Costs attributable to hypercholesterolemia in a single period and over the life cycle.

Hypercholesterolemia is a major risk factor for atherosclerotic cardiovascular disease leading to reduced (healthy) life years. The aim of this study is to quantify the societal costs associated with hypercholesterolemia. We use epidemiologic data on the distribution of cholesterol levels as well as data on relative risks regarding ischemic heart disease, stroke, and other cardiovascular diseases. The analytical approach is based on the use of population-attributable fractions applied to direct medical, direct non-medical and indirect costs using data of Austria. Within a life-cycle analysis we sum up the costs of hypercholesterolemia for the population of 2019 and, thus, consider future morbidity and mortality effects on this population. Epidemiologic data suggest that approximately half of Austria's population have low-density lipoprotein cholesterol (LDL-C) levels above the target levels (i.e., are exposed to increased risk). We estimate that 8.2% of deaths are attributable to hypercholesterolemia. Total costs amount to about 0.33% of GDP in the single-period view. In the life-cycle perspective, total costs amount to €806.06 million, €312.1 million of which are medical costs, and about €494 million arise due to production loss associated with hypercholesterolemia. The study points out that significant shares of deaths, entries into disability pension and care allowance, full-time equivalents lost to the labor market as well as monetary costs for the health system and the society could be avoided if LDL-C-levels of the population were reduced.

The role of primary care during the pandemic: shared experiences from providers in five European countries.

BACKGROUND: The COVID-19 pandemic necessitated wide-ranging adaptations to the organisation of health systems, and primary care is no exception. This article aims to collate insights on the role of primary care during the pandemic. The gained knowledge helps to increase pandemic preparedness and resilience. METHODS: The role of primary care during the pandemic in five European countries (Austria, Denmark, France, Hungary, Italy) was investigated using a qualitative approach, namely case study, based on document analysis and semi-structured interviews. In total, 31 interviews were conducted with primary care providers between June and August 2022. The five country case studies were subjected to an overarching analysis focusing on successful strategies as well as gaps and failures regarding pandemic management in primary care. RESULTS: Primary care providers identified disruptions to service delivery as a major challenge emerging from the pandemic which led to a widespread adoption of telehealth. Despite the rapid increase in telehealth usage and efforts of primary care providers to organise face-to-face care delivery in a safe way, some patient groups were particularly affected by disruptions in service delivery. Moreover, primary care providers perceived a substantial propagation of misinformation about COVID-19 and vaccines among the population, which also threatened patient-physician relationships. At the same time, primary care providers faced an increased workload, had to work with insufficient personal protective equipment and were provided incongruous guidelines from public authorities. There was a consensus among primary care providers that they were mostly sidelined by public health policy in the context of pandemic management. Primary care providers tackled these problems through a diverse set of measures including home visits, implementing infection control measures, refurbishing used masks, holding internal meetings and relying on their own experiences as well as information shared by colleagues. CONCLUSION: Primary care providers were neither well prepared nor the focus of initial policy making. However, they implemented creative solutions to the problems they faced and applying the learnings from the pandemic could help in increasing the resilience of primary care. Attributes of an integrated health system with a strong primary care component proved beneficial in addressing immediate effects of the pandemic.

Exploring the effectiveness of demand-side retail pharmaceutical expenditure reforms : Cross-country evidence from weighted-average least squares estimation.

Increasing expenditures on retail pharmaceuticals bring a critical challenge to the financial stability of healthcare systems worldwide. Policy makers have reacted by introducing a range of measures to control the growth of public pharmaceutical expenditure (PPE). Using panel data on European and non-European OECD member countries from 1990 to 2015, we evaluate the effectiveness of six types of demand-side expenditure control measures including physician-level behaviour measures, system-level price-control measures and substitution measures, alongside a proxy for cost-sharing and add a new dimension to the existing empirical evidence hitherto based on national-level and meta-studies. We use the weighted-average least squares regression framework adapted for estimation with panel-corrected standard errors. Our empirical analysis suggests that direct patient cost-sharing and some-but not all-demand-side measures successfully dampened PPE growth in the past. Cost-sharing schemes stand out as a powerful mechanism to curb PPE growth, but bear a high risk of adverse effects. Other demand-side measures are more limited in effect, though may be more equitable. Due to limitations inherent in the study approach and the data, the results are only explorative.

