therapy With a Simultaneous Integrated Boost in Anal Squamous Cell Carcinoma

Purpose: To describe the patterns and predictors of treatment failure in patients receiving definitive chemoradiotherapy (CRT) for anal squamous cell carcinoma (ASCC), delivered using intensity modulated radiotherapy (IMRT). Materials and methods: A retrospective cohort analysis of consecutive patients treated with curative intent for ASCC using CRT delivered with a standardised IMRT technique in five UK cancer centres. Patients were included from the start of UK IMRT guidance in February 2013 to 31st October 2017. Collected data included baseline demographics, treatment details, tumour control, sites of relapse and overall survival. Statistical analysis to calculate outcomes and predictive factors for outcome measures were performed using SPSS and R. Results: The medical records of 385 consecutive patients were analysed. Median follow-up was 24.0 months. 86.7% of patients achieved a complete response (CR) within 6 months of completing chemoradiotherapy. 3yr disease free survival (DFS) and overall survival (OS) were 75.6% and 85.6% respectively. Of all relapses, 83.4% occurred at the site of primary disease. There were two isolated relapses in regional nodes not involved at outset. Predictive factors for cancer recurrence included male sex, high N-stage and failure to complete radiotherapy as planned. Conclusions: The treatment results compare favourably to published outcomes from similar cohorts using 3D conformal CRT. The observed patterns of failure support the current UK IMRT voluming guidelines and dose levels, highlighting our prophylactic nodal dose is sufficient to prevent isolated regional relapse in uninvolved nodes. Further investigation into strategies to optimise CR should remain a priority in ASCC, as the site of primary disease remains the overwhelming site of relapse

Retention of the posterior cruciate ligament versus the posterior stabilized design in total knee arthroplasty: a prospective randomized controlled clinical trial

Background: Prosthetic design for the use in primary total knee arthroplasty has evolved into designs that preserve the posterior cruciate ligament (PCL) and those in which the ligament is routinely sacrificed (posterior stabilized). In patients with a functional PCL the decision which design is chosen depends largely on the favour and training of the surgeon. The objective of this study is to determine whether the patient's perceived outcome and speed of recovery differs between a posterior cruciate retaining total knee arthroplasty and a posterior stabilized total knee arthroplasty. Methods/Design: A randomized controlled trial will be conducted. Patients who are admitted for primary unilateral TKA due to primary osteoarthrosis are included when the following inclusion criteria are met: non-fixed fixed varus or valgus deformity less than 10 degrees, age between 55 and 85 years, body mass index less than 35 kg/m(2) and ASA score (American Society of Anaesthesiologists) I or II. Patients are randomized in 2 groups. Patients in the posterior cruciate retaining group will receive a prosthesis with a posterior cut-out for the posterior cruciate ligament and relatively flat topography. In patients allocated to the posterior stabilized group, in which the posterior cruciate ligament is excised, the design may substitute for this function by an intercondylar tibial prominence that articulates with the femur in flexion. Measurements will take place preoperatively and 6 weeks, 3 months, 6 months and 1 year postoperatively. At all measurement points patient's perceived outcome will be assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Secondary outcome measures are quality of life (SF-36) and physician reported functional status and range of motion as determined with the Knee Society Clinical Rating System (KSS). Discussion: In the current practice both posterior cruciate retaining and posterior stabilized designs for total knee arthroplasty are being used. To date no studies have been performed determining whether there is a difference in patient's perceived outcome between the two designs. Additionally, there is a lack of studies determining the speed of recovery in both designs as most studies only determine the final outcome. This randomised controlled study has been designed to determine whether the patient's perceived outcome and speed of recovery differs between a posterior cruciate retaining total knee arthroplasty and a posterior stabilized total knee arthroplasty

Fifteen Year Outcome of the Ceraver Hermes Posterior-Stabilized Total Knee Arthroplasty: Safety of the Procedure with Experienced and Inexperienced Surgeons

We wished to determine whether total knee replacement (TKA) performed by young surgeons increased rates of mortality and complications compared with TKA performed by senior surgeons using the same model of arthroplasty. There were no significant pre-operative differences between the groups in terms of age, gender, height, weight, body mass index, diagnosis, comorbidity and duration of follow-up, which was a mean of 15 years in both groups. Hence, we assessed the 15 year survival of the first 150 Ceraver Posterior-Stabilized total knee arthroplasties undertaken by young surgeons (aged of less than 30 years) in formation in a single university hospital setting (Group B). We used survival curve analysis, with strict definitions regarding end-points, and evaluated a number of different endpoint criteria to assess the outcome and to compare the results with those obtained by the two seniors (aged of more than 40 years) with their 50 first implantations (Group A). The clinical results and survival rate of implants at intermediate to long-term follow-up were similar in both Groups. Kaplan-Meier survival analysis, with revision as the endpoint for failure, showed that the rate of survival at ten years was 96% (95% CI, 93 to 100) in both groups. At fifteen years the rate of survival was 91% (95% CI, 85 to 97) in group B, and 92% (95% CI, 90 to 94) in group A. The implant used in this series appears particularly safe since the usual complications observed with posterior stabilized arthroplasties were not observed even with young surgeons

