The addition of the sFlt-1/PlGF ratio to the protein/creatinine ratio in multiple pregnancy: Post-hoc analysis of the PREPARE cohort study.

OBJECTIVE: To assess the predictive accuracy of the sFlt-1/PlGF ratio cut-off 38 in addition to the standard-of-care spot urine protein/creatinine ratio (PCr) for multiple pregnancies in women with suspected pre-eclampsia. STUDY DESIGN: Post-hoc analysis of a prospective cohort study. MAIN OUTCOME MEASURES: Primary outcome was the occurrence of pre-eclampsia in one and four weeks after presentation with suspected pre-eclampsia. Test characteristics with 95% confidence intervals (CI) were calculated on pre-eclampsia development in one and four weeks. RESULTS: Twenty-three multiple pregnancies with suspected pre-eclampsia between 20 and 37 weeks gestation were included for analysis. Women who eventually developed pre-eclampsia had a significantly higher PCr (34.0 vs. 16.5, p = 0.015), sFlt-1 (17033 vs. 5270 pg/ml, p = 0.047) and sFlt-1/PlGF ratio (99 vs. 25, p = 0.033) at baseline. Furthermore, PCr ≥ 30 and sFlt-1/PlGF ratio > 38 was respectively seen in 1/16 (6.3 %) and 3/16 (18.8 %) of the women who did not develop pre-eclampsia. For predicting pre-eclampsia within one week the sFlt-1/PlGF ratio sensitivity was 75.0 % [95 % CI 19.4-99.4] and the negative predictive value 93.8 % [73.0-98.8], while no pre-eclampsia developed when PCr was < 30. Consequently, the combination of these tests did not lead to an improvement in test characteristics, with non-significant differences in positive predictive value (50.0 % [29.5-70.5] versus 80.0 % [37.3-96.4]) compared to PCr alone for pre-eclampsia development in one week. CONCLUSIONS: In addition to standard-of-care spot urine PCr measurements, this study has not been able to demonstrate that the sFlt-1/PlGF ratio cut-off 38 is of added value in the prediction of pre-eclampsia in multiple pregnancy. TRIAL REGISTRATION: Netherlands Trial Register (NL8308).

Design and rationale of the efficacy of spinal cord stimulation in patients with refractory angina pectoris (SCRAP) trial.

BACKGROUND: The use of spinal cord stimulation (SCS) in patients with refractory angina pectoris (RAP) is still under debate. Studies up to date have shown a positive effect with an improvement in quality of life. However, no double blinded randomized controlled trials have been performed. HYPOTHESIS & METHODS: The objective of this trial is to investigate if high density SCS leads to a significant reduction in the amount of myocardial ischemia in patients with RAP. Eligible patients must meet the criteria for RAP, have proven ischemia and a positive transcutaneous electrical nerve stimulator treadmill test. Patients who meet the inclusion criteria will receive an implanted spinal cord stimulator. Patients receive 6 months of high density SCS and 6 months of no stimulation using a cross-over design. The order of the treatment options is determined using randomization. The primary endpoint is the effect of SCS measured by the change in percentage of myocardial ischemia using myocardial perfusion positron emission tomography scan. Key secondary endpoints are patient related outcome measures, major cardiac adverse events and safety endpoints. The follow-up period is 1 year for the primary and key secondary endpoints. RESULTS: The SCRAP trial began enrollment on December 21, 2021 and is set to complete the primary assessments in June 2025. To date, January 2, 2023, 18 patients have been enrolled in the study and 3 patients have completed the 1-year follow-up. CONCLUSIONS: The SCRAP trial is an investigator-initiated, single-center, double-blind, placebo-controlled, and cross-over randomized controlled trial investigating the efficacy of SCS in patients with RAP. (ClinicalTrials. gov Identifier: NCT04915157).

Long-term efficacy and safety of spinal cord stimulation in patients with refractory angina pectoris.

Background: The number of patients with refractory angina pectoris (RAP), associated with poor quality of life, has been steadily increasing. Spinal cord stimulation (SCS) is a last resort treatment option leading to significant improvement in quality of life over a one year follow-up. The aim of this prospective, single-centre, observational cohort study is to determine the long-term efficacy and safety of SCS in patients with RAP. Methods: All patients with RAP who received a spinal cord stimulator from the period July 2010 up to November 2019 were included. In May 2022 all patients were screened for long-term follow-up. If the patient was alive the Seattle Angina (SAQ) and RAND-36 questionnaire were completed and if the patient had passed away cause of death was determined. The primary endpoint is the change in SAQ summary score at long-term follow-up compared to baseline. Results: From July 2010 up to November 2019 132 patients received a spinal cord stimulator due to RAP. The mean follow-up period was 65.2 ± 32.8 months. Seventy-one patients completed the SAQ at baseline and long-term follow-up. The SAQ SS showed an improvement of 24.32U (95% confidence interval [CI]: 18.71 - 29.93; p < 0.001). Conclusions: The main findings of the study show that long-term SCS in patients with RAP leads to significant improvement in quality of life, significant reduction in angina frequency, significantly less use of short-acting nitrates and a low risk of spinal cord stimulator related complications over a mean follow-up period of 65.2 ± 32.8 months.