Regulation of the COPII secretory machinery via focal adhesions and extracellular matrix signaling.

Proteins that enter the secretory pathway are transported from their place of synthesis in the endoplasmic reticulum to the Golgi complex by COPII-coated carriers. The networks of proteins that regulate these components in response to extracellular cues have remained largely elusive. Using high-throughput microscopy, we comprehensively screened 378 cytoskeleton-associated and related proteins for their functional interaction with the coat protein complex II (COPII) components SEC23A and SEC23B. Among these, we identified a group of proteins associated with focal adhesions (FERMT2, MACF1, MAPK8IP2, NGEF, PIK3CA, and ROCK1) that led to the downregulation of SEC23A when depleted by siRNA. Changes in focal adhesions induced by plating cells on ECM also led to the downregulation of SEC23A and decreases in VSVG transport from ER to Golgi. Both the expression of SEC23A and the transport defect could be rescued by treatment with a focal adhesion kinase inhibitor. Altogether, our results identify a network of cytoskeleton-associated proteins connecting focal adhesions and ECM-related signaling with the gene expression of the COPII secretory machinery and trafficking.

The patient at the centre: evidence from 17 European integrated care programmes for persons with complex needs.

BACKGROUND: As the prevalence of multi-morbidity increases in ageing societies, health and social care systems face the challenge of providing adequate care to persons with complex needs. Approaches that integrate care across sectors and disciplines have been increasingly developed and implemented in European countries in order to tackle this challenge. The aim of the article is to identify success factors and crucial elements in the process of integrated care delivery for persons with complex needs as seen from the practical perspective of the involved stakeholders (patients, professionals, informal caregivers, managers, initiators, payers). METHODS: Seventeen integrated care programmes for persons with complex needs in 8 European countries were investigated using a qualitative approach, namely thick description, based on semi-structured interviews and document analysis. In total, 233 face-to-face interviews were conducted with stakeholders of the programmes between March and September 2016. Meta-analysis of the individual thick description reports was performed with a focus on the process of care delivery. RESULTS: Four categories that emerged from the overarching analysis are discussed in the article: (1) a holistic view of the patient, considering both mental health and the social situation in addition to physical health, (2) continuity of care in the form of single contact points, alignment of services and good relationships between patients and professionals, (3) relationships between professionals built on trust and facilitated by continuous communication, and (4) patient involvement in goal-setting and decision-making, allowing patients to adapt to reorganised service delivery. CONCLUSIONS: We were able to identify several key aspects for a well-functioning integrated care process for complex patients and how these are put into actual practice. The article sets itself apart from the existing literature by specifically focussing on the growing share of the population with complex care needs and by providing an analysis of actual processes and interpersonal relationships that shape integrated care in practice, incorporating evidence from a variety of programmes in several countries.

In vivo cardiac pacemaker function of differentiated human mesenchymal stem cells from adipose tissue transplanted into porcine hearts.