Toward optimal implementation of cancer prevention and control programs in public health: A study protocol on mis-implementation

Abstract Background Much of the cancer burden in the USA is preventable, through application of existing knowledge. State-level funders and public health practitioners are in ideal positions to affect programs and policies related to cancer control. Mis-implementation refers to ending effective programs and policies prematurely or continuing ineffective ones. Greater attention to mis-implementation should lead to use of effective interventions and more efficient expenditure of resources, which in the long term, will lead to more positive cancer outcomes. Methods This is a three-phase study that takes a comprehensive approach, leading to the elucidation of tactics for addressing mis-implementation. Phase 1: We assess the extent to which mis-implementation is occurring among state cancer control programs in public health. This initial phase will involve a survey of 800 practitioners representing all states. The programs represented will span the full continuum of cancer control, from primary prevention to survivorship. Phase 2: Using data from phase 1 to identify organizations in which mis-implementation is particularly high or low, the team will conduct eight comparative case studies to get a richer understanding of mis-implementation and to understand contextual differences. These case studies will highlight lessons learned about mis-implementation and identify hypothesized drivers. Phase 3: Agent-based modeling will be used to identify dynamic interactions between individual capacity, organizational capacity, use of evidence, funding, and external factors driving mis-implementation. The team will then translate and disseminate findings from phases 1 to 3 to practitioners and practice-related stakeholders to support the reduction of mis-implementation. Discussion This study is innovative and significant because it will (1) be the first to refine and further develop reliable and valid measures of mis-implementation of public health programs; (2) bring together a strong, transdisciplinary team with significant expertise in practice-based research; (3) use agent-based modeling to address cancer control implementation; and (4) use a participatory, evidence-based, stakeholder-driven approach that will identify key leverage points for addressing mis-implementation among state public health programs. This research is expected to provide replicable computational simulation models that can identify leverage points and public health system dynamics to reduce mis-implementation in cancer control and may be of interest to other health areas

Role of Esrrg in the Fibrate-Mediated Regulation of Lipid Metabolism Genes in Human ApoA-I Transgenic Mice

We have used a new ApoA-I transgenic mouse model to identify by global gene expression profiling, candidate genes that affect lipid and lipoprotein metabolism in response to fenofibrate treatment. Multilevel bioinformatical analysis and stringent selection criteria (2-fold change, 0% false discovery rate) identified 267 significantly changed genes involved in several molecular pathways. The fenofibrate-treated group did not have significantly altered levels of hepatic human APOA-I mRNA and plasma ApoA-I compared with the control group. However, the treatment increased cholesterol levels to 1.95-fold mainly due to the increase in high-density lipoprotein (HDL) cholesterol. The observed changes in HDL are associated with the upregulation of genes involved in phospholipid biosynthesis and lipid hydrolysis, as well as phospholipid transfer protein. Significant upregulation was observed in genes involved in fatty acid transport and β-oxidation, but not in those of fatty acid and cholesterol biosynthesis, Krebs cycle and gluconeogenesis. Fenofibrate changed significantly the expression of seven transcription factors. The estrogen receptor-related gamma gene was upregulated 2.36-fold and had a significant positive correlation with genes of lipid and lipoprotein metabolism and mitochondrial functions, indicating an important role of this orphan receptor in mediating the fenofibrate-induced activation of a specific subset of its target genes.National Institutes of Health (HL48739 and HL68216); European Union (LSHM-CT-2006-0376331, LSHG-CT-2006-037277); the Biomedical Research Foundation of the Academy of Athens; the Hellenic Cardiological Society; the John F Kostopoulos Foundatio

Is the "Glasgow effect" of cigarette smoking explained by socio-economic status?: A multilevel analysis

