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Abstract Background Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory condition. Given patients with COPD continue to experience exacerbations despite the availability of effective therapies, anti-inflammatory treatments targeting novel pathways are needed. Kinases, notably the phosphoinositide 3-kinases (PI3K), are thought to be involved in chronic airway inflammation, with this pathway proposed as a critical regulator of inflammation and oxidative stress response in COPD. CHF6523 is an inhaled PI3Kδ inhibitor that has shown positive preclinical results. This manuscript reports the results of a study of CHF6523 in patients with stable COPD (chronic bronchitis phenotype), and who had evidence of type-2 inflammation. Methods This randomised, double-blind, placebo-controlled, two-way crossover study comprised two 28-day treatment periods separated by a 28-day washout. Patients (N = 44) inhaled CHF6523 in one period, and placebo in the other, both twice daily. The primary objective was to assess the safety and tolerability of CHF6523; the secondary objective was to assess CHF6523 pharmacokinetics. Exploratory endpoints included target engagement (the relative reduction in phosphatidylinositol (3,4,5)-trisphosphate [PIP3]), pharmacodynamic evaluations such as airflow obstruction, and hyperinflation, and to identify biomarker(s) of drug response using proteomics and transcriptomics. Results CHF6523 plasma pharmacokinetics were characterised by an early maximum concentration (Cmax), reached 15 and 10 min after dosing on Days 1 and 28, respectively, followed by a rapid decline. Systemic exposure on Day 28 showed limited accumulation, with ratios

