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Background: Hypertension is the single leading risk factor for premature death in Sub-Saharan Africa (SSA). Prevalence is high, but awareness, treatment, and control are low. Community-centred interventions show promise for effective hypertension management, but embedding such interventions sustainably requires a good understanding of the wider context within which they are being introduced. This study aims to conduct a systematic health system assessment exploring the micro (patients/carers), meso (health care workers and facilities), and macro (broader system) contexts in rural Gambia and Kenya., Methods: This study will utilise various qualitative approaches. We will conduct (i) focus group discussions with people living with hypertensive to map a 'typical' patient journey through health systems, and (ii) in-depth interviews with patients and family carers, health care workers, decision-makers, and NCD partners to explore their experiences of managing hypertension and assess the capacity and readiness of the health systems to strengthen hypertension management. We will also review national guidelines and policy documents to map the organisation of services and guidance on hypertension management. We will use thematic analysis to analyse data, guided by the cumulative complexity model, and theories of organisational readiness and dissemination of innovations., Expected Findings: This study will describe the current context for the management of hypertension from the perspective of those involved in seeking (patients), delivering (health care workers) and overseeing (decision-makers) health services in rural Gambia and Kenya. It will juxtapose what should be happening according to health system guidance and what is happening in practice, drawing on the experiences of study participants. It will outline the various barriers to and facilitators of hypertension management, as perceived by patients, providers, and decision-makers, and the conditions that would need to be in place for effective and sustainable implementation of a community-centred intervention to improve the management of hypertension in rural settings., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Diallo BA et al.)

The Primary Health Integrated Care for Chronic Conditions (PIC4C) pilot project was launched in 2018 to strengthen prevention and control of four non-communicable conditions at primary health care level in western Kenya. We conducted a qualitative study to explore the extent to which PIC4C integrated services supported people with hypertension and/or diabetes towards timely diagnosis and referral, treatment, follow-up and adherence, from the perspective of those receiving care. Semi-structured interviews were conducted with a purposively sampled patient cohort at two time points, with the intention of capturing changes over time (total (n) = 43, completion of both interviews (n) = 37). We extracted existing survey data to describe socio-demographic characteristics and analyzed qualitative data thematically. We identified two cross-cutting contextual factors, individual's financial resources and their social situation, which shaped each stage of their interactions with PIC4C services. The PIC4C model successfully engaged people in accessing screening services to enable timely diagnosis and referred them to enter care. Free community level screening services and decentralization of care to lower level facilities reduced cost barriers for patients. However, retention in care and adherence to treatment were affected by the wider system context in which PIC4C was operating, including inconsistencies in medication availability and patients' limited financial capacity. Individually tailored advice from health care workers to work around some of these challenges supported self-management strategies. Further development of the service should focus on supporting health care workers to adopt flexible, contextually responsive approaches in order to support patients facing economic and other constraints to engage in (self) care., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Naanyu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: Evidence on reappraisals of health technologies in Germany is limited, and for rare disease treatments (RDTs), the Federal Joint Committee follows different processes (limited or regular), depending on whether an annual revenue threshold has been exceeded. Our objective is to better understand (re)appraisal processes and their outcomes for RDTs in Germany., Methods: We analyzed appraisal documents of 55 RDT indications for which an initial appraisal and a reappraisal were conducted between 2011 and 2023. We extracted information for the type of evidence, the risk of bias, the availability of additional evidence, and the change in the maturity of survival data as proxies for evidence quality. Specifically, we reviewed the reasons for conducting reappraisals, examined how evidence quality and the clinical benefit rating (CBR) differed between initial appraisals and reappraisals, and explored the association between evidence quality and (1) the CBR and (2) the change in the CBR after reappraisal., Results: Most reappraisals were conducted because the annual revenue threshold was exceeded or the initial appraisal resolution was time limited. Almost all initial appraisals used the limited process, whereas the majority of reappraisals used the regular process. The CBR increased in only 9 and decreased in 21 of 55 reappraisals. There was some evidence that reappraisals with an accepted randomized controlled trial were significantly more likely to achieve a higher CBR., Conclusions: Findings confirmed that reasons and processes for conducting reappraisals of RDTs in Germany differ. Further, high CBRs in reappraisals were not common and evidence quality in initial appraisals and reappraisals was limited., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2024. Published by Elsevier Inc.)

Background: In 2012, Luxembourg introduced a Referring Doctor (RD) policy, whereby patients voluntarily register with a primary care practitioner, who coordinates patients' health care and ensures optimal follow-up. We contribute to the limited evidence base on patient registration by evaluating the effects of the RD policy., Methods: We used data on 16,775 people with type 2 diabetes on oral medication (PWT2D), enrolled with the Luxembourg National Fund from 2010 to 2018. We examined the utilisation of primary and specialist outpatient care, quality of care process indicators, and reimbursed prescribed medicines over the short- (until 2015) and medium-term (until 2018). We used propensity score matching to identify comparable groups of patients with and without an RD. We applied difference-in-differences methods that accounted for patients' registration with an RD in different years., Results: There was low enrolment of PWT2D in the RD programme. The differences-in-differences parallel trends assumption was not met for: general practitioner (GP) consultations, GP home visits (medium-term), HbA1c test (short-term), complete cholesterol test (short-term), kidney function (urine) test (short-term), and the number of repeat prescribed cardiovascular system medicines (short-term). There was a statistically significant increase in the number of: HbA1c tests (medium-term: 0.09 (95% CI: 0.01 to 0.18)); kidney function (blood) tests in the short- (0.10 (95% CI: 0.01 to 0.19)) and medium-term (0.11 (95% CI: 0.03 to 0.20)); kidney function (urine) tests (medium-term: 0.06 (95% CI: 0.02 to 0.10)); repeat prescribed medicines in the short- (0.19 (95% CI: 0.03 to 0.36)) and medium-term (0.18 (95% CI: 0.02 to 0.34)); and repeat prescribed cardiovascular system medicines (medium-term: 0.08 (95% CI: 0.01 to 0.15)). Sensitivity analyses also revealed increases in kidney function (urine) tests (short-term: 0.07 (95% CI: 0.03 to 0.11)) and dental consultations (short-term: 0.06, 95% CI: 0.00 to 0.11), and decreases in specialist consultations (short-term: -0.28, 95% CI: -0.51 to -0.04; medium-term: -0.26, 95% CI: -0.49 to -0.03)., Conclusions: The RD programme had a limited effect on care quality indicators and reimbursed prescribed medicines for PWT2D. Future research should extend the analysis beyond this cohort and explore data linkage to include clinical outcomes and socio-economic characteristics., (© 2024. The Author(s).)

