Pharmaco-invasive therapy: Early implementation of statins and proprotein convertase subtilisin/kexin type 9 inhibitors after acute coronary syndrome.

Elevated LDL-cholesterol (LDL-C) plays a major role in atheroma formation and inflammation. Medical therapy to lower elevated LDL-C is the cornerstone for reducing the progression of atherosclerotic cardiovascular disease. Statin therapy, and more recently, other drugs such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, have proven efficacy in long-term lowering of LDL-C and therefore diminish cardiovascular risk. During an acute coronary syndrome (ACS), a systemic inflammatory response can destabilize other non-culprit atherosclerotic plaques. Patients with these vulnerable plaques are at high risk of experiencing recurrent cardiovascular events in the first few years post-ACS. Initiating intensive LDL-C lowering therapy in these patients with statins or PCSK9 inhibitors can be beneficial via several pathways. High-intensity statin therapy can reduce inflammation by directly lowering LDL-C, but also through its pleiotropic effects. PCSK9 inhibitors can directly lower LDL-C to recommended guideline thresholds, and could have additional effects on inflammation and plaque stability. We discuss the potential role of early implementation of statins combined with PCSK9 inhibitors to influence these cascades and to mediate the associated cardiovascular risk, over and above the well-known long-term beneficial effects of chronic LDL-C lowering.

2020 ESC Guidelines on acute coronary syndrome without ST-segment elevation : Recommendations and critical appraisal from the Dutch ACS and Interventional Cardiology working groups.

Recently, the European Society of Cardiology (ESC) has updated its guidelines for the management of patients with acute coronary syndrome (ACS) without ST-segment elevation. The current consensus document of the Dutch ACS working group and the Working Group of Interventional Cardiology of the Netherlands Society of Cardiology aims to put the 2020 ESC Guidelines into the Dutch perspective and to provide practical recommendations for Dutch cardiologists, focusing on antiplatelet therapy, risk assessment and criteria for invasive strategy.

Coronary angiography findings in patients with shock-resistant ventricular fibrillation cardiac arrest.

INTRODUCTION: Shock-resistant ventricular fibrillation (VF) poses a therapeutic challenge during out-of-hospital cardiac arrest (OHCA). For these patients, new treatment strategies are under active investigation, yet underlying trigger(s) and substrate(s) have been poorly characterised, and evidence on coronary angiography (CAG) data is often limited to studies without a control group. METHODS: In our OHCA-registry, we studied CAG-findings in OHCA-patients with VF who underwent CAG after hospital arrival. We compared baseline demographics, arrest characteristics, CAG-findings and outcomes between patients with VF that was shock-resistant (defined as >3 shocks) or not shock-resistant (≤3 shocks). RESULTS: Baseline demographics, arrest location, bystander resuscitation and AED-use did not differ between 105 patients with and 196 patients without shock-resistant VF. Shock-resistant VF-patients required more shocks, with higher proportions endotracheal intubation, mechanical CPR, amiodaron and epinephrine. In both groups, significant coronary artery disease (≥1 stenosis >70%) was highly prevalent (78% vs. 77%, p = 0.76). Acute coronary occlusions (ACOs) were more prevalent in shock-resistant VF-patients (41% vs. 26%, p = 0.006). Chronic total occlusions did not differ between groups (29% vs. 33%, p = 0.47). There was an association between increasing numbers of shocks and a higher likelihood of ACO. Shock-resistant VF-patients had lower proportions 24-h survival (75% vs. 93%, p < 0.001) and survival to discharge (61% vs. 78%, p = 0.002). CONCLUSION: In this cohort of OHCA-patients with VF and CAG after transport, acute coronary occlusions were more prevalent in patients with shock-resistant VF compared to VF that was not shock-resistant, and their clinical outcome was worse. Confirmative studies are warranted for this potentially reversible therapeutic target.

Small-Angle X-Ray Scattering Studies of Block Copolymer Nano-Objects: Formation of Ordered Phases in Concentrated Solution During Polymerization-Induced Self-Assembly.

