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Abstract Background Older patients with type 2 diabetes mellitus (T2D) have an increased risk of hypoglycaemic episodes when using sulphonylureas or insulin. In the Netherlands, guidelines exist for reducing glucose-lowering medication in older patients. However, evidence is lacking that a medication reduction in older patients can be safely pursued. Here, we will examine if promoting the deprescribing of insulin/sulphonylureas with a deprescribing programme (DPP) in general practice affects T2D-complications in older overtreated patients. Methods We will perform a 1:1 cluster randomised controlled trial in 86 general practices in the Netherlands. The DPP will consist of education sessions with general practitioners and practice nurses about reducing glucose-lowering medication in older patients (≥ 70 years). Topics of the sessions include the necessity of deprescribing, tools to initiate deprescribing and strategies to discuss deprescribing with patients (shared decision making). The DPP further includes a support programme with practice visits. The study will employ a selection tool to identify possibly overtreated older patients from the electronic medical records of the general practitioner. Eligibility for enrolment in the study will be based on HbA1c targets indicated by the Dutch guidelines, which depend on age, diabetes duration, presence of frailty, and life expectancy. The control group will provide usual care. We aim to include 406 patients. The follow-up period will be 2 years. For the primary outcome, the effect of the DPP on T2D-complications will be assessed by counting the cumulative incidence of events related to under- and overtreatment in T2D as registered in the electronic medical records. We shall perform an intention-to-treat analysis and an analysis including only patients for whom deprescribing was initiated. The implementation of the DPP in general practice will be evaluated quantitatively and qualitatively using the Extended Normalisation Process Theory (ENPT) and the Reach, Efficacy – Adoption, Implementation and Maintenance (RE-AIM) model. Other secondary outcomes include quality of life, cognitive functioning, events related to overtreatment or undertreatment, biomarkers of health, amount of blood glucose-lowering medication prescriptions, and cost-effectiveness. Discussion This study will provide insight into the safety and feasibility of a programme aimed at deprescribing sulphonylureas/insulin in older people with T2D who are treated in general practice. Trial registration ISRCTN Registry, ISRCTN50008265 , registered 09 March, 2023.

Background: Premature atrial contractions (PACs) are potential markers for imminent onset of both atrial fibrillation (AF) and brain ischemia (BI; transient ischemic attack [TIA] or ischemic stroke). We investigated the association of PACs with incident AF and BI events separately, and of incident AF with BI events in people with type 2 diabetes (T2D) without pre-existing AF or cerebrovascular disease. Methods: A prospective longitudinal study of 12,242 people with T2D without known AF or cerebrovascular disease from the Hoorn Diabetes Care System cohort. Annual measurements (1998–2018) included cardiovascular risk factors, over 85,000 ECGs, and self-reported cardiovascular events. We assessed the association of PACs with incident AF and BI events and of incident AF with BI events using time-dependent Cox-regression models, adjusted for time-varying cardiovascular risk factors and medication use (Hazard Ratios with 95%CIs). Results: The baseline mean age was 62.2 ± 11.9 years. During a median follow-up of 7.0 (IQR 3.4–11.0) years, 1031 (8.4 %) participants had PACs, and 566 (4.6 %) had incident AF at any of the median 6 (IQR 3–10) annual ECG recordings. BI events occurred in 517 (4.2 %) people (304 TIAs, 213 ischemic strokes). After adjustment, PACs were associated with incident AF (Hazard Ratio, 1.96 (95%CI, 1.53–2.50)), but not with overall BI events (1.09 (0.76–1.56)), or with TIA (0.91 (0.57–1.46)) or ischemic stroke (1.50 (0.88–2.54)) separately. AF was not associated with BI events (0.95 (0.55–1.63)). Conclusions: In people with T2D without a history of AF or BI events, PACs are associated with a two-fold increased risk of incident AF.

Abstract Background Despite many studies evaluating the effectiveness of integrated care, evidence remains inconsistent. There is increasing commentary pointing out the mismatch between the ability to capture the somewhat ‘illusive’ impact of integrated care initiatives and programmes, and the most appropriate way to do this. Focusing on methodology, this paper describes and critically reviews the experiences of SUSTAIN, a Horizon 2020 funded project (2015–2019) with the purpose of advancing knowledge and understanding of cross-European integrated care evaluation. SUSTAIN sought to improve integrated care initiatives for older people in seven countries, and to maximise the potential for knowledge transfer and application across Europe. The methods approach drew from implementation research, employing the participative Evidence Integration Triangle (EIT) and incorporating a mixed method, multiple embedded case study design. A core set of qualitative and quantitative indicators, alongside context and process data, were created and tested within four key project domains (person-centredness, prevention-orientation, safety and efficiency). The paper critically discusses the overall approach, highlighting the value of the EIT and case study design, and signalling the challenges of data collection with frail older people and stakeholder involvement at the sites, as well as difficulties developing the core set of indicators. Conclusions Lessons learned and recommendations for advancing integrated care evaluation are put forward that focus on the status of integrated care as a complex intervention and a process. The use of implementation research methods and case study design are recommended as an additional evaluation approach for researchers to consider, alongside suggested ways of improving methods of data collection with frail populations and cost analysis.

Abstract Background Many older people live at home, often with complex and chronic health and social care needs. Integrated care programs are increasingly being implemented as a way to better address these needs. To support older people living at home, it is also essential to maintain their safety. Integrated care programs have the potential to address a wide range of risks and problems that could undermine older people’s ability to live independently at home. The aim of this scoping review is to provide insight into how integrated care programs address safety risks faced by older people living at home - an area that is rather underexplored. Methods Safety was conceptualised as preventing or reducing the risk of problems, associated with individual functioning and behaviour, social and physical environments, and health and social care management, which could undermine older people’s ability to live independently at home. For this scoping review a systematic literature search was performed to identify papers describing integrated care programs where at least one intervention component addressed safety risks. Data were extracted on the programs’ characteristics, safety risks addressed, and the activities and interventions used to address them. Results None of the 11 programs included in this review explicitly mentioned safety in their goals. Nevertheless, following the principles of our conceptual framework, the programs appeared to address risks in multiple domains. Most attention was paid to risks related to older people’s functioning, behaviour, and the health and social care they receive. Risks related to people’s physical and social environments received less attention. Conclusion Even though prevention of safety risks is not an explicit goal of integrated care programs, the programs address a wide range of risks on multiple domains. The need to address social and environmental risks is becoming increasingly important given the growing number of people receiving care and support at home. Prioritising a multidimensional approach to safety in integrated care programs could enhance the ability of health and social care systems to support older people to live safely at home.

