Landelijke monitor populatiemanagement : Deel 1: beschrijving proeftuinen

In Nederland zijn verschillende initiatieven gestart om zorg en ondersteuning op regionaal niveau anders vorm te geven. Deze regionale populatiegerichte aanpak wordt ook wel populatiemanagement genoemd. Doel van de initiatieven is de gezondheid van de populatie en de kwaliteit van de zorg te verbeteren en de kosten van de zorg te beheersen. Het ministerie van VWS heeft op voordracht van de zorgverzekeraars negen van deze regionale initiatieven geselecteerd als 'proeftuinen'. Het RIVM volgt deze proeftuinen om beter zicht te krijgen op het implementatieproces, op de succes- en faalfactoren en op het effect van de initiatieven op de gezondheid van de populatie en de kwaliteit en kosten van de zorg. Op dit moment zijn de proeftuinen sterk in ontwikkeling. Begin 2014 vormen de proeftuinen netwerken, vastgelegd in convenanten of samenwerkingsovereenkomsten. In de proeftuinen nemen veelal eerstelijnszorgorganisaties, ziekenhuizen en zorgverzekeraars deel, in variërende mate aangevuld met andere actoren zoals de gemeente. De populaties van de proeftuinen zijn op verschillende manieren afgebakend: geografisch (alle inwoners van een of meerdere gemeenten), op basis van het verzorgingsgebied van de betrokken huisartsen of zorggroepen, en ten slotte wordt nog onderscheid gemaakt tussen wel of niet verzekerd zijn bij de betrokken zorgverzekeraar. Iedere proeftuin heeft verschillende programma's (thema's) en een bijbehorende set interventies opgesteld. De scope van de programma's is breed en varieert tussen de proeftuinen. De interventies richten zich vaak op thema's als substitutie van zorg (verschuiving van zorg van tweede lijn naar eerste lijn), integratie van zorg (eventueel met welzijn) en preventie. In eerste instantie worden de interventies vooral toegepast op chronische zorg, medicatiegebruik en zorg rondom ontslag. De proeftuinen richten zich grotendeels nog op de eerste- en tweedelijnszorg. Wel is er de ambitie om dit gaandeweg uit te breiden met interventies in andere domeinen, zoals GGZ en jeugdzorg. De projectplannen van de proeftuinen zijn de afgelopen maanden verder uitgewerkt en de eerste interventies worden vanaf 2014 getest en/of geïmplementeerd. Nog niet voor alle geplande interventies is (structurele) financiering verworven. Vooralsnog zijn er tussen de deelnemende zorgaanbieder(s) en zorgverzekeraars in de proeftuinen geen definitieve afspraken gemaakt over uitkomstbekostiging en shared savings. Er zijn op dit gebied wel (voorzichtige) ontwikkelingen gaande, maar het is nog onduidelijk welke vorm dit gaat krijgen.In the Netherlands, several initiatives have emerged that aim to rearrange health services and promote intersectoral collaboration at regional level. These initiatives focus on the health needs of a specified population, resembling the ideas of population (health) management. The main goal is to improve population health and quality of care and to control health care costs. The Dutch Ministry of Health, Welfare and Sport designated nine of these initiatives as 'pioneer sites'. In the coming years, the National Institute for Public Health and the Environment (RIVM) will monitor these sites in order to get insight into the implementation process, the determinants of successful population management in the Dutch context, and the impact of the initiatives in terms of population health, quality of care and health spending. Currently, the nine pioneer sites are under development. Early 2014, they represent organizational networks including different types of organizations. Agreements were signed to confirm the intended cooperation within the network. All pioneer sites contain primary care organizations, hospitals and a health insurer. Other stakeholders or care providers in the health system, such as local governments, participate to varying degrees. Each pioneer site identified its target population in one of the following ways: geographically (including all citizens living in one or more municipalities); based on the catchment area of specific care providers; or enrollment in a health insurance program. Each pioneer site defined a set of programs or themes with accompanying interventions to achieve its goals. The scope of these programs is rather broad and varies between the sites. Often, interventions focus on intermediate goals such as substitution of care (from secondary to primary care), integration of services (possibly including welfare) and improved preventive care. At the start, most interventions concern chronic care, the use of medicines and the organization of care around hospital discharge. The pioneer sites aim to include other domains in the future, such as mental health care and youth care. In the past months, the pioneer sites have elaborated their project plans. Most interventions will be tested and/or implemented from 2014 onwards. More detailed financing arrangements will be made at the intervention level and at the level of the entire site. As yet, there are no definitive contracts between the health insurers and providers of care that are involved in the sites. Forthcoming contracts may include arrangements with respect to pay for performance or shared savings, but this will become clearer in the near future.Ministerie van VW