Background As a matter of policy, voluntary, community and social enterprises contribute substantially to the English health and care system. Few studies explain how the National Health Service and local authorities commission them, what outputs result, what contexts influence these outcomes and what differentiates this kind of commissioning. Objectives To explain how voluntary, community and social enterprises are commissioned, the consequences, what barriers both parties face and what absorptive capacities they need. Design Observational mixed-methods realist analysis: exploratory scoping, cross-sectional analysis of National Health Service Clinical Commissioning Group spending on voluntary, community and social enterprises, systematic comparison of case studies, action learning. Social prescribing, learning disability support and end-of-life care were tracers. Setting Maximum-variety sample of six English local health and care economies, 2019–23. Participants Commissioning staff; voluntary, community and social enterprise members. Interventions None; observational study. Main outcome measures How the consequences of commissioning compared with the original aims of the commissioners and the voluntary, community and social enterprises: predominantly qualitative (non-measurable) outcomes. Data sources Data sources were: 189 interviews, 58 policy and position papers, 37 items of rapportage, 692,659 Clinical Commissioning Group invoices, 102 Freedom of Information enquiries, 131 survey responses, 18 local project group meetings, 4 national action learning set meetings. Data collected in England during 2019–23. Results Two modes of commissioning operated in parallel. Commodified commissioning relied on creating a principal–agent relationship between commissioner and the voluntary, community and social enterprises, on formal competitive selection (‘procurement’) of providers. Collaborative commissioning relied on ‘embedded’ interorganisational relationships, mutual recognition of resource dependencies, a negotiated division of labour between organisations, and control through persuasion. Commissioners and voluntary, community and social enterprises often worked around the procurement regulations. Both modes were present everywhere but the balance depended inter alia on the number and size of voluntary, community and social enterprises in each locality, their past commissioning experience, the character of the tracer activity, and the level of deprivation and the geographic dispersal of the populations served. The COVID-19 pandemic produced a shift towards collaborative commissioning. Voluntary, community and social enterprises were not always funded at the full cost of their activity. Integrated Care System formation temporarily disrupted local co-commissioning networks but offered a longer-term prospect of greater voluntary, community and social enterprise influence on co-commissioning. To develop absorptive capacity, commissioners needed stronger managerial and communication capabilities, and voluntary, community and social enterprises needed greater capability to evidence what outcomes their proposals would deliver. Limitations Published data quality limited the spending profile accuracy, which did not include local authority commissioning. Case studies did not cover London, and focused on three tracer activities. Absorptive capacity survey was not a random sample. Conclusions The two modes of commissioning sometimes conflicted. Workarounds arose from organisations’ embeddedness and collaboration, which the procurement regulations often disrupted. Commissioning activity at below its full cost appears unsustainable. Future work Spending profiles of local authority commissioning; analysis of commissioning in London and of activities besides the present tracers. Analysis of absorptive capacity and its consequences, adjusting the concept for application to voluntary, community and social enterprises. Comparison with other health systems’ commissioning of voluntary, community and social enterprises. 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: NIHR128107) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 39. See the NIHR Funding and Awards website for further award information. Plain language summary National Health Service commissioners and local councils often buy health and care services from voluntary, community and social enterprises. This study aimed to explore how commissioners and voluntary, community and social enterprises worked together and where improvements could be made. We talked to commissioners and voluntary, community and social enterprises in six areas across England and focused on services for learning disabilities, social prescribing and end-of-life care. We analysed National Health Service financial accounts to see how much the National Health Service was spending on services provided by voluntary, community and social enterprises. We surveyed how commissioners and voluntary, community and social enterprises were using information and knowledge to make decisions. We organised events bringing together commissioners and voluntary, community and social enterprises to share knowledge and experience. We found there were two ways commissioners bought services from voluntary, community and social enterprises. One was commodified (a buying-and-selling model), the other collaborative (based on working together). Both were happening at the same time in all the areas of the study, but usually one of them was more present than the other. We saw a general move towards collaboration, but some areas were further along with this than others. Various things helped commissioners and voluntary, community and social enterprises collaborate, such as: paying voluntary, community and social enterprises enough for their services; having people and networks that encouraged others to work with voluntary, community and social enterprises; and including voluntary, community and social enterprises in making decisions about health and care. Commissioners and voluntary, community and social enterprises might therefore lean further towards working together to see how collaborative commissioning can be further developed; how to make contract prices cover voluntary, community and social enterprises’ costs; how to enable longer-term contracts; and how to enable less hurried, more considered ways of renewing contracts (e.g. by putting draft contract specifications out to pre-tender consultation). The new Integrated Care Systems in local areas could encourage all this to happen, but pressures elsewhere in the health and care sector might make it more difficult. Scientific summary Background This study examines how the NHS and local authorities commissioned voluntary, community and social enterprises (VCSEs); some outcomes for commissioners, VCSEs and the health system; and which contexts affected these outcomes. Existing studies describe how the public funding of independent providers occurs through a commissioning cycle of service specification, provider selection, contract-letting and monitoring of the activities actually delivered. The original policy (and theoretical) formulations of this cycle presupposed a clear separation of commissioners from providers. In practice, however, the cycle is partly implemented, and attenuated, by co-commissioning activities, collaborations in which potential providers, citizens and the public contribute at each stage. Commissioning has been explained as, inter alia, a means by which governments continued to exercise governance (not direct control) over independent providers of public-funded services through six main media of power: managerial techniques, negotiated order, discursive control, resource dependencies, provider competition, and juridical control. Each particular combination constitutes a ‘mode of commissioning’. Previous studies have examined the modes of commissioning applied elsewhere, but not to VCSEs, and then usually from the standpoint of policy-makers’ aims and intended service outcomes of commissioning. Fewer studies have explored commissioning from the VCSE standpoint. Some that did reported largely negative consequences for the commissioned VCSEs: a loss of freedom to criticise policy and a ‘degeneration’ of the VCSEs’ democratic internal regimes. Still fewer studies have closely examined the interactions between commissioners and VCSEs as they engage in the commissioning cycle and in co-commissioning. The practical import of these questions is whether the commissioning of health-related VCSEs enables them to supplement the reach of NHS activities and strengthen users’ voice in the health system, or whether it undermines the characteristics of VCSEs which first motivated the commissioning of them. Because commissioning involves two main groups of agents, their interactions involve not just one but two context–mechanism–outcome configurations (CMOCs). In one, the commissioners are the focal actor (as in most realist evaluations); in the other, VCSEs are. The two configurations intersect at the commissioning mechanisms, where the parties interact. Earlier studies suggested that the parties’ absorptive capacity (ACAP) to acquire, assimilate, transform and exploit externally sourced knowledge was an important context affecting what interactions occurred, and to what effect. Objectives This study aimed to produce knowledge about which factors strengthen (or weaken) collaboration between healthcare commissioners and VSCEs, and make commissioning relationships between the commissioners and VCSEs more productive for all. Research questions were: RQ1. How do healthcare commissioners address the task of commissioning VCSEs as service providers, and what barriers do they face? RQ2. What are the consequences for VCSEs of the public bodies commissioning services from them? RQ3. How are VCSEs involved in Clinical Commissioning Group (CCG), local authority and other [e.g. Integrated Care System (ICS), NHS England] commissioning decisions? RQ4. What ACAPs do healthcare commissioners and VCSEs respectively need for enabling VCSEs to be commissioned, and for co-commissioning? Methods This study was a mixed-methods realist analysis of the mechanisms by which English health-related VCSEs are commissioned. To investigate the intersecting CMOCs, we used five main methods: Preliminary scoping work with national-level NHS and VCSE organisations to identify important current developments in this domain and likely data sources, based on interviews and content analysis of policy documents. A cross-sectional profile of CCG spending on VCSEs, which provided data about patterns of VCSE commissioning and was a sampling frame for the three following work packages. We content-analysed 226,138 CCG invoices (for sums over £25k) from 2018 to 2019 to discover the distribution of CCG spending on VCSEs and how it compared with CCG spending on non-VCSE providers. Using findings from the preceding work packages, we drew a sample of six places contrasted by their proportion of spending on VCSEs. We systematically compared case studies of VCSE–commissioner collaboration in formulating local commissioning strategies (‘co-commissioning’) in them (2020–2). Commissioners’ and VCSEs’ aims when engaging in commissioning were examined separately for either side, as were the outcomes relevant to each, but not the structures and activities through which they interacted. A systematic comparison of case studies of the commissioning of VCSEs, using the same study sites, methods and unit of analysis as the preceding work package (late 2020 to summer 2022). Action learning activities (2020–3) in the same sites: Local project reference groups supported the project in each study site and combined as: national action learning workshops a preliminary, exploratory (not randomised sample) survey