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Introduction Empowering people living with multimorbidity (multiple chronic conditions) to gain greater confidence in managing their health can enhance their quality of life. Education focused on self-management is a key tool for fostering patient empowerment and is mostly provided on an individual basis. Virtual communities of practice (VCoP) present a unique opportunity for online education in chronic condition self-management within a social context. This research aims to evaluate the effectiveness/cost-effectiveness of individualised, online self-management education compared with VCoP among middle-aged individuals living with multiple chronic conditions.Methods and analysis People aged 30–60, living with ≥2 chronic conditions and receiving care in primary care (PC) centres and outpatient hospital-based clinics in Madrid and Canary Islands will enrol in an 18-month parallel-design, blinded (intervention assessment and data analysts), pragmatic (adhering to the intention-to-treat principle), individually randomised trial. The trial will compare two 12-month web-based educational offers of identical content; one delivered individually (control) and the other with online social interaction (VCoP, intervention). Using repeated measures mixed linear models, with the patient as random effect and allocation groups and time per group as fixed effects, we will estimate between-arm differences in the change in Patient Activation Measure from baseline to 12 months (primary endpoint), including measurements at 6-month and 18-month follow-up. Other outcomes will include measures of depression and anxiety, treatment burden, quality of life. In addition to a process evaluation of the VCoP, we will conduct an economic evaluation estimating the relative cost-effectiveness of the VCoP from the perspectives of both the National Health System and the Community.Ethics and dissemination The trial was approved by Clinical Research Ethics Committees of Gregorio Marañón University Hospital in Madrid/Nuestra Señora Candelaria University Hospital in Santa Cruz de Tenerife. The results will be disseminated through workshops, policy briefs, peer-reviewed publications and local/international conferences.Trial registration number NCT06046326.

Abstract Background Understanding how to implement innovations in primary care practices is key to improve primary health care. Aiming to contribute to this understanding, we investigate the implementation of a clinical decision support system (CDSS) as part of the innovation fund project AdAM (01NVF16006). Originating from complexity theory, the practice change and development model (PCD) proposes several interdependent factors that enable organizational-level change and thus accounts for the complex settings of primary care practices. Leveraging the PCD, we seek to answer the following research questions: Which combinations of internal and external factors based on the PCD contribute to successful implementation in primary care practices? Given these results, how can implementation in the primary care setting be improved? Methods We analyzed the joint contributions of internal and external factors on implementation success using qualitative comparative analysis (QCA). QCA is a set-theoretic approach that allows to identify configurations of multiple factors that lead to one outcome (here: successful implementation of a CDSS in primary care practices). Using survey data, we conducted our analysis based on a sample of 224 primary care practices. Results We identified two configurations of internal and external factors that likewise enable successful implementation. The first configuration enables implementation based on a combination of Strong Inside Motivation, High Capability for Development, and Strong Outside Motivation; the second configuration based on a combination of Strong Inside Motivators, Many Options for Development and the absence of High Capability for Development. Conclusion In line with the PCD, our results demonstrate the importance of the combination of internal and external factors for implementation outcomes. Moreover, the two identified configurations show that different ways exist to achieve successful implementation in primary care practices. Trial registration AdAM was registered on ClinicalTrials.gov ( NCT03430336 ) on February 6, 2018.

BackgroundThe transition of patients between inpatient and outpatient care can lead to adverse events and medication-related problems due to medication and communication errors, such as medication discontinuation, the frequency of (re-)hospitalizations, and increased morbidity and mortality. Older patients with multimorbidity and polypharmacy are particularly at high risk during transitions of care. Previous research highlighted the need for interventions to improve transitions of care in order to support information continuity, coordination, and communication. The HYPERION-TransCare project aims to improve the continuity of medication management for older patients during transitions of care.Methods and findingsUsing a qualitative design, 32 expert interviews were conducted to explore the perspectives of key stakeholders, which included healthcare professionals, patients and one informal caregiver, on transitions of care. Interviews were conducted between October 2020 and January 2021, transcribed verbatim and analyzed using content analysis. We narratively summarized four main topics (stakeholders' tasks, challenges, ideas for solutions and best practice examples, and patient-related factors) and mapped them in a patient journey map. Lacking or incomplete information on patients' medication and health conditions, inappropriate communication and collaboration between healthcare providers within and across settings, and insufficient digital support limit the continuity of medication management.ConclusionsThe study confirms that medication management during transitions of care is a complex process that can be compromised by a variety of factors. Legal requirements and standardized processes are urgently needed to ensure adequate exchange of information and organization of medication management before, during and after hospital admissions. Despite the numerous barriers identified, the findings indicate that involved healthcare professionals from both the inpatient and outpatient care settings have a common understanding.

Introduction Atherosclerotic cardiovascular disease (ASCVD) was the main cause of death in Germany in 2021, with major risk factors (ie, hypertension, diabetes, dyslipidaemia, obesity and certain lifestyle factors) being highly prevalent. Preventing ASCVD by assessment and modification of these risk factors is an important challenge for general practitioners. This study aims to systematically review and synthesise recent recommendations of national and international guidelines regarding the primary prevention of ASCVD in adults in primary care.Methods and analysis We will conduct a systematic review of clinical practice guidelines (CPGs) to evaluate primary prevention strategies for ASCVD. CPGs will be retrieved from MEDLINE and the Turning Research Into Practice database, guideline-specific databases and websites of guidelines-producing societies, with searches limited to publications from 2016 onwards. We will include CPGs in English, Spanish, German or Dutch languages that provide evidence-based recommendations for ASCVD prevention. The study population will include adults without diagnosed ASCVD. Two independent reviewers will assess guideline eligibility and quality by means of the mini-checklist MiChe, and extract study characteristics and relevant recommendations for further consistency analysis. A third reviewer will resolve disagreements. Findings will be presented as a narrative synthesis and in tabular form.Ethics and dissemination This review does not require ethical approval. Our systematic review will inform the CPG of the German College of General Practitioners and Family Physicians on the primary prevention of ASCVD. The review results will also be disseminated through publications in peer-reviewed journals and presentations at local, national and international conferences.PROSPERO registration number CRD42023394605.