BACKGROUND: Mesenchymal stem cells (MSC) modified by gene transfer to express cardiac pacemaker channels such as HCN2 or HCN4 were shown to elicit pacemaker function after intracardiac transplantation in experimental animal models. Human MSC derived from adipose tissue (haMSC) differentiate into cells with pacemaker properties in vitro, but little is known about their behavior after intracardiac transplantation. AIM: To investigate whether haMSC elicit biological pacemaker function in vivo after transplantation into pig hearts. METHODS: haMSC under native conditions (nhaMSC) or after pre-conditioning by medium differentiation (dhaMSC) (n = 6 pigs each, 5 × 106 cells/animal) were injected into the porcine left ventricular free wall. Animals receiving PBS injection served as controls (n = 6). Four weeks later, total atrioventricular (AV)-block was induced by radiofrequency catheter ablation, and electronic pacemaker devices were implanted for backup stimulation and heart rate monitoring. Ventricular rate and rhythm of pigs were evaluated during a follow-up of 15 d post ablation by 12-lead-ECG with heart rate assessment, 24-h continuous rate monitoring recorded by electronic pacemaker, assessment of escape recovery time, and pharmacological challenge to address catecholaminergic rate response. Finally, hearts were analyzed by histological and immunohistochemical investigations. RESULTS: In vivo transplantation of dhaMSC into the left ventricular free wall of pigs elicited spontaneous and regular rhythms that were pace-mapped to ventricular injection sites (mean heart rate 72.2 ± 3.6 bpm; n = 6) after experimental total AV block. Ventricular rhythms were stably detected over a 15-d period and were sensitive to catecholaminergic stimulation (mean maximum heart rate 131.0 ± 6.2 bpm; n = 6; P < 0.001). Pigs, which received nhaMSC or PBS presented significantly lower ventricular rates (mean heart rates 47.2 ± 2.5 bpm and 37.4 ± 3.2 bpm, respectively; n = 6 each; P < 0.001) and exhibited little sensitivity towards catecholaminergic stimulation (mean maximum heart rates 76.4 ± 3.1 bpm and 60.5 ± 3.1 bpm, respectively; n = 6 each; P < 0.05). Histological and immunohistochemical evaluation of hearts treated with dhaMSC revealed local clusters of transplanted cells at the injection sites that lacked macrophage or lymphocyte infiltrations or tumor formation. Intense fluorescence signals at these sites indicated membrane expression of HCN4 and other pacemaker-specific proteins involved in cardiac automaticity and impulse propagation. CONCLUSION: dhaMSC transplanted into pig left ventricles sustainably induced rate-responsive ventricular pacemaker activity after in vivo engraftment for four weeks. The data suggest that pre-conditioned MSC may further differentiate along a pacemaker-related lineage after myocardial integration and may establish superior pacemaker properties in vivo.

Displaced cratonic mantle concentrates deep carbon during continental rifting.

Continental rifts are important sources of mantle carbon dioxide (CO2) emission into Earth's atmosphere1-3. Because deep carbon is stored for long periods in the lithospheric mantle4-6, rift CO2 flux depends on lithospheric processes that control melt and volatile transport1,3,7. The influence of compositional and thickness differences between Archaean and Proterozoic lithosphere on deep-carbon fluxes remains untested. Here we propose that displacement of carbon-enriched Tanzanian cratonic mantle concentrates deep carbon below parts of the East African Rift System. Sources and fluxes of CO2 and helium are examined over a 350-kilometre-long transect crossing the boundary between orogenic (Natron and Magadi basins) and cratonic (Balangida and Manyara basins) lithosphere from north to south. Areas of diffuse CO2 degassing exhibit increasing mantle CO2 flux and 3He/4He ratios as the rift transitions from Archaean (cratonic) to Proterozoic (orogenic) lithosphere. Active carbonatite magmatism also occurs near the craton edge. These data indicate that advection of the root of thick Archaean lithosphere laterally to the base of the much thinner adjacent Proterozoic lithosphere creates a zone of highly concentrated deep carbon. This mode of deep-carbon extraction may increase CO2 fluxes in some continental rifts, helping to control the production and location of carbonate-rich magmas.

Digital Health Transformation of Integrated Care in Europe: Overarching Analysis of 17 Integrated Care Programs.

BACKGROUND: Digital health tools comprise a wide range of technologies to support health processes. The potential of these technologies to effectively support health care transformation is widely accepted. However, wide scale implementation is uneven among countries and regions. Identification of common factors facilitating and hampering the implementation process may be useful for future policy recommendations. OBJECTIVE: The aim of this study was to analyze the implementation of digital health tools to support health care and social care services, as well as to facilitate the longitudinal assessment of these services, in 17 selected integrated chronic care (ICC) programs from 8 European countries. METHODS: A program analysis based on thick descriptions-including document examinations and semistructured interviews with relevant stakeholders-of ICC programs in Austria, Croatia, Germany, Hungary, the Netherlands, Norway, Spain, and the United Kingdom was performed. A total of 233 stakeholders (ie, professionals, providers, patients, carers, and policymakers) were interviewed from November 2014 to September 2016. The overarching analysis focused on the use of digital health tools and program assessment strategies. RESULTS: Supporting digital health tools are implemented in all countries, but different levels of maturity were observed among the programs. Only few ICC programs have well-established strategies for a comprehensive longitudinal assessment. There is a strong relationship between maturity of digital health and proper evaluation strategies of integrated care. CONCLUSIONS: Notwithstanding the heterogeneity of the results across countries, most programs aim to evolve toward a digital transformation of integrated care, including implementation of comprehensive assessment strategies. It is widely accepted that the evolution of digital health tools alongside clear policies toward their adoption will facilitate regional uptake and scale-up of services with embedded digital health tools.