BackgroundMany Muslims with diabetes choose to fast against medical advice during Ramadan, potentially increasing their risk of acute complications. Patients are often reluctant to disclose fasting to their health care providers, and their needs regarding Ramadan are not met in consultations. For healthcare professionals to provide patient-centred care, it is important to gain more insight into patients' decision-making process. This study therefore aims to explore how Muslims with diabetes decide whether to fast during Ramadan.MethodsA qualitative study was conducted consisting of 15 focus groups with Muslims with diabetes within a constructivist paradigm. Convenience sampling was used. All focus groups were transcribed verbatim and analyzed using Braun and Clarke's reflexive thematic analysis.ResultsFour themes were found to be important in the decision on whether to fast: (1) values and beliefs concerning Ramadan, (2) experiences and emotions concerning Ramadan, (3) the perception of illness, and (4) advice from health care professionals, imams and family. Many participants indicated fasting against medical advice and trusting their subjective assessments on whether they could fast. Moreover, three main stages in the decision-making process for eventually refraining from fasting were identified: (1) the stage where positive experiences with fasting dominate, (2) the stage where one encounters challenges but their determination to fast prevails and (3) the stage where one decides to refrain from fasting after experiencing too many physical difficulties with fasting.ConclusionsMuslims with diabetes experience autonomy in their decisions on Ramadan fasting. The decision to refrain from fasting often resulted from a difficult and dynamic decision-making process and was often made after participants reached their physical limits. These findings highlight the importance of not only shared decision-making to empower patients to make well-informed decisions on Ramadan fasting but also pre-Ramadan diabetes education to help people with diabetes have a safe Ramadan.

Abstract Background Glycemic variation has been suggested to be a risk factor for diabetes-related complications. Previous studies did not address confounding of diabetes duration, number of visits and length of follow-up. Here, we characterize glycemic variability over time and whether its relation to diabetes-related complications and mortality is independent from diabetes- and follow-up duration. Materials and methods Individuals with type 2 diabetes (n = 6770) from the Hoorn Diabetes Care System cohort were included in this study. The coefficient of variation (CV) was calculated over 5-year sliding intervals. People divided in quintiles based on their CV. Cox proportional hazard models were used to investigate the role of glycemic CV as risk factor in diabetes-related complications and mortality. Results The coefficient of variation of glucose (FG-CV) increased with time, in contrast to HbA1c (HbA1c-CV). People with a high FG-CV were those with an early age of diabetes onset (ΔQ5–Q1 = − 2.39 years), a higher BMI (ΔQ5–Q1 = + 0.92 kg/m2), an unfavorable lipid profile, i.e. lower levels of HDL-C (ΔQ5–Q1 = − 0.06 mmol/mol) and higher triglycerides (ΔQ5–Q1 =+ 1.20 mmol/mol). People with the highest FG-CV in the first 5-year interval showed an increased risk of insulin initiation, retinopathy, macrovascular complications and mortality independent of mean glycemia, classical risk factors and medication use. For HbA1c, the associations were weaker and less consistent. Conclusions Individuals with a higher FG-CV have an unfavorable metabolic profile and have an increased risk of developing micro- and macrovascular complications and mortality. The association of HbA1c-CV with metabolic outcomes and complications was less consistent in comparison to FG-CV.

Introduction Early recognition of individuals with increased risk of sudden cardiac arrest (SCA) remains challenging. SCA research so far has used data from cardiologist care, but missed most SCA victims, since they were only in general practitioner (GP) care prior to SCA. Studying individuals with type 2 diabetes (T2D) in GP care may help solve this problem, as they have increased risk for SCA, and rich clinical datasets, since they regularly visit their GP for check-up measurements. This information can be further enriched with extensive genetic and metabolic information.Aim To describe the study protocol of the REcognition of Sudden Cardiac arrest vUlnErability in Diabetes (RESCUED) project, which aims at identifying clinical, genetic and metabolic factors contributing to SCA risk in individuals with T2D, and to develop a prognostic model for the risk of SCA.Methods The RESCUED project combines data from dedicated SCA and T2D cohorts, and GP data, from the same region in the Netherlands. Clinical data, genetic data (common and rare variant analysis) and metabolic data (metabolomics) will be analysed (using classical analysis techniques and machine learning methods) and combined into a prognostic model for risk of SCA.Conclusion The RESCUED project is designed to increase our ability at early recognition of elevated SCA risk through an innovative strategy of focusing on GP data and a multidimensional methodology including clinical, genetic and metabolic analyses.

ObjectivesTo assess the interobserver agreement in categories of electrocardiogram (ECG) abnormalities using the Minnesota Code criteria.MethodsWe used a random sample of 180 ECGs from people with type 2 diabetes. ECG abnormalities were classified and coded using the Minnesota ECG Classification. Each ECG was independently rated on several abnormalities by an experienced rater (rater 1) and by two cardiologists (raters 2 and 3) trained to apply the Minnesota codes on four Minnesota codes; 1-codes as an indication for myocardial infarction, 4 en 5-codes as an indication for ischemic abnormalities, 3-codes as an indication for left ventricle hypertrophy, 7-1-codes as an indication for ventricular conduction abnormalities, and 8-3-codes as an indication for atrial fibrillation / atrial flutter. After all pairwise tables were summed, the overall agreement, the specific positive and negative agreement were calculated with a 95% confidence interval (CI) for each abnormality. Also, Kappa's with a 95% CI were calculated.ResultsThe overall agreement (with 95% CI) were for myocardial infarction, ischemic abnormalities, left ventricle hypertrophy, conduction abnormalities and atrial fibrillation/atrial flutter respectively: 0.87 (0.84-0.91), 0.79 (0.74-0.84), 0.81 (0.76-0.85), 0.93 (0.90-0.95), 0.96 (0.93-0.97).ConclusionThis study shows that the overall agreement of the Minnesota code is good to excellent.