Plain English summary Digital patient and public involvement (PPI) activities differ from in-person meetings. For example, some forms of non-verbal cues and body language are limited and technical barriers may exist. Therefore, some research teams were hesitant to switch to a digital PPI format during the COVID-19 pandemic and postponed their PPI activities. In this paper, we aim to describe, how we adapted a PPI workshop series to a digital format, how patients and health care professionals experienced these digital workshops, and which conclusions we have drawn for future digital PPI activities. The workshop evaluation encompassed workshop observation protocols, participants’ feedback via chat on their chance to speak and the feasibility of the digital tools, and telephone interviews on participants’ experiences. The study results showed that moderators had an active role in verbally encouraging every participant to get involved. Technical challenges occurred, but were in most cases immediately addressed and solved. Most participants rated their chance to speak and the feasibility of the digital format as “very good”. They described the atmosphere as inclusive and on equal footing without hierarchy between different stakeholder groups. Participants reported benefits of the digital format such as overcoming geographical distance, saving time and combining workshop participation with professional or childcare obligations. They stressed technical support as a condition for getting actively involved in digital PPI. We conclude that some advantages of digital PPI may persist beyond the pandemic. Therefore, we encourage research teams to discuss the question of digital or in-person PPI with the involved patients and health professionals and decide on a case-by-case basis.

Abstract Background The progressive ageing of the population is leading to an increase in multimorbidity and polypharmacy, which in turn may increase the risk of hospitalization and mortality. The enhancement of care with information and communications technology (ICT) can facilitate the use of prescription evaluation tools and support system for decision-making (DSS) with the potential of optimizing the healthcare delivery process. Objective To assess the effectiveness and cost-effectiveness of the complex intervention MULTIPAP Plus, compared to usual care, in improving prescriptions for young-old patients (65-74 years old) with multimorbidity and polypharmacy in primary care. Methods/design This is a pragmatic cluster-randomized clinical trial with a follow-up of 18 months in health centres of the Spanish National Health System. Unit of randomization: family physician. Unit of analysis: patient. Population Patients aged 65–74 years with multimorbidity (≥ 3 chronic diseases) and polypharmacy (≥ 5 drugs) during the previous 3 months were included. Sample size n = 1148 patients (574 per study arm). Intervention Complex intervention based on the ARIADNE principles with three components: (1) family physician (FP) training, (2) FP-patient interview, and (3) decision-making support system. Outcomes The primary outcome is a composite endpoint of hospital admission or death during the observation period measured as a binary outcome, and the secondary outcomes are number of hospital admission, all-cause mortality, use of health services, quality of life (EQ-5D-5L), functionality (WHODAS), falls, hip fractures, prescriptions and adherence to treatment. Clinical and sociodemographic factors will be explanatory variables. Statistical analysis The main result is the difference in percentages in the final composite endpoint variable at 18 months, with its corresponding 95% CI. Adjustments by the main confounding and prognostic factors will be performed through a multilevel analysis. All analyses will be carried out in accordance to the intention-to-treat principle. Discussion It is important to prevent the cascade of negative health and health care impacts attributable to the multimorbidity-polypharmacy binomial. ICT-enhanced routine clinical practice could improve the prescription process in patient care. Trial registration ClinicalTrials.gov NCT04147130 . Registered on 22 October 2019

BackgroundAnticholinergic burden has been associated with adverse outcomes such as falls. To date, no gold standard measure has been identified to assess anticholinergic burden, and no conclusion has been drawn on which of the different measure algorithms best predicts falls in older patients from general practice. This study compared the ability of five measures of anticholinergic burden to predict falls. To account for patients' individual susceptibility to medications, the added predictive value of typical anticholinergic symptoms was further quantified in this context.Methods and findingsTo predict falls, models were developed and validated based on logistic regression models created using data from two German cluster-randomized controlled trials. The outcome was defined as "≥ 1 fall" vs. "no fall" within a 6-month follow-up period. Data from the RIME study (n = 1,197) were used in model development, and from PRIMUM (n = 502) for external validation. The models were developed step-wise in order to quantify the predictive ability of anticholinergic burden measures, and anticholinergic symptoms. In the development set, 1,015 patients had complete data and 188 (18.5%) experienced ≥ 1 fall within the 6-month follow-up period. The overall predictive value of the five anticholinergic measures was limited, with neither the employed anticholinergic variable (binary / count / burden), nor dose-dependent or dose-independent measures differing significantly in their ability to predict falls. The highest c-statistic was obtained using the German Anticholinergic Burden Score (0.73), whereby the optimism-corrected c-statistic was 0.71 after interval validation using bootstrapping and 0.63 in the external validation. Previous falls and dizziness / vertigo had the strongest prognostic value in all models.ConclusionsThe ability of anticholinergic burden measures to predict falls does not appear to differ significantly, and the added value they contribute to risk classification in fall-prediction models is limited. Previous falls and dizziness / vertigo contributed most to model performance.

BackgroundHalf the US population uses drugs with anticholinergic properties. Their potential harms may outweigh their benefits. Amitriptyline is among the most frequently prescribed anticholinergic medicinal products, is used for multiple indications, and rated as strongly anticholinergic. Our objective was to explore and quantify (anticholinergic) adverse drug reactions (ADRs) in patients taking amitriptyline vs. placebo in randomized controlled trials (RCTs) involving adults and healthy individuals.MethodsWe searched electronic databases from their inception until 09/2022, and clinical trial registries from their inception until 09/2022. We also performed manual reference searches. Two independent reviewers selected RCTs with ≥100 participants of ≥18 years, that compared amitriptyline (taken orally) versus placebo for all indications. No language restrictions were applied. One reviewer extracted study data, ADRs, and assessed study quality, which two others verified. The primary outcome was frequency of anticholinergic ADRs as a binary outcome (absolute number of patients with/without anticholinergic ADRs) in amitriptyline vs. placebo groups.ResultsTwenty-three RCTs (mean dosage 5mg to 300mg amitriptyline/day) and 4217 patients (mean age 40.3 years) were included. The most frequently reported anticholinergic ADRs were dry mouth, drowsiness, somnolence, sedation, fatigue, constitutional, and unspecific anticholinergic ADRs. Random-effects meta-analyses showed anticholinergic ADRs had a higher odd's ratio for amitriptyline versus placebo (OR = 7.41; [95% CI, 4.54 to 12.12]). Non-anticholinergic ADRs were as frequent for amitriptyline as placebo. Meta-regression analysis showed anticholinergic ADRs were not dose-dependent.DiscussionThe large OR in our analysis shows that ADRs indicative of anticholinergic activities can be attributed to amitriptyline. The low average age of participants in our study may limit the generalizability of the frequency of anticholinergic ADRs in older patients. A lack of dose-dependency may reflect limited reporting of the daily dosage when the ADRs occurred. The exclusion of small studies (RegistrationPROSPERO: CRD42020111970.

