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Objectives With rising poverty and widening health inequity among children in the UK, the objective of this study is to evaluate the impact of the Sure Start programme on child health outcomes in disadvantaged children.Design Systematic review.Data sources We conducted a comprehensive search of three databases: Embase, Medline and Social Policy and Practice, with grey literature searched using Open Grey, Social Care Online and Google Scholar. The search was conducted in January 2024.Eligibility criteria for selecting studies All primary studies investigating health outcomes in children as a result of Sure Start intervention were eligible for inclusion, without limitations on study design.Data extraction and synthesis Full-text articles in English were independently screened according to the eligibility criteria by two researchers. Results were synthesised and presented in both a quantitative and narrative format. We assessed the risk of bias in each included study.Results Our initial search identified 585 records, of which 9 met our inclusion criteria with a further 3 grey literature reports included. Three themes were identified: physical health, social functioning and neurodevelopmental disorders. In terms of physical health, our findings indicate significant reductions in hospitalisations in older children, accidental injury and obesity prevalence. Furthermore, Sure Start increased the prevalence of breastfeeding and improved dental hygiene in children. In the social functioning domain, the Sure Start programme produced mixed findings: with children from certain backgrounds observing adverse effects as a result of the intervention. Yet, Sure Start demonstrated significant improvement in education attainment, with a maximal improvement of grade improvement in children from low socio-economic and ethnic minority backgrounds. For neurodevelopmental disorders, Sure Start was able to significantly improve conduct disorder and attention-deficit hyperactivity disorder symptomatology with long-term clinical stabilisation, as well as improving screening rates for developmental disorders.Conclusion This study examines the evidence of the Sure Start programme, as an example of an early-years community-based intervention, to mitigate health inequity among disadvantaged children. The findings suggest the Sure Start programme to be effective in health generation across the domains of physical health and neurodevelopmental disorders for disadvantaged children, but with mixed findings for social development that can only partially be explained by methodological flaws.Trial registration number PROSPERO CRD42024503234.

Definitive radiotherapy (RT) has been shown to be a successful method of treating prostate cancer (PCa) patients. Through radiomics, a quantitative analysis of medical images, it is possible to adapt treatment early on, which may prevent or mitigate future adverse events. During RT of PCa, low-field magnetic resonance (MR) images, taken with a LINAC onboard imaging system in a process known as magnetic resonance-guided radiotherapy (MRgRT), are used to improve treatment accuracy via superior setup compared to x-ray methods. This work investigated baseline repeatability of radiomic features (RFs) by comparing planning MR images (pMR) with first-fraction setup images (FX1) taken with onboard MRI. The changes in RFs following RT were also looked at with the use of last-fraction setup images (FX5). Earlier research has investigated the use of planning images from cone beam CT (CBCT), but to our knowledge no research has previously shown the relationship with onboard MRI. The correlation between FX1 images and 3T diagnostic MR (dT2) images was also studied. Forty-three first and second order radiomic features extracted from these images were compared by calculating Lin’s concordance correlation coefficient (with Benjamini-Hochberg correction for multiple comparisons) between the modalities. FX1 and pMR images were correlated (p

Purpose: The aim of this study is to develop a framework for quantitative analysis of longitudinal T2-weighted MRIs (T2w) following radiotherapy (RT) for prostate cancer. Materials and methods: The developed methodology includes: (i) deformable image registration of longitudinal series to pre-RT T2w for automated detection of prostate, peripheral zone (PZ), and gross tumor volume (GTV); and (ii) T2w signal-intensity harmonization based on three reference tissues. The REgistration and HARMonization (REHARM) framework was applied on T2w acquired in a clinical trial consisting of two pre-RT and three post-RT MRI exams. Image registration was assessed by the DICE coefficient between automatic and manual contours, and intensity normalization via inter-patient histogram intersection. Longitudinal consistency was evaluated by the repeatability coefficient and Pearson correlation (r) between the two T2w exams before RT. Results: T2w from 107 MRI exams (23 patients) were utilized. Following REHARM, the histogram intersections for prostate, PZ and GTV increased from median = 0.43/0.16/0.13 to 0.66/0.44/0.46. The repeatability in T2w intensity estimation was better for the automatic than the manual contours for all three regions of interest (r = 0.9, p

Abstract Extracting longitudinal image quantitative data, known as delta-radiomics, has the potential to capture changes in a patient’s anatomy throughout the course of radiation treatment for prostate cancer. Some of the major challenges of delta-radiomics studies are contouring the structures for individual fractions and accruing patients’ data in an efficient manner. The manual contouring process is often time consuming and would limit the efficiency of accruing larger sample sizes for future studies. The problem is amplified because the contours are often made by highly trained radiation oncologists with limited time to dedicate to research studies of this nature. This work compares the use of automated prostate contours generated using a deformable image-based algorithm to make predictive models of genitourinary and changes in total international prostate symptom score in comparison to manually contours for a cohort of fifty patients. Area under the curve of manual and automated models were compared using the Delong test. This study demonstrated that the delta-radiomics models were similar for both automated and manual delta-radiomics models.

Background Quality improvement (QI) is used by healthcare organisations internationally to improve care. Unless QI explicitly addresses equity, projects that aim to improve care may exacerbate health and care inequalities for disadvantaged groups. There are several QI frameworks used in primary care, but we do not know the extent to which they consider equity. This work aimed to investigate whether primary care QI frameworks consider equity.Methods We conducted a search of MEDLINE, EMBASE and key websites to compile a list of the QI frameworks used in primary care. This list was refined by an expert panel. Guidance documents for each of the QI frameworks were identified from national websites or QI organisations. We undertook a document analysis of the guidance using NVivo.Results We analysed 15 guidance documents. We identified the following themes: (1) there was a limited discussion of equity or targeted QI for disadvantaged groups in the documents, (2) there were indirect considerations of inequalities via patient involvement or targeting QI to patient demographics and (3) there was a greater focus on efficiency than equity in the documents.Conclusion There is limited consideration of equity in QI frameworks used in primary care. Where equity is discussed, it is implicit and open to interpretation. This research demonstrates a need for frameworks to be revised with an explicit equity focus to ensure the distribution of benefits from QI is equitable.