The C-terminal HCN4 variant P883R alters channel properties and acts as genetic modifier of atrial fibrillation and structural heart disease.

Atrial fibrillation (AF) is the most frequent sustained arrhythmia and can lead to structural cardiac changes, known as tachycardia-induced cardiomyopathy (TIC). HCN4 is implicated in spontaneous excitation of the sinoatrial node, while channel dysfunction has been associated with sinus bradycardia, AF and structural heart disease. We here asked whether HCN4 mutations may contribute to the development of TIC, as well. Mutation scanning of HCN4 in 60 independent patients with AF and suspected TIC followed by panel sequencing in carriers of HCN4 variants identified the HCN4 variant P883R [minor allele frequency (MAF): 0,88%], together with the KCNE1 variant S38G (MAF: 65%) in three unrelated patients. Family histories revealed additional cases of AF, sudden cardiac death and cardiomyopathy. Patch-clamp recordings of HCN4-P883R channels expressed in HEK293 cells showed remarkable alterations of channel properties shifting the half-maximal activation voltage to more depolarized potentials, while channel deactivation was faster compared to wild-type (WT). Co-transfection of WT and mutant subunits, resembling the heterozygous cellular situation of our patients, revealed significantly higher current densities compared to WT. In conclusion HCN4-P883R may increase ectopic trigger and maintenance of AF by shifting the activation voltage of If to more positive potentials and producing higher current density. Together with the common KCNE1 variant S38G, previously proposed as a genetic modifier of AF, HCN4-P883R may provide a substrate for the development of AF and TIC.

The SELFIE framework for integrated care for multi-morbidity: Development and description.

BACKGROUND: The rise of multi-morbidity constitutes a serious challenge in health and social care organisation that requires a shift from disease- towards person-centred integrated care. The aim of the current study was to develop a conceptual framework that can aid the development, implementation, description, and evaluation of integrated care programmes for multi-morbidity. METHODS: A scoping review and expert discussions were used to identify and structure concepts for integrated care for multi-morbidity. A search of scientific and grey literature was conducted. DISCUSSION: meetings were organised within the SELFIE research project with representatives of five stakeholder groups (5Ps): patients, partners, professionals, payers, and policy makers. RESULTS: In the scientific literature 11,641 publications were identified, 92 were included for data extraction. A draft framework was constructed that was adapted after discussion with SELFIE partners from 8 EU countries and 5P representatives. The core of the framework is the holistic understanding of the person with multi-morbidity in his or her environment. Around the core, concepts were grouped into adapted WHO components of health systems: service delivery, leadership & governance, workforce, financing, technologies & medical products, and information & research. Within each component micro, meso, and macro levels are distinguished. CONCLUSION: The framework structures relevant concepts in integrated care for multi-morbidity and can be applied by different stakeholders to guide development, implementation, description, and evaluation.

Relevant models and elements of integrated care for multi-morbidity: Results of a scoping review.