Introduction: While many different factors can undermine older people’s ability to live safely at home, safety as an explicit aspect of integrated care for older people living at home is an underexplored topic in research. In the context of a European project on integrated care, this study aims to improve our understanding of how safety is addressed in integrated care practices across Europe. Methods: This multiple case study included thirteen integrated care sites from seven European countries. The Framework Method guided content analyses of the case study reports. Activities were clustered into activities aimed at identifying and managing risks, or activities addressing specific risks related to older people’s functioning, behaviour, social environment, physical environment and health and social care receipt. Results: Case studies included a broad range of activities addressing older people’s safety. Although care providers felt they sufficiently addressed safety issues, older people were often concerned and insecure about their safety. Attention to the practical and social aspects of safety was often insufficient. Conclusions and discussion: Integrated care services across Europe address older people’s safety in many ways. Further integration of health and social care solutions is necessary to enhance older people’s perceptions of safety.

Introduction: Although person-centredness is a key principle of integrated care, successfully embedding and improving person-centred care for older people remains a challenge. In the context of a cross-European project on integrated care for older people living at home, the objective of this paper is to provide insight at an overarching level, into activities aimed at improving person-centredness within the participating integrated care sites. The paper describes experiences with these activities from the service providers’ and service users’ perspectives. Methods: A multiple embedded case study design was conducted that included thirteen integrated care sites for older people living at home. Results: Service providers were positive about the activities that aimed to promote person-centred care and thought that most activities (e.g. comprehensive needs assessment) positively influenced person-centredness. Experiences of service users were mixed. For some activities (e.g. enablement services), discrepancies were identified between the views of service providers and those of service users. Discussion and conclusion: Evaluating activities aimed at promoting person-centredness from both the service providers’ and service users’ perspectives showed that not all efforts were successful or had the intended consequences for older people. Involvement of older people in designing improvement activities could ensure that care and support reflect their needs and preferences, and build positive experiences of care and support.

AimSubclasses of different glycaemic disturbances could explain the variation in characteristics of individuals with type 2 diabetes (T2D). We aimed to examine the association between subgroups based on their glucose curves during a five-point mixed-meal tolerance test (MMT) and metabolic traits at baseline and glycaemic deterioration in individuals with T2D.MethodsThe study included 787 individuals with newly diagnosed T2D from the Diabetes Research on Patient Stratification (IMI-DIRECT) Study. Latent class trajectory analysis (LCTA) was used to identify distinct glucose curve subgroups during a five-point MMT. Using general linear models, these subgroups were associated with metabolic traits at baseline and after 18 months of follow up, adjusted for potential confounders.ResultsAt baseline, we identified three glucose curve subgroups, labelled in order of increasing glucose peak levels as subgroup 1-3. Individuals in subgroup 2 and 3 were more likely to have higher levels of HbA1c, triglycerides and BMI at baseline, compared to those in subgroup 1. At 18 months (n = 651), the beta coefficients (95% CI) for change in HbA1c (mmol/mol) increased across subgroups with 0.37 (-0.18-1.92) for subgroup 2 and 1.88 (-0.08-3.85) for subgroup 3, relative to subgroup 1. The same trend was observed for change in levels of triglycerides and fasting glucose.ConclusionsDifferent glycaemic profiles with different metabolic traits and different degrees of subsequent glycaemic deterioration can be identified using data from a frequently sampled mixed-meal tolerance test in individuals with T2D. Subgroups with the highest peaks had greater metabolic risk.

Introduction: The topic of patient safety, which is traditionally viewed as preventing harm stemming from healthcare treatment, has been extensively researched in hospital and institutional settings. However, less attention has been given to addressing safety at home even though an increasing number of older people receive care and support at home, for example through integrated care programs. Care provided in the context of integrated programs for older people living at home differs from care in institutional settings in that it takes place in less controlled environments and often involves multiple health and social care providers as well as informal caregivers. Knowledge on safety in relation to integrated care is scarce. Therefore, this review aims to provide insight into how safety is currently being addressed in integrated care programs for older people living at home. Methods: This review adopted a multidimensionalperspective on safety, operationalised as reducing health risks by preventing predictable harm. These risks exist in various domains (e.g. patient characteristics and behaviour, patients’ physical or social environments, health and social care delivery). Papers describing integrated care programs where at least one intervention component explicitly aimed at safety were included in the review. Data were extracted on the safety components of the interventions and the domains they focused on. Results: Ten integrated care programs were included in the review. The extent to which these programs addressed safety varied. Programs addressed risks related to patient characteristics and behaviour (e.g. falls, substance abuse, medication adherence), or health and social care management (e.g. polypharmacy, care transitions). Several tools and interventions were used to promote safety, such as needs assessments, evidence based care plans, medication reviews and case management methods. There was generally less attention to risks related to patients’ physical and social environment, although one program specifically addressed home safety by providing a handyman. Discussion: The identified programstarget a variety of safety risks at different domains, and they differ in the extent to which safety is addressed from a multidimensional perspective. Currently, attention to safety is primarily focused on risks related to health care management and patient characteristics and behaviour, while risks related to people’s physical and social environments are less often addressed. Additional interventions, targeting specific safety risks, could be incorporated in integrated care programs in order to address safety more comprehensively. Conclusions and lessons learned: Only a few of the many integrated care programs for older people at home that are described in literature explicitly address safety. Within these programs, more attention is needed for the risks related to people’s physical and social environments. Limitations: Our review only included programs that explicitly addressed safety, as documented in the research literature. Therefore, we may have missed some programs that addressed safety if this was not clearly described in the literature. Suggestions for future research: Future research might focus on the effects of integrated care programs on the multiple domains of safety.