Background Socio-economic inequalities in health have been in the public agenda for decades. General practice has an influential role to play in mitigating the impact of inequalities especially regarding chronic conditions. At the moment, general practice is dealing with serious challenges in relation to workforce shortages, increasing workload and the impact of the COVID-19 pandemic. It is important to identify effective ways so that general practice can play its role in reducing health inequalities. Objectives We explored what types of interventions and aspects of routine care in general practice decrease or increase inequalities in health and care-related outcomes. We focused on cardiovascular disease, cancer, diabetes and/or chronic obstructive pulmonary disease. We explored for whom these interventions and aspects of care work best, why, and in what circumstances. Our main objective was to synthesise this evidence into specific guidance for healthcare professionals and decision-makers about how best to achieve equitable general practice. Design Realist review. Main outcome measures Clinical or care-related outcomes by socio-economic group, or other PROGRESS-Plus criteria. Review methods Realist review based on Pawson’s five steps: (1) locating existing theories, (2) searching for evidence, (3) selecting articles, (4) extracting and organising data and (5) synthesising the evidence. Results Three hundred and twenty-five studies met the inclusion criteria and 159 of them were selected for the evidence synthesis. Evidence about the impact of general practice interventions on health inequalities is limited. To reduce health inequalities, general practice needs to be: connected so that interventions are linked and coordinated across the sector; intersectional to account for the fact that people’s experience is affected by many of their characteristics; flexible to meet patients’ different needs and preferences; inclusive so that it does not exclude people because of who they are; community-centred so that people who receive care engage with its design and delivery. These qualities should inform action across four domains: structures like funding and workforce distribution, organisational culture, everyday regulated procedures involved in care delivery, interpersonal and community relationships. Limitations The reviewed evidence offers limited detail about the ways and the extent to which specific interventions increase or decrease inequalities in general practice. Therefore, we focused on the underpinning principles that were common across interventions to produce higher-level, transferrable conclusions about ways to achieve equitable care. Conclusions Inequalities in general practice result from complex processes across four different domains that include structures, ideas, regulated everyday procedures, and relationships among individuals and communities. To achieve equity, general practice needs to be connected, intersectional, flexible, inclusive and community-centred. Future work Future work should focus on how these five essential qualities can be better used to shape the organisational development of future general practice. Study registration This trial is registered as PROSPERO CRD42020217871. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: NIHR130694) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 7. See the NIHR Funding and Awards website for further award information. Plain language summary Health inequalities are unfair differences in health across different groups of the population. In the United Kingdom, the health inequality gap in life expectancy between the richest and poorest is increasing and is caused mostly by differences in long-term conditions like cancer and cardiovascular disease and respiratory conditions, such as chronic obstructive pulmonary disease. Partly National Health Service inequalities arise in delays in seeing a doctor and care provided through doctors’ surgery, such as delays in getting tests. This study explored how general practice services can increase or decrease inequalities in cancer, cardiovascular disease, diabetes and chronic obstructive pulmonary disease, under what circumstances and for whom. It also produced guidance for general practice, both local general practices and the wider general practice system, to reduce inequalities. We reviewed existing studies using a realist methodology. This methodology helps us understand the different contexts in which interventions work or not. We found that inequalities in general practice result from complex processes across different areas. These include funding and workforce, perceptions about health and disease among patients and healthcare staff, everyday procedures involved in care delivery, and relationships among individuals and communities. To reduce inequalities in general practice, action should be taken in all these areas and services need to be connected (i.e. linked and coordinated across the sector), intersectional (i.e. accounting for the fact that people’s experience is affected by many of their characteristics like their gender and socio-economic position), flexible (i.e. meeting patients’ different needs and preferences), inclusive (i.e. not excluding people because of who they are) and community-centred (i.e. working with the people who will receive care when designing and providing it). There is no one single intervention that will make general practice more equitable, rather it requires long-term organisational change based on these principles. Scientific summary Background Socio-economic inequalities in health have been in the public health discourse and policy agenda for decades. There is ample evidence showing that inequalities in premature mortality are mainly driven by inequalities in chronic diseases and especially cancer, cardiovascular and respiratory disease. In the most deprived areas of the country, patients with cardiovascular disease (CVD) deal with a four times higher possibility of premature death than patients in the least deprived areas. In this context, general practice as the front door to the healthcare system has an important role to play in reducing inequalities especially when it comes to chronic conditions. The COVID-19 pandemic has highlighted both the range of health inequalities and the importance of general practice in addressing and tackling the problem. However, it has also revealed chronic deficiencies of the sector which combined with the pressure during the pandemic have resulted in a physically and emotionally exhausted workforce and greater scarcity of resources. In this climate, there is an urgent need for action to secure general practice’s future as more equitable and effective for its patients, their families and carers, but also for its workforce. Objectives Our study explored what types of interventions and aspects of routine care in general practice decrease or increase inequalities in healthcare and outcomes among people with or at risk of CVD, cancer, diabetes and/or chronic obstructive pulmonary disease, and for whom these interventions and aspects of care work best, why, and in what circumstances. Our main objective was to synthesise this evidence to produce specific guidance for healthcare professionals and decision-makers about how best to tackle health inequalities in general practice. Methods We conducted a realist review following Pawson’s five iterative steps: (1) locating existing theories, (2) searching for evidence, (3) selecting articles, (4) extracting and organising data and (5) synthesising the evidence. We started with an exploratory literature search and discussions with experts in the field, to identify existing theories that explain how, for whom, why and in what circumstances interventions or care delivered in general practice may increase or decrease health inequalities. Next, we conducted a literature review in two steps. First, we conducted an initial search of systematic reviews of interventions delivered in general practice and focused on CVD, cancer, diabetes and/or chronic obstructive pulmonary disease (COPD) across the Medical Literature Analysis and Retrieval System Online, Excerpta Medica Database, Cumulative Index to Nursing and Allied Health Literature, Psychological Information Database, the Web of Science and the Cochrane Library. Second, we extracted all the primary studies included in the systematic reviews which met our inclusion criteria, and we screened them searching for interventions which reported on clinical outcomes or care-related outcomes by socio-economic group, or other PROGRESS-Plus criteria. To be able to review the included studies within the study timeline, we combined steps 3 and 4, so the selection of articles took place at the same time with the data extraction. The data synthesis followed a realist logic which suggests that outcomes are the results of specific causal mechanisms which are triggered only within specific contexts. Accordingly, we combined the evidence into statements of causal relationships (what in realist terms are called context–mechanism–outcome configurations) which connect a context with an outcome through an underlying mechanism. Results We identified 7998 review studies, of which 251 met the inclusion criteria. From the included reviews, we retrieved 6555 primary studies and proceeded with a second round of screening. In total, 325 studies met the inclusion criteria for primary studies and were grouped into three categories: those focusing primarily on inequalities (n = 56), those focusing on an intervention, or an aspect of care targeted at specific disadvantaged groups (n = 137) and those assessing the impact of an intervention without focusing on inequalities but accounting for one or more PROGRESS-Plus criteria (n = 132). The studies involved a wide range of designs, with almost half of them being randomised controlled trials or other experimental design (n = 157). Our review revealed that there is limited research on interventions that aim to decrease inequalities in general practice or evidence about the effect of general practice interventions by PROGRESS-Plus criteria. Given the diversity of the included articles and the lack of in-depth information, instead of specific characteristics of interventions we focused on the underlying principles that informed care and interventions and the ways they can be employed to achieve equitable care in general practice. We found that in order to decrease inequalities general practice needs to be connected (i.e. programmes and interventions should be coordinated across the sector), intersectional (i.e. care should account for the fact that people’s experience is affected by many of their characteristics like their gender and socio-economic position), flexible (i.e. care should meet patients’ different needs and preferences), inclusive (i.e. care should not exclude people because of who they are) and community-centred (i.e. working with the people who will receive care when designing and providing it). These five qualities of equitable general practice should be employed to inform action across four different domains of power organisation. In the structural domain action should focus on funding allocation, workforce size and diversity, premises convenience and pre-existing inequalities in the social determinants of health (SDH). In the cultural domain action should focus on integrating an understanding of patient worldviews, beliefs and values, and developing culturally sensitive communication and educational material. Moreover, action in the cultural domain should involve shifting away from designing educational or training interventions outside the social and cultural context of patients. Finally, it should involve tackling biases among general practice staff (clinical and non-clinical). In the disciplinary domain, which involves regulated procedures taking place in the everyday delivery of care, action should focus on how disadvantaged patients are excluded from quality assessment standards, and the effective collection and use of patient socio-demographic information, especially socio-economic status and ethnicity, in risk assessment and quality evaluation. Further, emphasis should be put on invitation methods to prevention services, the working hours of services and the contact time between patients and healthcare staff, continuity of care, as well as on the employment of multidisciplinary care teams and the support of all members of staff to engage in prevention services for disadvantaged patients. Finally, in the interpersonal domain, empathetic and trusting relationships between patients and healthcare staff and personalised communication should be a special focus for services. Further, balanced relationships among staff members across professional hierarchies and mutual respect for each other’s leadership skills is another meaningful area of action. Conclusions Inequalities in general practice result from complex processes and power imbalances across four different domains that include structures, ideas, regulations and bureaucracies, and relationships among individuals and communities. To achieve equity, general practice needs to be connected, intersectional, flexible, inclusive and community-centred and effective action implies: Creating a positive vision for general practice. Policy-makers may find it helpful to work on a positive vision of what equitable general practice looks like. It is recommended that reducing health inequalities remains high in the policy-makers agenda and solutions are planned based on a long-term perspective and the integration of different policy domains, including social policy. This among others requires involving front-line workers in general practice and disadvantaged groups in the development of a health-inequality-related strategy. Making effective use of diversity to promote equity in care outcomes. This among other things could involve tackling structural racism and sexism; inclusion work covering sexual orientation, disability, religion and caring responsibilities; cultivating a less Western-centric organisational culture; including social-sciences and humanities modules in medical training; and increasing cultural competence at the practice level with the recruitment and progression of local clinical and non-clinical staff. Workforce support so that staff are recruited and retained in disadvantaged and remote areas. This can be achieved through providing additional training for less experienced employees; financial and career development incentives in disadvantaged and rural areas; medical school placements; developing a subspecialty related to providing care in highly socio-economically disadvantaged areas; and providing training to nurses, healthcare assistants and administrative staff to improve the overall capacity of practices and also staff experience. Equitable distribution of funding so that it accounts better for differences in need of the served populations. This among other things can take the form of updating the Carr-Hill formula so that it integrates patient socio-economic status and ethnicity and higher patient list weights for practices in disadvantaged areas. Tackling accessibility barriers. This can take the form of co-locating practices with local services such as foodbanks or citizens’ advice offices; locating services close to community landmarks such as schools, libraries and cultural or recreational centres; contributing to the development of community transport options; providing targeted home visits; and remote consultation options. Investing in collecting and disaggregating high-quality data by social/socio-demographic categories, such as socio-economic group, or ethnicity. This among other things could involve securing the necessary time for data collection and update during or around consultation time; making data collection and maintenance a specific part of the professional role of clinical and non-clinical staff; and making the best use of IT resources for the development of accurate and up-to-date patient registers. Increasing continuity of care for long-term conditions and patients with complex health problems and social circumstances. This can be achieved through improving working conditions and providing incentives (e.g. financial, training, social) for staff to remain in their post; focusing on continuity between micro-teams and patients instead of individual general practitioners (GPs) and patients; and involving GP teams in invitations to prevention services. Balancing autonomy to facilitate local community-oriented solutions with standardised care. Local general practices need relative autonomy to decide how to do their work better in terms of reducing inequalities. This can involve increased consultation time for patients with complex needs; translation services specific to the needs of the served population; working hours that work better for the community; and the use of community spaces for the delivery of care and promotion of services. Future research should Prioritise inequalities and apply a health-inequalities perspective to broader research and evaluation work. Systematise evidence on health inequalities and develop platforms which will allow easy and effective access to the evidence. Re-consider the effectiveness of PROGRESS-Plus criteria and their suitability as dimensions of inequality. Integrate and operationalise intersectionality. Use qualitative and mixed-methods approaches to provide detailed information about the transferable evidence-based principles behind specific interventions and upstream drivers of inequalities in SDH. Focus more on conditions intrinsically associated with disadvantage, such as COPD, and specific models of local general practice which are designed to address inequalities. Focus on the cultural domain and explore the interconnection(s) between structural racism, healthcare worker and patient experiences of discrimination, and care outcomes in general practice. Study registration This trial is registered as PROSPERO CRD42020217871. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: NIHR130694) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 7. See the NIHR Funding and Awards website for further award information.

