Sex-specific association of visceral and subcutaneous adipose tissue volumes with systemic inflammation and innate immune cells in people living with obesity.

BACKGROUND AND AIMS: Obesity predisposes to metabolic and cardiovascular diseases. Adipose tissue inflammation and systemic inflammation contribute to these complications. There are strong sex differences in adipose tissue distribution and in systemic inflammation. Women have more subcutaneous adipose tissue (SAT) and less visceral adipose tissue (VAT) than men. We explored the sex differences in the association between the different adipose compartments and inflammatory markers that are important in cardiometabolic disease pathophysiology. METHODS: Single-center observational cohort study with 302 individuals with a BMI ≥ 27 kg/m2. We were unable to acquire MRI data from seven individuals and from another 18 the MRI data were not usable, resulting in 277 people (155 men, 122 women), aged 55-81 years. INTERVENTION: We performed the following measurements: abdominal magnetic resonance imaging to measure VAT, and SAT (deep and superficial) volumes; circulating leukocyte counts and cytokine production capacity of peripheral blood mononuclear cells (PBMCs), circulating cytokines, adipokines, and targeted proteomics; abdominal sSAT biopsies for histology and gene expression. RESULTS: Only in women, (s)SAT volume was associated with circulating leukocytes, monocytes, and neutrophils. Circulating IL-6 and IL-18BP were associated with SAT volume in women and VAT in men. Several circulating proteins, including monocyte-colony-stimulating factor 1 and hepatocyte growth factor, are associated with sSAT in women and VAT in men. Only in women, SAT volume is associated with SAT expression of inflammatory proteins, including leptin, CD68, TNFα and IL-1α. CONCLUSION: In women living with obesity, abdominal SAT volume, especially sSAT, is associated with circulating leukocytes and inflammatory proteins. In men, these parameters mainly show associations with VAT volume. This could be because only in women, sSAT volume is associated with sSAT expression of inflammatory proteins. These findings underscore that future research on adipose tissue in relation to cardiometabolic and cardiovascular disease should take sex differences into account.

Learning collaboration at the primary-secondary care interface: a dual-method study to define design principles for interventions in postgraduate training programmes.

BACKGROUND: Collaboration between primary and secondary care (PSCC) is important to provide patient-centered care. Postgraduate training programmes should provide training to learn PSCC. With a design based research (DBR) approach design principles can be formulated for designing effective interventions in specific contexts. The aim of this study is to determine design principles for interventions aimed to learn PSCC in postgraduate training programmes. METHODS: DBR is characterised by multi-method studies. We started with a literature review on learning collaboration between healthcare professionals from different disciplines within the same profession (intraprofessional) to extract preliminary design principles. These were used to inform and feed group discussions among stakeholders: trainees, supervisors and educationalists in primary and secondary care. Discussions were audiotaped, transcribed and analysed using thematic analysis to formulate design principles. RESULTS: Eight articles were included in the review. We identified four preliminary principles to consider in the design of interventions: participatory design, work process involvement, personalised education and role models. We conducted three group discussions with in total eighteen participants. We formulated three design principles specific for learning PSCC in postgraduate training programmes: (1) The importance of interaction, being able to engage in a learning dialogue. (2) Facilitate that the learning dialogue concerns collaboration. (3) Create a workplace that facilitates engagement in a learning dialogue. In the last design principle we distinguished five subcategories: intervention emphasises the urge for PSCC and is based on daily practice, the presence of role models, the work context creates time for learning PSCC, learning PSCC is formalised in curricula and the presence of a safe learning environment. CONCLUSION: This article describes design principles for interventions in postgraduate training programmes with the aim to learn PSCC. Interaction is key in learning PSCC. This interaction should concern collaborative issues. Furthermore, it is essential to include the workplace in the intervention and make adjacent changes in the workplace when implementing interventions. The knowledge gathered in this study can be used to design interventions for learning PSCC. Evaluation of these interventions is needed to acquire more knowledge and adjust design principles when necessary.

Reduced concentrations of the B cell cytokine interleukin 38 are associated with cardiovascular disease risk in overweight subjects.

