Healthy Cities Phase V evaluation: further synthesizing realism

In this article we reflect on the quality of a realist synthesis paradigm applied to the evaluation of Phase V of the WHO European Healthy Cities Network. The programmatic application of this approach has led to very high response rates and a wealth of important data. All articles in this Supplement report that cities in the network move from small-scale, time-limited projects predominantly focused on health lifestyles to the significant inclusion of policies and programmes on systems and values for good health governance. The evaluation team felt that, due to time and resource limitations, it was unable to fully exploit the potential of realist synthesis. In particular, the synthetic integration of different strategic foci of Phase V designation areas did not come to full fruition. We recommend better and more sustained integration of realist synthesis in the practice of Healthy Cities in future Phase

Variations and value improvement in back pain care in one area of England

Abstract The pursuit of value and equity have been put on a legal footing in the NHS with the arrival of the legal duty for all in the NHS to improve health and well-being of the population served, to provide fair access to high quality healthcare, and to use resources sustainably and efficiently. Recognising this we used analysis of variation to help us understand the degree to which we were fulfilling our new duty for people with back pain in Mid-Nottinghamshire and where there might be opportunities for value improvement. MSK Together is a group of clinical and managerial representatives from providers, purchasers, local government, and patients who work collectively to optimise the use of resources for people with MSK conditions in Mid-Nottinghamshire. Back pain is the third largest burden of disease in the locality, and the largest cause of disability, so it is of strategic importance to MSK Together—we wanted to know about, and act on, opportunities for value improvement across the population of people with back pain. In 2019/20, after adjusting for age and sex, we found a greater than three-fold variation among general practices in age-sex standardised rates of all hospital service usage for back pain conditions. When looking at a four-year period (2016/17–2019/20), the observed variation increased to eight-fold for (with narrow 95% confidence intervals). When looking at procedures (e.g., surgery or injections), the standardised variation among general practices was six-fold in 2019/20. The deprivation score of the general practice (a heterogenous measure given the mixed neighbourhoods many general practices serve) showed little correlation to the rates observed and did not appear to justify the variation. When we looked at the deprivation of the neighbourhood from which the individuals receiving back pain procedures came, there appeared to be a weak correlation in terms of lower rates of intervention in the least-deprived compared with the most-deprived communities. This correlation was not tested statistically. People receiving hospital services for back pain appeared to receive the first episode of care most often in their 40s (working age), compared with people from the least-deprived areas who received care most commonly in their 60s (approaching retirement). When we looked at the interventions provided in Mid-Nottinghamshire for back pain, 29 interventions were provided to 17,225 people. Using a recent NICE evaluation of cost-effectiveness of back pain interventions, we established that, of these 29 interventions, 16 have evidence of improving the quality of life, for nine there was no evidence of benefit or harm, for three there was evidence that they do not provide an improvement in quality of life, and for one there was possible evidence of harm. The total cost of interventions was estimated at £4.5 million and, using the evidence from the NICE review, the total quality adjusted life year (QALY) gain to the treated population of people with back pain was calculated to be 4,571 QALYs. After discussions among the MSK Together group, it was agreed that some interventions could be stopped or scaled down, and new interventions introduced (in particular, in more-deprived neighbourhoods). Within the same estimated cost envelope of £4.5 million, the QALY gain was predicted to increase to 7702 QALYs and, by targeting QALY-related interventions to people from deprived neighbourhoods, reduce inequity (and therefore health inequalities). Using variation helped us identify areas for improvement and generated a momentum for change among the MSK Together group. By examining what we were doing, the associated costs, and the likely QALY benefits (from research evidence), we identified lower value interventions to stop or reduce and new interventions to introduce, achieving greater health gain for people with back pain with no additional resource requirements

Wraparound: the health impact assessment of the all-inclusive Wraparound scheme

This report describes the process, findings and recommendations of the Health Impact Assessment of the All-Inclusive Wraparound Scheme. The scheme is a three year multi-agency and multi-professional programme delivering services to children with disabilities and their families and carers in the Southern Health and Social Services Board, Northern Ireland

Healthy Cities Phase V evaluation: further synthesizing realism.

In this article we reflect on the quality of a realist synthesis paradigm applied to the evaluation of Phase V of the WHO European Healthy Cities Network. The programmatic application of this approach has led to very high response rates and a wealth of important data. All articles in this Supplement report that cities in the network move from small-scale, time-limited projects predominantly focused on health lifestyles to the significant inclusion of policies and programmes on systems and values for good health governance. The evaluation team felt that, due to time and resource limitations, it was unable to fully exploit the potential of realist synthesis. In particular, the synthetic integration of different strategic foci of Phase V designation areas did not come to full fruition. We recommend better and more sustained integration of realist synthesis in the practice of Healthy Cities in future Phases

Preclinical Antitumor Activity of a Novel Anti–c-KIT Antibody–Drug Conjugate against Mutant and Wild-type c-KIT–Positive Solid Tumors

Purpose: c-KIT overexpression is well recognized in cancers such as gastrointestinal stromal tumors (GIST), small cell lung cancer (SCLC), melanoma, non–small cell lung cancer (NSCLC), and acute myelogenous leukemia (AML). Treatment with the small-molecule inhibitors imatinib, sunitinib, and regorafenib resulted in resistance (c-KIT mutant tumors) or limited activity (c-KIT wild-type tumors). We selected an anti–c-KIT ADC approach to evaluate the anticancer activity in multiple disease models. Experimental Design: A humanized anti–c-KIT antibody LMJ729 was conjugated to the microtubule destabilizing maytansinoid, DM1, via a noncleavable linker (SMCC). The activity of the resulting ADC, LOP628, was evaluated in vitro against GIST, SCLC, and AML models and in vivo against GIST and SCLC models. Results: LOP628 exhibited potent antiproliferative activity on c-KIT–positive cell lines, whereas LMJ729 displayed little to no effect. At exposures predicted to be clinically achievable, LOP628 demonstrated single administration regressions or stasis in GIST and SCLC xenograft models in mice. LOP628 also displayed superior efficacy in an imatinib-resistant GIST model. Further, LOP628 was well tolerated in monkeys with an adequate therapeutic index several fold above efficacious exposures. Safety findings were consistent with the pharmacodynamic effect of neutropenia due to c-KIT–directed targeting. Additional toxicities were considered off-target and were consistent with DM1, such as effects in the liver and hematopoietic/ lymphatic system. Conclusions: The preclinical findings suggest that the c-KIT–directed ADC may be a promising therapeutic for the treatment of mutant and wild-type c-KIT–positive cancers and supported the clinical evaluation of LOP628 in GIST, AML, and SCLC patients