Objectives To determine whether general practitioner (GP) workforce contributes to the link between practice funding and patient experience. Specifically, to determine whether increased practice funding is associated with better patient experience, and to what degree an increase in workforce accounts for this relationship.Setting Primary care practice level analysis of workforce, funding and patient experience of all NHS practices in England.Primary and secondary outcome measures The link between NHS-provided funding to general practice (payments per patient) and patient experience, as per the General Practice Patient Survey, was evaluated. Subsequently, mediation analysis, adjusted for covariates, was used to scrutinise the extent to which GP workforce accounts for this relationship (measured as the number of GPs per 10 000 patients).Participants We included all general practices in England for which there was relevant data for each primary variable. Atypical practices were excluded, such as those with a patient list size of 0 or where the workforce variable was recorded as being more than 3 SD from the mean. After exclusion, 6139 practices were included in the final analysis.Results We found that workforce (GPs per 10 000 population) significantly (p

Abstract Real-time magnetic resonance image guided stereotactic ablative radiotherapy (MRgSBRT) is used to treat abdominal tumors. Longitudinal data is generated from daily setup images. Our study aimed to identify delta radiomic texture features extracted from these images to predict for local control in patients with liver tumors treated with MRgSBRT. Retrospective analysis of an IRB-approved database identified patients treated with MRgSBRT for primary liver and secondary metastasis histologies. Daily low field strength (0.35 T) images were retrieved, and the gross tumor volume was identified on each image. Next, images’ gray levels were equalized, and 39 s-order texture features were extracted. Delta-radiomics were calculated as the difference between feature values on the initial scan and after delivered biological effective doses (BED, α/β = 10) of 20 Gy and 40 Gy. Then, features were ranked by the Gini Index during training of a random forest model. Finally, the area under the receiver operating characteristic curve (AUC) was estimated using a bootstrapped logistic regression with the top two features. We identified 22 patients for analysis. The median dose delivered was 50 Gy in 5 fractions. The top two features identified after delivery of BED 20 Gy were gray level co-occurrence matrix features energy and gray level size zone matrix based large zone emphasis. The model generated an AUC = 0.9011 (0.752–1.0) during bootstrapped logistic regression. The same two features were selected after delivery of a BED 40 Gy, with an AUC = 0.716 (0.600–0.786). Delta-radiomic features after a single fraction of SBRT predicted local control in this exploratory cohort. If confirmed in larger studies, these features may identify patients with radioresistant disease and provide an opportunity for physicians to alter management much sooner than standard restaging after 3 months. Expansion of the patient database is warranted for further analysis of delta-radiomic features.