The IL-1 family member IL-38 (IL1F10) suppresses inflammatory and autoimmune conditions. Here, we report that plasma concentrations of IL-38 in 288 healthy Europeans correlate positively with circulating memory B cells and plasmablasts. IL-38 correlated negatively with age (p = 0.02) and was stable in 48 subjects for 1 year. In comparison with primary keratinocytes, IL1F10 expression in CD19+ B cells from PBMC was lower, whereas cell-associated IL-38 expression was comparable. In vitro, IL-38 is released from CD19+ B cells after stimulation with rituximab. Intravenous LPS in humans failed to induce circulating IL-38, compared to 100-fold induction of IL-6 and IL-1 receptor antagonist. In a cohort of 296 subjects with body mass index > 27 at high risk for cardiovascular disease, IL-38 plasma concentrations were significantly lower than in healthy subjects (p < 0.0001), and lowest in those with metabolic syndrome (p < 0.05). IL-38 also correlated inversely with high sensitivity C-reactive protein (p < 0.01), IL-6, IL-1Ra, and leptin (p < 0.05). We conclude that a relative deficiency of the B cell product IL-38 is associated with increased systemic inflammation in aging, cardiovascular and metabolic disease, and is consistent with IL-38 as an anti-inflammatory cytokine.

Exploring power dynamics and their impact on intraprofessional learning.

BACKGROUND: During postgraduate training, considerable efforts for intraprofessional education are in place to prepare primary care residents (PC residents) and medical specialty residents (MS residents) for intraprofessional collaboration (intraPC). Power dynamics are inherently present in such hierarchical medical contexts. This affects intraPC (learning). Yet little attention has been paid to factors that impact power dynamics. This study aims to explore power dynamics and their impact on intraPC learning between PC residents and MS residents during hospital placements. METHODS: This study expands on previously published ethnographic research investigating opportunities and barriers for intraPC learning among residents in five Dutch hospitals. We analysed transcripts of observations and in-depth interviews using template analysis. A critical theory paradigm was employed. Discourse analysis additionally informed the data. RESULTS: We defined five interrelated themes that describe characteristics of power dynamics in intraPC learning during hospital placements: beliefs; power distribution; interaction style; subjection; and fearless learning. Power dynamics operate both within and between the themes: power distribution between PC residents, MS residents and MS supervisors seemed to be an attribution affected by underlying beliefs about professional norms or about other professions; beliefs influenced the way PC residents, MS residents and MS supervisors interacted; power distribution based on inequity could lead to subjection of PC residents; power distribution based on equity could lead to fearless learning; and open interactions enabled fearless intraPC learning. CONCLUSIONS: Power dynamics have an impact on intraPC learning among residents in hospitals. Constructive power dynamics occur when power distribution is based on equity, combined with sincere open interactions, actively inviting each other into discussions and enlisting the support of MS supervisors to foster fearless learning. This can be achieved by creating awareness of implicit beliefs and making them explicit, recognising interaction that encourages intraPC learning and creating policies that support fearless intraPC learning.

Designing the learning of intraprofessional collaboration among medical residents.

BACKGROUND: To preserve quality and continuity of care, collaboration between primary-care and secondary-care physicians is becoming increasingly important. Therefore, learning intraprofessional collaboration (intraPC) requires explicit attention during postgraduate training. Hospital placements provide opportunities for intraPC learning, but these opportunities require interventions to support and enhance such learning. Design-Principles guide the design and development of educational activities when theory-driven Design-Principles are tailored into context-sensitive Design-Principles. The aim of this study was to develop and substantiate a set of theory-driven and context-sensitive Design-Principles for intraPC learning during hospital placements. METHODS: Based on our earlier research, we formulated nine theory-driven Design-Principles. To enrich, refine and consolidate these principles, three focus group sessions with stakeholders were conducted using a Modified Nominal Group Technique. Next, two work conferences were conducted to test the feasibility and applicability of the Design-Principles for developing intraPC educational activities and to sharpen the principles into a final set of Design-Principles. RESULTS: The theoretical Design-Principles were discussed and modified iteratively. Two new Design-Principles were added during focus group 1, and one more Design-Principle was added during focus group 2. The Design-Principles were categorised into three clusters: (i) Culture: building collaborative relations in a psychologically safe context where patterns or feelings of power dynamics between primary and secondary care physicians can be discussed; (ii) Connecting Contexts: making residents and supervisors mutually understand each other's work contexts and activities; and (iii) Making the Implicit Explicit: having supervising teams act as role models demonstrating intraPC and continuously pursuing improvement in intraPC to make intraPC explicit. Participants were unanimous in their view that the Design-Principles in the Culture cluster were prerequisites to facilitate intraPC learning. CONCLUSION: This study led to the development of 12 theory-driven and context-sensitive Design-Principles that may guide the design of educational activities to support intraPC learning during hospital placements.