Chronic obstructive pulmonary disease (COPD) is a progressive lung disease for which there is no cure. Accumulating research results suggest a role for extracellular vesicles (EVs) in the pathogenesis of COPD. This study aimed to uncover the involvement of EVs and their molecular cargo in the progression of COPD by identification of EV-associated protein and microRNA (miRNA) profiles. We isolated EVs from the bronchial alveolar lavage fluid (BALF) of 18 patients with COPD and 11 healthy controls using size-exclusion chromatography. EV isolates were characterized using nanoparticle tracking analysis and protein content. Proteomic analysis revealed a higher abundance of 284 proteins (log2FC > 1) and a lower abundance of 3 proteins (log2FC < -1) in EVs derived from patients with COPD. Ingenuity pathway analysis showed that proteins enriched in COPD-associated EVs trigger inflammatory responses, including neutrophil degranulation. Variances in surface receptors and ligands associated with COPD EVs suggest a preferential interaction with alveolar cells. Small RNAseq analysis identified a higher abundance of ten miRNAs and a lower abundance of one miRNA in EVs from COPD versus controls (Basemean > 100, FDR < 0.05). Our data indicate that the molecular composition of EVs in the BALF of patients with COPD is altered compared to healthy control EVs. Several components in COPD EVs were identified that may perpetuate inflammation and alveolar tissue destruction.

Introduction: In Kenya, non-communicable diseases (NCDs) are estimated to account for almost one-third of all deaths and this is likely to rise by over 50% in the next 10 years. The Primary Health Integrated Care for Chronic Conditions (PIC4C) project aims to strengthen primary care by integrating comprehensive NCD care into existing HIV primary care platform. This paper evaluates the association of PIC4C implementation on clinical outcomes., Methods: Outcomes included proportion of new patients, systolic blood pressure (SBP), fasting plasma glucose (FPG), diastolic blood pressure, hypertension control, random plasma glucose, diabetes control, viral load and HIV viral suppression. We used interrupted time series and binomial regression with random effects for facility-level data and generalised mixed-effects regression for visit-level data to examine the association between PIC4C and outcomes between January 2017 and December 2021. We conducted sensitivity analysis with restrictions on sites and the number of visits., Results: Data from 66 641 visits of 13 046 patients with hypertension, 24 005 visits of 7267 patients with diabetes and 84 855 visits of 21 186 people with HIV were analysed. We found evidence of association between PIC4C and increase in proportion of new patients per month with hypertension (adjusted OR (aOR) 1.57, 95% CI 1.39 to 1.78) and diabetes (aOR 1.31, 95% CI 1.19 to 1.45), small increase in SBP (adjusted beta (aB) 1.7, 95% CI 0.8 to 2.7) and FPG (aB 0.6, 95% CI 0.0 to 1.1). There was no strong evidence of association between PIC4C and viral suppression (aOR 1.20, 95% CI 0.98 to 1.47). In sensitivity analysis, there was no strong evidence of association between PIC4C and SBP (aB 1.74, 95% CI -0.70 to 4.17) or FPG (aB 0.52, 95% CI -0.64 to 1.67)., Conclusions: PIC4C implementation was associated with increase in proportion of new patients attending clinics and a slight increase in SBP and FPG. The immediate post-PIC4C implementation period coincided with the COVID-19 pandemic, which is likely to explain some of our findings., Competing Interests: Competing interests None declared.

Purpose: Achieving greater health and social care integration is a policy priority in many countries, but challenges remain. We focused on governance and accountability for integrated care and explored arrangements that shape more integrated delivery models or systems in Italy, the Netherlands and Scotland. We also examined how the COVID-19 pandemic affected existing governance arrangements., Design/methodology/approach: A case study approach involving document review and semi-structured interviews with 35 stakeholders in 10 study sites between February 2021 and April 2022. We used the Transparency, Accountability, Participation, Integrity and Capability (TAPIC) framework to guide our analytical enquiry., Findings: Study sites ranged from bottom-up voluntary agreements in the Netherlands to top-down mandated integration in Scotland. Interviews identified seven themes that were seen to have helped or hindered integration efforts locally. Participants described a disconnect between what national or regional governments aspire to achieve and their own efforts to implement this vision. This resulted in blurred, and sometimes contradictory, lines of accountability between the centre and local sites. Flexibility and time to allow for national policies to be adapted to local contexts, and engaged local leaders, were seen to be key to delivering the integration agenda. Health care, and in particular acute hospital care, was reported to dominate social care in terms of policies, resource allocation and national monitoring systems, thereby undermining better collaboration locally. The pandemic highlighted and exacerbated existing strengths and weaknesses but was not seen as a major disruptor to the overall vision for the health and social care system., Research Limitations: We included a relatively small number of interviews per study site, limiting our ability to explore complexities within sites., Originality: This study highlights that governance is relatively neglected as a focus of attention in this context but addressing governance challenges is key for successful collaboration., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2024 The Author(s).)