Abstract Background To investigate patients’ perspectives on polypharmacy and the use of a digital decision support system to assist general practitioners (GPs) in performing medication reviews. Methods Qualitative interviews with patients or informal caregivers recruited from participants in a cluster-randomized controlled clinical trial (cRCT). The interviews were transcribed verbatim and analyzed using thematic analysis. Results We conducted 13 interviews and identified the following seven themes: the patients successfully integrated medication use in their everyday lives, used medication plans, had both good and bad personal experiences with their drugs, regarded their healthcare providers as the main source of medication-related information, discussed medication changes with their GPs, had trusting relationships with them, and viewed the use of digital decision support tools for medication reviews positively. No unwanted adverse effects were reported. Conclusions Despite drug-related problems, patients appeared to cope well with their medications. They also trusted their GPs, despite acknowledging polypharmacy to be a complex field for them. The use of a digital support system was appreciated and linked to the hope that reasons for selecting specific medication regimens would become more comprehensible. Further research with a more diverse sampling might add more patient perspectives. Trial registration ClinicalTrials.gov, NCT03430336 . Registered on February 6, 2018.

Abstract Objective Formative evaluation of the implementation process for a digitally supported intervention in polypharmacy in Germany. Qualitative research was conducted within a cluster randomized controlled trial (C-RCT). It focused on understanding how the intervention influences behavior-related outcomes in the prescription and medication review process. Methods/setting Twenty-seven general practitioners (GPs) were included in the study in the two groups of the C-RCT, the intervention, and the wait list control group. Behavior-related outcomes were investigated using three-step data analysis (content analytic approach, documentary method, and design of a model of implementation pathways). Results Content analysis showed that physicians were more intensely aware of polypharmacy-related risks, described positive learning effects of the digital technology on their prescribing behavior, and perceived a change in communication with patients and pharmacists. Conversely, they felt uncertain about their own responsibility when prescribing. Three main dimensions were discovered which influenced adoption behavior: (1) the physicians’ interpretation of the relevance of pharmaceutical knowledge provided by the intervention in changing decision-making situations in polypharmacy; (2) their medical code of ethics for clinical decision making in the context of progressing digitalization; and (3) their concepts of evidence-based medicine on the basis of professional experiences with polypharmacy in primary care settings. In our sample, both simple and complex pathways from sensitization to adoption were observed. The resulting model on adoption behavior includes a paradigmatic description of different pathways and a visualization of different observed levels and applied methodological approaches. We assumed that the GP habitus can weaken or strengthen interventional effects towards intervention uptake. This formative evaluation strategy is beneficial for the identification of behavior-related implementation barriers and facilitators. Conclusion Our analyses of the adoption behavior of a digitally supported intervention in polypharmacy revealed both simple and complex pathways from awareness to adoption, which may impact the implementation of the intervention and therefore, its effectiveness. Future consideration of adoption behavior in the planning and evaluation of digitally supported interventions may enhance uptake and support the interpretation of effects. Trial registration NCT03430336 , 12 February 2018.

Abstract Background Unwanted anticholinergic effects are both underestimated and frequently overlooked. Failure to identify adverse drug reactions (ADRs) can lead to prescribing cascades and the unnecessary use of over-the-counter products. The objective of this systematic review and meta-analysis is to explore and quantify the frequency and severity of ADRs associated with amitriptyline vs. placebo in randomized controlled trials (RCTs) involving adults with any indication, as well as healthy individuals. Methods A systematic search in six electronic databases, forward/backward searches, manual searches, and searches for Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval studies, will be performed. Placebo-controlled RCTs evaluating amitriptyline in any dosage, regardless of indication and without restrictions on the time and language of publication, will be included, as will healthy individuals. Studies of topical amitriptyline, combination therapies, or including

Introduction Older patients with multimorbidity, polypharmacy and related complex care needs represent a growing proportion of the population and a challenge for healthcare systems. Particularly in transitional care (hospital admission and hospital discharge), medical errors, inappropriate treatment, patient concerns and lack of confidence in healthcare are major problems that may arise from a lack of information continuity. The aim of this study is to develop an intervention to improve informational continuity of care at the interface between general practice and hospital care.Methods and analysis A qualitative approach will be used to develop our participatory intervention. Overall, 32 semistructured interviews with relevant stakeholders will be conducted and analysed. The stakeholders will include healthcare professionals from the outpatient setting (general practitioners, healthcare assistants, ambulatory care nurses) and the inpatient setting (clinical doctors, nurses, pharmacists, clinical information scientists) as well as patients and informal caregivers. At a series of workshops based on the results of the stakeholder analyses, we aim to develop a participatory intervention that will then be implemented in a subsequent pilot study. The same stakeholder groups will be invited for participation in the workshops.Ethics and dissemination Ethical approval for this study was waived by the Ethics Committee of Goethe University Frankfurt because of the nature of the proposed study. Written informed consent will be obtained from all study participants prior to participation. Results will be tested in a pilot study and disseminated at (inter)national conferences and via publication in peer-reviewed journals.Trial registation number Clinical Trials Register: registration number DRKS00027649.