Gut Microbial Associations to Plasma Metabolites Linked to Cardiovascular Phenotypes and Risk.

RATIONALE: Altered gut microbial composition has been linked to cardiovascular diseases (CVDs), but its functional links to host metabolism and immunity in relation to CVD development remain unclear. OBJECTIVES: To systematically assess functional links between the microbiome and the plasma metabolome, cardiometabolic phenotypes, and CVD risk and to identify diet-microbe-metabolism-immune interactions in well-documented cohorts. METHODS AND RESULTS: We assessed metagenomics-based microbial associations between 231 plasma metabolites and microbial species and pathways in the population-based LLD (Lifelines DEEP) cohort (n=978) and a clinical obesity cohort (n=297). After correcting for age, sex, and body mass index, the gut microbiome could explain ≤11.1% and 16.4% of the variation in plasma metabolites in the population-based and obesity cohorts, respectively. Obese-specific microbial associations were found for lipid compositions in the VLDL, IDL, and LDL lipoprotein subclasses. Bacterial L-methionine biosynthesis and a Ruminococcus species were associated to cardiovascular phenotypes in obese individuals, namely atherosclerosis and liver fat content, respectively. Integration of microbiome-diet-inflammation analysis in relation to metabolic risk score of CVD in the population cohort revealed 48 microbial pathways associated to CVD risk that were largely independent of diet and inflammation. Our data also showed that plasma levels rather than fecal levels of short-chain fatty acids were relevant to inflammation and CVD risk. CONCLUSIONS: This study presents the largest metagenome-based association study on plasma metabolism and microbiome relevance to diet, inflammation, CVD risk, and cardiometabolic phenotypes in both population-based and clinical obesity cohorts. Our findings identified novel bacterial species and pathways that associated to specific lipoprotein subclasses and revealed functional links between the gut microbiome and host health that provide a basis for developing microbiome-targeted therapy for disease prevention and treatment.

Sex-Specific Regulation of Inflammation and Metabolic Syndrome in Obesity.

OBJECTIVE: Metabolic dysregulation and inflammation are important consequences of obesity and impact susceptibility to cardiovascular disease. Anti-inflammatory therapy in cardiovascular disease is being developed under the assumption that inflammatory pathways are identical in women and men, but it is not known if this is indeed the case. In this study, we assessed the sex-specific relation between inflammation and metabolic dysregulation in obesity. Approach and Results: Three hundred two individuals were included, half with a BMI 27 to 30 kg/m2 and half with a BMI>30 kg/m2, 45% were women. The presence of metabolic syndrome was assessed according to the National Cholesterol Education Program-ATPIII criteria, and inflammation was studied using circulating markers of inflammation, cell counts, and ex vivo cytokine production capacity of isolated immune cells. Additionally, lipidomic and metabolomic data were gathered, and subcutaneous fat biopsies were histologically assessed. Metabolic syndrome is associated with an increased inflammatory profile that profoundly differs between women and men: women with metabolic syndrome show a lower concentration of the anti-inflammatory adiponectin, whereas men show increased levels of several pro-inflammatory markers such as IL (interleukin)-6 and leptin. Adipose tissue inflammation showed similar sex-specific associations with these markers. Peripheral blood mononuclear cells isolated from men, but not women, with metabolic syndrome display enhanced cytokine production capacity. CONCLUSIONS: We identified sex-specific pathways that influence inflammation in obesity. Excessive production of proinflammatory cytokines was observed in men with metabolic syndrome. In contrast, women typically showed reduced levels of the anti-inflammatory adipokine adiponectin. These different mechanisms of inflammatory dysregulation between women and men with obesity argue for sex-specific therapeutic strategies.

Unraveling the medical residency selection game.