Background: The Glasgow area has elevated levels of deprivation and is known for its poor health and associated negative health-related behaviours, which are socially patterned. Of interest is whether high smoking rates are explained by the area's socio-economic profile.<p></p> Methods: Data on age, sex, current/previous smoking status, area deprivation, social class, education, economic activity, postcode sector, and health board region were available from Scottish Health Surveys conducted in 1995, 1998 and 2003. Multilevel logistic regression models were applied by sex, unadjusted and adjusted for age, survey year, and socio-economic factors, accounting for geographical hierarchy and missing data.<p></p> Results: Compared with the rest of Scotland, men living in Greater Glasgow were 30% and women 43% more likely to smoke [odds ratio (OR) = 1.30, (95% CI = 1.08–1.56) and (OR = 1.43, CI = 1.22–1.68), respectively] before adjustment. In adjusted results, the association between living in Greater Glasgow and current smoking was attenuated [OR = 0.92, CI = 0.78–1.09 for men, and OR = 1.08, CI = 0.94–1.23 for women; results based on multiply imputed data to account for missing values remained borderline significant for women]. Accounting for individuals who had been told to give up smoking by a medical person/excluding ex-smokers did not alter results.<p></p> Conclusion: High levels of smoking in Greater Glasgow were attributable to its poorer socio-economic position and the strong social patterning of smoking. Tackling Glasgow's, and indeed Scotland's, poor health must involve policies to alleviate problems associated with poverty.<p></p&gt

Determining Peptide Partitioning Properties via Computer Simulation

The transfer of polypeptide segments into lipid bilayers to form transmembrane helices represents the crucial first step in cellular membrane protein folding and assembly. This process is driven by complex and poorly understood atomic interactions of peptides with the lipid bilayer environment. The lack of suitable experimental techniques that can resolve these processes both at atomic resolution and nanosecond timescales has spurred the development of computational techniques. In this review, we summarize the significant progress achieved in the last few years in elucidating the partitioning of peptides into lipid bilayer membranes using atomic detail molecular dynamics simulations. Indeed, partitioning simulations can now provide a wealth of structural and dynamic information. Furthermore, we show that peptide-induced bilayer distortions, insertion pathways, transfer free energies, and kinetic insertion barriers are now accurate enough to complement experiments. Further advances in simulation methods and force field parameter accuracy promise to turn molecular dynamics simulations into a powerful tool for investigating a wide range of membrane active peptide phenomena

Identifying Trends in Masterplanning: A Typological Classification System

This document is the Accepted Manuscript version of the following article: Robert Adam, and Claire Jamieson, ‘Identifying trends in masterplanning: A typological classification system’, URBAN DESIGN International, Vol. 19 (4): 274-290, December 2014. The final publication is available at Springer via https://doi.org/10.1057/udi.2013.24.This article reports research carried out to develop a new typological method for the analysis of masterplans. This quantitative method of analysis can be used to produce comparative data that will help in the comparison of urban design typologies and their development over time. This article sets out the research to date, describing how the initial aims have developed from simple analysis to the creation of an analytical tool with wide applications. Comprising a detailed taxonomy of urban design features gathered from a wide database of recent and emerging masterplans, the system provides opportunities for further study such as trends, qualitative comparison against quantitative measurement, and comparison of aims and outcomes. This article will describe the methodology and process of research, while elaborating on the potential of the tool.Peer reviewedFinal Accepted Versio

Altered Neurocircuitry in the Dopamine Transporter Knockout Mouse Brain

The plasma membrane transporters for the monoamine neurotransmitters dopamine, serotonin, and norepinephrine modulate the dynamics of these monoamine neurotransmitters. Thus, activity of these transporters has significant consequences for monoamine activity throughout the brain and for a number of neurological and psychiatric disorders. Gene knockout (KO) mice that reduce or eliminate expression of each of these monoamine transporters have provided a wealth of new information about the function of these proteins at molecular, physiological and behavioral levels. In the present work we use the unique properties of magnetic resonance imaging (MRI) to probe the effects of altered dopaminergic dynamics on meso-scale neuronal circuitry and overall brain morphology, since changes at these levels of organization might help to account for some of the extensive pharmacological and behavioral differences observed in dopamine transporter (DAT) KO mice. Despite the smaller size of these animals, voxel-wise statistical comparison of high resolution structural MR images indicated little morphological change as a consequence of DAT KO. Likewise, proton magnetic resonance spectra recorded in the striatum indicated no significant changes in detectable metabolite concentrations between DAT KO and wild-type (WT) mice. In contrast, alterations in the circuitry from the prefrontal cortex to the mesocortical limbic system, an important brain component intimately tied to function of mesolimbic/mesocortical dopamine reward pathways, were revealed by manganese-enhanced MRI (MEMRI). Analysis of co-registered MEMRI images taken over the 26 hours after introduction of Mn^(2+) into the prefrontal cortex indicated that DAT KO mice have a truncated Mn^(2+) distribution within this circuitry with little accumulation beyond the thalamus or contralateral to the injection site. By contrast, WT littermates exhibit Mn^(2+) transport into more posterior midbrain nuclei and contralateral mesolimbic structures at 26 hr post-injection. Thus, DAT KO mice appear, at this level of anatomic resolution, to have preserved cortico-striatal-thalamic connectivity but diminished robustness of reward-modulating circuitry distal to the thalamus. This is in contradistinction to the state of this circuitry in serotonin transporter KO mice where we observed more robust connectivity in more posterior brain regions using methods identical to those employed here