Introduction: The cross-European research project SUSTAIN (2015-2019) was initiated to take a step forward in the development of integrated care for older people living at home. During the project, SUSTAIN research partners collaborated with local stakeholders from integrated care initiatives to design, implement and evaluate actions and activities to improve current practice, in terms of person-centredness, prevention-orientation, safety, efficiency and coordination. The comparison and integration of findings from these evaluations were expected to increase understanding of what works and with what outcomes when making improvements to integrated care. Methods: Thirteen established integrated care initiatives (sites) in seven European countries were studied, using a multiple embedded case study design. In all initiatives, qualitative and quantitative data were collected from multiple sources and analyzed using standardized procedures and tools to ensure uniformity of approach. After conducting site-specific analysis, an overarching analysis was performed, in which findings from the site-specific evaluations were compared and integrated to identify general lessons learned. Results: The objectives of the integrated care improvements of the different sites could be divided into two groups: (i) improving or expanding collaboration, communication and coordination between organizations and professionals (not yet) involved in the site; (ii) improving the actual care delivery process, for instance by making care delivery more person-centred. The extent to which integrated care improvements lead to a more person-centred, prevention-orientated, safe, efficient and coordinated way of working differed between sites and types of stakeholders. Professionals involved in implementing the improvements were often positive about outcomes of the improvements, while in some sites, a number of users and carers did not notice much of the changes that were implemented. Furthermore, similar facilitators for the implementation of improvements were identified across the sites, on different levels of the health and social care system, such as strong leadership, and shared and realistic goals. Also challenges towards implementation of improvements were identical among the sites, including factors such as lack of ownership, uncertainties about funding, high staff turnover and incompatible shared IT systems. Discussion, conclusions and lessons learned: Across sites, several actions and activities had been implemented to improve person-centred, prevention-orientated, safe, efficient and coordinated care delivery. Many actions appeared to achieve some success, particularly according to professionals. Among users, however, there were mixed views on the improvements. While initiatives had been able to improve their current practices, they also encountered several challenges towards delivering and improving integrated care. A supportive context on different levels of the health and social care system is required for achieving sustainable integrated care improvements. Limitations: Where improving care is a challenge in itself, on top of that integrated care intiatives were required to implement improvements in a limited time span and often without additional resources, which may have influenced outcomes. A long-term approach and sufficient resources are recommended for achieving successful and sustainable integrated care improvements. Suggestions for further research: Sites participating in the SUSTAIN project experienced similar challenges in delivering and improving integrated care. Further research on how these barriers can be overcome is needed.

Introduction: In the northwest of the Netherlands, health and social care professionals have sought to structure and coordinate care and support for older people living at home with multiple health and social care needs. The region was selected as one of the case sites of a European project called SUSTAIN, which aimed to facilitate and evaluate improvements to established integrated care initiatives for older people living at home. By participating in the SUSTAIN project, local stakeholders collaborated with researchers to further improve their way of working. This case study describes the process and outcomes of the development and implementation of improvements, as well as the factors that influenced this improvement process. Insight into this process may provide valuable lessons that could be transferable to other integrated care initiatives Methods: Using a participatory approach, guided by the Evidence Integration Triangle (Glasgow, 2012), local stakeholders defined and implemented a tailored intervention aimed at improving collaboration and communication between health and social care professionals. Researchers monitored and evaluated this improvement process. Multiple data sources were used, including the Team Climate Inventory (n=11), interviews with managers and professionals delivering health and social care (n=8), meeting minutes (n=10) and field notes. Results and Discussion: The tailored intervention consisted of regular intervision meetings (i.e. meetings consisting of peer supervision and methodical discussion to reflect on professional development) as well as workplace visits. According to professionals, the intervention resulted in improved communication and collaboration. Facilitating factors included the safe and informal setting in which the meetings took place and the personal relationships that developed during the project. Managers also valued the intervention, although they voiced concerns about the scale and sustainability of the implementation. Issues such as staff shortages, time constraints and privacy regulations made it difficult to implement the intervention on a larger scale. In addition, lack of ownership and accountability among managers and different organizational cultures and interests hindered the improvement process. Still, this bottom-up participatory approach encouraged the development of trust, shared goals and a shared sense of urgency on the level of both managers and professionals. Conclusions: A shared sense of urgency, personal relationships and trust on different organisational levels were important factors facilitating the improvement of an established integrated care initiative in the Netherlands. Lessons Learned: This case study highlights that participatory approaches, in which interventions are co-created and tailored to local priorities and needs, can help in the development of shared goals and trust between stakeholders with competing interests. Limitations: Our study sample is relatively smalldue to the limited number of participating stakeholders. Still, similar patterns were found in the different data sources. In addition, given the relatively short implementation period, we were not able to assess whether the improvement impacted older people’s experiences with care and support. Suggestions for further research: Further research may focus on the sustainability of improvements to established integrated care initiatives, and look into possibilities to scale up these improvement activities.

Objectives: To describe how principles of self-regulation and social support could be integrated in a group intervention to improve self-management of people with type 2 diabetes mellitus in the early phase of illness and to pilot its suitability in a primary care setting. Methods: Principles of the Common-Sense Model of Self-Regulation, Social Cognitive Theory of Self-Regulation and social support theories were integrated in the intervention. Based on this, a three-session group course was developed to challenge illness perceptions of participants that discourage adequate self-management, to practice goal-setting and behavioural actions and to create a supportive environment. The intervention was piloted with persons with early-stage (1–3 years post diagnosis) type 2 diabetes mellitus selected in general practice in the Netherlands. Data about the suitability of the intervention were retrieved by means of observation and audio-recording of the sessions, an evaluation form filled in by the participants and an evaluation meeting with the group leaders. Results: In total, 16 type 2 diabetes mellitus patients participated in the pilot, who were divided into a group of single participants (N = 8) and a group (N = 8) who participated with their partner. Discrepancies between perceptions of one’s own condition and type 2 diabetes mellitus in general were observed. Goal-setting and developing action plans appeared to be difficult tasks for many participants, whereas others felt these exercises were not useful as they did not feel a need to make changes in living with diabetes. The group-based format was appreciated as was the participation of partners. Conclusion: Challenging the illness perceptions of persons with early-stage type 2 diabetes mellitus by a brief interactive group course is feasible and important, as many of these people tend to underestimate the seriousness of their diabetes. However, motivating persons with early-stage type 2 diabetes mellitus to participate in self-management interventions remains a challenge. Offering the intervention as an integral part of type 2 diabetes mellitus management in primary care is desirable.

Introduction: Hypertension is considered an important public health issue. Inadequate disease management and non-adherence to antihypertensive medication may result in suboptimal clinical outcomes thereby imposing a financial burden on society. This study evaluates the cost-effectiveness of a patient-tailored, pharmacist-led intervention program aimed to enhance adherence to antihypertensive medication in comparison with usual care.Materials and Methods: An economic evaluation was conducted alongside a pragmatic randomized controlled trial with 9-months follow-up among 170 patients using antihypertensive medication. Effect outcomes included self-reported adherence (MARS-5), beliefs about medicines (BMQ Concern and Necessity scales) and quality-adjusted life-years (QALYs). Costs were measured from a societal perspective. Missing cost and effect data were imputed using multiple imputation. Bootstrapping was used to estimate uncertainty around the cost-differences and the incremental cost-effectiveness ratios. Cost-effectiveness planes and acceptability curves were estimated.Results: There were no significant differences in costs or effects between the intervention program and usual care. The probability of cost-effectiveness of the intervention in comparison with usual care was 0.27 at a willingness-to-pay value of 0 €/unit of effect gained. At a willingness-to-pay value of 20,000 €/unit of effect gained, the probability of cost-effectiveness was 0.70, 0.27, 0.64, 0.87, and 0.36 for the continuous MARS-5 score, dichotomized MARS-5 score, BMQ Concern scale, BMQ Necessity scale and QALYs, respectively.Discussion: In patients with hypertension, the patient-tailored, pharmacist-led intervention program to enhance medication adherence was not considered cost-effective as compared to usual care with regard to self-reported medication adherence, beliefs about medicines and QALYs.