The diversity of modern society is often not represented in the medical workforce. This might be partly due to selection practices. We need to better understand decision-making processes by selection committees in order to improve selection procedures with regard to diversity. This paper reports on a qualitative study with a socio-constructivist perspective conducted in 2015 that explored how residency selection decision-making occurred within four specialties in two regions in the Netherlands. Data included transcripts of the decision-making meetings and of one-on-one interviews with committee members before and after the group decision-making meetings. Candidates struggled to portray themselves favorably as they had to balance playing by the rules and being authentic; between fitting in and standing out. Although admissions committees had a welcoming stance to diversity, their practices were unintentionally preventing them from hiring underrepresented minority (URM) candidates. While negotiating admissions is difficult for all candidates, it is presumably even more complicated for URM candidates. This seems to be having a negative influence on attaining workforce diversity. Current beliefs, which make committees mistakenly feel they are acting fairly, might actually justify biased practices. Awareness of the role of committee members in these processes is an essential first step.

Chances for learning intraprofessional collaboration between residents in hospitals.

CONTEXT: Intraprofessional collaboration (intraPC) between primary care (PC) doctors and medical specialists (MSs) is becoming increasingly important. Patient safety issues are often related to intraPC. In order to equip doctors well for their task of providing good quality and continuity of care, intraPC needs explicit attention, starting in postgraduate training. Worldwide, PC residents undertake a hospital placement during their postgraduate training, where they work in proximity with MS residents. This placement offers the opportunity to learn intraPC. It is yet unknown whether and how residents learn intraPC and what barriers to and opportunities for exist in learning intraPC during hospital placements. METHODS: We performed an ethnographic non-participatory observational study in three emergency departments and three geriatric departments of five hospitals in the Netherlands. This was followed by 42 in-depth interviews with the observed residents and supervisors. The observations were used to feed the questions for the in-depth interviews. We analysed the interviews iteratively following the data collection using template analysis. RESULTS: Hospital wards are rich in opportunities for learning intraPC. These opportunities, however, are seldom exploited for various reasons: intraPC receives limited attention when formulating placement goals, so purposeful learning of intraPC hardly takes place; residents lack awareness of the learning of intraPC; MS residents are not accustomed to searching for expertise from PC residents; PC residents adapt to the MS role and they contribute very little of their PC knowledge, and power dynamics in the hospital department negatively influence the learning of intraPC. Therefore, improvements in mindset, professional identity and power dynamics are crucial to facilitate and promote intraPC. CONCLUSIONS: Intraprofessional collaboration is not learned spontaneously during hospital placements. To benefit from the abundant opportunities to learn intraPC, adjustments to the set-up of these placements are necessary. Learning intraPC is promoted when there is a collaborative culture, hierarchy is limited, and there is dedicated time for intraPC and support from the supervisor.

Competencies to promote collaboration between primary and secondary care doctors: an integrative review.

BACKGROUND: In a society where ageing of the population and the increasing prevalence of long-term conditions are major issues, collaboration between primary and secondary care is essential to provide continuous, patient-centred care. Doctors play an essential role at the primary-secondary care interface in realising 'seamless' care. Therefore, they should possess collaborative competencies. However, knowledge about these collaborative competencies is scarce. In this review we explore what competencies doctors need to promote collaboration between doctors at the primary-secondary care interface. METHODS: We conducted an integrative literature review. After a systematic search 44 articles were included in the review. They were analysed using a thematic analysis approach. RESULTS: We identified six themes regarding collaborative competencies: 'patient-centred care: a common concern', 'roles and responsibilities', 'mutual knowledge and understanding', 'collaborative attitude and respect', 'communication' and 'leadership'. In every theme we specified components of knowledge, skills and attitudes as found in the reviewed literature. The results show that doctors play an important role, not only in the way they collaborate in individual patient care, but also in how they help shaping organisational preconditions for collaboration. CONCLUSIONS: This review provides an integrative view on competencies necessary for collaborative practice at the primary-secondary care interface. They are part of several domains, showing the complexity of collaboration. The information gathered in this review can support doctors to enhance and learn collaboration in daily practice and can be used in educational programmes in all stages of medical education.