Objectives: The association between labral injuries and acetabular fractures is unknown. This study aimed to identify the frequency and characteristics of labral injuries in operatively treated acetabular fractures that cannot be identified on preoperative imaging., Methods: ., Design: Prospective observational cohort., Setting: Level I trauma center., Patient Selection Criteria: Adult patients with an acetabular fracture operatively treated through a posterior approach., Outcome Measures and Comparisons: The frequency and characteristics of labral injuries., Results: Fifty-three of 71 acetabular fractures (75%; 95% confidence interval, 63%-83%) demonstrated a labral injury visible via the posterior approach. Posterior labral injuries occurred in 89% of operative acetabular fracture patterns involving the posterior wall and most commonly represent a detachment of the posteroinferior labrum (n = 39, 75%). Fractures with a labral injury were more likely to have gluteus minimus damage (93% vs. 61%, P = 0.02), femoral head lesions (38% vs. 17%, P = 0.03), joint capsule detachment (60% vs. 33%, P = 0.05), and fracture patterns involving the posterior wall (89% vs. 50%, P = 0.05)., Conclusions: This study describes the high rate (89%) of posterior labral injuries in posterior wall fractures, the most common injury pattern being a detachment of the posteroinferior labrum. Labral injuries in acetabular fractures may have important clinical implications and this study is the first to identify the frequency and characteristics of these injuries. Further studies should assess the relationship between labral injuries, treatment strategies, and the progression to post-traumatic osteoarthritis., Level of Evidence: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: N. N. O'Hara receives stock or stock options from Arbutus Medical, Inc. unrelated to this research. G. P. Slobogean receives research funding from the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health, and serves as a paid consultant with Smith & Nephew and Zimmer, all unrelated to this research. R. V. O’Toole serves as a paid consultant with Stryker, receives stock options from Imagen, and receives royalties from Lincotek, all unrelated to this research. The remaining authors report no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Primary care is widely seen as a core component of resilient and sustainable health systems, yet its efficiency is not well understood and there is a lack of evidence about how primary care efficiency is associated with health system characteristics. We examine this issue through the lens of diabetes care, which has a well-established evidence base for effective treatment and has previously been used as a tracer condition to measure health system performance., Methods: We developed a conceptual framework to guide the analysis of primary care efficiency. Using data on 18 European countries during 2010-2016 from several international databases, we applied a two-stage data envelopment analysis to estimate (i) technical efficiency of primary care and (ii) the association between efficiency and health system characteristics., Results: Countries varied widely in terms of primary care efficiency, with efficiency scores depending on the range of population characteristics adjusted for. Higher efficiency was associated with bonus payments for the prevention and management of chronic conditions, nurse-led follow-up, and a financial incentive or requirement for patients to obtain a referral to specialist care. Conversely, lower efficiency was associated with higher rates of curative care beds and financial incentives for patients to register with a primary care provider., Conclusions: Our results underline the importance of considering differences in population characteristics when comparing country performance on primary care efficiency. We highlight several policies that could enhance the efficiency of primary care. Improvements in data collection would enable more comprehensive assessments of primary care efficiency across countries, which in turn could more effectively inform policymaking., (© 2023. The Author(s).)

Background: Cancer is a leading cause of premature mortality globally. This study estimates premature deaths at ages 30-69 years and distinguishes these as deaths that are preventable (avertable through primary or secondary prevention) or treatable (avertable through curative treatment) in 185 countries worldwide., Methods: For this population-based study, estimated cancer deaths by country, cancer, sex, and age groups were retrieved from the International Agency for Research on Cancer's GLOBOCAN 2020 database. Crude and age-adjusted cancer-specific years of life lost (YLLs) were calculated for 36 cancer types., Findings: Of the estimated all-ages cancer burden of 265·6 million YLLs, 182·8 million (68·8%) YLLs were due to premature deaths from cancer globally in 2020, with 124·3 million (68·0%) preventable and 58·5 million (32·0%) treatable. Countries with low, medium, or high human development index (HDI) levels all had greater proportions of YLLs at premature ages than very high HDI countries (68·9%, 77·0%, and 72·2% vs 57·7%, respectively). Lung cancer was the leading contributor to preventable premature YLLs in medium to very high HDI countries (17·4% of all cancers, or 29·7 million of 171·3 million YLLs), whereas cervical cancer led in low HDI countries (26·3% of all preventable cancers, or 1·83 million of 6·93 million YLLs). Colorectal and breast cancers were major treatable cancers across all four tiers of HDI (25·5% of all treatable cancers in combination, or 14·9 million of 58·5 million YLLs)., Interpretation: Alongside tailored programmes of early diagnosis and screening linked to timely and comprehensive treatment, greater investments in risk factor reduction and vaccination are needed to address premature cancer inequalities., Funding: Erasmus Mundus Exchange Programme and the International Agency for Research on Cancer., Translations: For the German, French, Spanish and Chinese translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Cell culture-conditioned medium (CCM) is a valuable source of extracellular vesicles (EVs) for basic scientific, therapeutic and diagnostic applications. Cell culturing parameters affect the biochemical composition, release and possibly the function of CCM-derived EVs (CCM-EV). The CCM-EV task force of the Rigor and Standardization Subcommittee of the International Society for Extracellular Vesicles aims to identify relevant cell culturing parameters, describe their effects based on current knowledge, recommend reporting parameters and identify outstanding questions. While some recommendations are valid for all cell types, cell-specific recommendations may need to be established for non-mammalian sources, such as bacteria, yeast and plant cells. Current progress towards these goals is summarized in this perspective paper, along with a checklist to facilitate transparent reporting of cell culturing parameters to improve the reproducibility of CCM-EV research., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Authors. Journal of Extracellular Biology published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.)