AIMS:To evaluate the immediate and six-month effectiveness of a group-based self-management support program for people diagnosed with type 2 diabetes (1-3 years post diagnosis) on diabetes self-care, distress and cognitions. METHODS:People with type 2 diabetes were randomized into the intervention (four group-based interactive sessions) or the control group (a single educational lecture) with their partners. Outcomes were measured at baseline, immediately after the third course session and six months later using validated questionnaires on diabetes self-care, distress, illness perceptions, diabetes-related attitudes, empowerment and partner support. Multilevel analyses were conducted according to the intention-to-treat principle using the data from 82 intervention and 86 control group participants, to test for differences in changes over time between the two groups. RESULTS:The intervention group showed a significantly higher increase in physical activity and fruit and vegetable intake immediately after the program, whereas the low baseline levels of diabetes distress remained unaffected. Furthermore, the intervention group believed their illness to be more likely to be caused by chance/bad luck, but also felt more empowered to handle their condition and its treatment immediately after the program compared with the control group. Six months later, only the differences in empowerment had persisted. CONCLUSIONS:Group-based self-management support results in favorable short-term behavioral changes and more persistent alterations in (perceived) empowerment in people living in the first years of type 2 diabetes. In order to achieve more sustainable behavioral changes, more prolonged support is necessary. This could be achieved by integrating attention to patients' illness perceptions and continuous self-management support in regular diabetes care. TRIAL REGISTRATION:Netherlands Trial Registry NL3158.

Introduction: Non-adherence to medication is a complex health care problem. In spite of substantial efforts, up till now little progress has been made to effectively tackle the problem with adherence-enhancing interventions. The aim of this study was to investigate the effectiveness of a patient-tailored, pharmacist-led and theory-driven intervention program aimed to enhance self-reported adherence to antihypertensive medication.Materials and Methods: A parallel-group randomized controlled trial in 20 community pharmacies with nine months follow-up was conducted. Patients (45–75 years) using antihypertensive medication and considered non-adherent based on both pharmacy dispensing data and a self-report questionnaire were eligible to participate. The intervention program consisted of two consultations with the pharmacist to identify participants’ barriers to adhere to medication and to counsel participants in overcoming these barriers. The primary outcome was self-reported medication adherence. Secondary outcomes were beliefs about medicines, illness perceptions, quality of life and blood pressure. Mixed-model and generalized estimating equation (GEE) analyses were used to assess overall effects of the intervention program and effects per time point.Results: 170 patients were included. No significant differences between intervention and control groups were found in self-reported adherence, quality of life, illness perceptions, beliefs about medicines (concern scale), and blood pressure. After nine months, intervention participants had significantly stronger beliefs about the necessity of using their medicines as compared to control participants (mean difference 1.25 [95% CI: 0.27 to 2.24], p = 0.012).Discussion: We do not recommend to implement the intervention program in the current form for this study population. Future studies should focus on how to select eligible patient groups with appropriate measures in order to effectively target adherence-enhancing interventions.Trial Register: NTR5017 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5017.

[This corrects the article DOI: 10.1371/journal.pone.0191172.].

Aims. To date, studies on the role of eating traits in weight loss success have only included obese people without type 2 diabetes mellitus (T2DM), thereby disregarding negative effects of T2DM-related metabolic changes. Our aim was to assess the association between eating traits and weight change after a lifestyle intervention in people with T2DM. Methods. For the current study, we reexamined data from a six-month intervention in 120 participants. We determined eating traits at baseline, using the DEBQ, which were used to produce three groups: unsuccessful dietary restrained (high restraint, high emotional/external eating scores), successful dietary restrained (high restraint, low emotional/external eating scores), and reference (low restraint, high or low emotional/external eating scores). Linear regression was used to study the association between the eating trait groups and weight changes after six months, while correcting for possible confounders. Results. On average, the weight loss success was limited, with a third of the participants being weight stable, a third losing weight > −1 kg (average loss −2.6 ± 1.9 kg), and a third gaining weight > +1 kg (average gain +3.3 ± 1.9 kg). When compared to the reference group, the unsuccessful dietary restrained gained weight during the intervention (beta = 1.2 kg, confidence interval (CI)% = 0.1; 2). No significant change was observed in the succesful dietary restrained group. Conclusions. The eating trait of being unsuccessfully dietary restrained is associated with weight-loss failure after a six-month lifestyle intervention in people with T2DM.

Introduction: Integrated care programmes are increasingly being put in place to provide care to older people who live at home. Knowledge of how to further develop integrated care and how to transfer successful initiatives to other contexts is still limited. Therefore, a cross-European research project, called Sustainable Tailored Integrated Care for Older People in Europe (SUSTAIN), has been initiated with a twofold objective: 1. to collaborate with local stakeholders to support and monitor improvements to established integrated care initiatives for older people with multiple health and social care needs. Improvements focus on person-centredness, prevention orientation, safety and efficiency; 2. to make these improvements applicable and adaptable to other health and social care systems, and regions in Europe. This paper presents the overall structure and approach of the SUSTAIN project. Methods: SUSTAIN uses a multiple embedded case study design. In three phases, SUSTAIN partners: (i) conduct interviews and workshops with stakeholders from fourteen established integrated care initiatives to understand where they would prefer improvements to existing ways of working; (ii) collaborate with local stakeholders to support the design and implementation of improvement plans, evaluate implementation progress and outcomes per initiative, and carry out overarching analyses to compare the different initiatives, and; (iii) translate knowledge and experience to an online roadmap. Discussion: SUSTAIN aims to generate evidence on how to improve integrated care, and apply and transfer the knowledge gained to other health and social care systems, and regions. Lessons learned will be brought together in practical tools to inform and support policy-makers and decision-makers, as well as other stakeholders involved in integrated care, to manage and improve care for older people living at home.