Abstract For prostate cancer (PCa) patients treated with definitive radiotherapy (RT), acute and late RT-related genitourinary (GU) toxicities adversely impact disease-specific quality of life. Early warning of potential RT toxicities can prompt interventions that may prevent or mitigate future adverse events. During intensity modulated RT (IMRT) of PCa, daily cone-beam computed tomography (CBCT) images are used to improve treatment accuracy through image guidance. This work investigated the performance of CBCT-based delta-radiomic features (DRF) models to predict acute and sub-acute International Prostate Symptom Scores (IPSS) and Common Terminology Criteria for Adverse Events (CTCAE) version 5 GU toxicity grades for 50 PCa patients treated with definitive RT. Delta-radiomics models were built using logistic regression, random forest for feature selection, and a 1000 iteration bootstrapping leave one analysis for cross validation. To our knowledge, no prior studies of PCa have used DRF models based on daily CBCT images. AUC of 0.83 for IPSS and greater than 0.7 for CTCAE grades were achieved as early as week 1 of treatment. DRF extracted from CBCT images showed promise for the development of models predictive of RT outcomes. Future studies will include using artificial intelligence and machine learning to expand CBCT sample sizes available for radiomics analysis.

Cognitive decline can be observed due to a myriad of causes. Clinicians would benefit from a noninvasive quantitative tool to screen and monitor brain function based on direct measures of neural features. In this study, we used neuroimaging data from magnetoencephalography (with a whole-head Elekta Neuromag 306 sensor system) to derive a set of features that strongly correlate with brain function. We propose that simple signal characteristics related to peak variability, timing, and abundance can be used by clinicians as a screening tool to investigate cognitive function in at-risk individuals. Using a minimalistic set of features, we were able to perfectly distinguish between participants with normative and nonnormative brain function, and we were also able to successfully predict participants’ Mini-Mental Test score (r=0.99; P

Abstract Regularized regression analysis is a mature analytic approach to identify weighted sums of variables predicting outcomes. We present a novel Coarse Approximation Linear Function (CALF) to frugally select important predictors and build simple but powerful predictive models. CALF is a linear regression strategy applied to normalized data that uses nonzero weights + 1 or − 1. Qualitative (linearly invariant) metrics to be optimized can be (for binary response) Welch (Student) t-test p-value or area under curve (AUC) of receiver operating characteristic, or (for real response) Pearson correlation. Predictor weighting is critically important when developing risk prediction models. While counterintuitive, it is a fact that qualitative metrics can favor CALF with ± 1 weights over algorithms producing real number weights. Moreover, while regression methods may be expected to change most or all weight values upon even small changes in input data (e.g., discarding a single subject of hundreds) CALF weights generally do not so change. Similarly, some regression methods applied to collinear or nearly collinear variables yield unpredictable magnitude or the direction (in p-space) of the weights as a vector. In contrast, with CALF if some predictors are linearly dependent or nearly so, CALF simply chooses at most one (the most informative, if any) and ignores the others, thus avoiding the inclusion of two or more collinear variables in the model.

Using active tumor-targeting nanoparticles, fluorescence imaging can provide highly sensitive and specific tumor detection, and precisely guide radiation in translational radiotherapy study. However, the inevitable presence of non-specific nanoparticle uptake throughout the body can result in high levels of heterogeneous background fluorescence, which limits the detection sensitivity of fluorescence imaging and further complicates the early detection of small cancers. In this study, background fluorescence emanating from the baseline fluorophores was estimated from the distribution of excitation light transmitting through tissues, by using linear mean square error estimation. An adaptive masked-based background subtraction strategy was then implemented to selectively refine the background fluorescence subtraction. First, an in vivo experiment was performed on a mouse intratumorally injected with passively targeted fluorescent nanoparticles, to validate the reliability and robustness of the proposed method in a stringent situation wherein the target fluorescence was overlapped with the strong background. Then, we conducted in vivo studies on 10 mice which were inoculated with orthotopic breast tumors and intravenously injected with actively targeted fluorescent nanoparticles. Results demonstrated that active targeting combined with the proposed background subtraction method synergistically increased the accuracy of fluorescence molecular imaging, affording sensitive tumor detection.

Increasing water-soluble carbohydrate (WSC) content in white clover is important for improving nutritional quality and reducing environmental impacts from pastoral agriculture. Elucidation of genes responsible for foliar WSC variation would enhance genetic improvement by enabling molecular breeding approaches. The aim of the present study was to identify single nucleotide polymorphisms (SNPs) associated with variation in foliar WSC in white clover. A set of 935 white clover individuals, randomly sampled from five breeding pools selectively bred for divergent (low or high) WSC content, were assessed with 14,743 genotyping-by-sequencing SNPs, using three outlier detection methods: PCAdapt, BayeScan and KGD-FST. These analyses identified 33 SNPs as discriminating between high and low WSC populations and putatively under selection. One SNP was located in the intron of ERD6-like 4, a gene coding for a sugar transporter located on the vacuole membrane. A genome-wide association study using a subset of 605 white clover individuals and 5,757 SNPs, identified a further 12 SNPs, one of which was associated with a starch biosynthesis gene, glucose-1-phosphate adenylyltransferase, glgC. Our results provide insight into genomic regions underlying WSC accumulation in white clover, identify candidate genomic regions for further functional validation studies, and reveal valuable information for marker-assisted or genomic selection in white clover.