of ACAP in the study sites local co-researchers who conducted local research projects into the commissioning of VCSEs and whom the research team mentored As tracer studies we examined social prescribing, end-of-life care and support for learning disabilities, on the assumption that this selection gave variety in the scale and number of VCSEs involved, and type of activity (clinical vs. preventive). Framework analyses were used to synthesise the five sets of findings and map them onto the research questions. Results Two modes of commissioning VCSEs existed in parallel: A commodified mode centred on the commissioning cycle, financial dependencies, formalised procurement [a regulatory (i.e. juridically based) practice] and provider competition. Consulted VCSEs were often excluded at either service specification or provider selection stage in the cycle. The financial dependency of VCSEs was a central medium of power for commissioners. Juridical power was in the background but seldom used in practice. The paradigm form of this mechanism was a direct bilateral principal–agent relationship between one commissioner and one VCSE, with the latter wielding less power. This was a commodified mode of commissioning. To reduce their transaction work (costs), commissioners were introducing larger contracts (e.g. with one large ‘lead’ provider subcontracting many smaller VCSEs). Networks for negotiating what activities were commissioned and how they were implemented. Commissioners and VCSEs were both embedded in these networks, which constituted an interorganisational negotiated order among commissioners, among VCSEs, and between commissioners and VCSEs. Persuasion and legitimation were the main discursive media of power, supplemented by relationality (mutual trust) and mutual ‘real-side’ (as opposed to financial) resource dependency. Workarounds such as alliance and lead provider commissioning were important media of managerial power, adopted in order to diminish the expected, and in some cases observed, adverse consequences of commodified commissioning. VCSEs’ commissioning and co-commissioning activities overlapped considerably. The networking mechanisms supplemented and attenuated the quasi-market mechanisms, and indeed were partly intended to. This was a collaborative mode of commissioning. It was not that where one mode of commissioning existed, the other did not; both coexisted and interacted everywhere but the balance between them varied. Certain contexts affected how these mechanisms worked in practice: Local health and care system characteristics: Fiscal constraints upon commissioners constrained how much VCSE activity could be commissioned, compelled commissioners to prioritise VCSE activities that appeared to offer immediate cost savings elsewhere in the health system, and destabilised VCSE income. Diverse ownership mix of provider organisations (e.g. in learning disability services) motivated more cautious, commodified commissioning insofar as commissioners anticipated challenges to their decisions from unsuccessful bidders. Having a small number of stable VCSEs (e.g. in end-of-life care) enabled and necessitated collaborative commissioning. Geographical and historical characteristics: Population deprivation motivated commissioners and VCSEs to respond through collaborative commissioning. Spatial dispersion increased the practical difficulty and costs of, and the number of networks involved in, collaborative commissioning. Co-terminosity of commissioners minimised the number of interorganisational interfaces that the networks had to span. Local policies, ethos and history strongly influenced whether collaboration and trust between commissioners and VCSEs was long-established, and thus how collaborative commissioning could be. The presence and nature of networking spaces, in particular which VCSEs participated, and how much voice they had when they did participate, affected how collaborative co-commissioning could be. Organisational characteristics: ACAP affected commissioners’ ability to know what resources VCSEs could offer, and what VCSEs were aiming for, in becoming involved in commissioning, and vice versa. Commissioners relied on formal sources of information and evidence more than VCSEs tended to. Discursive (translation) gaps between VCSEs and commissioners were widespread. Organisational systems, culture and bureaucracy: the more narrowly procurement regulations were interpreted and implemented, the more commissioning was commodified rather than collaborative. Individuals’ role, discretion and influence: individuals who lobbied for VCSEs to engage, or be engaged, in commissioning and who were boundary-spanners with knowledge of both commissioning and VCSEs facilitated the development of collaborative commissioning, as did ‘maverick’ individuals who devised workarounds when procurement regulations appeared to obstruct the commissioning of VCSEs, especially collaborative commissioning. The nature of VCSE activity: Statutory or non-statutory status: statutory requirements for service provision exposed commissioners’ resource dependence on VCSEs, which led to more collaborative, flexible commissioning. Tracer group characteristics: tracer groups’ characteristics affected commissioning partly through the above contexts; that is, whether VCSEs were few and large (e.g. hospices) or the opposite (social prescribing); undertaking statutorily mandated activity (e.g. hospices, some learning disability support). The degree of specialisation of VCSE work affected the number and mix of providers. Stability of demand for a VCSE’s activity favoured more collaborative commissioning. A temporal context: the COVID-19 pandemic shifted the commissioning of VCSEs substantially towards a more collaborative mode, and this change had not fully reverted. The outcomes of these mechanisms included some that approximated to commissioners’ and VCSEs’ respective aims in using the above commissioning mechanisms. For commissioners the main outcomes were to obtain the use of VCSE resources, sometimes at below the full cost of provision. It was often claimed that VCSE activities had relieved, or would relieve, pressure on NHS services, but firm evidence was scarce. Commissioning VCSEs also offered a way for commissioners to pilot test possible innovations (e.g. for self-help in maintaining health) and a ready-made route to access patient, carer and public opinions. For VCSEs the main outcome was income, although the income flow was often unstable, which made it hard to retain paid staff, and below the cost of their activities. Some VCSEs also increased their voice in the local health system, but we also found a large periphery of VCSEs that did not participate in the networks described above and were not commissioned. We found a more nuanced picture than previous studies’ account of the internal ‘degeneration’ of VCSEs as a result of being commissioned. Most VCSEs reported little change to their aims or ‘mission’, and some had increased the professionalism of their management. We also found emergent, unforeseen outcomes. There was a general shift towards collaborative commissioning away from commodified commissioning, but it made the discursive gap between commissioners and VCSEs more apparent. The undercosting of some VCSE activities amounted to a hidden subsidy to commissioners from VCSEs. VCSE activities added a new category of public health activities, those of preventive self-care at a personal and family level, to the longer-established models of clinical prevention (vaccination, etc.) and the ‘new’ public health (legislative and policy changes, e.g. food labelling controls). ICS formation tended to disrupt co-commissioning networks in the short term, but offered a longer-term prospect of greater VCSE input into co-commissioning. Conclusions By research question: RQ1. Commissioners used two commissioning mechanisms in parallel. Each embodied a different kind of governance structure and a different mode of commissioning. Centred on the commissioning cycle, the quasi-market mechanisms implemented a heavily commodified mode of commissioning whose paradigm was a principal–agent relationship between commissioner and VCSE. The networking mechanisms of collaborative commissioning consisted of a triple negotiated order: networking among commissioners, networking among VCSEs and networking between commissioners and VCSEs. A barrier to using this hybrid mechanism was that at certain points in the commissioning cycle, especially provider selection, the mechanisms conflicted. Unfavourable contexts were other barriers: more specialised VCSE activities, dependence on a few individuals, non-coterminous commissioners, possible competition from corporate and public providers, population dispersal and fiscal austerity. RQ2. For VCSEs, consequences of being commissioned depended on the mode of commissioning but were mainly some extension of VCSE activities, including advocacy; marginal adjustments (not drift) in mission; and additional funding, but often unstable and below the full cost of these activities. RQ3. VCSE involvement in co-commissioning occurred through networking rather than quasi-market mechanisms. VCSEs with long-established working relationships with commissioners were often the ones involved, and were often larger VCSEs. Small local VCSEs were involved vicariously through their participation in VCSE infrastructure bodies or networks which were more directly involved, but a large periphery of small VCSEs remained outside these networks. RQ4. The ACAPs that commissioners needed were a combination of managerial and communication skills: to routinise ‘acquiring’ and ‘assimilating’ information from VCSEs; to specify calls for practical proposals or bids from VCSEs so as to elicit responses from suitable VCSEs; and then to apply (‘exploit’) information and ideas from VCSEs in ways that did not then penalise the VCSEs which provided them (e.g. by excluding them from tendering). VCSEs needed to develop the capacities to supply evidence, both hard and soft intelligence, about why they wished to supplement or amend commissioners’ assumptions and proposals, and to express what outcomes their proposals would offer, what metrics could be used to verify that, and more generally how the VCSE’s proposals would add social value. In ACAP terms, the commissioners appeared to need to develop their knowledge acquisition and exploitation capacities especially, while VCSEs needed to develop their knowledge acquisition and transformation capacities. Implications for health and care Below-cost funding for VCSE activity is not sustainable in the long term because VCSE activities require paid-for inputs, even when volunteer labour is used. The instability of VCSE income from commissioners contributed to VCSE staff turnover. If it continues, commissioners’ move towards longer contracts implies that a stratification and concentration of the VCSE side of the quasi-market may occur. Research recommendations are, in descending priority order, for research to: Quantify the impacts of VCSE activity on demand on NHS services. Extend our analysis of NHS commissioner spending on health-related VCSE activity to include local authority spending, and longitudinally. Test whether our findings apply to the commissioning of large (cross-England) VCSEs engaged in health-related activity. Assess the nature, effects and development of ACAP in commissioners and VCSEs by means that combine representative sample surveys (e.g. using the survey instrument developed for this study) and deeper analysis of the specific mechanisms by which ACAP affects commissioning practice. 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: NIHR128107) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 39. See the NIHR Funding and Awards website for further award information.