Increased proteinase 3 and neutrophil elastase plasma concentrations are associated with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is becoming a major health problem worldwide. Inflammation plays an important role in disease pathogenesis and recent studies have shown a potential role for the neutrophil serine proteases (NSPs) proteinase-3 (PR3) and neutrophil elastase (NE) in NAFLD as well as an imbalance between NSPs and their natural inhibitor alpha-1 antitrypsin (AAT). The aim of this study was to investigate whether PR3 and NE plasma concentrations are associated with NAFLD and/or type 2 diabetes. METHODS: To explore this hypothesis we used several cohorts: a cohort of 271 obese individuals with liver steatosis, a cohort of 41 patients with biopsy-proven NAFLD, a cohort of 401 obese type 2 diabetes patients and a cohort of 205 lean healthy controls; and measured PR3 and NE plasma concentrations. In addition, we measured AAT plasma concentrations in order to investigate if the ratios between NSPs and their natural inhibitor were altered in NAFLD and type 2 diabetes when compared to healthy controls. RESULTS: Our data shows an increase in PR3 and NE concentrations and a decrease in AAT concentrations in obese patients when compared to controls. Moreover, PR3 plasma concentrations are increased in patients with liver steatosis. Furthermore, PR3 and NE concentrations in the liver are associated with the advanced stages of NAFLD characterized by NASH and/ or liver fibrosis. Additionally, PR3 and NE concentrations were up-regulated in patients with type 2 diabetes when compared to lean and obese controls. CONCLUSION: We conclude that circulating levels of NSPs associate with obesity-related metabolic disorders. Further research is needed to clearly establish the role of these proteases and investigate whether they could be used as non-invasive markers for NAFLD and/or type 2 diabetes.

Using conversation analysis to explore feedback on resident performance.

Feedback on clinical performance of residents is seen as a fundamental element in postgraduate medical education. Although literature on feedback in medical education is abundant, many supervisors struggle with providing this feedback and residents experience feedback as insufficiently constructive. With a detailed analysis of real-world feedback conversations, this study aims to contribute to the current literature by deepening the understanding of how feedback on residents' performance is provided, and to formulate recommendations for improvement of feedback practice. Eight evaluation meetings between program directors and residents were recorded in 2015-2016. These meetings were analyzed using conversation analysis. This is an ethno-methodological approach that uses a data-driven, iterative procedure to uncover interactional patterns that structure naturally occurring, spoken interaction. Feedback in our data took two forms: feedback as a unidirectional activity and feedback as a dialogic activity. The unidirectional feedback activities prevailed over the dialogic activities. The two different formats elicit different types of resident responses and have different implications for the progress of the interaction. Both feedback formats concerned positive as well as negative feedback and both were often mitigated by the participants. Unidirectional feedback and mitigating or downplaying feedback is at odds with the aim of feedback in medical education. Dialogic feedback avoids the pitfall of a program director-dominated conversation and gives residents the opportunity to take ownership of their strengths and weaknesses, which increases chances to change resident behavior. On the basis of linguistic analysis of our real-life data we suggest implications for feedback conversations.

Judging residents' performance: a qualitative study using grounded theory.

BACKGROUND: Although program directors judge residents' performance for summative decisions, little is known about how they do this. This study examined what information program directors use and how they value this information in making a judgment of residents' performance and what residents think of this process. METHODS: Sixteen semi-structured interviews were held with residents and program directors from different hospitals in the Netherlands in 2015-2016. Participants were recruited from internal medicine, surgery and radiology. Transcripts were analysed using grounded theory methodology. Concepts and themes were identified by iterative constant comparison. RESULTS: When approaching semi-annual meetings with residents, program directors report primarily gathering information from the following: assessment tools, faculty members and from their own experience with residents. They put more value on faculty's comments during meetings and in the corridors than on feedback provided in the assessment tools. They are influenced by their own beliefs about learning and education in valuing feedback. Residents are aware that faculty members discuss their performance in meetings, but they believe the assessment tools provide the most important proof to demonstrate their clinical competency. CONCLUSIONS: Residents think that feedback in the assessment tools is the most important proof to demonstrate their performance, whereas program directors scarcely use this feedback to form a judgment about residents' performance. They rely heavily on remarks of faculty in meetings instead. Therefore, residents' performance may be better judged in group meetings that are organised to enhance optimal information sharing and decision making about residents' performance.

A Splice Region Variant in LDLR Lowers Non-high Density Lipoprotein Cholesterol and Protects against Coronary Artery Disease.