Objectives: To assess the responsiveness of the National Health Insurance Fund (NHIF) Supa Cover benefit package to the needs of individuals with diabetes and hypertension in Kenya., Design, Setting and Participants: We carried out a qualitative study and collected data using key informant interviews (n=39) and focus group discussions (n=4) in two purposively selected counties in Western Kenya. Study participants were drawn from NHIF officials, county government officials, health facility managers, healthcare workers and individuals with hypertension and diabetes who were enrolled in NHIF. We analysed data using a thematic approach., Results: Study participants reported that the NHIF Supa Cover benefit package expanded access to services for people living with hypertension and diabetes. However, the NHIF members and healthcare workers had inadequate awareness of the NHIF service entitlements. The NHIF benefit package inadequately covered the range of services needed by people living with hypertension and diabetes and the benefits package did not prioritise preventive and promotive services. Sometimes patients were discriminated against by healthcare providers who preferred cash-paying patients, and some NHIF-empanelled health facilities had inadequate structural inputs essential for quality of care. Study participants felt that the NHIF premium for the general scheme was unaffordable, and NHIF members faced additional out-of-pocket costs because of additional payments for services not available or covered., Conclusion: Whereas NHIF has reduced financial barriers for hypertension and diabetes patients, to enhance its responsiveness to patient needs, NHIF should implement mechanisms to increase benefit package awareness among members and providers. In addition, preventive and promotive services should be included in NHIF's benefits package and mechanisms to monitor and hold contracted providers accountable should be strengthened., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: The workload health and social care service users and caregivers take on, and their capacity to do this work is important. It may play a key part in shaping the implementation of innovations in health service delivery and organisation; the utilisation and satisfaction with services; and the outcomes of care. Previous research has often focused on experiences of a narrow range of long-term conditions, and on factors that shape adherence to self-care regimes., Aims: With the aim of deriving policy and practice implications for service redesign, this evidence synthesis will extend our understanding of service user and caregiver workload and capacity by comparing how they are revealed in qualitative studies of lived experience of three kinds of illness trajectories: long-term conditions associated with significant disability (Parkinson's disease, schizophrenia); serious relapsing remitting disease (Inflammatory Bowel Disease, bipolar disorder); and rapidly progressing acute disease (brain cancer, early onset dementia)., Methods: We will review and synthesise qualitative studies of lived experience of participation in health and social care that are shaped by interactions between experienced treatment burdens, social inequalities and illness trajectories. The review will involve:   1.  Construction of a theory-informed coding manual; systematic search of bibliographic databases to identify, screen and quality assess full-text papers.   2.  Analysis of papers using manual coding techniques, and text mining software; construction of taxonomies of service user and caregiver work and capacity.   3.  Designing a model of core components and identifying common factors across conditions, trajectories, and contexts.   4.  Work with practitioners, and a Patient and Public Involvement (PPI) group, to explore the validity of the models produced; to develop workload reduction strategies; and to consider person-centred service design., Dissemination: We will promote workload reduction models to support service users and caregivers and produce policy briefs and peer-reviewed publications for practitioners, policy-makers, and researchers., Competing Interests: No competing interests were disclosed., (Copyright: © 2023 May CR et al.)

In Kenya, non-communicable diseases (NCDs) are an increasingly important cause of morbidity and mortality, requiring both better access to health care services and self-care support. Evidence suggests that treatment burdens can negatively affect adherence to treatment and quality of life. In this study, we explored the treatment and self-management burden among people with NCDs in in two counties in Western Kenya. We conducted a cross-sectional survey of people newly diagnosed with diabetes and/or hypertension, using the Patient Experience with Treatment and Self-Management (PETS) instrument. A total of 301 people with diabetes and/or hypertension completed the survey (63% female, mean age = 57 years). They reported the highest treatment burdens in the domains of medical and health care expenses, monitoring health, exhaustion related to self-management, diet and exercise/physical therapy. Treatment burden scores differed by county, age, gender, education, income and number of chronic conditions. Younger respondents (<60 years) reported higher burden for medication side effects (p<0.05), diet (p<0.05), and medical appointments (p = 0.075). Those with no formal education or low income also reported higher burden for diet and for medical expenses. People with health insurance cover reported lower (albeit still comparatively high) burden for medical expenses compared to those without it. Our findings provide important insights for Kenya and similar settings where governments are working to achieve universal health coverage by highlighting the importance of financial protection not only to prevent the economic burden of seeking health care for chronic conditions but also to reduce the associated treatment burden., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Koros et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Over the last decade, research interest in defining how extracellular vesicles (EVs) shape cross-species communication has grown rapidly. Parasitic helminths, worm species found in the phyla Nematoda and Platyhelminthes, are well-recognised manipulators of host immune function and physiology. Emerging evidence supports a role for helminth-derived EVs in these processes and highlights EVs as an important participant in cross-phylum communication. While the mammalian EV field is guided by a community-agreed framework for studying EVs derived from model organisms or cell systems [e.g., Minimal Information for Studies of Extracellular Vesicles (MISEV)], the helminth community requires a supplementary set of principles due to the additional challenges that accompany working with such divergent organisms. These challenges include, but are not limited to, generating sufficient quantities of EVs for descriptive or functional studies, defining pan-helminth EV markers, genetically modifying these organisms, and identifying rigorous methodologies for in vitro and in vivo studies. Here, we outline best practices for those investigating the biology of helminth-derived EVs to complement the MISEV guidelines. We summarise community-agreed standards for studying EVs derived from this broad set of non-model organisms, raise awareness of issues associated with helminth EVs and provide future perspectives for how progress in the field will be achieved., (© 2023 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)