Background: Interventional studies on polypharmacy often fail to significantly improve patient-relevant outcomes, or confine themselves to measuring surrogate parameters. Interventions and settings are complex, with many factors affecting results. The AdAM study’s aim is to reduce hospitalization and death by requiring general practitioners (GPs) to use a computerized decision-support system (CDSS). The study will undergo a process evaluation to identify factors for successful implementation and to assess whether the intervention was implemented as intended. Objective: To evaluate our complex intervention, based on the Medical Research Council’s guideline dimensions. Research Questions: We will assess implementation (reach, fidelity, dose, tailoring) by asking: (1) Who took part in the intervention (proportion of GPs using the CDSS, proportion of patients enrolled in them)? Information on GPs’ and patients’ characteristics will also be collected. (2) How many and which medication alerts were dealt with? (3) Was the intervention implemented as intended? (4) On what days did GPs use the intervention tool? Methods: The process evaluation is part of a stepped-wedge cluster-randomized controlled trial. Characteristics of practices, GPs and patients using the CDSS will be compared with the non-participating population. CDSS log data will be analyzed to evaluate how the number of medication alerts changed between baseline and 2 months later, and to identify the kind of alerts that were dealt with. Comparison of enrolled patients on weekdays versus weekends will shed light on GPs’ use of the CDSS in the absence or presence of patients. Outcomes will be presented using descriptive statistics, and significance tests will be used to identify associations between them. We will conduct subgroup analyses, including time effects to account for software improvements. Discussion: This study protocol is the basis for conducting analyses of the quantitative process evaluation. By providing insight into how GPs conduct medication reviews, the evaluation will provide context to the trial results and support their interpretation. The evaluation relies on the proper documentation by GPs, potentially limiting its explanatory power.

Introduction Clinically complex patients often require multiple medications. Polypharmacy is associated with inappropriate prescriptions, which may lead to negative outcomes. Few effective tools are available to help physicians optimise patient medication. This study assesses whether an electronic medication management support system (eMMa) reduces hospitalisation and mortality and improves prescription quality/safety in patients with polypharmacy.Methods and analysis Planned design: pragmatic, parallel cluster-randomised controlled trial; general practices as randomisation unit; patients as analysis unit. As practice recruitment was poor, we included additional data to our primary endpoint analysis for practices and quarters from October 2017 to March 2021. Since randomisation was performed in waves, final study design corresponds to a stepped-wedge design with open cohort and step-length of one quarter. Scope: general practices, Westphalia-Lippe (Germany), caring for BARMER health fund-covered patients. Population: patients (≥18 years) with polypharmacy (≥5 prescriptions). Sample size: initially, 32 patients from each of 539 practices were required for each study arm (17 200 patients/arm), but only 688 practices were randomised after 2 years of recruitment. Design change ensures that 80% power is nonetheless achieved. Intervention: complex intervention eMMa. Follow-up: at least five quarters/cluster (practice). recruitment: practices recruited/randomised at different times; after follow-up, control group practices may access eMMa. Outcomes: primary endpoint is all-cause mortality and hospitalisation; secondary endpoints are number of potentially inappropriate medications, cause-specific hospitalisation preceded by high-risk prescribing and medication underuse. Statistical analysis: primary and secondary outcomes are measured quarterly at patient level. A generalised linear mixed-effect model and repeated patient measurements are used to consider patient clusters within practices. Time and intervention group are considered fixed factors; variation between practices and patients is fitted as random effects. Intention-to-treat principle is used to analyse primary and key secondary endpoints.Ethics and dissemination Trial approved by Ethics Commission of North-Rhine Medical Association. Results will be disseminated through workshops, peer-reviewed publications, local and international conferences.Trial registration NCT03430336. ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT03430336).

Objective To explore factors that potentially impact external validation performance while developing and validating a prognostic model for hospital admissions (HAs) in complex older general practice patients.Study design and setting Using individual participant data from four cluster-randomised trials conducted in the Netherlands and Germany, we used logistic regression to develop a prognostic model to predict all-cause HAs within a 6-month follow-up period. A stratified intercept was used to account for heterogeneity in baseline risk between the studies. The model was validated both internally and by using internal-external cross-validation (IECV).Results Prior HAs, physical components of the health-related quality of life comorbidity index, and medication-related variables were used in the final model. While achieving moderate discriminatory performance, internal bootstrap validation revealed a pronounced risk of overfitting. The results of the IECV, in which calibration was highly variable even after accounting for between-study heterogeneity, agreed with this finding. Heterogeneity was equally reflected in differing baseline risk, predictor effects and absolute risk predictions.Conclusions Predictor effect heterogeneity and differing baseline risk can explain the limited external performance of HA prediction models. With such drivers known, model adjustments in external validation settings (eg, intercept recalibration, complete updating) can be applied more purposefully.Trial registration number PROSPERO id: CRD42018088129.

Abstract Astrogliosis and activation of microglia are hallmarks of prion diseases in humans and animals. Both were viewed to be rather independent events in disease pathophysiology, with proinflammatory microglia considered to be the potential neurotoxic species at late disease stages. Recent investigations have provided substantial evidence that a proinflammatory microglial cytokine cocktail containing TNF-α, IL-1α and C1qa reprograms a subset of astrocytes to change their expression profile and phenotype, thus becoming neurotoxic (designated as A1-astrocytes). Knockout or antibody blockage of the three cytokines abolish formation of A1-astrocytes, therefore, this pathway is of high therapeutic interest in neurodegenerative diseases. Since astrocyte polarization profiles have never been investigated in prion diseases, we performed several analyses and could show that C3+-PrPSc-reactive-astrocytes, which may represent a subtype of A1-astrocytes, are highly abundant in prion disease mouse models and human prion diseases. To investigate their impact on prion disease pathophysiology and to evaluate their potential therapeutic targeting, we infected TNF-α, IL-1α, and C1qa Triple-KO mice (TKO-mice), which do not transit astrocytes into A1, with prions. Although formation of C3+-astrocytes was significantly reduced in prion infected Triple-KO-mice, this did not affect the amount of PrPSc deposition or titers of infectious prions. Detailed characterization of the astrocyte activation signature in thalamus tissue showed that astrocytes in prion diseases are highly activated, showing a mixed phenotype that is distinct from other neurodegenerative diseases and were therefore termed C3+-PrPSc-reactive-astrocytes. Unexpectedly, Triple-KO led to a significant acceleration of prion disease course. While pan-astrocyte and -microglia marker upregulation was unchanged compared to WT-brains, microglial homeostatic markers were lost early in disease in TKO-mice, pointing towards important functions of different glia cell types in prion diseases.