Through high coverage whole-genome sequencing and imputation of the identified variants into a large fraction of the Icelandic population, we found four independent signals in the low density lipoprotein receptor gene (LDLR) that associate with levels of non-high density lipoprotein cholesterol (non-HDL-C) and coronary artery disease (CAD). Two signals are novel with respect to association with non-HDL-C and are represented by non-coding low frequency variants (between 2-4% frequency), the splice region variant rs72658867-A in intron 14 and rs17248748-T in intron one. These two novel associations were replicated in three additional populations. Both variants lower non-HDL-C levels (rs72658867-A, non-HDL-C effect = -0.44 mmol/l, Padj = 1.1 × 10⁻8° and rs17248748-T, non-HDL-C effect = -0.13 mmol/l, Padj = 1.3 × 10⁻¹²) and confer protection against CAD (rs72658867-A, OR = 0.76 and Padj = 2.7 × 10⁻8 and rs17248748-T, OR = 0.92 and Padj = 0.022). The LDLR splice region variant, rs72658867-A, located at position +5 in intron 14 (NM_000527:c.2140+5G>A), causes retention of intron 14 during transcription and is expected to produce a truncated LDL receptor lacking domains essential for function of the receptor. About half of the transcripts generated from chromosomes carrying rs72658867-A are characterized by this retention of the intron. The same variant also increases LDLR mRNA expression, however, the wild type transcripts do not exceed levels in non-carriers. This demonstrates that sequence variants that disrupt the LDL receptor can lower non-HDL-C and protect against CAD.

Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis.

BACKGROUND: Plasmacytoid dendritic cells have been implicated in the pathogenesis of systemic sclerosis through mechanisms beyond the previously suggested production of type I interferon. METHODS: We isolated plasmacytoid dendritic cells from healthy persons and from patients with systemic sclerosis who had distinct clinical phenotypes. We then performed proteome-wide analysis and validated these observations in five large cohorts of patients with systemic sclerosis. Next, we compared the results with those in patients with systemic lupus erythematosus, ankylosing spondylitis, and hepatic fibrosis. We correlated plasma levels of CXCL4 protein with features of systemic sclerosis and studied the direct effects of CXCL4 in vitro and in vivo. RESULTS: Proteome-wide analysis and validation showed that CXCL4 is the predominant protein secreted by plasmacytoid dendritic cells in systemic sclerosis, both in circulation and in skin. The mean (±SD) level of CXCL4 in patients with systemic sclerosis was 25,624±2652 pg per milliliter, which was significantly higher than the level in controls (92.5±77.9 pg per milliliter) and than the level in patients with systemic lupus erythematosus (1346±1011 pg per milliliter), ankylosing spondylitis (1368±1162 pg per milliliter), or liver fibrosis (1668±1263 pg per milliliter). CXCL4 levels correlated with skin and lung fibrosis and with pulmonary arterial hypertension. Among chemokines, only CXCL4 predicted the risk and progression of systemic sclerosis. In vitro, CXCL4 down-regulated expression of transcription factor FLI1, induced markers of endothelial-cell activation, and potentiated responses of toll-like receptors. In vivo, CXCL4 induced the influx of inflammatory cells and skin transcriptome changes, as in systemic sclerosis. CONCLUSIONS: Levels of CXCL4 were elevated in patients with systemic sclerosis and correlated with the presence and progression of complications, such as lung fibrosis and pulmonary arterial hypertension. (Funded by the Dutch Arthritis Association and others.).

Learning intraprofessional collaboration by participating in a consultation programme: what and how did primary and secondary care trainees learn?