Cancer policy differences might help to explain international variation in cancer survival, but empirical evidence is scarce. We reviewed cancer policies in 20 International Cancer Benchmarking Partnership jurisdictions in seven countries and did exploratory analyses linking an index of cancer policy consistency over time, with monitoring and implementation mechanisms, to survival from seven cancers in a subset of ten jurisdictions from 1995 to 2014. All ten jurisdictions had structures in place to oversee or deliver cancer control policies and had published at least one major cancer plan. Few cancer plans had explicit budgets for implementation or mandated external evaluation. Cancer policy consistency was positively correlated with improvements in survival over time for six of the seven cancer sites. Jurisdictions that scored the highest on policy consistency had large improvements in survival for most sites. Our analysis provides an important first step to systematically capture and evaluate what are inherently complex policy processes. The findings can help guide policy makers seeking approaches and frameworks to improve cancer services and, ultimately, cancer outcomes., Competing Interests: Decleration of interests ML reports having received honoraria unrelated to to this work from Bayer, Carnall Farrar, Novartis, Pfizer, and Roche. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The differences in cancer survival across countries and over time are well recognised, with progress varying even among high-income countries with comparable health systems. Previous research has examined several possible explanations, but the role of leadership in systems providing cancer care has attracted little attention. As part of the International Cancer Benchmarking Partnership (ICBP), this study looked at diverse aspects of leadership to identify drivers of change and opportunities for improvement across seven high-income countries., Methods: Key informants in 13 jurisdictions were interviewed: Australia (2 states), Canada (3 provinces), Denmark, Ireland, New Zealand, Norway and United Kingdom (4 countries). Participants represented a range of stakeholders at different tiers of the system. They were recruited through a combination of purposive and 'snowball' strategies and participated in semi-structured telephone interviews. Interview transcripts were analysed thematically drawing on the World Health Organization (WHO) health systems framework and previous work analysing national cancer control programmes (NCCPs)., Results: Several facets of leadership were perceived as important for improving outcomes. These included political leadership to initiate and maintain progress, intellectual leadership to support those engaged in local implementation of national policies and drive change, and a coherent vision from leaders at different levels of the system. Clinical leadership was also viewed as vital for translating policy into action., Conclusion: Certain aspects of cancer care leadership emerged as underpinning and sustaining improvements, such as appointing a central agency, involving clinicians at every stage, ensuring strong leadership of cancer care with a consistent political mandate. Improving cancer outcomes is challenging and complex, but it is unlikely to be achieved without effective leadership, both political and clinical., (© 2022 The Author(s); Published by Kerman University of Medical Sciences This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Background: Differences in cancer survival are shaped by differences in health system capacity in workforce and infrastructure. Part of the International Cancer Benchmarking Partnership (ICBP), this study explored stakeholders' perceptions of the role of health system capacity necessary for cancer care in influencing cancer survival in 7 high-income countries., Methods: We conducted semi-structured interviews with 79 key informants from national, regional, and local tiers of health systems, professional bodies, patient associations, and academic experts in Australia, Canada, Denmark, Ireland, New Zealand, Norway, and the United Kingdom. Data collection was guided by a conceptual model linking characteristics of health systems and cancer survival along the cancer patient journey, from recognition of symptoms at pre-diagnostic stages through to survivorship or death. Data were analysed using a thematic approach., Results: We identified 3 themes as important in shaping cancer outcomes: primary care and access to diagnostic evaluation, specialist care and access to treatment, and workforce pertaining to diagnostic and treatment phases. Improved infrastructure for diagnosis and treatment had improved cancer outcomes in all jurisdictions. However, this was seen as insufficient if staffing was inadequate. Consolidation of services and greater surgical specialisation was important in some jurisdictions if accompanied by a reconfiguration of services, in particular the creation of specialist multidisciplinary teams, along with supporting capacity in the wider health system. Staff shortages were commonly cited as reasons why some jurisdictions lagged behind others., Conclusion: Continued improvement in cancer outcomes will require sustained investment in plans to deliver and maintain the workforce engaged in cancer care and in the infrastructure on which they depend. However, strategic plans must recognise that systems for cancer care do not work in isolation from the rest of the health system and a whole systems approach is essential if we are to improve outcomes for an ageing, increasingly multimorbid population., (© 2022 The Author(s); Published by Kerman University of Medical Sciences This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Competing Interests: Declaration of interests KH, DB, NB, DE and TP-J were funded by a grant from the Bill & Melinda Gates Foundation. DH has received funding from the Bill & Melinda Gates Foundation for various activities at UNICEF, including on health system strengthening and community health, both of which are mentioned in this report. In the period during which the report was developed, AE and HWa were employed by the Bill & Melinda Gates Foundation and were involved in data analysis, interpretation and writing of the report. All other authors declared no conflict of interest.