Polypharmacy is associated with a risk of negative health outcomes. Potentially inappropriate medications, interactions resulting from contradicting medical guidelines, and inappropriate monitoring, all increase the risk. This process evaluation (PE) of the AdAM study investigates implementation and use of a computerized decision-support system (CDSS). The CDSS analyzes medication appropriateness by including claims data, and hence provides general practitioners (GPs) with full access to patients’ medical treatments. We based our PE on pseudonymized logbook entries into the CDSS and used the four dimensions of the Medical Research Council PE framework. Reach, which examines the extent to which the intended study population was included, and Dose, Fidelity, and Tailoring, which examine how the software was actually used by GPs. The PE was explorative and descriptive. Study participants were representative of the target population, except for patients receiving a high level of nursing care, as they were treated less frequently. GPs identified and corrected inappropriate prescriptions flagged by the CDSS. The frequency and intensity of interventions documented in the form of logbook entries lagged behind expectations, raising questions about implementation barriers to the intervention and the limitations of the PE. Impossibility to connect the CDSS to GPs’ electronic medical records (EMR) of GPs due to technical conditions in the German healthcare system may have hindered the implementation of the intervention. Data logged in the CDSS may underestimate medication changes in patients, as documentation was voluntary and already included in EMR.

Background: Cumulative anticholinergic exposure, also known as anticholinergic burden, is associated with a variety of adverse outcomes. However, studies show that anticholinergic effects tend to be underestimated by prescribers, and anticholinergics are the most frequently prescribed potentially inappropriate medication in older patients. The grading systems and drugs included in existing scales to quantify anticholinergic burden differ considerably and do not adequately account for patients’ susceptibility to medications. Furthermore, their ability to link anticholinergic burden with adverse outcomes such as falls is unclear. This study aims to develop a prognostic model that predicts falls in older general practice patients, to assess the performance of several anticholinergic burden scales, and to quantify the added predictive value of anticholinergic symptoms in this context.Methods: Data from two cluster-randomized controlled trials investigating medication optimization in older general practice patients in Germany will be used. One trial (RIME, n = 1,197) will be used for the model development and the other trial (PRIMUM, n = 502) will be used to externally validate the model. A priori, candidate predictors will be selected based on a literature search, predictor availability, and clinical reasoning. Candidate predictors will include socio-demographics (e.g. age, sex), morbidity (e.g. single conditions), medication (e.g. polypharmacy, anticholinergic burden as defined by scales), and well-being (e.g. quality of life, physical function). A prognostic model including sociodemographic and lifestyle-related factors, as well as variables on morbidity, medication, health status, and well-being, will be developed, whereby the prognostic value of extending the model to include additional patient-reported symptoms will be also assessed. Logistic regression will be used for the binary outcome, which will be defined as “no falls” vs. “≥1 fall” within six months of baseline, as reported in patient interviews.Discussion: As the ability of different anticholinergic burden scales to predict falls in older patients is unclear, this study may provide insights into their relative importance as well as into the overall contribution of anticholinergic symptoms and other patient characteristics. The results may support general practitioners in their clinical decision-making and in prescribing fewer medications with anticholinergic properties.

Background Polypharmacy interventions are resource-intensive and should be targeted to those at risk of negative health outcomes. Our aim was to develop and internally validate prognostic models to predict health-related quality of life (HRQoL) and the combined outcome of falls, hospitalisation, institutionalisation and nursing care needs, in older patients with multimorbidity and polypharmacy in general practices.Methods Design: two independent data sets, one comprising health insurance claims data (n=592 456), the other data from the PRIoritising MUltimedication in Multimorbidity (PRIMUM) cluster randomised controlled trial (n=502). Population: ≥60 years, ≥5 drugs, ≥3 chronic diseases, excluding dementia. Outcomes: combined outcome of falls, hospitalisation, institutionalisation and nursing care needs (after 6, 9 and 24 months) (claims data); and HRQoL (after 6 and 9 months) (trial data). Predictor variables in both data sets: age, sex, morbidity-related variables (disease count), medication-related variables (European Union-Potentially Inappropriate Medication list (EU-PIM list)) and health service utilisation. Predictor variables exclusively in trial data: additional socio-demographics, morbidity-related variables (Cumulative Illness Rating Scale, depression), Medication Appropriateness Index (MAI), lifestyle, functional status and HRQoL (EuroQol EQ-5D-3L). Analysis: mixed regression models, combined with stepwise variable selection, 10-fold cross validation and sensitivity analyses.Results Most important predictors of EQ-5D-3L at 6 months in best model (Nagelkerke’s R² 0.507) were depressive symptoms (−2.73 (95% CI: −3.56 to −1.91)), MAI (−0.39 (95% CI: −0.7 to −0.08)), baseline EQ-5D-3L (0.55 (95% CI: 0.47 to 0.64)). Models based on claims data and those predicting long-term outcomes based on both data sets produced low R² values. In claims data-based model with highest explanatory power (R²=0.16), previous falls/fall-related injuries, previous hospitalisations, age, number of involved physicians and disease count were most important predictor variables.Conclusions Best trial data-based model predicted HRQoL after 6 months well and included parameters of well-being not found in claims. Performance of claims data-based models and models predicting long-term outcomes was relatively weak. For generalisability, future studies should refit models by considering parameters representing well-being and functional status.