BACKGROUND: A growing number of patients require overview and management in both primary and secondary care. This situation requires that primary and secondary care professionals have well developed collaborative skills. While knowledge about interprofessional collaboration and education is rising, little is known about intraprofessional collaboration and education between physicians of various disciplines. This study examines a newly developed consultation programme for trainees in general practice and internal medicine to acquire intraprofessional collaboration skills. METHODS: Focus groups were conducted with trainees and their supervisors and mentors to explore what and how the trainees learned by participating in the consultation programme. RESULTS: Trainees reported that they gained knowledge about and skills in collaboration and consultation they could not have gained otherwise. Furthermore, the programme gave the opportunity to gain other competencies relevant for becoming the medical expert trainees they are expected to be. Learning outcomes were comparable to those described in interprofessional education literature. Interaction, by meeting each other and by discussing cases with mentors or supervisors, appeared to be a key factor in the learning process. Meetings, discussing preconceptions and enthusiasm of the mentors and supervisors facilitated the learning. Technical problems and lack of information hampered the learning. These influencing factors are important for future development of intraprofessional learning programmes. CONCLUSIONS: Participants in an innovative consultation programme for GP- and IM-trainees reported that they acquired consultation and collaboration skills they could not have gained otherwise. Interaction appeared to be an important factor in the learning process. The findings of this study can inform developers of intraprofessional education programmes between primary and secondary care trainees.

Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome.

AIMS: Homozygous autosomal dominant hypercholesterolaemia (hoADH), an orphan disease caused by mutations in low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin-kexin type 9 (PCSK9), is characterized by elevated plasma low-density lipoprotein-cholesterol (LDL-C) levels and high risk for premature cardiovascular disease (CVD). The exact prevalence of molecularly defined hoADH is unknown. Therefore, we investigated the prevalence and phenotypical characteristics of this disease in an open society, i.e. the Netherlands. METHODS AND RESULTS: The database of the nationwide ADH molecular diagnostic center was queried to identify all molecularly defined hoADH patients. Carriers of non-pathogenic mutations were excluded. Medical records were analysed for data regarding lipid levels and CVD events. Of 104,682 individuals screened for molecular defects, 49 were classified as hoADH (0.05%); 20 were true homozygotes, 25 were compound heterozygotes for LDLR mutations, and 4 were homozygous for APOB mutations. No bi-allelic PCSK9 mutation carriers were identified. Consequently, the prevalence of hoADH was estimated to be ∼1 : 300,000. Mean LDL-C levels prior to lipid-lowering treatment were 12.9 ± 5.1 mmol/L (range 4.4-21.5 mmol/L). Surprisingly, only 50% of the patients met the clinical criteria for hoADH (LDL-C >13.0 mmol/L); 29% of patients suffered from a CVD event. CONCLUSION: The prevalence of molecularly defined hoADH is much higher and the clinical phenotype is more variable than previously assumed. In light of the fact that novel therapies are, or will be registered for the treatment of hoADH patients, an uniform definition of hoADH either as a phenotypic or molecular entity is warranted in order to identify patients who are considered to be eligible for these novel agents.

The effect of an apolipoprotein A-I-containing high-density lipoprotein-mimetic particle (CER-001) on carotid artery wall thickness in patients with homozygous familial hypercholesterolemia: The Modifying Orphan Disease Evaluation (MODE) study.

BACKGROUND: Patients with homozygous familial hypercholesterolemia (HoFH) are at extremely elevated risk for early cardiovascular disease because of exposure to elevated low-density lipoprotein cholesterol (LDL-C) plasma levels from birth. Lowering LDL-C by statin therapy is the cornerstone for cardiovascular disease prevention, but the residual risk in HoFH remains high, emphasizing the need for additional therapies. In the present study, we evaluated the effect of serial infusions with CER-001, a recombinant human apolipoprotein A-I (apoA-I)-containing high-density lipoprotein-mimetic particle, on carotid artery wall dimensions in patients with HoFH. METHODS AND RESULTS: Twenty-three patients (mean age 39.4 ± 13.5 years, mean LDL-C 214.2 ± 81.5 mg/dL) with genetically confirmed homozygosity or compound heterozygosity for LDLR, APOB, PCSK9, or LDLRAP1 mutations received 12 biweekly infusions with CER-001 (8 mg/kg). Before and 1 hour after the first infusion, lipid values were measured. Magnetic resonance imaging (3-T magnetic resonance imaging) scans of the carotid arteries were acquired at baseline and after 24 weeks to assess changes in artery wall dimensions. After CER-001 infusion, apoA-I increased from 114.8 ± 20.7 mg/dL to 129.3 ± 23.0 mg/dL. After 24 weeks, mean vessel wall area (primary end point) decreased from 17.23 to 16.75 mm(2) (P = .008). A trend toward reduction of mean vessel wall thickness was observed (0.75 mm at baseline and 0.74 mm at follow-up, P = .0835). CONCLUSIONS: In HoFH, 12 biweekly infusions with an apoA-I-containing high-density lipoprotein-mimetic particle resulted in a significant reduction in carotid mean vessel wall area, implying that CER-001 may reverse atherogenic changes in the arterial wall on top of maximal low-density lipoprotein-lowering therapy. This finding supports further clinical evaluation of apoA-I-containing particles in patients with HoFH.