Abstract This study provides a quantitative assessment of the accuracy of a commercially available deformable image registration (DIR) algorithm to automatically generate prostate contours and additionally investigates the robustness of radiomic features to differing contours. Twenty-eight prostate cancer patients enrolled on an institutional review board (IRB) approved protocol were selected. Planning CTs (pCTs) were deformably registered to daily cone-beam CTs (CBCTs) to generate prostate contours (auto contours). The prostate contours were also manually drawn by a physician. Quantitative assessment of deformed versus manually drawn prostate contours on daily CBCT images was performed using Dice similarity coefficient (DSC), mean distance-to-agreement (MDA), difference in center-of-mass position (ΔCM) and difference in volume (ΔVol). Radiomic features from 6 classes were extracted from each contour. Lin’s concordance correlation coefficient (CCC) and mean absolute percent difference in radiomic feature-derived data (mean |%Δ|RF) between auto and manual contours were calculated. The mean (± SD) DSC, MDA, ΔCM and ΔVol between the auto and manual prostate contours were 0.90 ± 0.04, 1.81 ± 0.47 mm, 2.17 ± 1.26 mm and 5.1 ± 4.1% respectively. Of the 1,010 fractions under consideration, 94.8% of DIRs were within TG-132 recommended tolerance. 30 radiomic features had a CCC > 0.90 and 21 had a mean |%∆|RF

Objectives The purpose of this systematic review is to explore the effectiveness of the National Health Inequality Strategy, which was conducted in England between 1999 and 2010.Design Three databases (Ovid Medline, Embase and PsycINFO) and grey literature were searched for articles published that reported on changes in inequalities in health outcomes in England over the implementation period. Articles published between January 1999 and November 2021 were included. Title and abstracts were screened according to an eligibility criteria. Data were extracted from eligible studies, and risk of bias was assessed using the Risk of Bias in Non-randomized Studies of Interventions tool.Results The search strategy identified 10 311 unique studies, which were screened. 42 were reviewed in full text and 11 were included in the final review. Six studies contained data on inequalities of life expectancy or mortality, four on disease-specific mortality, three on infant mortality and three on morbidities. Early government reports suggested that inequalities in life expectancy and infant mortality had increased. However, later publications using more accurate data and more appropriate measures found that absolute and relative inequalities had decreased throughout the strategy period for both measures. Three of four studies found a narrowing of inequalities in all-cause mortality. Absolute inequalities in mortality due to cancer and cardiovascular disease decreased, but relative inequalities increased. There was a lack of change, or widening of inequalities in mental health, self-reported health, health-related quality of life and long-term conditions.Conclusions With respect to its aims, the strategy was broadly successful. Policymakers should take courage that progress on health inequalities is achievable with long-term, multiagency, cross-government action.Trial registration number This study was registered in PROSPERO (CRD42021285770).

Introduction Smoking is harmful to human health and programmes to help people stop smoking are key public health efforts that improve individual and population health outcomes. Research shows that financial incentives improve the success of stop smoking programmes. However, a better understanding of how they work is needed to better inform policy and to support building capability for implementation.The aims of this study: (1) To review the international literature to understand: How, why, in what circumstances and for whom financial incentives improve the success of stop smoking interventions among general population groups and among pregnant women. (2) To provide recommendations for how to best use financial incentives in efforts to promote smoking cessation.Methods and analysis A realist review of published international literature will be undertaken to understand how, why, for whom and in which circumstances financial incentives contribute to success in stopping smoking for general population groups and among pregnant women. Systematic searches were undertaken on 16 February 2022 of five academic databases: MEDLINE (ovid), Embase.com, CIHAHL, Scopus and PsycINFO. Iterative searching using citation tracking and of grey literature will be undertaken as needed. Using Pawson and Tilley’s iterative realist review approach, data collected will be screened, selected, coded, analysed and synthesised into a set of explanatory theoretical findings.Ethics and dissemination Ethical approval is not required for this review as data sources to be included are previously published. The study will provide important findings for policy-makers and health system leaders to guide the development of stop smoking services which use incentives, for example, as part of the Health Service Executive’s Tobacco Free Programme in Ireland. Understanding how contextual factors impact implementation and programmatic success is key to developing a more effective public health approach to stop smoking. Our dissemination strategy will be developed with our stakeholders.PROSPERO registration number CRD42022298941.

Background/HypothesisMRI-guided online adaptive radiotherapy (MRI-g-OART) improves target coverage and organs-at-risk (OARs) sparing in radiation therapy (RT). For patients with locally advanced cervical cancer (LACC) undergoing RT, changes in bladder and rectal filling contribute to large inter-fraction target volume motion. We hypothesized that deep learning (DL) convolutional neural networks (CNN) can be trained to accurately segment gross tumor volume (GTV) and OARs both in planning and daily fractions’ MRI scans.Materials/MethodsWe utilized planning and daily treatment fraction setup (RT-Fr) MRIs from LACC patients, treated with stereotactic body RT to a dose of 45-54 Gy in 25 fractions. Nine structures were manually contoured. MASK R-CNN network was trained and tested under three scenarios: (i) Leave-one-out (LOO), using the planning images of N- 1 patients for training; (ii) the same network, tested on the RT-Fr MRIs of the “left-out” patient, (iii) including the planning MRI of the “left-out” patient as an additional training sample, and tested on RT-Fr MRIs. The network performance was evaluated using the Dice Similarity Coefficient (DSC) and Hausdorff distances. The association between the structures’ volume and corresponding DSCs was investigated using Pearson’s Correlation Coefficient, r.ResultsMRIs from fifteen LACC patients were analyzed. In the LOO scenario the DSC for Rectum, Femur, and Bladder was >0.8, followed by the GTV, Uterus, Mesorectum and Parametrium (0.6-0.7). The results for Vagina and Sigmoid were suboptimal. The performance of the network was similar for most organs when tested on RT-Fr MRI. Including the planning MRI in the training did not improve the segmentation of the RT-Fr MRI. There was a significant correlation between the average organ volume and the corresponding DSC (r = 0.759, p = 0.018).ConclusionWe have established a robust workflow for training MASK R-CNN to automatically segment GTV and OARs in MRI-g-OART of LACC. Albeit the small number of patients in this pilot project, the network was trained to successfully identify several structures while challenges remain, especially in relatively small organs. With the increase of the LACC cases, the performance of the network will improve. A robust auto-contouring tool would improve workflow efficiency and patient tolerance of the OART process.

PurposeThe purpose of this work is to explore delta-radiomics texture features for predicting response using setup images of pancreatic cancer patients treated with magnetic resonance image guided (MRI-guided) stereotactic ablative radiotherapy (SBRT).MethodsThe total biological effective dose (BED) was calculated for 30 patients treated with MRI-guided SBRT that delivered physical doses of 30–60 Gy in three to five fractions. Texture features were then binned into groups based upon BED per fraction by dividing BED by the number of fractions. Delta-radiomics texture features were calculated after delivery of 20 Gy BED (BED20 features) and 40 Gy BED (BED40 features). A random forest (RF) model was constructed using BED20 and then BED40 features to predict binary outcome. During model training, the Gini Index, a measure of a variable’s importance for accurate prediction, was calculated for all features, and the two features that ranked the highest were selected for internal validation. The two features selected from each bin were used in a bootstrapped logistic regression model to predict response and performance quantified using the area under the receiver operating characteristic curve (AUC). This process was an internal validation analysis.ResultsAfter RF model training, the Gini Index was highest for gray-level co-occurrence matrix-based (GLCM) sum average, and neighborhood gray tone difference matrix-based (NGTDM) busyness for BED20 features and gray-level size zone matrix-based (GLSZM) large zones low gray-level emphasis and gray-level run length matrix-based (GLRLM) run percentage was selected from the BED40-based features. The mean AUC obtained using the two BED20 features was AUC = 0.845 with the 2.5 percentile and 97.5 percentile values ranging from 0.794 to 0.856. Internal validation of the BED40 delta-radiomics features resulted in a mean AUC = 0.567 with a 2.5 and 97.5 percentile range of 0.502–0.675.ConclusionEarly changes in treatment quantified with the BED20 delta-radiomics texture features in low field images acquired during MRI-guided SBRT demonstrated better performance in internal validation than features calculated later in treatment. Further analysis of delta-radiomics texture analysis in low field MRI is warranted.