Introduction: Amid the rising number of people with non-communicable diseases (NCDs), Kenya has invested in strengthening primary care and in efforts to expand existing service delivery platforms to integrate NCD care. One such approach is the AMPATH (Academic Model Providing Access to Healthcare) model in western Kenya, which provides the platform for the Primary Health Integrated Care Project for Chronic Conditions (PIC4C), launched in 2018 to further strengthen primary care services for the prevention and control of hypertension, diabetes, breast and cervical cancer. This study seeks to understand how well PIC4C delivers on its intended aims and to inform and support scale up of the PIC4C model for integrated care for people with NCDs in Kenya., Methods and Analysis: The study is guided by a conceptual framework on implementing, sustaining and spreading innovation in health service delivery. We use a multimethod design combining qualitative and quantitative approaches, involving: (1) in-depth interviews with health workers and decision-makers to explore experiences of delivering PIC4C; (2) a cross-sectional survey of patients with diabetes or hypertension and in-depth interviews to understand how well PIC4C meets patients' needs; (3) a cohort study with an interrupted time series analysis to evaluate the degree to which PIC4C leads to health benefits such as improved management of hypertension or diabetes; and (4) a cohort study of households to examine the extent to which the national hospital insurance chronic care package provides financial risk protection to people with hypertension or diabetes within PIC4C., Ethics and Dissemination: The study has received approvals from Moi University Institutional Research and Ethics Committee (FAN:0003586) and the London School of Hygiene & Tropical Medicine (17940). Workshops with key stakeholders at local, county, national and international levels will ensure early and wide dissemination of our findings to inform scale up of this model of care. We will also publish findings in peer-reviewed journals., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Skin/nipple-sparing mastectomies (SSM/NSSM) have been reported to have acceptable complication rates and good aesthetic outcomes with high patient satisfaction. However, in this relatively young and rapidly expanding field of reconstructive plastic surgery, differences in perioperative management are noted between breast centers. Prospective studies of complication rates using a titanized polypropylene mesh (TiLOOP® Bra) are currently lacking., Methods: A prospective subgroup analysis was performed based on the data set of the prospective, single-arm, multicenter observational study (PRO-BRA). Early complication rates after skin/nipple-sparing mastectomy with implant-based immediate or secondary reconstruction using a titanized polypropylene mesh (TiLOOP® Bra) subpectorally were investigated in relation to demographic factors, as well as intra-and postoperative management. The subgroup consists of 258 patients. Complications were categorised into necrosis, infection, postoperative bleeding or hematoma, seroma, wound healing delays and R1-situations., Results: Early complication rates of SSM/NSSM using titanium-based meshes are comparable to complication-rates using ADM's. Logistic regression shows significantly higher risk for wound healing delays, necrosis and seroma with increasing BMI, abladat- and implant-weight (OR 1,17 -1,66, p-value < 0,001). Smokers have significantly higher necrosis rates (20.7%) compared to non-smokers (5.5%) (p-value = 0.002). Discharge with drainage results in a trend toward higher rates of wound healing complications., Conclusion: The use of TiLOOP® Bra meshes was shown to have acceptable complication rates. Complication rates depend on certain demographic and intraoperative risk factors and should be considered in indications and information of patients., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Diabetic peripheral neuropathy (DPN) is a complication of diabetes whose pathophysiology is linked to altered mitochondrial bioenergetics (mtBE). KU-596 is a small molecule neurotherapeutic that reverses symptoms of DPN, improves sensory neuron mtBE, and decreases the pro-oxidant protein, thioredoxin-interacting protein (Txnip) in a heat shock protein 70 (Hsp70)-dependent manner. However, the mechanism by which KU-596 improves mtBE and the role of Txnip in drug efficacy remains unknown. Mitophagy is a quality-control mechanism that selectively targets damaged mitochondria for degradation. The goal of this study was to determine if KU-596 therapy improved DPN, mtBE, and mitophagy in an Hsp70- and Txnip-dependent manner. Mito-QC (MQC) mice express a mitochondrially targeted mCherry-GFP fusion protein that enables visualizing mitophagy. Diabetic MQC, MQC × Hsp70 knockout (KO), and MQC × Txnip KO mice developed sensory and nerve conduction dysfunctions consistent with the onset of DPN. KU-596 therapy improved these measures, and this was dependent on Hsp70 but not Txnip. In MQC mice, diabetes decreased mtBE and increased mitophagy and KU-596 treatment reversed these effects. In contrast, KU-596 was unable to improve mtBE and decrease mitophagy in MQC × Hsp70 and MQC × Txnip KO mice. These data suggest that Txnip is not necessary for the development of the sensory symptoms and mitochondrial dysfunction induced by diabetes. KU-596 therapy may improve mitochondrial tolerance to diabetic stress to decrease mitophagic clearance in an Hsp70- and Txnip-dependent manner.

The search for novel anti-cancer compounds which can circumvent chemotherapeutic drug resistance and limit systemic toxicity remains a priority. 2-Ethyl-3- O -sulphamoyl-estra-1,3,5(10)15-tetraene-3-ol-17one (ESE-15-one) and 2-ethyl-3- O -sulphamoyl-estra-1,3,5(10)16-tetraene (ESE-16) are sulphamoylated 2-methoxyestradiol (2-ME) analogues designed by our research team. Although their cytotoxicity has been demonstrated in vitro, the temporal and mechanistic responses of the initiated intracellular events are yet to be determined. In order to do so, assays investigating the compounds' effects on microtubules, cell cycle progression, signalling cascades, autophagy and apoptosis were conducted using HeLa cervical- and MDA-MB-231 metastatic breast cancer cells. Both compounds reversibly disrupted microtubule dynamics as an early event by binding to the microtubule colchicine site, which blocked progression through the cell cycle at the G 1 /S- and G 2 /M transitions. This was supported by increased pRB and p27 Kip1 phosphorylation. Induction of apoptosis with time-dependent signalling involving the p-JNK, Erk1/2 and Akt/mTOR pathways and loss of mitochondrial membrane potential was demonstrated. Inhibition of autophagy attenuated the apoptotic response. In conclusion, the 2-ME analogues induced a time-dependent cross-talk between cell cycle checkpoints, apoptotic signalling and autophagic processes, with an increased reactive oxygen species formation and perturbated microtubule functioning appearing to connect the processes. Subtle differences in the responses were observed between the two compounds and the different cell lines.