We report that polymerization-induced self-assembly (PISA) can be used to prepare lyotropic phases comprising diblock copolymer nano-objects in non-polar media. RAFT dispersion polymerization of benzyl methacrylate (BzMA) at 90 °C using a trithiocarbonate-capped hydrogenated polybutadiene (PhBD) steric stabilizer block in n-dodecane produces either spheres or worms that exhibit long-range order at 40 % w/w solids. NMR studies enable calculation of instantaneous copolymer compositions for each phase during the BzMA polymerization. As the PBzMA chains grow longer when targeting PhBD80 -PBzMA40 , time-resolved small-angle X-ray scattering reveals intermediate body-centered cubic (BCC) and hexagonally close-packed (HCP) sphere phases prior to formation of a final hexagonal cylinder phase (HEX). The HEX phase is lost on serial dilution and the aligned cylinders eventually form disordered flexible worms. The HEX phase undergoes an order-disorder transition on heating to 150 °C and a pure HCP phase forms on cooling to 20 °C.

The outcome of pulmonary hypertension and its association with pulmonary artery dilatation.

BACKGROUND: Pulmonary artery (PA) dilatation is often seen in pulmonary hypertension (PH) and is considered a long-term consequence of elevated pressure. The PA dilates over time and therefore may reflect disease severity and duration. Survival is related to the stage of the disease at the time of diagnosis and therefore PA diameter might be used to predict prognosis. This study evaluates the outcome of patients with pulmonary arterial hypertension (PAH) and chronic thrombo-embolic pulmonary hypertension (CTEPH) and investigates whether PA diameter at the time of diagnosis is associated with mortality. METHODS: Patients visiting an outpatient clinic of a tertiary centre between 2004 and 2018 with a cardiac catheterisation confirmed diagnosis of PAH or CTEPH and a CT scan available for PA diameter measurement were included. PA diameter and established predictors of survival were collected (New York Heart Association (NYHA) class, N­terminal pro-brain natriuretic peptide (NT-proBNP) level and 6­min walking distance (6MWD)). RESULTS: In total 217 patients were included (69% female, 71% NYHA class ≥III). During a median follow-up of 50 (22-92) months, 54% of the patients died. Overall survival was 87% at 1 year, 70% at 3 years and 58% at 5 years. The mean PA diameter was 34.2 ± 6.2 mm and was not significantly different among all the diagnosis groups. We found a weak correlation between PA diameter and mean PA pressure ( r = 0.23, p < 0.001). Male sex, higher age, shorter 6MWD and higher NT-proBNP level were independently associated with mortality, but PA diameter was not. CONCLUSION: The prognosis of PAH and CTEPH is still poor. Known predictors of survival were confirmed, but PA diameter at diagnosis was not associated with survival in PAH or CTEPH patients.

Unique aqueous self-assembly behavior of a thermoresponsive diblock copolymer.

It is well-recognized that block copolymer self-assembly in solution typically produces spheres, worms or vesicles, with the relative volume fraction of each block dictating the copolymer morphology. Stimulus-responsive diblock copolymers that can undergo either sphere/worm or vesicle/worm transitions are also well-documented. Herein we report a new amphiphilic diblock copolymer that can form spheres, worms, vesicles or lamellae in aqueous solution. Such self-assembly behavior is unprecedented for a single diblock copolymer of fixed composition yet is achieved simply by raising the solution temperature from 1 °C (spheres) to 25 °C (worms) to 50 °C (vesicles) to 70 °C (lamellae). Heating increases the degree of hydration (and hence the effective volume fraction) of the core-forming block, with this parameter being solely responsible for driving the sphere-to-worm, worm-to-vesicle and vesicle-to-lamellae transitions. The first two transitions exhibit excellent reversibility but the vesicle-to-lamellae transition exhibits hysteresis on cooling. This new thermoresponsive diblock copolymer provides a useful model for studying such morphological transitions and is likely to be of significant interest for theoretical studies.

Haemodynamic efficacy of microaxial left ventricular assist device in cardiogenic shock: a systematic review and meta-analysis.

The Impella percutaneous mechanical circulatory support device is designed to augment cardiac output and reduce left ventricular wall stress and aims to improve survival in cases of cardiogenic shock. In this meta-analysis we investigated the haemodynamic effects of the Impella device in a clinical setting. We systematically searched all articles in PubMed/Medline and Embase up to July 2019. The primary outcomes were cardiac power (CP) and cardiac power index (CPI). Survival rates and other haemodynamic data were included as secondary outcomes. For the critical appraisal, we used a modified version of the U.S. Department of Health and Human Services quality assessment form. The systematic review included 12 studies with a total of 596 patients. In 258 patients the CP and/or CPI could be extracted. Our meta-analysis showed an increase of 0.39 W [95% confidence interval (CI): 0.24, 0.54], (p = 0.01) and 0.22 W/m2 (95% CI: 0.18, 0.26), (p < 0.01) for the CP and CPI, respectively. The overall survival rate was 56% (95% CI: 0.50, 0.62), (p = 0.09). The quality of the studies was moderate, mostly due to the presence of confounders. Our study suggests that in patients with cardiogenic shock, Impella support seems effective in augmenting CP(I). This study merely investigates the haemodynamic effectiveness of the Impella device and does not reflect the complete clinical impact for the patient.

