Development of a patient decision aid for children and adolescents following anterior cruciate ligament rupture: an international mixed-methods study

AIM: To develop and user test an evidence-based patient decision aid for children and adolescents who are considering anterior cruciate ligament (ACL) reconstruction.DESIGN: Mixed-methods study describing the development of a patient decision aid.SETTING: A draft decision aid was developed by a multidisciplinary steering group (including various types of health professionals and researchers, and consumers) informed by the best available evidence and existing patient decision aids.PARTICIPANTS: People who ruptured their ACL when they were under 18 years old (ie, adolescents), their parents, and health professionals who manage these patients. Participants were recruited through social media and the network outreach of the steering group.PRIMARY AND SECONDARY OUTCOMES: Semistructured interviews and questionnaires were used to gather feedback on the decision aid. The feedback was used to refine the decision aid and assess acceptability. An iterative cycle of interviews, refining the aid according to feedback and further interviews, was used. Interviews were analysed using reflexive thematic analysis.RESULTS: We conducted 32 interviews; 16 health professionals (12 physiotherapists, 4 orthopaedic surgeons) and 16 people who ruptured their ACL when they were under 18 years old (7 were adolescents and 9 were adults at the time of the interview). Parents participated in 8 interviews. Most health professionals, patients and parents rated the aid's acceptability as good-to-excellent. Health professionals and patients agreed on most aspects of the decision aid, but some health professionals had differing views on non-surgical management, risk of harms, treatment protocols and evidence on benefits and harms.CONCLUSION: Our patient decision aid is an acceptable tool to help children and adolescents choose an appropriate management option following ACL rupture with their parents and health professionals. A clinical trial evaluating the potential benefit of this tool for children and adolescents considering ACL reconstruction is warranted.</p

Development of the Reporting Infographics and Visual Abstracts of Comparative studies (RIVA-C) checklist and guide

People often use infographics (also called visual or graphical abstracts) as a substitute for reading the full text of an article. This is a concern because most infographics do not present sufficient information to interpret the research appropriately and guide wise health decisions. The Reporting Infographics and Visual Abstracts of Comparative studies (RIVA-C) checklist and guide aims to improve the completeness with which research findings of comparative studies are communicated and avoid research findings being misinterpreted if readers do not refer to the full text. The primary audience for the RIVA-C checklist and guide is developers of infographics that summarise comparative studies of health and medical interventions. The need for the RIVA-C checklist and guide was identified by a survey of how people use infographics. Possible checklist items were informed by a systematic review of how infographics report research. We then conducted a two-round, modified Delphi survey of 92 infographic developers/designers, researchers, health professionals and other key stakeholders. The final checklist includes 10 items. Accompanying explanation and both text and graphical examples linked to the items were developed and pilot tested over a 6-month period. The RIVA-C checklist and guide was designed to facilitate the creation of clear, transparent and sufficiently detailed infographics which summarise comparative studies of health and medical interventions. Accurate infographics can ensure research findings are communicated appropriately and not misinterpreted. By capturing the perspectives of a wide range of end users (eg, authors, informatics editors, journal editors, consumers), we are hopeful of rapid endorsement and implementation of RIVA-C.</p

Large-Scale Gene-Centric Meta-Analysis across 39 Studies Identifies Type 2 Diabetes Loci

To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with similar to 2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 x 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p <2.4 x 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 x 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 x 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 x 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

The role of Apc in medulloblastoma

Medulloblastomas represent the most frequent malignant brain tumour in children, and are thought to develop in the posterior fossa of the cerebellum. Some patients with medulloblastomas have a deficiency in the tumour suppressor gene Apc (Turcot’s syndrome). Although the majority of medulloblastomas arise sporadically, people with Apc mutations are 92 times more likely to develop medulloblastomas. Apc encodes a very large protein known to function as a regulator of the Wnt signalling pathway. Activation of the canonical Wnt pathway leads to the stabilisation of beta-catenin. In response to Wnt signals, beta-catenin translocates to the nucleus where it interacts with the LEF/TCF family of transcription factors to activate transcription of target genes such as c-myc and cyclinD1. Mutations of Apc that cause an increase in beta-catenin are found to be tumourgenic, whereas other mutations are not. Therefore it is thought that the main tumour suppression function of Apc is in its ability to destabilise and hence reduce cytoplasmic beta-catenin. The central hypothesis of this thesis is that the loss of Apc can lead to the development of medulloblastoma. Work from other groups has reported activation of Wnt signalling in a proportion of primary medulloblastomas. We undertook a study to assess this by using the cre-loxP recombination system to mutate Apc in a temporal and spatial manner. This approach is necessary as Apc has many functions in development and Apc mutant mice (Apcmin) do not develop past embryonic day 6.5 (E6.5). To date, there are no known cre-strains available to mutate Apc specifically in the cerebellum at early postnatal stages, so we combined the creloxP method with an avian retrovirus mediated method for tissue specific gene delivery (RCAS/tv-a system), in an attempt to create a strain of mice which carried the genotype Ntv-a +;ApcLoxP/LoxP. This would allow us to infect an RCAS-cre virus directly into the hindbrain at postnatal day 4 (P4). However subsequent genotyping of these animals showed that none carried the desired genotype of Ntv-a +;ApcLoxP/LoxP, making it impossible for both copies of Apc to be mutated in a mouse most likely because both the Ntv-a and Apc transgenes were located on the same chromosome. Consistent with this, out of a total of 265 mice none were found to have the Ntv-a +;ApcLoxP/LoxP genotype. We then adopted an alternative method for mutating Apc by infecting ApcLoxP/LoxP mice directly with an AdCre virus. PCR analysis showed that Apc was mutated, however the AdCre virus did not infect cells of the cerebellum, and instead only infected the choroid plexus. In these animals, 7 of 94 (7%) developed hydrocephalus indicating that losing Apc in the choroid plexus may promote hydrocephalus. Finally, to address the role of Apc in normal hindbrain development, we crossed our ApcLoxP/LoxP mice to an En1cre strain which caused mutation in Apc from E8.5 in the midhindbrain region. The resulting En1cre+;ApcLoxP/LoxP mutants displayed hydrocephalus in all ventricles and an in-growth of mesenchyme tissue at the mid-hindbrain border, closely associated with a tumour-like area of cells showing activated Wnt signalling. No mice were found to live past E18.5. In conclusion, the role of Apc in medulloblastoma remains unclear. Future studies could use a different technique to mutate Apc such as crossing ApcLoxP/LoxP mice to the new nestin-creER strain and inducting cre with administration of tamoxifen.EThOS - Electronic Theses Online ServiceGBUnited Kingdo