Introduction End-of-life care is an essential task performed by most healthcare providers and often involves decision-making about how and where patients want to receive care. To provide decision support to healthcare professionals and patients in this difficult situation, we will systematically review a knowledge cluster of the end-of-life care preferences of older patients with multimorbidity that we previously identified using an evidence map.Methods and analysis We will systematically search for studies reporting end-of-life care preferences of older patients (mean age ≥60) with multimorbidity (≥2 chronic conditions) in MEDLINE, CINAHL, PsycINFO, Social Sciences Citation Index, Social Sciences Citation Index Expanded, PSYNDEX and The Cochrane Library from inception to September 2019. We will include all primary studies that use quantitative, qualitative and mixed methodologies, irrespective of publication date and language.Two independent reviewers will assess eligibility, extract data and describe evidence in terms of study/population characteristics, preference assessment method and end-of-life care elements that matter to patients (eg, life-sustaining treatments). Risk of bias/applicability of results will be independently assessed by two reviewers using the Mixed-Methods Appraisal Tool. Using a convergent integrated approach on qualitative/quantitative studies, we will synthesise information narratively and, wherever possible, quantitatively.Ethics and dissemination Due to the nature of the proposed systematic review, ethics approval is not required. Results from our research will be disseminated at relevant (inter-)national conferences and via publication in peer-reviewed journals. Synthesising evidence on end-of-life care preferences of older patients with multimorbidity will improve shared decision-making and satisfaction in this final period of life.PROSPERO registration number CRD42020151862.

Abstract Background Treatment complexity rises in line with the number of drugs, single doses, and administration methods, thereby threatening patient adherence. Patients with multimorbidity often need flexible, individualised treatment regimens, but alterations during the course of treatment may further increase complexity. The objective of our study was to explore medication changes in older patients with multimorbidity and polypharmacy in general practice. Methods We retrospectively analysed data from the cluster-randomised PRIMUM trial (PRIoritisation of MUltimedication in Multimorbidity) conducted in 72 general practices. We developed an algorithm for active pharmaceutical ingredients (API), strength, dosage, and administration method to assess changes in physician-reported medication data during two intervals (baseline to six-months: ∆1; six- to nine-months: ∆2), analysed them descriptively at prescription and patient levels, and checked for intervention effects. Results Of 502 patients (median age 72 years, 52% female), 464 completed the study. Changes occurred in 98.6% of patients (changes were 19% more likely in the intervention group): API changes during ∆1 and ∆2 occurred in 414 (82.5%) and 338 (67.3%) of patients, dosage alterations in 372 (74.1%) and 296 (59.2%), and changes in API strength in 158 (31.5%) and 138 (27.5%) respectively. Administration method changed in 79 (16%) of patients in both ∆1 and ∆2. Simvastatin, metformin and aspirin were most frequently subject to alterations. Conclusion Medication regimens in older patients with multimorbidity and polypharmacy changed frequently. These are mostly due to discontinuations and dosage alterations, followed by additions and restarts. These findings cast doubt on the effectiveness of cross-sectional assessments of medication and support longitudinal assessments where possible. Trial registration. 1. Prospective registration: Trial registration number: NCT01171339; Name of registry: ClinicalTrials.gov; Date of registration: July 27, 2010; Date of enrolment of the first participant to the trial: August 12, 2010. 2. Peer reviewed trial registration: Trial registration number: ISRCTN99526053; Name of registry: Controlled Trials; Date of registration: August 31, 2010; Date of enrolment of the first participant to the trial: August 12, 2010.

Objectives: We previously found large variations in general practitioner (GP) hypertension treatment probability in oldest-old (>80 years) between countries. We wanted to explore whether differences in country-specific cardiovascular disease (CVD) burden and life expectancy could explain the differences. Design: This is a survey study using case-vignettes of oldest-old patients with different comorbidities and blood pressure levels. An ecological multilevel model analysis was performed. Setting: GP respondents from European General Practice Research Network (EGPRN) countries, Brazil and New Zeeland. Subjects: This study included 2543 GPs from 29 countries. Main outcome measures: GP treatment probability to start or not start antihypertensive treatment based on responses to case-vignettes; either low (80 years of age). • In this study including 1947 GPs from 29 countries, we found that a high country-specific cardiovascular disease (CVD) burden (i.e. myocardial infarction and/or stroke) was associated with a higher GP treatment probability in patients aged >80 years. • However, the association was modified by country-specific life expectancy at age 60. While there was a positive association for GPs in countries with a low life expectancy at age 60, there was no association in countries with a high life expectancy at age 60. • These findings help explaining some of the large variation seen in the decision as to whether or not to treat hypertension in the oldest-old.

Abstract Background Although polypharmacy can cause adverse health outcomes, patients often know little about their medication. A regularly conducted medication review (MR) can help provide an overview of a patient’s medication, and benefit patients by enhancing their knowledge of their drugs. As little is known about patient attitudes towards MRs in primary care, the objective of this study was to gain insight into patient-perceived barriers and facilitators to the implementation of an MR. Methods We conducted a qualitative study with a convenience sample of 31 patients (age ≥ 60 years, ≥3 chronic diseases, taking ≥5 drugs/d); in Hesse, Germany, in February 2016. We conducted two focus groups and, in order to ensure the participation of elderly patients with reduced mobility, 16 telephone interviews. Both relied on a semi-structured interview guide dealing with the following subjects: patients’ experience of polypharmacy, general design of MRs, potential barriers and facilitators to implementation etc. Interviews were audio-recorded, transcribed verbatim, and analysed by two researchers using thematic analysis. Results Patients’ average age was 74 years (range 62–88 years). We identified barriers and facilitators for four main topics regarding the implementation of MRs in primary care: patient participation, GP-led MRs, pharmacist-led MRs, and the involvement of healthcare assistants in MRs. Barriers to patient participation concerned patient autonomy, while facilitators involved patient awareness of medication-related problems. Barriers to GP-led MRs concerned GP’s lack of resources while facilitators related to the trusting relationship between patient and GP. Pharmacist-led MRs might be hindered by a lack of patients’ confidence in pharmacists’ expertise, but facilitated by pharmacies’ digital records of the patients’ medications. Regarding the involvement of healthcare assistants in MRs, a potential barrier was patients’ uncertainty regarding the extent of their training. Patients could, however, imagine GPs delegating some aspects of MRs to them. Conclusions Our study suggests that patients regard MRs as beneficial and expect indications for their medicines to be checked, and possible interactions to be identified. To foster the implementation of MRs in primary care, it is important to consider barriers and facilitators to the four identified topics.