Novel X-ray image noise reduction technology reduces patient radiation dose while maintaining image quality in coronary angiography.

AIMS: The consequences of high radiation dose for patient and staff demand constant improvements in X-ray dose reduction technology. This study assessed non-inferiority of image quality and quantified patient dose reduction in interventional cardiology for an anatomy-specific optimised cine acquisition chain combined with advanced real-time image noise reduction algorithms referred to as 'study cine', compared with conventional angiography. METHODS: Fifty patients underwent two coronary angiographic acquisitions: one with advanced image processing and optimised exposure system settings to enable dose reduction (study cine) and one with standard image processing and exposure settings (reference cine). The image sets of 39 patients (18 females, 21 males) were rated by six experienced independent reviewers, blinded to the patient and image characteristics. The image pairs were randomly presented. Overall 85 % of the study cine images were rated as better or equal quality compared with the reference cine (95 % CI 0.81-0.90). The median dose area product per frame decreased from 55 to 26 mGy.cm(2)/frame (53 % reduction, p < 0.001). CONCLUSION: This study demonstrates that the novel X-ray imaging technology provides non-inferior image quality compared with conventional angiographic systems for interventional cardiology with a 53 % patient dose reduction.

Patients with left bundle branch block pattern and high cardiac risk myocardial SPECT: does the current management suffice?

INTRODUCTION: Myocardial perfusion SPECT (MPS) is frequently used for cardiovascular risk stratification. The significance of MPS in patients with abnormal electrical ventricular activation is often questionable. This review assesses the value of MPS for risk stratification of patients with intrinsic left bundle branch block or that due to right ventricular apical pacing. METHODS: We reviewed the literature by a search of the MEDLINE database (January 1980 to September 2010). The terms prognosis or prognostic value were combined with SPECT and LBBB or pacing or pacemakers. MPS was categorised as low and high risk according to the original definitions. RESULTS: We identified 11 studies suitable for review. A low-risk MPS is associated with a low risk of cardiac events whereas high-risk MPS carries a 4.8-fold increased risk, 95% CI [3.2 - 7.2] (p < 0.0001). Despite secondary prevention and an improved medical and interventional care, these figures have hardly changed over time. CONCLUSION AND CLINICAL IMPLICATIONS: A low-risk MPS permits a policy of watchful waiting whereas a high-risk MPS requires further analysis and treatment. The persistent high cardiac death and acute myocardial infarction rate after a high-risk MPS suggest that the current management of these patients does not suffice and needs reconsideration.

Safety, reactogenicity and immunogenicity of Francisella tularensis live vaccine strain in humans.

We evaluated the safety, reactogenicity and immunogenicity of escalating doses of a new Francisella tularensis Live Vaccine Strain (LVS) lot by scarification (SCAR) or subcutaneously (SQ) in humans. Subjects (N=10/group) received one dose of LVS via SCAR at 10(5),10(7) or 10(9)cfu/ml or SQ at 10(2), 10(3),10(4) or 10(5)cfu/ml; 14 subjects received placebo. All doses/routes were well tolerated. When compared to placebo, vaccination with 10(7) SCAR and 10(9) SCAR resulted in significantly higher serologic response frequencies, as measured by ELISA for IgG, IgM, IgA and microagglutination; whereas vaccination with 10(5) SCAR, 10(7) SCAR 10(9) SCAR and 10(5) SQ elicited a significantly higher interferon-gamma response frequency.

[International medical graduates in Dutch health care: the new assessment procedure]. / Artsen met een buitenlands diploma in de Nederlandse patiëntenzorg: de nieuwe assessmentprocedure.