Objectives The purpose of this systematic review is to explore whether health equity audits (HEAs) are effective in improving the equity of service provision and reducing health inequalities.Design Three databases (Ovid Medline, Embase, Web of Science) and grey literature (Opengrey, Google Scholar) were systematically searched for articles published after 2000, reporting on the effectiveness of HEA. Title and abstracts were screened according to an eligibility criteria to identify studies which included a full audit cycle (eg, initial equity analysis, service changes and review). Data were extracted from studies meeting the eligibility criteria after full text review and risk of bias assessed using the ROBINS-I tool.Results The search strategy identified 596 articles. Fifteen records were reviewed in full text and three records were included in final review. An additional HEA report was identified through contact with an author. Three different HEAs were included from one peer-reviewed journal article, two published reports and one unpublished report (n=4 records on n=3 HEAs). This included 102 851 participants and over 148 practices/pharmacies (information was not recorded for all records). One study reviewed health equity impacts of HEA implementation in key indicators for coronary heart disease, type 2 diabetes and chronic obstructive pulmonary disease. Two HEAs explored Stop Smoking Services on programme access and equity. All reported some degree of reduction in health inequalities compared with prior HEA implementation. However, impact of HEA implementation compared with other concurrent programmes and initiatives was unclear. All included studies were judged to have moderate to serious risk of bias.Conclusions There is an urgent need to identify effective interventions to address health inequalities. While HEAs are recommended, we only identified limited weak evidence to support their use. More evidence is needed to explore whether HEA implementation can reduce inequalities and which factors are influencing effectiveness.Trial registration number The study was registered prior to its conduction in PROSPERO (CRD 42020218642).

Abstract Background Primary care access can be challenging for older, rural, socio-economically disadvantaged populations. Here we report the I-ACT cluster feasibility trial which aims to assess the feasibility of trial design and context-sensitive intervention to improve primary care access for this group and so expand existing theory. Methods Four general practices were recruited; three randomised to intervention and one to usual care. Intervention practices received £1500, a support manual and four meetings to develop local, innovative solutions to improve the booking system and transport. Patients aged over 64 years old and without household car access were recruited to complete questionnaires when booking an appointment or attending the surgery. Outcome measures at 6 months included: self-reported ease of booking an appointment and transport; health care use; patient activation; capability; and quality of life. A process evaluation involved observations and interviews with staff and participants. Results Thirty-four patients were recruited (26 female, eight male, mean age 81.6 years for the intervention group and 79.4 for usual care) of 1143 invited (3% response rate). Most were ineligible because of car access. Twenty-nine participants belonged to intervention practices and five to usual care. Practice-level data was available for all participants, but participant self-reported data was unavailable for three. Fifty-six appointment questionnaires were received based on 150 appointments (37.3%). Practices successfully designed and implemented the following context-sensitive interventions: Practice A: a stacked telephone system and promoting community transport; Practice B: signposting to community transport, appointment flexibility, mobility scooter charging point and promoting the role of receptionists; and Practice C: local taxi firm partnership and training receptionists. Practices found the process acceptable because it gave freedom, time and resource to be innovative or provided an opportunity to implement existing ideas. Data collection methods were acceptable to participants, but some found it difficult remembering to complete booking and appointment questionnaires. Expanded theory highlighted important mechanisms, such as reassurance, confidence, trust and flexibility. Conclusions Recruiting older participants without access to a car proved challenging. Retention of participants and practices was good but only about a third of appointment questionnaires were returned. This study design may facilitate a shift from one-size-fits-all interventions to more context-sensitive interventions. Trial registration ISRCTN18321951, Registered on 6 March 2017.

Metal nanoparticles are effective radiosensitizers that locally enhance radiation doses in targeted cancer cells. Compared with other metal nanoparticles, gold nanoparticles (GNPs) exhibit high biocompatibility, low toxicity, and they increase secondary electron scatter. Herein, we investigated the effects of active-targeting GNPs on the radiation-induced bystander effect (RIBE) in prostate cancer cells. The impact of GNPs on the RIBE presents implications for secondary cancers or spatially fractionated radiotherapy treatments. Anti-prostate-specific membrane antigen (PSMA) antibodies were conjugated with PEGylated GNPs through EDC–NHS chemistry. The media transfer technique was performed to induce the RIBE on the non-irradiated bystander cells. This study focused on the LNCaP cell line, because it can model a wide range of stages relating to prostate cancer progression, including the transition from androgen dependence to castration resistance and bone metastasis. First, LNCaP cells were pretreated with phosphate buffered saline (PBS) or PSMA-targeted GNPs (PGNPs) for 24 h and irradiated with 160 kVp X-rays (0–8 Gy). Following that, the collected culture media were filtered (sterile 0.45 µm polyethersulfone) in order to acquire PBS- and PGNP- conditioned media (CM). Then, PBS- and PGNP-CM were transferred to the bystander cells that were loaded with/without PGNPs. MTT, γ-H2AX, clonogenic assays and reactive oxygen species assessments were performed to compare RIBE responses under different treatments. Compared with 2 Gy-PBS-CM, 8 Gy-PBS-CM demonstrated a much higher RIBE response, thus validating the dose dependence of RIBE in LNCaP cells. Compared with PBS-CM, PGNP-CM exhibited lower cell viability, higher DNA damage, and a smaller survival fraction. In the presence of PBS-CM, bystander cells loaded with PGNPs showed increased cell death compared with cells that did not have PGNPs. These results demonstrate the PGNP-boosted expression and sensitivity of RIBE in prostate cancer cells.