La multimorbilidad, definida como la presencia de dos o más enfermedades crónicas en un mismo individuo, conlleva consecuencias negativas para la persona e importantes retos para los sistemas sanitarios. En atención primaria, donde recae esencialmente la atención de este grupo de pacientes, la consulta es más compleja que la de un paciente con una única enfermedad debido, entre otros, al hecho de tener que manejar mayor cantidad de información clínica, disponer de poca evidencia científica para abordar la multimorbilidad, y tener que coordinar la labor de múltiples profesionales para garantizar la continuidad asistencial. Además, para poder implementar correctamente los planes de tratamiento en estos pacientes es necesario un proceso de toma de decisiones compartida médico-paciente. Entre las distintas herramientas disponibles para apoyar dicho proceso, recientemente se ha desarrollado una dirigida específicamente a pacientes con multimorbilidad en atención primaria y que se describe en el presente artículo: los principios Ariadne.

Abstract Background In oldest-old patients (>80), few trials showed efficacy of treating hypertension and they included mostly the healthiest elderly. The resulting lack of knowledge has led to inconsistent guidelines, mainly based on systolic blood pressure (SBP), cardiovascular disease (CVD) but not on frailty despite the high prevalence in oldest-old. This may lead to variation how General Practitioners (GPs) treat hypertension. Our aim was to investigate treatment variation of GPs in oldest-olds across countries and to identify the role of frailty in that decision. Methods Using a survey, we compared treatment decisions in cases of oldest-old varying in SBP, CVD, and frailty. GPs were asked if they would start antihypertensive treatment in each case. In 2016, we invited GPs in Europe, Brazil, Israel, and New Zealand. We compared the percentage of cases that would be treated per countries. A logistic mixed-effects model was used to derive odds ratio (OR) for frailty with 95% confidence intervals (CI), adjusted for SBP, CVD, and GP characteristics (sex, location and prevalence of oldest-old per GP office, and years of experience). The mixed-effects model was used to account for the multiple assessments per GP. Results The 29 countries yielded 2543 participating GPs: 52% were female, 51% located in a city, 71% reported a high prevalence of oldest-old in their offices, 38% and had >20 years of experience. Across countries, considerable variation was found in the decision to start antihypertensive treatment in the oldest-old ranging from 34 to 88%. In 24/29 (83%) countries, frailty was associated with GPs’ decision not to start treatment even after adjustment for SBP, CVD, and GP characteristics (OR 0.53, 95%CI 0.48–0.59; ORs per country 0.11–1.78). Conclusions Across countries, we found considerable variation in starting antihypertensive medication in oldest-old. The frail oldest-old had an odds ratio of 0.53 of receiving antihypertensive treatment. Future hypertension trials should also include frail patients to acquire evidence on the efficacy of antihypertensive treatment in oldest-old patients with frailty, with the aim to get evidence-based data for clinical decision-making.

Abstract Background Multimorbidity is associated with negative effects both on people’s health and on healthcare systems. A key problem linked to multimorbidity is polypharmacy, which in turn is associated with increased risk of partly preventable adverse effects, including mortality. The Ariadne principles describe a model of care based on a thorough assessment of diseases, treatments (and potential interactions), clinical status, context and preferences of patients with multimorbidity, with the aim of prioritizing and sharing realistic treatment goals that guide an individualized management. The aim of this study is to evaluate the effectiveness of a complex intervention that implements the Ariadne principles in a population of young-old patients with multimorbidity and polypharmacy. The intervention seeks to improve the appropriateness of prescribing in primary care (PC), as measured by the medication appropriateness index (MAI) score at 6 and 12 months, as compared with usual care. Methods/Design Design: pragmatic cluster randomized clinical trial. Unit of randomization: family physician (FP). Unit of analysis: patient. Scope: PC health centres in three autonomous communities: Aragon, Madrid, and Andalusia (Spain). Population: patients aged 65–74 years with multimorbidity (≥3 chronic diseases) and polypharmacy (≥5 drugs prescribed in ≥3 months). Sample size: n = 400 (200 per study arm). Intervention: complex intervention based on the implementation of the Ariadne principles with two components: (1) FP training and (2) FP-patient interview. Outcomes: MAI score, health services use, quality of life (Euroqol 5D-5L), pharmacotherapy and adherence to treatment (Morisky-Green, Haynes-Sackett), and clinical and socio-demographic variables. Statistical analysis: primary outcome is the difference in MAI score between T0 and T1 and corresponding 95% confidence interval. Adjustment for confounding factors will be performed by multilevel analysis. All analyses will be carried out in accordance with the intention-to-treat principle. Discussion It is essential to provide evidence concerning interventions on PC patients with polypharmacy and multimorbidity, conducted in the context of routine clinical practice, and involving young-old patients with significant potential for preventing negative health outcomes. Trial registration Clinicaltrials.gov, NCT02866799