AIMS:Carotid intima media thickness (CIMT) predicts cardiovascular (CVD) events, but the predictive value of CIMT change is debated. We assessed the relation between CIMT change and events in individuals at high cardiovascular risk. METHODS AND RESULTS:From 31 cohorts with two CIMT scans (total n = 89070) on average 3.6 years apart and clinical follow-up, subcohorts were drawn: (A) individuals with at least 3 cardiovascular risk factors without previous CVD events, (B) individuals with carotid plaques without previous CVD events, and (C) individuals with previous CVD events. Cox regression models were fit to estimate the hazard ratio (HR) of the combined endpoint (myocardial infarction, stroke or vascular death) per standard deviation (SD) of CIMT change, adjusted for CVD risk factors. These HRs were pooled across studies. In groups A, B and C we observed 3483, 2845 and 1165 endpoint events, respectively. Average common CIMT was 0.79mm (SD 0.16mm), and annual common CIMT change was 0.01mm (SD 0.07mm), both in group A. The pooled HR per SD of annual common CIMT change (0.02 to 0.43mm) was 0.99 (95% confidence interval: 0.95-1.02) in group A, 0.98 (0.93-1.04) in group B, and 0.95 (0.89-1.04) in group C. The HR per SD of common CIMT (average of the first and the second CIMT scan, 0.09 to 0.75mm) was 1.15 (1.07-1.23) in group A, 1.13 (1.05-1.22) in group B, and 1.12 (1.05-1.20) in group C. CONCLUSIONS:We confirm that common CIMT is associated with future CVD events in individuals at high risk. CIMT change does not relate to future event risk in high-risk individuals.

This article describes the development of the social network-based intervention Powerful Together with Diabetes which aims to improve diabetes self-management (DSM) among patients with type 2 diabetes living in socioeconomically deprived neighborhoods by stimulating social support for DSM and diminishing social influences hindering DSM (e.g., peer pressure and social norms). The intervention was specifically developed for patients with Dutch, Turkish, Moroccan, and Surinamese backgrounds. The intervention was developed according to Intervention Mapping. This article describes the first four steps of Intervention Mapping: (1) the needs assessment; (2) development of performance and change objectives; (3) selection of theory-based methods and strategies; and (4) the translation of these into an organized program. These four steps resulted in Powerful Together with Diabetes, a 10-month group-based intervention consisting of 24 meetings, 6 meetings for significant others, and 2 meetings for participants and their spouses. The IM method resulted in a tailored approach with a specific focus on the social networks of its participants. This article concludes that the IM method helped our planning team to tailor the intervention to the needs of our target population and facilitated our evaluation design. However, in hindsight, the intervention could have been improved by investing more in participatory planning and community involvement.

BACKGROUND:Vitamin D deficiency may be a risk factor for mortality but previous meta-analyses lacked standardization of laboratory methods for 25-hydroxyvitamin D (25[OH]D) concentrations and used aggregate data instead of individual participant data (IPD). We therefore performed an IPD meta-analysis on the association between standardized serum 25(OH)D and mortality. METHODS:In a European consortium of eight prospective studies, including seven general population cohorts, we used the Vitamin D Standardization Program (VDSP) protocols to standardize 25(OH)D data. Meta-analyses using a one step procedure on IPD were performed to study associations of 25(OH)D with all-cause mortality as the primary outcome, and with cardiovascular and cancer mortality as secondary outcomes. This meta-analysis is registered at ClinicalTrials.gov, number NCT02438488. FINDINGS:We analysed 26916 study participants (median age 61.6 years, 58% females) with a median 25(OH)D concentration of 53.8 nmol/L. During a median follow-up time of 10.5 years, 6802 persons died. Compared to participants with 25(OH)D concentrations of 75 to 99.99 nmol/L, the adjusted hazard ratios (with 95% confidence interval) for mortality in the 25(OH)D groups with 40 to 49.99, 30 to 39.99, and

AIMS/HYPOTHESIS:To develop a prediction model that can predict HbA1c levels after six years in the non-diabetic general population, including previously used readily available predictors. METHODS:Data from 5,762 initially non-diabetic subjects from three population-based cohorts (Hoorn Study, Inter99, KORA S4/F4) were combined to predict HbA1c levels at six year follow-up. Using backward selection, age, BMI, waist circumference, use of anti-hypertensive medication, current smoking and parental history of diabetes remained in sex-specific linear regression models. To minimize overfitting of coefficients, we performed internal validation using bootstrapping techniques. Explained variance, discrimination and calibration were assessed using R2, classification tables (comparing highest/lowest 50% HbA1c levels) and calibration graphs. The model was externally validated in 2,765 non-diabetic subjects of the population-based cohort METSIM. RESULTS:At baseline, mean HbA1c level was 5.6% (38 mmol/mol). After a mean follow-up of six years, mean HbA1c level was 5.7% (39 mmol/mol). Calibration graphs showed that predicted HbA1c levels were somewhat underestimated in the Inter99 cohort and overestimated in the Hoorn and KORA cohorts, indicating that the model's intercept should be adjusted for each cohort to improve predictions. Sensitivity and specificity (95% CI) were 55.7% (53.9, 57.5) and 56.9% (55.1, 58.7) respectively, for women, and 54.6% (52.7, 56.5) and 54.3% (52.4, 56.2) for men. External validation showed similar performance in the METSIM cohort. CONCLUSIONS/INTERPRETATION:In the non-diabetic population, our DIRECT-DETECT prediction model, including readily available predictors, has a relatively low explained variance and moderate discriminative performance, but can help to distinguish between future highest and lowest HbA1c levels. Absolute HbA1c values are cohort-dependent.