Active targeting gold nanoparticles (AuNPs) are a very promising avenue for cancer treatment with many publications on AuNP mediated radiosensitization at kilovoltage (kV) photon energies. However, uncertainty on the effectiveness of AuNPs under clinically relevant megavoltage (MV) radiation energies hinders the clinical translation of AuNP-assisted radiation therapy (RT) paradigm. The aim of this study was to investigate radiosensitization mediated by PSMA-targeted AuNPs irradiated by a 6 MV radiation beam at different depths to explore feasibility of AuNP-assisted prostate cancer RT under clinically relevant conditions. PSMA-targeted AuNPs (PSMA-AuNPs) were synthesized by conjugating PSMA antibodies onto PEGylated AuNPs through EDC/NHS chemistry. Confocal fluorescence microscopy was used to verify the active targeting of the developed PSMA-AuNPs. Transmission electron microscopy (TEM) was used to demonstrate the intracellular biodistribution of PSMA-AuNPs. LNCaP prostate cancer cells treated with PSMA-AuNPs were irradiated on a Varian 6 MV LINAC under varying depths (2.5 cm, 10 cm, 20 cm, 30 cm) of solid water. Clonogenic assays were carried out to determine the in vitro cell survival fractions. A Monte Carlo (MC) model developed on TOPAS platform was then employed to determine the nano-scale radial dose distribution around AuNPs, which was subsequently used to predict the radiation dose response of LNCaP cells treated with AuNPs. Two different cell models, with AuNPs located within the whole cell or only in the cytoplasm, were used to assess how the intracellular PSMA-AuNP biodistribution impacts the prostate cancer radiosensitization. Then, MC-based microdosimetry was combined with the local effect model (LEM) to calculate cell survival fraction, which was benchmarked against the in vitro clonogenic assays at different depths. In vitro clonogenic assay of LNCaP cells demonstrated the depth dependence of AuNP radiosensitization under clinical megavoltage beams, with sensitization enhancement ratio (SER) of 1.14 ± 0.03 and 1.55 ± 0.05 at 2.5 cm depth and 30 cm depth, respectively. The MC microdosimetry model showed the elevated percent of low-energy photons in the MV beams at greater depth, consequently resulting in increased dose enhancement ratio (DER) of AuNPs with depth. The AuNP-induced DER reached ~5.7 and ~8.1 at depths of 2.5 cm and 30 cm, respectively. Microdosimetry based LEM accurately predicted the cell survival under 6 MV beams at different depths, for the cell model with AuNPs placed only in the cell cytoplasm. TEM results demonstrated the distribution of PSMA-AuNPs in the cytoplasm, confirming the accuracy of MC microdosimetry based LEM with modelled AuNPs distributed within the cytoplasm. We conclude that AuNP radiosensitization can be achieved under megavoltage clinical radiotherapy energies with a dependence on tumor depth. Furthermore, the combination of Monte Carlo microdosimetry and LEM will be a valuable tool to assist with developing AuNP-aided radiotherapy paradigm and drive clinical translation.

Introduction Healthcare organisations recognise the moral imperative to address inequalities in health outcomes but often lack an understanding of which types of interventions are likely to reduce them. This realist review will examine the existing evidence on the types of interventions or aspects of routine care in general practice that are likely to decrease or increase health inequalities (ie, inequality-generating interventions) across cardiovascular disease, cancer, diabetes and chronic obstructive pulmonary disease.Methods and analysis Our realist review will follow Pawson’s five iterative stages. We will start by developing an initial programme theory based on existing theories and discussions with stakeholders. To navigate the large volume of literature, we will access the primary studies through the identification of published systematic reviews of interventions delivered in general practice across the four key conditions. We will examine the primary studies included within each systematic review to identify those reporting on inequalities across PROGRESS-Plus categories. We will collect data on a range of clinical outcomes including prevention, diagnosis, follow-up and treatment. The data will be synthesised using a realist logic of analysis. The findings will be a description and explanation of the general practice interventions which are likely to increase or decrease inequalities across the major conditions.Ethics and dissemination Ethics approval is not required because this study does not include any primary research. The findings will be integrated into a series of guiding principles and a toolkit for healthcare organisations to reduce health inequalities. Findings will be disseminated through peer-reviewed publications, conference presentations and user-friendly summaries.PROSPERO registration number CRD42020217871.

Background: COVID-19 has led to rapid and widespread use of remote consultations in general practice, but the health inequalities impact remains unknown. Aim: To explore the impact of remote consultations in general practice, compared to face-to-face consultations, on utilisation and clinical outcomes across socioeconomic and disadvantaged groups. Design & setting: Systematic review. Method: The authors undertook an electronic search of MEDLINE, EMBASE, and Web of Science from inception to June 2020. The study included studies that compared remote consultations to face-to-face consultations in primary care and reported outcomes by PROGRESS Plus criteria. Risk of bias was assessed using ROBINS-I. Data were synthesised narratively. Results: Based on 13 studies that explored telephone and internet-based consultations, this review found that telephone consultations were used by younger people of working age, the very old, and non-immigrants, with internet-based consultations more likely to be used by younger people. Women consistently used more remote forms of consulting than men. Socioeconomic and ethnicity findings were mixed, with weak evidence that patients from more affluent areas were more likely to use internet-based communication. Remote consultations appeared to help patients with opioid dependence remain engaged with primary care. No studies reported on the impact on quality of care or clinical outcomes. Conclusion: Remote consultations in general practice are likely to be used more by younger, working people, non-immigrants, older patients, and women, with internet-based consultations more by younger, affluent, and educated groups. Widespread use of remote consultations should be treated with caution until the inequalities impact on clinical outcomes and quality of care is known.

Objective The objective of this study was to identify and understand the health system contexts and mechanisms that allow for homeless populations to access appropriate healthcare when needed.Design A realist review.Data sources Ovid MEDLINE, embase.com, CINAHL, ASSIA and grey literature until April 2019.Eligibility criteria for selecting studies The purpose of the review was to identify health system patterns which enable access to healthcare for people who experience homelessness. Peer-reviewed articles were identified through a systematic search, grey literature search, citation tracking and expert recommendations. Studies meeting the inclusion criteria were assessed for rigour and relevance and coded to identify data relating to contexts, mechanisms and/or outcomes.Analysis Inductive and deductive coding was used to generate context–mechanism–outcome configurations, which were refined and then used to build several iterations of the overarching programme theory.Results Systematic searching identified 330 review articles, of which 24 were included. An additional 11 grey literature and primary sources were identified through citation tracking and expert recommendation. Additional purposive searching of grey literature yielded 50 records, of which 12 were included, for a total of 47 included sources. The analysis found that healthcare access for populations experiencing homelessness is improved when services are coordinated and delivered in a way that is organised around the person with a high degree of flexibility and a culture that rejects stigma, generating trusting relationships between patients and staff/practitioners. Health systems should provide long-term, dependable funding for services to ensure sustainability and staff retention.Conclusions With homelessness on the rise internationally, healthcare systems should focus on high-level factors such as funding stability, building inclusive cultures and setting goals which encourage and support staff to provide flexible, timely and connected services to improve access.