Objectives To systematically identify knowledge clusters and research gaps in the health-related preferences of older patients with multimorbidity by mapping current evidence.Design Evidence map (systematic review variant).Data sources MEDLINE, EMBASE, PsycINFO, PSYNDEX, CINAHL and Science Citation Index/Social Science Citation Index/-Expanded from inception to April 2018.Study selection Studies reporting primary research on health-related preferences of older patients (mean age ≥60 years) with multimorbidity (≥2 chronic/acute conditions).Data extraction Two independent reviewers assessed studies for eligibility, extracted data and clustered the studies using MAXQDA-18 content analysis software.Results The 152 included studies (62% from North America, 28% from Europe) comprised 57 093 patients overall (range 9–9105). All used an observational design except for one interventional study: 63 (41%) were qualitative (59 cross-sectional, 4 longitudinal), 85 (57%) quantitative (63 cross-sectional, 22 longitudinal) and 3 (2%) used mixed methods. The setting was specialised care in 85 (56%) and primary care in 54 (36%) studies. We identified seven clusters of studies on preferences: end-of-life care (n=51, 34%), self-management (n=34, 22%), treatment (n=32, 21%), involvement in shared decision making (n=25, 17%), health outcome prioritisation/goal setting (n=19, 13%), healthcare service (n=12, 8%) and screening/diagnostic testing (n=1, 1%). Terminology (eg, preferences, views and perspectives) and concepts (eg, trade-offs, decision regret, goal setting) used to describe health-related preferences varied substantially between studies.Conclusion Our study provides the first evidence map on the preferences of older patients with multimorbidity. Included studies were mostly conducted in developed countries and covered a broad range of issues. Evidence on patient preferences concerning decision-making on screening and diagnostic testing was scarce. Differences in employed terminology, decision-making components and concepts, as well as the sparsity of intervention studies, are challenges for future research into evidence-based decision support seeking to elicit the preferences of older patients with multimorbidity and help them construct preferences.Trial registration number Open Science Framework (OSF): DOI 10.17605/OSF.IO/MCRWQ.

Introduction Interaction of conditions and treatments, complicated care needs and substantial treatment burden make patient–physician encounters involving multimorbid older patients highly complex. To optimally integrate patients’ preferences, define and prioritise realistic treatment goals and individualise care, a patient-centred approach is recommended. However, the preferences of older patients, who are especially vulnerable and frequently multimorbid, have not been systematically investigated with regard to their health status. The purpose of this evidence map is to explore current research addressing health-related preferences of older patients with multimorbidity, and to identify the knowledge clusters and research gaps.Methods and analysis To identify relevant research, we will conduct searches in the electronic databases MEDLINE, EMBASE, PsycINFO, PSYNDEX, CINAHL, Social Science Citation Index, Social Science Citation Index Expanded and the Cochrane library from their inception. We will check reference lists of relevant articles and carry out cited reference research (forward citation tracking). Two independent reviewers will screen titles and abstracts, check full texts for eligibility and extract the data. Any disagreement will be resolved and consensus reached with the help of a third reviewer. We will include both qualitative and quantitative studies, and address preferences from the patients’ perspectives in a multimorbid population of 60 years or older. There will be no restrictions on the publication language. Data extraction tables will present study and patient characteristics, aim of study, methods used to identify preferences and outcomes (ie, type of preferences). We will summarise the data using tables and figures (ie, bubble plot) to present the research landscape and to describe clusters and gaps.Ethics and dissemination Due to the nature of the proposed evidence map, ethics approval will not be required. Results from our research will be disseminated by means of specifically prepared materials for patients, at relevant (inter)national conferences and via publication in peer-reviewed journals.

Alzheimer’s disease (AD) is characterized by intracellular tau aggregates and extracellular deposition of amyloid-β (Aβ). The major genetic risk factor to develop AD is the Apolipoprotein E isoform 4 (ApoE4). ApoE4 may directly affect Aβ pathology, yet the exact role of ApoE4 in the progression of AD remains unclear. Although astrocytes are the main source of ApoE in brain tissue, other cell types might contribute to ApoE isotype-dependent effects. While ApoE expression does not play a relevant role in homeostatic microglia, we and others could recently show that ApoE expression is significant upregulated in disease-associated microglia including AD-mouse models and human AD. ApoE has been supposed to have an anti-inflammatory effect, with ApoE4 being less effective than ApoE3. However, ApoE-isotype specific effects on microglia function in disease have not been thoroughly investigated to date. In contrast to this, the role of ApoE2, the third most common major ApoE isoform, in neurodegeneration has not been characterized in detail, but it has been shown to delay the onset of disease in familial AD. To elucidate the differential roles of the three-major human ApoE isoforms on microglia function we each expressed the human ApoE isoforms in murine N9 microglia cells. We could show that ApoE4 specifically influences actin cytoskeleton rearrangement and morphology. In migration assays, ApoE4 significantly promotes cell motility. To quantify phagocytosis by microglia we established an uptake assay based on imaging flow cytometry. Although expression of ApoE4 led to significantly reduced uptake of Aβ in contrast to the other isoforms, we could show that ApoE4 specifically increased phagocytosis of apoptotic neuronal cells. Our findings show that ApoE4 intrinsically affects microglia physiology by upregulating motility and phagocytic behavior in vitro and may therefore specifically contribute to microglia dysregulation in AD.

Multimorbidity is a major concern in primary care. Nevertheless, evidence of prevalence and patterns of multimorbidity, and their determinants, are scarce. The aim of this study is to systematically review studies of the prevalence, patterns and determinants of multimorbidity in primary care.Systematic review of literature published between 1961 and 2013 and indexed in Ovid (CINAHL, PsychINFO, Medline and Embase) and Web of Knowledge. Studies were selected according to eligibility criteria of addressing prevalence, determinants, and patterns of multimorbidity and using a pretested proforma in primary care. The quality and risk of bias were assessed using STROBE criteria. Two researchers assessed the eligibility of studies for inclusion (Kappa= 0.86).We identified 39 eligible publications describing studies that included a total of 70,057,611 patients in 12 countries. The number of health conditions analysed per study ranged from 5 to 335, with multimorbidity prevalence ranging from 12.9% to 95.1%. All studies observed a significant positive association between multimorbidity and age (odds ratio [OR], 1.26 to 227.46), and lower socioeconomic status (OR, 1.20 to 1.91). Positive associations with female gender and mental disorders were also observed. The most frequent patterns of multimorbidity included osteoarthritis together with cardiovascular and/or metabolic conditions.Well-established determinants of multimorbidity include age, lower socioeconomic status and gender. The most prevalent conditions shape the patterns of multimorbidity. However, the limitations of the current evidence base means that further and better designed studies are needed to inform policy, research and clinical practice, with the goal of improving health-related quality of life for patients with multimorbidity. Standardization of the definition and assessment of multimorbidity is essential in order to better understand this phenomenon, and is a necessary immediate step.