BACKGROUND:The relation of a single risk factor with atherosclerosis is established. Clinically we know of risk factor clustering within individuals. Yet, studies into the magnitude of the relation of risk factor clusters with atherosclerosis are limited. Here, we assessed that relation. METHODS:Individual participant data from 14 cohorts, involving 59,025 individuals were used in this cross-sectional analysis. We made 15 clusters of four risk factors (current smoking, overweight, elevated blood pressure, elevated total cholesterol). Multilevel age and sex adjusted linear regression models were applied to estimate mean differences in common carotid intima-media thickness (CIMT) between clusters using those without any of the four risk factors as reference group. RESULTS:Compared to the reference, those with 1, 2, 3 or 4 risk factors had a significantly higher common CIMT: mean difference of 0.026 mm, 0.052 mm, 0.074 mm and 0.114 mm, respectively. These findings were the same in men and in women, and across ethnic groups. Within each risk factor cluster (1, 2, 3 risk factors), groups with elevated blood pressure had the largest CIMT and those with elevated cholesterol the lowest CIMT, a pattern similar for men and women. CONCLUSION:Clusters of risk factors relate to increased common CIMT in a graded manner, similar in men, women and across race-ethnic groups. Some clusters seemed more atherogenic than others. Our findings support the notion that cardiovascular prevention should focus on sets of risk factors rather than individual levels alone, but may prioritize within clusters.

Outcomes of proactive home visit programs for frail, older people might be influenced by aspects of the caregiver–receiver interaction. We conducted a naturalistic case study to explore the interactional process between a nurse and an older woman during two home visits. Using an ethics of care, we posit that a trusting relationship is pivotal for older people to accept care that is proactively offered to them. Trust can be build when nurses meet the relational needs of older people. Nurses can achieve insight in these needs by exploring older people’s value systems and life stories. We argue that a strong focus on older people’s relational needs might contribute to success of proactive home visits for frail, older people.

In this exploratory study we examined the associations between several social network characteristics and lifestyle behaviours in adults at increased risk of diabetes and cardiovascular diseases. In addition, we explored whether similarities in lifestyle between individuals and their network members, or the level of social support perceived by these individuals, could explain these associations.From the control group of the Hoorn Prevention Study, participants with high and low educational attainment were approached for a structured interview between April and August 2010. Inclusion was stopped when fifty adults agreed to participate. Participants and a selection of their network members (e.g. spouses, best friends, neighbours, colleagues) completed a questionnaire on healthy lifestyle that included questions on fruit and vegetable intake, daily physical activity and leisure-time sedentary behaviour. We first examined associations between network characteristics and lifestyle using regression analyses. Second, we assessed associations between network characteristics and social support, social support and lifestyle, and compared the participants' lifestyles to those of their network members using concordance correlation coefficients.Fifty adults (50/83 x 100 = 62% response) and 170 of their network members (170/192 x 100 = 89% response) participated in the study. Individuals with more close-knit relationships, more friends who live nearby, and a larger and denser network showed higher levels of vegetable consumption and physical activity, and lower levels of sedentary behaviour. Perceived social norms or perceived support for behavioural change were not related to healthy lifestyle. Except for spousal concordance for vegetable intake, the lifestyle of individuals and their network members were not alike.Study results suggest that adults with a larger and denser social network have a healthier lifestyle. Underlying mechanisms for these associations should be further explored, as the current results suggest a minimal role for social support and modelling by network members.

Introduction: Despite the expected beneficial effects on quality of care, patient involvement in diabetes care groups, which deliver a bundled paid integrated care programme for diabetes type 2, seems to be limited. The aim of this study was to gain insight into levels and methods of patient involvement, into facilitators and barriers, and into the future preferences of care groups and patient representatives. Theory and methods: Semi-structured interviews were held with 10 representatives of care groups and 11 representatives of patient advocacy groups. An adapted version of Arnstein's ladder of citizen participation was used to define five levels of patient involvement. Results: Patient involvement in care groups was mostly limited to informing and consulting patients. Higher levels, i.e., advising, co-producing and decision-making, were less frequently observed. Care groups and patient representatives perceived largely the same barriers and facilitators and had similar preferences regarding future themes and design of patient involvement. Conclusion: Constructive collaboration between diabetes care groups and patient representatives to enhance patient involvement in the future seems viable. Several issues such as the lack of evidence for effectiveness of patient involvement, differences in viewpoints on the role and responsibilities of care groups and perceived barriers need to be addressed.

Introduction: Arterial remodeling is an adaptive phenomenon aimed at maintaining circumferential wall stress (CWS) within operating limits. It is characterized by widening of the inter-adventitial diameter (IAD) and increases in intima-media thickness (IMT). This process is maladaptive when CWS increases despite remodeling. Type 2 Diabetes (T2D) is associated with increased carotid CWS, but its association with cardiovascular disease (CVD) is unknown. Methods: The cohort consisted of 277 individuals with normal glucose metabolism (NGM), 162 with impaired glucose metabolism (IGM) and 131 with T2D (age 69.6 ± 6.4, 51.0% women, systolic pressure 141.9 ± 20.6 mmHg, bmi 26.9 ± 3.5 kg/m2, prior CVD 50.1%). Carotid arterial properties (IAD, IMT, lumen diameter (LD)) were quantified by ultrasonography. CWS was calculated as PP·LD/(2IMT), where PP is the brachial pulse pressure. A morbidity and mortality register was kept on all individuals. Results: After a median of 7.7 [IQR 7.0-8.1] years of follow up, 130 CVD events and 93 deaths were recorded. CWS was 31.7, 31.5 and 34.4 kPa in NGM, IGM and T2D, respectively (Ptrend= 0.06). Greater CWS was associated with incident CVD in T2D only (hazard ratio(95%CI) per SD increase in CWS for NGM: 0.92 (0.70–1.21); IGM: 1.02 (0.66–1.58) and T2D 1.52 (1.09–2.14), after adjustment for age, sex, height and other CVD risk factors.. No associations were observed between CWS and all-cause mortality. Conclusion: T2D is associated with greater CWS compared to NGM and IGM. Greater carotid CWS is associated with incident CVD in T2D but not in NGM or IGM.

Introduction: Central (aortic or carotid) pulse pressure (PP) is more strongly associated with local organ damage and possibly mortality than brachial PP. Aim: To investigate for the first time the association of femoral (f) PP with all-cause mortality, and incident cardiovascular disease (CVD), coronary heart disease (CHD) and cerebrovascular disease (CerVD) events, as well as with markers of renal function (estimated glomerular filtration rate, eGFR, and microalbuminuria). Methods: We used data from a population-based study, by design including 50% type 2 diabetes and impaired glucose metabolism (IGM). The baseline examination included non-invasive PP assessment at the brachial, aorta (Sphygmocor device), carotid and femoral (ultrasound distention waves calibrated by brachial mean and diastolic pressure) arteries. Results: After 7.8 years of follow-up (n = 449, age: 68.9 ± 6.0 males: 52%), 66 participants had died, 102 had a CVD event, 45 a CHD event, and 31 a CerVD event. PP at all sites was associated with incident all-cause mortality and CVD events. Only fPP was, however, associated with incident CHD events, even after adjustment for CVD risk factors (HRs 1.31 [1.07–1.61 95% CIs]). No association between PP and incident CerVD events was found – possibly due to the small number of events. fPP was associated with renal function but this was similar to other PP indices. No interaction between each any local PP index and glucose metabolism status or renal function was present. Conclusion: Beyond anatomical topography, local fPP provide important information related to CVD events. This possibility and the underlying mechanisms should be further investigated.