BACKGROUND: In order to provide adequate care for the growing group of persons with multi-morbidity, innovative integrated care programmes are appearing. The aims of the current scoping review were to i) identify relevant models and elements of integrated care for multi-morbidity and ii) to subsequently identify which of these models and elements are applied in integrated care programmes for multi-morbidity. METHODS: A scoping review was conducted in the following scientific databases: Cochrane, Embase, PubMed, PsycInfo, Scopus, Sociological Abstracts, Social Services Abstracts, and Web of Science. A search strategy encompassing a) models, elements and programmes, b) integrated care, and c) multi-morbidity was used to identify both models and elements (aim 1) and implemented programmes of integrated care for multi-morbidity (aim 2). Data extraction was done by two independent reviewers. Besides general information on publications (e.g. publication year, geographical region, study design, and target group), data was extracted on models and elements that publications refer to, as well as which models and elements are applied in recently implemented programmes in the EU and US. RESULTS: In the review 11,641 articles were identified. After title and abstract screening, 272 articles remained. Full text screening resulted in the inclusion of 92 articles on models and elements, and 50 articles on programmes, of which 16 were unique programmes in the EU (n=11) and US (n=5). Wagner's Chronic Care Model (CCM) and the Guided Care Model (GCM) were most often referred to (CCM n=31; GCM n=6); the majority of the other models found were only referred to once (aim 1). Both the CCM and GCM focus on integrated care in general and do not explicitly focus on multi-morbidity. Identified elements of integrated care were clustered according to the WHO health system building blocks. Most elements pertained to 'service delivery'. Across all components, the five elements referred to most often are person-centred care, holistic or needs assessment, integration and coordination of care services and/or professionals, collaboration, and self-management (aim 1). Most (n=10) of the 16 identified implemented programmes for multi-morbidity referred to the CCM (aim 2). Of all identified programmes, the elements most often included were self-management, comprehensive assessment, interdisciplinary care or collaboration, person-centred care and electronic information system (aim 2). CONCLUSION: Most models and elements found in the literature focus on integrated care in general and do not explicitly focus on multi-morbidity. In line with this, most programmes identified in the literature build on the CCM. A comprehensive framework that better accounts for the complexities resulting from multi-morbidity is needed.

Diagnosis of cryptococcal and tuberculous meningitis in a resource-limited African setting.

OBJECTIVES: Cryptococcal meningitis (CM) and tuberculous meningitis (TBM) are common in HIV-infected adults in Africa and difficult to diagnose. Inaccurate diagnosis results in adverse outcomes. We describe patterns of meningitis in a Malawian hospital, focusing on features which differentiate CM and TBM with the aim to derive an algorithm using only clinical and basic laboratory data available in this resource-poor setting. METHODS: Consecutive patients admitted with meningitis were prospectively recruited, clinical features were recorded and cerebrospinal fluid (CSF) was examined. RESULTS: A total of 573 patients were recruited, and 263 (46%) had CSF consistent with meningitis. One hundred and twelve (43%) had CM and 46 (18%) had TBM. CM was associated with high CSF opening pressure and low CSF leukocyte count. Fever, neck stiffness and reduced conscious level were associated with TBM. A diagnostic index was constructed demonstrating sensitivity 83%and specificity 79% for the differentiation of CM and TBM. An algorithm was derived with 92% sensitivity for the diagnosis of CM, but only 58% specificity. CONCLUSIONS: Although we demonstrate features associated with CM and TBM, a sufficiently sensitive and specific diagnostic algorithm could not be derived, suggesting that the diagnosis of CM and TBM in resource-limited settings still requires better access to laboratory tools.

Sphingosine-1-phosphate receptors stimulate macrophage plasma-membrane actin assembly via ADP release, ATP synthesis and P2X7R activation.

Eukaryotic plasma membranes assemble actin filaments within seconds of activation of many receptors, especially during chemotaxis. Here, serum or sphingosine-1-phosphate stimulation of J774 and RAW macrophages released ADP within seconds into the extracellular medium, along with an adenylate kinase activity that converted ADP to ATP. ATP then activated the P2X7 receptor (P2X7R) that was necessary for a peak of plasma-membrane actin assembly within 5 to 10 seconds in P2X7R-expressing J774, RAW and primary macrophages. Neither actin assembly nor characteristic P2X7R channel activity was seen in response to ATP in P2X7R-knockout macrophages, as detected by patch-clamp analysis. Since P2X7R has been shown previously to form a macromolecular complex with actin we propose that it is involved in the membrane assembly of actin. Our data reveal a surprisingly rapid and complex relay of signaling and externalization events that precede and control actin assembly induced by sphingosine-1-phosphate. The overall model we present is strongly supported by the data presented in the accompanying paper that focuses on latex bead phagosomes.