Simple and robust model to estimate live weight of Ethiopian Menz sheep

Heart girth (HG) bands have been predominantly used in Ethiopia by smallholder farmers, traders and extension workers to estimate live weight (LW) of livestock. They are produced using recommended and published predictive models from Ethiopia. More recently, some farmers and traders have abandoned the bands due to perceived inaccuracy of LW estimation and reverted to eye ball estimations. This study generated a novel algorithm using multiple criteria to develop a robust predictive model for LW estimation of Ethiopian Menz sheep using HG. Subsequently, recommended models currently in use in Ethiopia were evaluated for accuracy in predicting LW using data of this study. Live weight and HG of 420 Menz sheep were measured. Simple linear model (SLM), Box-Cox (SLM with LW0.75), quadratic and allometric models were used to describe the relationship between LW and HG. Algorithms used to validate the models included data exploration, model construction and model redeployment. Results revealed that all models had similar R2 (≈0.82). All models fitted the criteria of residuals analysis and robustness against extreme values. However, only Box-Cox was robust against data redeployment with 95th percentile of prediction error (PE) less than 10%. Accordingly, a Box-Cox model (LW0.75 = -9.71 + 0.289(HG)) is robust and can be used to accurately predict LW of Menz sheep. The 95th percentile of PE of existing, recommended models was higher than 10, thus they cannot be recommended to accurately predict LW of Menz sheep. This study concludes that an approach based on regressing LW on HG then selecting models with highest R2 is inadequate to generate accurate and robust prediction models. This highlights the importance of model redeployment to generate accurate prediction models. Calibrated HG bands are suitable alternatives to weighing scales in rural areas of Ethiopia because they are cheaper and not subject to maintenance. Thus, their accuracy and robustness in estimation of LW is vital for sustainable use

Implementation of child-centred outcome measures in routine paediatric healthcare practice: a systematic review

Background: Person-centred outcome measures (PCOMs) are commonly used in routine adult healthcare to measure and improve outcomes, but less attention has been paid to PCOMs in children’s services. The aim of this systematic review is to identify and synthesise existing evidence of the determinants, strategies, and mechanisms that influence the implementation of PCOMs into paediatric healthcare practice. Methods: The review was conducted and reported in accordance with PRISMA guidelines. Databased searched included CINAHL, Embase, Medline, and PsycInfo. Google scholar was also searched for grey literature on 25th March 2022. Studies were included if the setting was a children’s healthcare service, investigating the implementation or use of an outcome measure or screening tool in healthcare practice, and reported outcomes relating to use of a measure. Data were tabulated and thematically analysed through deductive coding to the constructs of the adapted-Consolidated Framework for Implementation Research (CFIR). Results were presented as a narrative synthesis, and a logic model developed. Results: We retained 69 studies, conducted across primary (n = 14), secondary (n = 13), tertiary (n = 37), and community (n = 8) healthcare settings, including both child self-report (n = 46) and parent-proxy (n = 47) measures. The most frequently reported barriers to measure implementation included staff lack of knowledge about how the measure may improve care and outcomes; the complexity of using and implementing the measure; and a lack of resources to support implementation and its continued use including funding and staff. The most frequently reported facilitators of implementation and continued use include educating and training staff and families on: how to implement and use the measure; the advantages of using PCOMs over current practice; and the benefit their use has on patient care and outcomes. The resulting logic model presents the mechanisms through which strategies can reduce the barriers to implementation and support the use of PCOMs in practice. Conclusions: These findings can be used to support the development of context-specific implementation plans through a combination of existing strategies. This will enable the implementation of PCOMs into routine paediatric healthcare practice to empower settings to better identify and improve child-centred outcomes. Trial registration: Prospero CRD 42022330013

Process evaluation of a peer-led antenatal breastfeeding class for fathers: perceptions of facilitators and participants

Background: The Parent Infant Feeding Initiative (PIFI) was a factorial, randomised controlled trial that aimed to prolong exclusive breastfeeding by targeting expecting fathers. One of the intervention strategies evaluated was a father-focused breastfeeding class facilitated by a male peer facilitator. The aim of this mixed-methods descriptive study was to 1) evaluate the feedback provided from participants of the class and 2) explore the motivations and experiences of volunteer male peer facilitators trained to deliver the class. Methods: Father-focused breastfeeding antenatal (FFAB) classes were conducted in six Western Australian hospitals between August 2015 and December 2016. Following each peer facilitated FFAB class, expecting father participants completed an evaluation form to assess their satisfaction with the format, facilitation and content, in addition to whether their expectations and confidence to manage breastfeeding problems had changed. Feedback to open-ended questions was analysed using content analysis to identify learnings and suggestions for improvements. At the completion of PIFI, individual telephone interviews were undertaken with 14 peer facilitators to gain insight into their motivations for volunteering and experiences of conducting the classes. Transcripts from interviews were analysed using Braun and Clarke’s six phases for thematic analysis. Results: Participant evaluation forms were completed by 678 of the 697 father participants (98%). Overall satisfaction with class format, facilitation and content was high with 90% or more of fathers either strongly agreeing or agreeing with each positively-phrased evaluation item. Class participants enjoyed interacting with other fathers, appreciated validation of their role, were not always aware of the importance of breastfeeding or potential difficulties, valued the anticipatory guidance around what to expect in the early weeks of parenting and appreciated learning practical breastfeeding support strategies. Peer facilitators indicated they felt well prepared and supported to conduct FFAB classes. Analysis of interview transcripts revealed common experiences of the peer facilitators incorporating four themes: ‘Highlights of being a facilitator’, ‘Challenges’, ‘Mourning the project completion’ and ‘Satisfaction with training and support’. Conclusion: Father-focused breastfeeding classes supported by volunteer male peer facilitators are a feasible and acceptable way of engaging fathers as breastfeeding supporters. Trial registration: ACTRN12614000605695. Registered 6 June 2014

Structure-Guided Evolution of Potent and Selective CHK1 Inhibitors through Scaffold Morphing

Pyrazolopyridine inhibitors with low micromolar potency for CHK1 and good selectivity against CHK2 were previously identified by fragment-based screening. The optimization of the pyrazolopyridines to a series of potent and CHK1-selective isoquinolines demonstrates how fragment-growing and scaffold morphing strategies arising from a structure-based understanding of CHK1 inhibitor binding can be combined to successfully progress fragment-derived hit matter to compounds with activity in vivo. The challenges of improving CHK1 potency and selectivity, addressing synthetic tractability, and achieving novelty in the crowded kinase inhibitor chemical space were tackled by multiple scaffold morphing steps, which progressed through tricyclic pyrimido[2,3-b]azaindoles to N-(pyrazin-2-yl)pyrimidin-4-amines and ultimately to imidazo[4,5-c]pyridines and isoquinolines. A potent and highly selective isoquinoline CHK1 inhibitor (SAR-020106) was identified, which potentiated the efficacies of irinotecan and gemcitabine in SW620 human colon carcinoma xenografts in nude mice

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

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