On December 1, 2005 in the Netherlands, a new procedure was introduced to assess international medical graduates (IMGs) with a diploma acquired outside the European Economic Area (EEA). This procedure includes (a) general tests on the active and passive use of Dutch medical language, English reading proficiency, basic IT skills and knowledge of the Dutch health care system, and (b) a specific set of tests of medical competence, including knowledge of basic sciences, clinical knowledge and clinical skills. IMGs who wish to get their diploma acknowledged and be registered as a physician are required to complete this assessment. With the introduction of this procedure, the Netherlands have joined a minority of countries inside and outside Europe with setting high standards for intake procedures. It is advocated that all European countries should devise such procedures, as a European Directive (2005/36/EC) on the recognition of professional qualifications prohibits the assessment of medical graduates with a diploma that is recognised in another EEA country.

Development of an instrument to assess professional behaviour of foreign medical graduates.

BACKGROUND: Foreign medical graduates have to overcome challenges such as language proficiency and cultural differences. Several studies indicate that foreign medical graduates show deficiencies in professional behaviour. For the assessment of foreign medical graduates' professional behaviour, a more specific and sensitive instrument was needed. The aim of this study was to develop such an instrument. The starting point was the Amsterdam Attitudes and Communications Scale (AACS). Two research questions were addressed: (a) What adaptations of the AACS are needed in order to assess foreign medical graduates' professional behaviour adequately? (b) Is the developed instrument reliable, valid and feasible? METHODS: Our study consisted of 4 phases: (1) a brief literature search; (2) consulting a panel of experts; (3) establishing the content-validity of the instrument; and (4) establishing the feasibility of the instrument as an assessment tool. RESULTS: From the literature and experts in the field we learned that deficiencies in professional behaviour of foreign medical graduates concern mainly language skills and culture related issues. In the instrument we developed special attention was given to these deficiencies. Sub-items were added to every dimension. These sub-items are behavioural descriptions of the respective dimension and serve as a basis for feedback. CONCLUSIONS: The sub-items should enhance constructive feedback, not only focussing on inappropriate behaviour but also by emphasizing adequate behaviours. The validity and reliability of the instrument has to be investigated further and confirmed along the way.

Dopamine D4 receptor and tyrosine hydroxylase genes in bipolar disorder: evidence for a role of DRD4.

The involvement of the mesocorticolimbic dopamine system in behaviors that are compromised in patients with mood disorder has led to the investigation of dopamine system genes as candidates for bipolar disorder. In particular, the functional VNTRs in the exon III of the dopamine D4 (DRD4) and in intron I of the tyrosine hydroxylase (TH) genes have been investigated in numerous association studies that have produced contrasting results. Likewise, linkage studies in multiplex bipolar families have shown both positive and negative results for markers in close proximity to DRD4 and TH on 11p15.5. We performed a linkage disequilibrium analysis of the DRD4 and TH VNTRs in a sample of 145 nuclear families comprised of DSM-IV bipolar probands and their biological parents. An excess of transmissions and non transmissions was observed for the DRD4 4- and 2-repeat alleles respectively. The biased transmission showed a parent of origin effect (POE) since it was derived almost exclusively from the maternal meiosis (4-repeat allele maternally transmitted 40 times vs 20 times non-transmitted; chi(2) = 6.667; df = 1; P = 0.009; while paternally transmitted 26 times vs 21 times non-transmitted; chi(2) = 0.531; df = 1; P = 0.46). The analysis of TH did not reveal biased transmission of intron I VNTR alleles. Although replication of our study is necessary, the fact that DRD4 exhibit POE and is located on 11p15.5, in close proximity to a cluster of imprinted genes, suggests that genomic imprinting may be operating in bipolar disorder.

[Initial experience with selection procedures for admission to medical school]. / De eerste ervaringen met selectie voor de artsopleiding.

Admittance to a medical school in the Netherlands has for decades been based on a grade point average weighted lottery system of secondary school leavers. Since 2000, the Dutch Higher Education and Scientific Research Act has given medical schools the option of selecting candidates. In 2000, two of the eight Dutch medical schools started selection experiments for 10 percent of their places. Leiden University Medical Center invited school leavers who had studied a more varied range of extra subjects to attend a 10-day summer school. All 54 candidates were ranked on the basis of assessments and tests; 24 of them were admitted. Utrecht University invited students with a higher education degree to a selection day. An application form, a structured interview and a questionnaire determined the ranking of 53 candidates; 24 of them were admitted. Both schools were satisfied with the manner in which the selection procedure worked. However, it is not yet possible to draw any definite conclusions about the effectiveness of the selection procedure.