**Background**: Synkinesis may develop following facial nerve palsy, impacting quality of life. Botulinum toxin treatment for synkinesis is commonly used, but buccinator muscle injection is less common. We aim to investigate buccinator botulinum toxin for management of synkinesis. **Methods**: Patients received botulinum toxin to synkinetic areas (standard botulinum toxin) with physiotherapy. Four months later they were re-treated at the same sites, with addition of buccinator injections. After both treatments, outcomes were measured using the Facial Disability Index and Synkinesis Assessment Questionnaire at baseline and five weeks later (four assessments in total). **Results**: Twenty-seven patients were recruited, 25 completing standard botulinum toxin treatment and 20 completing standard and buccinator botulinum toxin. Standard botulinum toxin showed improvements in the Synkinesis Assessment Questionnaire (63.5 v 50.3, _p_

Abstract Background QuADRANT was a study funded by the European Commission to evaluate clinical audit uptake and implementation across Europe, with an emphasis on clinical audit as mandated within the BSSD (Basic Safety Standards Directive). AIMS QuADRANT objectives—obtain an overview of European clinical audit activity; identify good practices and resources, barriers and challenges; provide guidance and recommendations going forwards; identify the potential for European Union action on quality and safety in the three core project specialties, radiology, radiotherapy and nuclear medicine. Findings and recommendations QuADRANT identified that developments in national clinical audit infrastructure are required. National professional societies can be pivotal in improving clinical audit implementation, but resource allocation and national prioritisation of clinical audit are needed in many countries. Lack of staff time and expertise are also barriers. Enablers to enhance clinical audit participation are not widely employed. Development of hospital accreditation programmes can facilitate clinical audit uptake. An active and formalised role for patients in clinical audit practice and policy development is recommended. There is persisting variation in European awareness of BSSD clinical audit requirements. Work is needed to improve dissemination of information on the legislative requirements relating to clinical audit in the BSSD and in relation to inspection processes to ensure these include clinical audit and that they encompass all clinics and specialties involved in medical applications using ionising radiation. Conclusion QuADRANT provides an important step towards enhancing clinical audit uptake and implementation across Europe and improving patient safety and outcomes.