Exposure to TARC alters beta2-adrenergic receptor signaling in human peripheral blood T lymphocytes

The beta(2)-adrenergic receptor (beta(2)-AR) negatively regulates T cell activity through the activation of the G(s)/adenylyl cyclase/cAMP pathway. beta(2)-AR desensitization, which can be induced by its phosphorylation, may have important consequences for the regulation of T cell function in asthma. In the present study we demonstrate that the C-C chemokine thymus and activation-regulated chemokine (TARC) impairs the ability of beta(2)-agonist fenoterol to activate the cAMP downstream effector cAMP-responsive element binding protein (CREB) in freshly isolated human T cells. The TARC-induced activation of Src kinases resulted in membrane translocation of both G protein-coupled receptor kinase (GRK) 2 and beta-arrestin. Moreover, TARC was able to induce Src-dependent serine phosphorylation of the beta(2)-AR as well as its association with GRK2 and beta-arrestin. Finally, in contrast to CREB, phosphorylation of Src and extracellular signal-regulated kinase was enhanced by fenoterol upon TARC pretreatment. In summary, we show for the first time that TARC exposure impairs beta(2)-AR function in T cells. Our data suggest that this is mediated by Src-dependent activation of GRK2, resulting in receptor phosphorylation, binding to beta-arrestin, and a switch from cAMP-dependent signaling to activation of the MAPK pathway. We propose that aberrant T cell control in the presence of endogenous beta-agonists promotes T cell-mediated inflammation in asthma

Mitochondrial dysfunction increases pro-inflammatory cytokine production and impairs repair and corticosteroid responsiveness in lung epithelium

COPD is characterized by chronic lung inflammation and irreversible lung tissue damage. Inhaled noxious gases, including cigarette smoke, are the major risk factor for COPD. Inhaled smoke first encounters the epithelial lining of the lungs, causing oxidative stress and mitochondrial dysfunction. We investigated whether a mitochondrial defect may contribute to increased lung epithelial pro-inflammatory responses, impaired epithelial repair and reduced corticosteroid sensitivity as observed in COPD. We used wild-type alveolar epithelial cells A549 and mitochondrial DNA-depleted A549 cells (A549 Rho-0) and studied pro-inflammatory responses using (multiplex) ELISA as well as epithelial barrier function and repair (real-time impedance measurements), in the presence and absence of the inhaled corticosteroid budesonide. We observed that A549 Rho-0 cells secrete higher levels of pro-inflammatory cytokines than wild-type A549 cells and display impaired repair upon wounding. Budesonide strongly suppressed the production of neutrophil attractant CXCL8, and promoted epithelial integrity in A549 wild-type cells, while A549 Rho-0 cells displayed reduced corticosteroid sensitivity compared to wild-type cells. The reduced corticosteroid responsiveness may be mediated by glycolytic reprogramming, specifically glycolysis-associated PI3K signaling, as PI3K inhibitor LY294002 restored the sensitivity of CXCL8 secretion to corticosteroids in A549 Rho-0 cells. In conclusion, mitochondrial defects may lead to increased lung epithelial pro-inflammatory responses, reduced epithelial repair and reduced corticosteroid responsiveness in lung epithelium, thus potentially contributing to the pathogenesis of COPD

Inhibition of beta-Catenin/CREB Binding Protein Signaling Attenuates House Dust Mite-Induced Goblet Cell Metaplasia in Mice