Background: Since a national lockdown was introduced across the UK in March, 2020, in response to the COVID-19 pandemic, cancer screening has been suspended, routine diagnostic work deferred, and only urgent symptomatic cases prioritised for diagnostic intervention. In this study, we estimated the impact of delays in diagnosis on cancer survival outcomes in four major tumour types., Methods: In this national population-based modelling study, we used linked English National Health Service (NHS) cancer registration and hospital administrative datasets for patients aged 15-84 years, diagnosed with breast, colorectal, and oesophageal cancer between Jan 1, 2010, and Dec 31, 2010, with follow-up data until Dec 31, 2014, and diagnosed with lung cancer between Jan 1, 2012, and Dec 31, 2012, with follow-up data until Dec 31, 2015. We use a routes-to-diagnosis framework to estimate the impact of diagnostic delays over a 12-month period from the commencement of physical distancing measures, on March 16, 2020, up to 1, 3, and 5 years after diagnosis. To model the subsequent impact of diagnostic delays on survival, we reallocated patients who were on screening and routine referral pathways to urgent and emergency pathways that are associated with more advanced stage of disease at diagnosis. We considered three reallocation scenarios representing the best to worst case scenarios and reflect actual changes in the diagnostic pathway being seen in the NHS, as of March 16, 2020, and estimated the impact on net survival at 1, 3, and 5 years after diagnosis to calculate the additional deaths that can be attributed to cancer, and the total years of life lost (YLLs) compared with pre-pandemic data., Findings: We collected data for 32 583 patients with breast cancer, 24 975 with colorectal cancer, 6744 with oesophageal cancer, and 29 305 with lung cancer. Across the three different scenarios, compared with pre-pandemic figures, we estimate a 7·9-9·6% increase in the number of deaths due to breast cancer up to year 5 after diagnosis, corresponding to between 281 (95% CI 266-295) and 344 (329-358) additional deaths. For colorectal cancer, we estimate 1445 (1392-1591) to 1563 (1534-1592) additional deaths, a 15·3-16·6% increase; for lung cancer, 1235 (1220-1254) to 1372 (1343-1401) additional deaths, a 4·8-5·3% increase; and for oesophageal cancer, 330 (324-335) to 342 (336-348) additional deaths, 5·8-6·0% increase up to 5 years after diagnosis. For these four tumour types, these data correspond with 3291-3621 additional deaths across the scenarios within 5 years. The total additional YLLs across these cancers is estimated to be 59 204-63 229 years., Interpretation: Substantial increases in the number of avoidable cancer deaths in England are to be expected as a result of diagnostic delays due to the COVID-19 pandemic in the UK. Urgent policy interventions are necessary, particularly the need to manage the backlog within routine diagnostic services to mitigate the expected impact of the COVID-19 pandemic on patients with cancer., Funding: UK Research and Innovation Economic and Social Research Council., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Implant-based or expander-supported breast reconstruction is an established surgical method after mastectomies due to cancer or to prophylactic reasons. Patient reported outcome (PRO) and cosmetic outcome after breast reconstruction with a synthetic surgical mesh was investigated in a prospective, single-arm, multi-center study., Material and Methods: Primary or secondary implant-based breast reconstruction with support of TiLOOP® Bra was performed in 269 patients during the PRO-BRA study. PRO 12 months after breast reconstruction was evaluated using Breast-Q questionnaire. Cosmetic outcome was evaluated by two independent experts by means of pictures taken preoperatively and at the follow-up visits., Results: Breast-Q and 12 months FU were completed by 210 women. Patients without adverse event had a significantly higher Breast-Q score for "sexual well-being" (p = 0.001); "psychosocial well-being" was negatively influenced by prior therapies (p < 0.01), and older patients had significantly lower scores at 12 months FU compared to pre-OP for "satisfaction with breasts" (p < 0.01) while the opposite was true for younger patients. Unilateral surgery resulted in reduced "satisfaction with breast" at 12 months FU (p < 0.01). Radiotherapy negatively influenced "satisfaction with breast", "sexual well-being" and "physical well-being chest". The cosmetic evaluation showed a significant difference (p < 0.001) in the evaluation by the patients and experts with the patients' assessment being worse compared to experts' assessment., Conclusion: Our study showed that two years after implant-based breast reconstruction with support of TiLOOP® Bra PRO is influenced by different factors. This information can be used to improve the decision-making process for women who chose implant-based breast reconstruction., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The co-expression of miRNAs and their target proteins was studied on tissue microarrays from different prostate cancer (PCa) patients. PCa of primary Gleason pattern 4 (GP4), lymph node metastases of GP4, distant metastases, and normal tissue from the transitional and peripheral zones were co-stained by fluorescent miRNA in situ hybridization (miRisH) and protein immunohistofluorescence (IHF). The miRNAs and corresponding target proteins include the pairs miR-145/ERG, miR-143/uPAR, and miR-375/SEC23A. The fluorescence-stained and scanned tissue microarrays (TMAs) were evaluated by experienced uropathologists. The pair miR-145/ERG showed an exclusive staining for miR-145 in the nuclei of stromal cells, both in tumor and normal tissue, and for ERG in the cytoplasm with/without co-expression in the nucleus of tumor cells. The pair miR-143/uPAR revealed a clear distinction between miR-143 in the nuclei of stromal cells and uPAR staining in the cytoplasm of tumor cells. Metastases (lymph node and distant) however, showed tumor cells with cytoplasmic staining for miR-143/uPAR. In normal tissues, beside the nuclei of the stroma cells, gland cells could also express miR-143 and uPAR in the cytoplasm. miR-375 showed particular staining in the nucleoli of GP4 and metastatic samples, suggesting that nucleoli play a special role in sequestering proteins and miRNAs. Combined miRisH/IHF allows for the study of miRNA expression patterns and their target proteins at the single-cell level.