Primary Hodgkin lymphoma of the central nervous system is an exceedingly rare condition with very few cases reported in the literature. Isolated intradural involvement of the spine is rarer still, with only two prior cases located in the extramedullary cervical and lumbosacral spine. We present a 48-year-old female who was presented with back pain, radiculopathy and a short history of sphincter disturbance and was subsequently found to have a lobulated homogenously enhancing exophytic lesion involving the conus medullaris and cauda equina on magnetic resonance imaging. Histopathological examination demonstrated the features of classic Hodgkin lymphoma. In this report, we present a case of primary intramedullary Hodgkin lymphoma involving the conus medullaris and cauda equina.

The lipid kinase VPS34 orchestrates diverse processes, including autophagy, endocytic sorting, phagocytosis, anabolic responses and cell division. VPS34 forms various complexes that help adapt it to specific pathways, with complexes I and II being the most prominent ones. We found that physicochemical properties of membranes strongly modulate VPS34 activity. Greater unsaturation of both substrate and non-substrate lipids, negative charge and curvature activate VPS34 complexes, adapting them to their cellular compartments. Hydrogen/deuterium exchange mass spectrometry (HDX-MS) of complexes I and II on membranes elucidated structural determinants that enable them to bind membranes. Among these are the Barkor/ATG14L autophagosome targeting sequence (BATS), which makes autophagy-specific complex I more active than the endocytic complex II, and the Beclin1 BARA domain. Interestingly, even though Beclin1 BARA is common to both complexes, its membrane-interacting loops are critical for complex II, but have only a minor role for complex I.