Clinical manifestations and outcomes of atherosclerotic disease differ between ethnic groups. In addition, the prevalence of risk factors is substantially different. Primary prevention programs are based on data derived from almost exclusively White people. We investigated how race/ethnic differences modify the associations of established risk factors with atherosclerosis and cardiovascular events.We used data from an ongoing individual participant meta-analysis involving 17 population-based cohorts worldwide. We selected 60,211 participants without cardiovascular disease at baseline with available data on ethnicity (White, Black, Asian or Hispanic). We generated a multivariable linear regression model containing risk factors and ethnicity predicting mean common carotid intima-media thickness (CIMT) and a multivariable Cox regression model predicting myocardial infarction or stroke. For each risk factor we assessed how the association with the preclinical and clinical measures of cardiovascular atherosclerotic disease was affected by ethnicity.Ethnicity appeared to significantly modify the associations between risk factors and CIMT and cardiovascular events. The association between age and CIMT was weaker in Blacks and Hispanics. Systolic blood pressure associated more strongly with CIMT in Asians. HDL cholesterol and smoking associated less with CIMT in Blacks. Furthermore, the association of age and total cholesterol levels with the occurrence of cardiovascular events differed between Blacks and Whites.The magnitude of associations between risk factors and the presence of atherosclerotic disease differs between race/ethnic groups. These subtle, yet significant differences provide insight in the etiology of cardiovascular disease among race/ethnic groups. These insights aid the race/ethnic-specific implementation of primary prevention.

OBJECTIVE: The objective of this study was to evaluate the cost-effectiveness of a Multidisciplinary Integrated Care (MIC) model compared to Usual Care (UC) in Dutch residential homes. METHODS: The economic evaluation was conducted from a societal perspective alongside a 6 month, clustered, randomized controlled trial involving 10 Dutch residential homes. Outcome measures included a quality of care weighted sum score, functional health (COOP WONCA) and Quality Adjusted Life-Years (QALY). Missing cost and effect data were imputed using multiple imputation. Bootstrapping was used to analyze differences in costs and cost-effectiveness. RESULTS: The quality of care sum score in MIC was significantly higher than in UC. The other primary outcomes showed no significant differences between the MIC and UC. The costs of providing MIC were approximately €225 per patient. Total costs were €2,061 in the MIC group and €1,656 for the UC group (mean difference €405, 95% -13; 826). The probability that the MIC was cost-effective in comparison with UC was 0.95 or more for ceiling ratios larger than €129 regarding patient related quality of care. Cost-effectiveness planes showed that the MIC model was not cost-effective compared to UC for the other outcomes. INTERPRETATION: Clinical effect differences between the groups were small but quality of care was significantly improved in the MIC group. Short term costs for MIC were higher. Future studies should focus on longer term economic and clinical effects. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN11076857.

BACKGROUND:Genome-wide association studies in Japanese populations recently identified common variants in the KCNQ1 gene to be associated with type 2 diabetes. We examined the association of these variants within KCNQ1 with type 2 diabetes in a Dutch population, investigated their effects on insulin secretion and metabolic traits and on the risk of developing complications in type 2 diabetes patients. METHODOLOGY:The KCNQ1 variants rs151290, rs2237892, and rs2237895 were genotyped in a total of 4620 type 2 diabetes patients and 5285 healthy controls from the Netherlands. Data on macrovascular complications, nephropathy and retinopathy were available in a subset of diabetic patients. Association between genotype and insulin secretion/action was assessed in the additional sample of 335 individuals who underwent a hyperglycaemic clamp. PRINCIPAL FINDINGS:We found that all the genotyped KCNQ1 variants were significantly associated with type 2 diabetes in our Dutch population, and the association of rs151290 was the strongest (OR 1.20, 95% CI 1.07-1.35, p = 0.002). The risk C-allele of rs151290 was nominally associated with reduced first-phase glucose-stimulated insulin secretion, while the non-risk T-allele of rs2237892 was significantly correlated with increased second-phase glucose-stimulated insulin secretion (p = 0.025 and 0.0016, respectively). In addition, the risk C-allele of rs2237892 was associated with higher LDL and total cholesterol levels (p = 0.015 and 0.003, respectively). We found no evidence for an association of KCNQ1 with diabetic complications. CONCLUSIONS:Common variants in the KCNQ1 gene are associated with type 2 diabetes in a Dutch population, which can be explained at least in part by an effect on insulin secretion. Furthermore, our data suggest that KCNQ1 is also associated with lipid metabolism.

BACKGROUND: There is a well recognized association between depression and diabetes. However, there is little empirical data about the prevalence of depressive symptoms and anxiety among different groups of glucose metabolism in population based samples. The aim of this study was to determine whether the prevalence of increased levels of depression and anxiety is different between patients with type 2 diabetes and subjects with impaired glucose metabolism (IGM) and normal glucose metabolism (NGM). METHODOLOGY/PRINCIPAL FINDINGS: Cross-sectional data from a population-based cohort study of 2667 residents, 1261 men and 1406 women aged 40-65 years from the Hoorn region, the Netherlands. Depressive symptoms and anxiety were measured using the Centre for Epidemiologic Studies Depression Scale (CES-D, score >or=16) and the Hospital Anxiety and Depression Scale--Anxiety Subscale (HADS-A, score >or=8), respectively. Glucose metabolism status was determined by oral glucose tolerance test. In the total study population the prevalence of depressive symptoms and anxiety for the NGM, IGM and type 2 diabetes were 12.5, 12.2 and 21.0% (P = 0.004) and 15.0, 15.3 and 19.9% (p = 0.216), respectively. In men, the prevalence of depressive symptoms was 7.7, 9.5 and 19.6% (p