Prioritization of THose aWaiting hip and knee ArthroplastY(PATHWAY) : protocol for development of a stakeholder led clinical prioritization tool

Open access funding The authors report that the open access funding for this manuscript is provided by the Chief Scientist Office Clinical Academic Fellowship (Grant ref: CAF/21/06). Funding statement The study is co-funded by the University of Aberdeen Knowledge Exchange Commission (Ref CF10693-29) and a Chief Scientist Office (CSO) Scotland Clinical Academic Fellowship, which will run from 08/2021 to 08/2024 (Grant ref: CAF/21/06).Peer reviewedPublisher PD

Epidemiology, prehospital care and outcomes of patients arriving by ambulance with dyspnoea: An observational study

Background: This study aimed to determine epidemiology and outcome for patients presenting to emergency departments (ED) with shortness of breath who were transported by ambulance. Methods: This was a planned sub-study of a prospective, interrupted time series cohort study conducted at three time points in 2014 and which included consecutive adult patients presenting to the ED with dyspnoea as a main symptom. For this sub-study, additional inclusion criteria were presentation to an ED in Australia or New Zealand and transport by ambulance. The primary outcomes of interest are the epidemiology and outcome of these patients. Analysis was by descriptive statistics and comparisons of proportions. Results: One thousand seven patients met inclusion criteria. Median age was 74 years (IQR 61-68) and 46.1 % were male. There was a high rate of co-morbidity and chronic medication use. The most common ED diagnoses were lower respiratory tract infection (including pneumonia, 22.7 %), cardiac failure (20.5%) and exacerbation of chronic obstructive pulmonary disease (19.7 %). ED disposition was hospital admission (including ICU) for 76.4 %, ICU admission for 5.6 % and death in ED in 0.9 %. Overall in-hospital mortality among admitted patients was 6.5 %. Discussion: Patients transported by ambulance with shortness of breath make up a significant proportion of ambulance caseload and have high comorbidity and high hospital admission rate. In this study, >60 % were accounted for by patients with heart failure, lower respiratory tract infection or COPD, but there were a wide range of diagnoses. This has implications for service planning, models of care and paramedic training. Conclusion: This study shows that patients transported to hospital by ambulance with shortness of breath are a complex and seriously ill group with a broad range of diagnoses. Understanding the characteristics of these patients, the range of diagnoses and their outcome can help inform training and planning of services

The Orphan Receptor CRF2-4 Is an Essential Subunit of the Interleukin 10 Receptor

The orphan receptor CRF2-4 is a member of the class II cytokine receptor family (CRF2), which includes the interferon receptors, the interleukin (IL) 10 receptor, and tissue factor. CRFB4, the gene encoding CRF2-4, is located within a gene cluster on human chromosome 21 that comprises three interferon receptor subunits. To elucidate the role of CRF2-4, we disrupted the CRFB4 gene in mice by means of homologous recombination. Mice lacking CRF2-4 show no overt abnormalities, grow normally, and are fertile. CRF2-4 deficient cells are normally responsive to type I and type II interferons, but lack responsiveness to IL-10. By ∼12 wk of age, the majority of mutant mice raised in a conventional facility developed a chronic colitis and splenomegaly. Thus, CRFB4 mutant mice recapitulate the phenotype of IL-10–deficient mice. These findings suggest that CRF2-4 is essential for IL-10–mediated effects and is a subunit of the IL-10 receptor

Evolution of complexity in the zebrafish synapse proteome

The proteome of human brain synapses is highly complex and mutated in over 130 diseases. This complexity arose from two whole genome duplications early in the vertebrate lineage. Zebrafish are used in modelling human diseases, however its synapse proteome is uncharacterised and whether the teleost-specific genome duplication (TSGD) influenced complexity is unknown. We report the characterisation of the proteomes and ultrastructure of central synapses in zebrafish and analyse the importance of the TSGD. While the TSGD increases overall synapse proteome complexity, the Post Synaptic Density (PSD) proteome of zebrafish has lower complexity than mammals. A highly conserved set of ~1000 proteins is shared across vertebrates. PSD ultrastructural features are also conserved. Lineage-specific proteome differences indicate vertebrate species evolved distinct synapse types and functions. The datasets are a resource for a wide range of studies and have important implications for the use of zebrafish in modelling human synaptic diseases

Contextualising social capital in online brand communities

Online brand communities (OBC) are growing in number and becoming an increasingly important interface where marketers can effectively facilitate the relationship between their brand and consumers. A qualitative study using a four-month netnography over three OBCs followed by focus groups with OBC members explored the dynamics of social capital in these communities. Findings indicate that social capital is an important driver in the success of OBCs, and all the elements of social capital including a shared language, shared vision, social trust and reciprocity are evident. Moreover, results from this study indicate that these elements are crucial in developing the network ties that are integral to building loyalty and brand equity

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

Does delay to theatre influence morbidity or mortality in femoral periprosthetic fractures?

Aims Femoral periprosthetic fractures are rising in incidence. Their management is complex and carries a high associated mortality. Unlike native hip fractures, there are no guidelines advising on time to theatre in this group. We aim to determine whether delaying surgical intervention influences morbidity or mortality in femoral periprosthetic fractures. Methods We identified all periprosthetic fractures around a hip or knee arthroplasty from our prospectively collated database between 2012 and 2021. Patients were categorized into early or delayed intervention based on time from admission to surgery (early = ≤ 36 hours, delayed > 36 hours). Patient demographics, existing implants, Unified Classification System fracture subtype, acute medical issues on admission, preoperative haemoglobin, blood transfusion requirement, and length of hospital stay were identified for all patients. Complication and mortality rates were compared between groups. Results A total of 365 patients were identified: 140 in the early and 225 in the delayed intervention group. Mortality rate was 4.1% at 30 days and 19.2% at one year. There was some indication that those who had surgery within 36 hours had a higher mortality rate, but this did not reach statistical significance at 30 days (p = 0.078) or one year (p = 0.051). Univariate analysis demonstrated that age, preoperative haemoglobin, acute medical issue on admission, and the presence of postoperative complications influenced 30-day and one-year mortality. Using a multivariate model, age and preoperative haemoglobin were independently predictive factors for one-year mortality (odds ratio (OR) 1.071; p < 0.001 and OR 0.980; p = 0.020). There was no association between timing of surgery and postoperative complications. Postoperative complications were more likely with increasing age (OR 1.032; p = 0.001) and revision arthroplasty compared to internal fixation (OR 0.481; p = 0.001). Conclusion While early intervention may be preferable to reduce prolonged immobilization, there is no evidence that delaying surgery beyond 36 hours increases mortality or complications in patients with a femoral periprosthetic fracture