Germinal centres (GCs) are T follicular helper cell (Tfh)-dependent structures that form in response to vaccination, producing long-lived antibody secreting plasma cells and memory B cells that protect against subsequent infection. With advancing age the GC and Tfh cell response declines, resulting in impaired humoral immunity. We sought to discover what underpins the poor Tfh cell response in ageing and whether it is possible to correct it. Here, we demonstrate that older people and aged mice have impaired Tfh cell differentiation upon vaccination. This deficit is preceded by poor activation of conventional dendritic cells type 2 (cDC2) due to reduced type 1 interferon signalling. Importantly, the Tfh and cDC2 cell response can be boosted in aged mice by treatment with a TLR7 agonist. This demonstrates that age-associated defects in the cDC2 and Tfh cell response are not irreversible and can be enhanced to improve vaccine responses in older individuals.

Antibody mediated immune responses to Streptococcus pneumoniae are crucial for the immune response to infection. Here the authors show hyper-activation of PI3Kδ promotes development of a subset of B cells that exacerbate infection in an antibody-independent manner and can be reversed by therapeutic targeting in vivo.

Histone post-translational modifications are known key regulators of gene expression. Here, the authors characterize histone crotonylation at histone H3 lysine 18 in intestinal epithelia and find that it is a highly dynamic cell cycle regulated mark under the regulation of the HDAC deacetylases.

Introduction: Organisational culture is believed to be an important facilitator for better integrated care, yet how organisational culture impacts integrated care remains underspecified. In an exploratory study, we assessed the relationship between organisational culture in primary care centres as perceived by primary care teams and patient-perceived levels of integrated care. Theory and methods: We analysed a sample of 2,911 patient responses and 17 healthcare teams in four primary care centres. We used three-level ordered logistic regression models to account for the nesting of patients within health care teams within primary care centres. Results: Our results suggest a non-linear relationship between organisational culture at the team level and integrated care. A combination of different culture types—including moderate levels of production-oriented, hierarchical and team-oriented cultures and low or high levels of adhocracy cultures—related to higher patient-perceived levels of integrated care. Conclusions and discussion: Organisational culture at the level of healthcare teams has significant associations with patient-perceived integrated care. Our results may be valuable for primary care organisations in their efforts to compose healthcare teams that are predisposed to providing better integrated care.

Context: With the increased availability of potent combination antiretroviral therapies, the life expectancy of people living with human immunodeficiency virus (PLHIV) has greatly increased. This rapid improvement in lifespan has served as a catalyst for a paradigm shift in human immunodeficiency virus (HIV) care. The focus of HIV care models has transitioned from the sole treatment of acute opportunistic infections to comprehensive management of chronic diseases, such as cardiovascular disease (CVD). Multiple studies have demonstrated that PLHIV are 50% more likely to develop acute myocardial infarction (AMI), compared to the general population. Cardiovascular risk prevention is becoming an essential component of the overarching HIV treatment plan. Aims: This meta-analysis aims to compare the rate of aspirin use for AMI prevention in indicated patients between PLHIV and general population. Methods: PubMed, EMBASE, Web of Science, Cochrane Library, CINAHL, and MEDLINE databases were used to identify observational cohort trials. Studies were assessed by two reviewers for inclusion criteria. Two separate random-effects meta-analyses' models were performed using the DerSimonian and Laird method. Heterogeneity was assessed using the I2 value. Meta-regression with study level variables was used to explore potential sources of heterogeneity. The funnel-plot-based trim-and-fill method was applied to detect and adjust for potential publication bias. Statistical tests were two-sided and P< 0.05 was considered statistically significant. Results: A total of 13 studies were included for analysis. In these trials, 30.4% of PLHIV with increased risk for coronary heart disease (CHD) used aspirin for AMI prevention, compared to 36.9% of patients at risk of CHD in the general population. Conclusions: The results of this meta-analysis provide evidence that aspirin is underutilized in both PLHIV and the general population across broad geographical zones. Aspirin use was found to be markedly lower in PLHIV compared to the general population. This is the first study to pool results from regional studies to assess disparities in aspirin use for AMI prevention between PLHIV and the general population across broad geographical zones.

Sphingosine-1-phosphate (S1P) is an important lipid signalling molecule. S1P is produced via intracellular phosphorylation of sphingosine (Sph). As a lipid with a single fatty alkyl chain, Sph may diffuse rapidly between cellular membranes and through the aqueous phase. Here, we show that the absence of microdomains generated by multimeric assemblies of flotillin proteins results in reduced S1P levels. Cellular phenotypes of flotillin knockout mice, including changes in histone acetylation and expression of Isg15, are recapitulated when S1P synthesis is perturbed. Flotillins bind to Sph in vitro and increase recruitment of Sph to membranes in cells. Ectopic re-localisation of flotillins within the cell causes concomitant redistribution of Sph. The data suggest that flotillins may directly or indirectly regulate cellular sphingolipid distribution and signalling.