Iron and hepcidin as risk factors in atherosclerosis: what do the genes say?

BACKGROUND: Previous reports suggested a role for iron and hepcidin in atherosclerosis. Here, we evaluated the causality of these associations from a genetic perspective via (i) a Mendelian randomization (MR) approach, (ii) study of association of atherosclerosis-related single nucleotide polymorphisms (SNPs) with iron and hepcidin, and (iii) estimation of genomic correlations between hepcidin, iron and atherosclerosis. RESULTS: Analyses were performed in a general population sample. Iron parameters (serum iron, serum ferritin, total iron-binding capacity and transferrin saturation), serum hepcidin and genome-wide SNP data were available for N = 1,819; non-invasive measurements of atherosclerosis (NIMA), i.e., presence of plaque, intima media thickness and ankle-brachial index (ABI), for N = 549. For the MR, we used 12 iron-related SNPs that were previously identified in a genome-wide association meta-analysis on iron status, and assessed associations of individual SNPs and quartiles of a multi-SNP score with NIMA. Quartile 4 versus quartile 1 of the multi-SNP score showed directionally consistent associations with the hypothesized direction of effect for all NIMA in women, indicating that increased body iron status is a risk factor for atherosclerosis in women. We observed no single SNP associations that fit the hypothesized directions of effect between iron and NIMA, except for rs651007, associated with decreased ferritin concentration and decreased atherosclerosis risk. Two of six NIMA-related SNPs showed association with the ratio hepcidin/ferritin, suggesting that an increased hepcidin/ferritin ratio increases atherosclerosis risk. Genomic correlations were close to zero, except for hepcidin and ferritin with ABI at rest [-0.27 (SE 0.34) and -0.22 (SE 0.35), respectively] and ABI after exercise [-0.29 (SE 0.34) and -0.30 (0.35), respectively]. The negative sign indicates an increased atherosclerosis risk with increased hepcidin and ferritin concentrations. CONCLUSIONS: Our results suggest a potential causal role for hepcidin and ferritin in atherosclerosis, and may indicate that iron status is causally related to atherosclerosis in women.

Serum hepcidin is associated with presence of plaque in postmenopausal women of a general population.

OBJECTIVE: Iron and the iron regulatory hormone hepcidin, major determinant of body iron distribution, are hypothesized to play a role in cardiovascular disease. Here, we assess the associations of hepcidin as well as ferritin, iron, total iron-binding capacity, and transferrin saturation (ie, iron parameters) with noninvasive measurements of atherosclerosis in men and women of a population-based cohort. APPROACH AND RESULTS: We included 766 participants of the Nijmegen Biomedical Study aged 46 to 67 years for whom serum measurements of hepcidin, iron parameters, and noninvasive measurements of atherosclerosis were available. Noninvasive measurements of atherosclerosis were presence of plaque, ankle-brachial index, and intima-media thickness. We performed multivariable logistic and linear regression analyses using quartiles of hepcidin and iron parameters. Analyses were stratified by sex and adjusted for several demographic, clinical, and biochemical determinants, including traditional risk factors of cardiovascular disease based on the Framingham risk score. Hepcidin and the hepcidin/ferritin ratio, reflecting hepcidin expression relative to iron stores, were significantly associated with the presence of plaque in women (adjusted odds ratios for quartile 4 versus quartile 1 [95% confidence intervals] of 3.07 [1.36-6.90] and 2.31 [1.03-5.18], respectively). The hepcidin/ferritin ratio was significantly and negatively associated with ankle-brachial index at rest in men and women (adjusted ß for quartile 4 versus quartile 1 [95% confidence intervals] of -0.03 [-0.07 to 0.00] and -0.04 [-0.06 to -0.01], respectively). CONCLUSIONS: Our results suggest that the body iron distribution as determined by hepcidin affects the development of atherosclerosis in women.