MIR143 is pathologically downregulated and may function as a tumor suppressor in prostate cancer. Likewise, the urokinase plasminogen activator receptor (UPAR) is overexpressed in prostate carcinoma, representing a negative prognostic marker and putative therapeutic target gene. In this paper, we establish UPAR as a new direct target of MIR143. Luciferase reporter gene constructs identify one of the two in silico-predicted binding sites as functionally relevant for direct MIR143 binding to the 3' UTR, and, concomitantly, transfection of MIR143 reduces UPAR protein levels in prostate carcinoma cells in vitro. Inhibitory effects on cell proliferation and colony formation, spheroid growth and integrity, and cell viability are extensively analyzed, and they are compared to direct small interfering RNA (siRNA)-mediated uPAR knockdown or combined microRNA (miRNA)-siRNA treatment. Switching to a therapeutically more relevant in vivo model, we demonstrate tumor-inhibitory effects of MIR143 replacement therapy by systemic treatment of mice bearing subcutaneous PC-3 tumor xenografts with MIR143 formulated in polymeric nanoparticles. This efficient, nanoparticle-mediated delivery of intact MIR143 mediates the marked downregulation of uPAR protein, but not mRNA levels, thus indicating translational inhibition rather than mRNA degradation. In summary, we identify UPAR as a direct target gene of MIR143, and we establish the therapeutic anti-tumor potential of nanoparticle-based MIR143 replacement in prostate cancer., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Multimorbidity, the simultaneous presence of multiple health conditions in an individual, is an increasingly common phenomenon globally. The systematic assessment of the quality of care delivered to people with multimorbidity will be key to informing the organization of services for meeting their complex needs. Yet, current assessments tend to focus on single conditions and do not capture the complex processes that are required for providing care for people with multimorbidity. We conducted a scoping review on quality of care and multimorbidity in selected databases in June 2018 and identified 87 documents as eligible for review, predominantly original research and reviews from North America, Europe and Australasia and mostly frequently related to primary care settings. We synthesized data qualitatively in terms of perceived challenges, evidence and proposed metrics. Findings reveal that the association between quality of care and multimorbidity is complex and depends on the conditions involved (quality appears to be higher for those with concordant conditions, and lower in the presence of discordant conditions) and the approach used for measuring quality (quality appears to be higher in people with multimorbidity when measured using condition/drug-specific process or intermediate outcome indicators, and worse when using patient-centred reports of experiences of care). People with discordant multimorbidity may be disadvantaged by current approaches to quality assessment, particularly when they are linked to financial incentives. A better understanding of models of care that best meet the needs of this group is needed for developing appropriate quality assessment frameworks. Capturing patient preferences and values and incorporate patients' voices in the form of patient-reported experiences and outcomes of care will be critical towards the achievement of high-performing health systems that are responsive to the needs of people with multimorbidity., (© 2019 The Association for the Publication of the Journal of Internal Medicine.)

The extent to which government should partner with business interests such as the alcohol, food, and other industries in order to improve public health is a subject of ongoing debate. A common approach involves developing voluntary agreements with industry or allowing them to self-regulate. In England, the most recent example of this was the Public Health Responsibility Deal (RD), a public⁻private partnership launched in 2011 under the then Conservative-led coalition government. The RD was organised around a series of voluntary agreements that aim to bring together government, academic experts, and commercial, public sector and voluntary organisations to commit to pledges to undertake actions of public health benefit. This paper brings together the main findings and implications of the evaluation of the RD using a systems approach. We analysed the functioning of the RD exploring the causal pathways involved and how they helped or hindered the RD; the structures and processes; feedback loops and how they might have constrained or potentiated the effects of the RD; and how resilient the wider systems were to change (i.e., the alcohol, food, and other systems interacted with). Both the production and uptake of pledges by RD partners were largely driven by the interests of partners themselves, enabling these wider systems to resist change. This analysis demonstrates how and why the RD did not meet its objectives. The findings have lessons for the development of effective alcohol, food and other policies, for defining the role of unhealthy commodity industries, and for understanding the limits of industry self-regulation as a public health measure.

Microtubules are cytoskeletal fibers formed by the assembly of α- and β-tubulin heterodimers. They contribute to cell morphology, mobility and polarity, as well as to cellular transport processes and cell division. The microtubular network constantly adapts to cellular needs and may be composed of very dynamic or more stable microtubules. To regulate their diverse functions in a spatio-temporal manner, microtubules are subjected to numerous reversible post-translational modifications, which generate the "tubulin code". This review focuses on two modifications characteristic of stable microtubules - acetylation and detyrosination of α-tubulin - and their deregulation in certain pathologies., (© 2018 médecine/sciences – Inserm.)