We assessed the habitat use patterns of the Amargosa vole Microtus californicus scirpensis, an endangered rodent endemic to wetland vegetation along a 3.5 km stretch of the Amargosa River in the Mojave Desert, USA. Our goals were to: (1) quantify the vole’s abundance, occupancy rates and habitat selection patterns along gradients of vegetation cover and spatial scale; (2) identify the processes that likely had the greatest influence on its habitat selection patterns. We trapped voles monthly in six 1 ha grids from January to May 2012 and measured habitat structure at subgrid (225m2) and trap (1m2) scales in winter and spring seasons. Regardless of scale, analyses of density, occupancy and vegetation structure consistently indicated that voles occurred in patches of bulrush (Schoenoplectus americanus; Cyperaceae) where cover >50%. The majority of evidence indicates the vole’s habitat selectivity is likely driven by bulrush providing protection from intense predation. However, a combination of selective habitat use and limited movement resulted in a high proportion of apparently suitable bulrush patches being unoccupied. This suggests the Amargosa vole’s habitat selection behavior confers individual benefits but may not allow the overall population to persist in a changing environment.

Amino acids are essential activators of mTORC1 via a complex containing RAG GTPases, RAGULATOR and the vacuolar ATPase. Sensing of amino acids causes translocation of mTORC1 to lysosomes, an obligate step for activation. To examine the spatial and temporal dynamics of this translocation, we used live imaging of the mTORC1 component RAPTOR and a cell permeant fluorescent analogue of di-leucine methyl ester. Translocation to lysosomes is a transient event, occurring within 2 min of aa addition and peaking within 5 min. It is temporally coupled with fluorescent leucine appearance in lysosomes and is sustained in comparison to aa stimulation. Sestrin2 and the vacuolar ATPase are negative and positive regulators of mTORC1 activity in our experimental system. Of note, phosphorylation of canonical mTORC1 targets is delayed compared to lysosomal translocation suggesting a dynamic and transient passage of mTORC1 from the lysosomal surface before targetting its substrates elsewhere.

The Hospital Consumer Assessment of Healthcare Providers and Systems survey (HCAHPS) is widely used to evaluate patients’ perceptions of their inpatient healthcare experiences. The HCAHPS is organized into 10 measures: six composite measures, two individual measures, and two global measures.1 In prior research on the link between patients’ care experiences and hospital’s quality and cost outcomes, scholars have grouped these measures in a variety of ways. The evident lack of consistency in these groupings along with the persistent lack of empirical justification for these groupings suggests a need to empirically examine the relational structure of HCAHPS measures. Accordingly, the purpose of this study is to determine the degree to which patient care evaluations captured by HCAHPS reflect unmeasured aspects of the patient experience. We use two-step factor analytic process on a nationally representative split sample of HCAHPS performance from 2007-2011. The results of the analysis reveal a single latent factor consisting of five measures that correspond conceptually to patients’ evaluations of care provider behaviors during their interpersonal interactions with them. We label this factor Interpersonal Care Experience (I.C.E) and argue that it may prove useful in future practical and scholarly explorations of the link between patient experience and other performance outcomes.

Research exploring older people and the participatory arts has tended to focus on notions of biomedical impact, often coupled with appeals to evasive notions of “well-being.” Rather than suggesting such approaches are invalid, this article proposes the need for their extension and proposes an alternative, critical approach to analysing older people’s experience of arts participation. Based on ethnographic participant observation and intensive consultation with a cohort of older people engaged in a programme of creative music and dance, we explore the complex processes and possibilities of transformation that the participatory arts can initiate, examining how performance can create intriguing linkages between past, present and future experiences. Taking a phenomenological approach to the study of memory, recollection, reminiscence and future anticipation, we discuss how arts participation can “actualise” potential memories in older participants, examining how and why this kind of expressive activity animates the idea of “virtual” selves (after Bergson).

Distal triceps rupture is a rare injury causing significant disability. Several techniques for treating distal triceps ruptures have been described using bone tunnels or suture anchors. More recent techniques have focused on re-creating the anatomic footprint of the distal triceps tendon. However, the increasing numbers of anchors used increase the risk to the articular surface, and all earlier techniques require knot tying and bulky knots beneath the thin posterior elbow soft-tissue envelope. We describe a technique combining the use of bone tunnels and a single suture anchor to create a knotless anatomic footprint repair of the distal triceps. By using this technique, we are able to create a tension-band construct that self-reinforces the anatomic repair and is very low profile while significantly decreasing risk to the articular surface.