Excessive mucus production is a major feature of allergic asthma. Disruption of epithelial junctions by allergens such as house dust mite (HDM) results in the activation of β-catenin signaling, which has been reported to stimulate goblet cell differentiation. β-catenin interacts with various co-activators including CREB binding protein (CBP) and p300, thereby regulating the expression of genes involved in cell proliferation and differentiation, respectively. We specifically investigated the role of the β-catenin/CBP signaling pathway in goblet cell metaplasia in a HDM-induced allergic airway disease model in mice using ICG-001, a small molecule inhibitor that blocks the binding of CBP to β-catenin. Female 6- 8-week-old BALB/c mice were sensitized to HDM/saline on days 0, 1, and 2, followed by intranasal challenge with HDM/saline with or without subcutaneous ICG-001/vehicle treatment from days 14 to 17, and samples harvested 24 h after the last challenge/treatment. Differential inflammatory cells in bronchoalveolar lavage (BAL) fluid were enumerated. Alcian blue (AB)/Periodic acid–Schiff (PAS) staining was used to identify goblet cells/mucus production, and airway hyperresponsiveness (AHR) was assessed using invasive plethysmography. Exposure to HDM induced airway inflammation, goblet cell metaplasia and increased AHR, with increased airway resistance in response to the non-specific spasmogen methacholine. Inhibition of the β-catenin/CBP pathway using treatment with ICG-001 significantly attenuated the HDM-induced goblet cell metaplasia and infiltration of macrophages, but had no effect on eosinophils, neutrophils, lymphocytes or AHR. Increased β-catenin/CBP signaling may promote HDM-induced goblet cell metaplasia in mice

COPD-derived fibroblasts secrete higher levels of senescence-associated secretory phenotype proteins

COPD-derived fibroblasts have increased cellular senescence. Senescent cell accumulation can induce tissue dysfunction by their senescence-associated secretory phenotype (SASP). We aimed to determine the SASP of senescent fibroblasts and COPD-derived lung fibroblasts, including severe, early-onset (SEO)-COPD. SASP protein secretion was measured after paraquat-induced senescence in lung fibroblasts using Olink Proteomics and compared between (SEO-)COPD-derived and control-derived fibroblasts. We identified 124 SASP proteins of senescent lung fibroblasts, of which 42 were secreted at higher levels by COPD-derived fibroblasts and 35 by SEO-COPD-derived fibroblasts compared with controls. Interestingly, the (SEO-)COPD-associated SASP included proteins involved in chronic inflammation, which may contribute to (SEO-)COPD pathogenesis

Acute cigarette smoke-induced eQTL affects formyl peptide receptor expression and lung function

Background and objective Cigarette smoking is one of the most prevalent causes of preventable deaths worldwide, leading to chronic diseases, including chronic obstructive pulmonary disease (COPD). Cigarette smoke is known to induce significant transcriptional modifications throughout the respiratory tract. However, it is largely unknown how genetic profiles influence the smoking-related transcriptional changes and how changes in gene expression translate into altered alveolar epithelial repair responses. Methods We performed a candidate-based acute cigarette smoke-induced eQTL study, investigating the association between SNP and differential gene expression of FPR family members in bronchial epithelial cells isolated 24 h after smoking and after 48 h without smoking. The effects FPR1 on lung epithelial integrity and repair upon damage in the presence and absence of cigarette smoke were studied in CRISPR-Cas9-generated lung epithelial knockout cells. Results One significant (FDR 2-fold change in gene expression. The minor allele of rs3212855 was associated with significantly higher gene expression of FPR1, FPR2 and FPR3 upon smoking. Importantly, the minor allele of rs3212855 was also associated with lower lung function. Alveolar epithelial FPR1 knockout cells were protected against CSE-induced reduction in repair capacity upon wounding. Conclusion We identified a novel smoking-related inducible eQTL that is associated with a smoke-induced increase in the expression of FPR1, FPR2 and FPR3, and with lowered lung function. in vitro FPR1 down-regulation protects against smoke-induced reduction in lung epithelial repair

From the pathophysiology of the human lung alveolus to epigenetic editing: Congress 2018 highlights from ERS Assembly 3 "Basic and Translational Science."

The European Respiratory Society (ERS) International Congress is the largest respiratory congress and brings together leading experts in all fields of respiratory medicine and research. ERS Assembly 3 shapes the basic and translational science aspects of this congress, aiming to combine cutting-edge novel developments in basic research with novel clinical findings. In this article, we summarise a selection of the scientific highlights from the perspective of the three groups within Assembly 3. In particular, we discuss new insights into the pathophysiology of the human alveolus, novel tools in organoid development and (epi)genome editing, as well as insights from the presented abstracts on novel therapeutic targets being identified for idiopathic pulmonary fibrosis.S