MRI is the standard modality to assess anatomy and response to treatment in brain and spine tumors given its superb anatomic soft tissue contrast (e.g., T1 and T2) and numerous additional intrinsic contrast mechanisms that can be used to investigate physiology (e.g., diffusion, perfusion, spectroscopy). As such, hybrid MRI and radiotherapy (RT) devices hold unique promise for Magnetic Resonance guided Radiation Therapy (MRgRT). In the brain, MRgRT provides daily visualizations of evolving tumors that are not seen with cone beam CT guidance and cannot be fully characterized with occasional standalone MRI scans. Significant evolving anatomic changes during radiotherapy can be observed in patients with glioblastoma during the 6-week fractionated MRIgRT course. In this review, a case of rapidly changing symptomatic tumor is demonstrated for possible therapy adaptation. For stereotactic body RT of the spine, MRgRT acquires clear isotropic images of tumor in relation to spinal cord, cerebral spinal fluid, and nearby moving organs at risk such as bowel. This visualization allows for setup reassurance and the possibility of adaptive radiotherapy based on anatomy in difficult cases. A review of the literature for MR relaxometry, diffusion, perfusion, and spectroscopy during RT is also presented. These techniques are known to correlate with physiologic changes in the tumor such as cellularity, necrosis, and metabolism, and serve as early biomarkers of chemotherapy and RT response correlating with patient survival. While physiologic tumor investigations during RT have been limited by the feasibility and cost of obtaining frequent standalone MRIs, MRIgRT systems have enabled daily and widespread physiologic measurements. We demonstrate an example case of a poorly responding tumor on the 0.35 T MRIgRT system with relaxometry and diffusion measured several times per week. Future studies must elucidate which changes in MR-based physiologic metrics and at which timepoints best predict patient outcomes. This will lead to early treatment intensification for tumors identified to have the worst physiologic responses during RT in efforts to improve glioblastoma survival.

Abstract Background Realist approaches seek to answer questions such as ‘how?’, ‘why?’, ‘for whom?’, ‘in what circumstances?’ and ‘to what extent?’ interventions ‘work’ using context-mechanism-outcome (CMO) configurations. Quantitative methods are not well-established in realist approaches, but structural equation modelling (SEM) may be useful to explore CMO configurations. Our aim was to assess the feasibility and appropriateness of SEM to explore CMO configurations and, if appropriate, make recommendations based on our access to primary care research. Our specific objectives were to map variables from two large population datasets to CMO configurations from our realist review looking at access to primary care, generate latent variables where needed, and use SEM to quantitatively test the CMO configurations. Methods A linked dataset was created by merging individual patient data from the English Longitudinal Study of Ageing and practice data from the GP Patient Survey. Patients registered in rural practices and who were in the highest deprivation tertile were included. Three latent variables were defined using confirmatory factor analysis. SEM was used to explore the nine full CMOs. All models were estimated using robust maximum likelihoods and accounted for clustering at practice level. Ordinal variables were treated as continuous to ensure convergence. Results We successfully explored our CMO configurations, but analysis was limited because of data availability. Two hundred seventy-six participants were included. We found a statistically significant direct (context to outcome) or indirect effect (context to outcome via mechanism) for two of nine CMOs. The strongest association was between ‘ease of getting through to the surgery’ and ‘being able to get an appointment’ with an indirect mediated effect through convenience (proportion of the indirect effect of the total was 21%). Healthcare experience was not directly associated with getting an appointment, but there was a statistically significant indirect effect through convenience (53% mediated effect). Model fit indices showed adequate fit. Conclusions SEM allowed quantification of CMO configurations and could complement other qualitative and quantitative techniques in realist evaluations to support inferences about strengths of relationships. Future research exploring CMO configurations with SEM should aim to collect, preferably continuous, primary data.

This study examines in detail the use of customer-based brand equity for a tourism destination (CBBETD) as a strategic tool for use with a specific city (Bandung City, Indonesia in this instance). The CBBETD scale developed by Konecnik (2005) and empiricized by Konecnik and Gartner (2007) was successfully adapted using qualitative and quantitative refinements for the city of Bandung. A sample of 400 visitors to Bandung was surveyed, and empirical psychometric assessment was run. The scale required minor adaptations but was found to be appropriate for use in this new context. The components of customer-based brand equity for a tourism destination were found to be: awareness, image, quality and loyalty. The successful adaptation of the scale is encouraging as it provides strategic insight on strengthening destination positioning in the minds of both current and future tourists. Managerial implications and suggestions for future research are provided.

We aim to explore the barriers to accessing primary care for socio-economically disadvantaged older people in rural areas.Using a community recruitment strategy, fifteen people over 65 years, living in a rural area, and receiving financial support were recruited for semi-structured interviews. Four focus groups were held with rural health professionals. Interviews and focus groups were audio-recorded and transcribed. Thematic analysis was used to identify barriers to primary care access.Older people's experience can be understood within the context of a patient perceived set of unwritten rules or social contract-an individual is careful not to bother the doctor in return for additional goodwill when they become unwell. However, most found it difficult to access primary care due to engaged telephone lines, availability of appointments, interactions with receptionists; breaching their perceived social contract. This left some feeling unwelcome, worthless or marginalised, especially those with high expectations of the social contract or limited resources, skills and/or desire to adapt to service changes. Health professionals' described how rising demands and expectations coupled with service constraints had necessitated service development, such as fewer home visits, more telephone consultations, triaging calls and modifying the appointment system.Multiple barriers to accessing primary care exist for this group. As primary care is re-organised to reduce costs, commissioners and practitioners must not lose sight of the perceived social contract and models of care that form the basis of how many older people interact with the service.

Abstract Drugs targeting atrial‐specific ion channels, Kv1.5 or Kir3.1/3.4, are being developed as new therapeutic strategies for atrial fibrillation. However, current preclinical studies carried out in non‐cardiac cell lines or animal models may not accurately represent the physiology of a human cardiomyocyte (CM). In the current study, we tested whether human embryonic stem cell (hESC)‐derived atrial CMs could predict atrial selectivity of pharmacological compounds. By modulating retinoic acid signaling during hESC differentiation, we generated atrial‐like (hESC‐atrial) and ventricular‐like (hESC‐ventricular) CMs. We found the expression of atrial‐specific ion channel genes, KCNA5 (encoding Kv1.5) and KCNJ3 (encoding Kir 3.1), in hESC‐atrial CMs and further demonstrated that these ion channel genes are regulated by COUP‐TF transcription factors. Moreover, in response to multiple ion channel blocker, vernakalant, and Kv1.5 blocker, XEN‐D0101, hESC‐atrial but not hESC‐ventricular CMs showed action potential (AP) prolongation due to a reduction in early repolarization. In hESC‐atrial CMs, XEN‐R0703, a novel Kir3.1/3.4 blocker restored the AP shortening caused by CCh. Neither CCh nor XEN‐R0703 had an effect on hESC‐ventricular CMs. In summary, we demonstrate that hESC‐atrial CMs are a robust model for pre‐clinical testing to assess atrial selectivity of novel antiarrhythmic drugs.