We disrupted the gene encoding lysophosphatidylinositol-acyltransferase-1 (LPIAT1) in the mouse with the aim of understanding its role in determining cellular phosphoinositide content. LPIAT1(-/-) mice were born at lower than Mendelian ratios and exhibited a severe developmental brain defect. We compared the phospholipid content of livers and brains from LPIAT1(-/-) and LPIAT1(+/+) littermates by LC-ESI/MS. In accord with previous studies, the most abundant molecular species of each phosphoinositide class (PtdIns, PtdInsP, PtdInsP2 and PtdInsP3) possessed a C38∶4 complement of fatty-acyl esters (C18∶0 and C20∶4 are usually assigned to the sn-1 and sn-2 positions, respectively). LPIAT1(-/-) liver and brain contained relatively less of the C38∶4 species of PtdIns, PtdInsP and PtdInsP2 (dropping from 95-97% to 75-85% of the total species measured for each lipid class) and relatively more of the less abundant species (PtdInsP3 less abundant species were below our quantification levels). The increases in the less abundant PtdIns and PtdInsP2 species did not compensate for the loss in C38∶4 species, resulting in a 26-44% reduction in total PtdIns and PtdInsP2 levels in both brain and liver. LPIAT1(-/-) brain and liver also contained increased levels of C18∶0 lyso-PtdIns (300% and 525% respectively) indicating a defect in the reacylation of this molecule. LPIAT1(-/-) brain additionally contained significantly reduced C38∶4 PC and PE levels (by 47% and 55% respectively), possibly contributing to the phenotype in this organ. The levels of all other molecular species of PC, PE, PS and PA measured in the brain and liver were very similar between LPIAT1(-/-) and LPIAT1(+/+) samples. These results suggest LPIAT1 activity plays a non-redundant role in maintaining physiological levels of PtdIns within an active deacylation/reacylation cycle in mouse tissues. They also suggest that this pathway must act in concert with other, as yet unidentified, mechanisms to achieve the enrichment observed in C38∶4 molecular species of phosphoinositides.

Abstract Background The proliferation of electronic health records (EHR) in health systems of many high-income countries has ushered in profound changes to how clinical information is used, stored, and disseminated. For patients, being able to easily access and share their health information electronically through interoperable EHRs can often impact safety and their experience when seeking care across healthcare providers. While extensive research exists examining how EHRs affected workflow and technical challenges such as limited interoperability, much of it was done from the viewpoint of healthcare staff rather than from patients themselves. This leaves a critical knowledge gap in our evidence base to inform better implementation of health information technologies which needs addressing. Aims and objectives This study aimed to explore how patients with chronic conditions or polypharmacy and their caregivers perceive the current state of EHR interoperability, identify instances where it was associated with negative health outcomes, and elucidate patient-driven recommendations to address concerns raised. Methods A total of 18 patients and caregivers participated in five online focus groups between May-July 2022. Thematic analysis was performed to generate codes and derive higher-order themes. Results Participants highlighted that EHR interoperability in the NHS does not meet patient needs and expectations. While patients’ understanding of the concept of EHR interoperability was mixed, most were able to describe how the inability to seamlessly share health information within EHR has negatively impacted care. Limited interoperability contributed to inaccurate medical records, perpetuated existing incorrect information, impaired clinical decision-making, and often required patients to resort to using workarounds. Patients also voiced ideas for potential solutions for consideration. These included a move towards a one-centralised system approach, strengthening data security measures to augment other efforts to increase interoperability, prioritising health information technology training for NHS staff, and involving more allied health professionals and patients themselves in the EHR data curation process. Conclusion Our study contributes to the existing body of literature by providing the perspectives of patients and carers most likely to encounter interoperability challenges and therefore those most ideally positioned to propose potential solutions. As highlighted by patients, researchers and policymakers should consider social, educational, and organisational solutions, in addition to technical solutions. Public interest Summary Lack of interoperability (i.e., the ability to share a patient’s health information electronically between healthcare providers) can affect the quality of care received. However, much of the existing research was done from the viewpoint of healthcare staff rather than from patients themselves. This study explored the views of patients regarding what they feel interoperability in the NHS is currently like, how they think it affects their care, and what they think can be done to improve it. Patients reported interoperability to often be poor. It caused inconvenience both to themselves and their healthcare provider, and negatively impacted their experience getting care overall. Patient suggestions for improvement included centralising and reducing the number of existing systems, having more training for healthcare staff, and supporting patients and other healthcare staff in managing their health data.