To what extent are anorectal function tests comparable? A study comparing digital rectal examination, anal electromyography, 3-dimensional high-resolution anal manometry, and transperineal ultrasound.

BACKGROUND: Anorectal function tests are helpful for objective investigation of anorectal (dys)function. A variety of tests are available, but there is no recommendation when to perform which test. Furthermore, which test is the most accurate is controversial and the correlation between these tests is not very clear. The aim of our study was to examine the correlation of anal pressures and the possibility to diagnose pelvic floor dyssynergia between digital rectal examination (DRE) and several anorectal function tests. METHODS: Between January 2020 and April 2022, all men and women aged 18 to 80 years, treated at the Proctos Clinic, who were referred for pelvic floor physical therapy (PFPT) by the surgeon and underwent anorectal function tests, were included. DRE was performed to establish the anal pressure at rest and during squeeze and straining. Anorectal function tests included 3D high-resolution anal manometry (3D-HRAM), balloon expulsion test (BET), transperineal ultrasound (TPUS), and surface electromyography (s-EMG). RESULTS: A total of 50 patients, 37 (74%) females, were included. Median age was 51 years. Twenty-three (62%) females had a history of two or more vaginal deliveries. The most frequent reason for referral for PFPT was fecal incontinence in 27 (54%) patients. The assessed pressures and pelvic floor function measured with DRE by the surgeon and the pelvic floor physical therapist during rest, squeeze, and straining correlated in 78%, 78%, and 84%, respectively. Correlation between DRE and 3D-HRAM or s-EMG was better for squeeze pressures than resting pressures. The correlation between s-EMG and 3D-HRAM was better during squeeze than at rest with an agreement of 59% and 37%, respectively. CONCLUSION: DRE by an experienced investigator is of sufficient value for daily clinical practice to detect dyssynergia and to measure sphincter tone. Commonly performed anorectal function tests correlate poorly with DRE and with other anorectal function tests. When conservative treatment fails, further investigation is warranted; however, these results should be interpreted with caution. WHAT DOES THIS PAPER ADD TO THE LITERATURE?: Anorectal function tests such as the 3D high-resolution anorectal manometry, balloon expulsion test, surface electromyography, and transperineal ultrasound are all frequently performed in the diagnostic workup in patients with defecation disorders. No previous study has compared these tests regarding their outcomes, nor has the interrater agreement been measured regarding the digital rectal examination by two experienced observers. Furthermore, transperineal ultrasound is in all probability not frequently used and therefore underexposed in the diagnostic workup of patients with dyssynergic defecation.

A Pilot Study on the Effect of Peer Support on Quality of Life of Adolescents with Autism Spectrum Disorder and Gender Dysphoria.

Gender dysphoria (GD) and Autism Spectrum Disorder (ASD) co-occur relatively often, but there is no evidence-based treatment for this specific group. Therefore, we examined the effects of a group intervention for adolescents with ASD and GD in a pilot study with a pre-post-test design. The adolescents completed questionnaires on quality of life, self-esteem, gender dysphoric feelings, and social responsiveness. Results show that participating in this peer support group seems to increase aspects of quality of life, i.e., increased parent-reported psychological well-being and decreased psychological complaints. Even though more research is needed, these results indicate that peer support is an invaluable part of treatment for adolescents with ASD and GD.

Is the Goligher classification a valid tool in clinical practice and research for hemorrhoidal disease?

BACKGROUND: The most widely used classification for hemorrhoidal disease (HD) is the Goligher classification, which ranks presence and severity of prolapse in four grades. Since physicians base this gradation on medical history and physical examination, it might be prone to interobserver variability. Furthermore, the gradation impacts the treatment of choice which makes reproducibility of utmost importance. The aim of this study was to determine the interobserver variability of Goligher classification among surgeons in the Netherlands. METHODS: A single-choice survey was used. The first part consisted of questions concerning baseline characteristics and the use of the Goligher classification in routine clinical practice. In the second part, to assess interobserver variability, we asked gastrointestinal surgeons and residents who routinely treat HD to review 25 photographs (with given timing as during rest or push) of patients with HD and classify the gradation using the Goligher classification. The survey was sent by email on April 19, 2021 and was available online until July 5, 2021. Interobserver variability was assessed using Fleiss' Kappa test. RESULTS: A total of 329 gastrointestinal surgeons, fellows and residents were sent an invitation email, of whom 95 (29%) completed the survey. Among the respondents, 87% indicated that they use the Goligher classification in clinical practice. Eighty-one percent found the classification helpful and 63% classified HD according to Goligher and followed the guidelines for treatment of HD accordingly. The interobserver variability showed an overall fair strength of agreement, with a Fleiss' Kappa (κ) of 0.376 (95% CI 0.373-0.380). There was a moderate agreement for grade I and IV HD with a κ statistic of 0.466 and 0.522, respectively. For grades II and III, there was a lower (fair) strength of agreement with 0.206 and 0.378, respectively. CONCLUSIONS: The fair interobserver variability is disappointing and demonstrates the need for a more reliable, and internationally accepted, classification for HD. A new classification should enable more uniformity in treating HD and in comparing outcomes of future trials and prospective registries. The protocol for a Delphi study for a new classification system is currently being prepared and led by an international research group.

Report on outcomes of valve-in-valve transcatheter aortic valve implantation and redo surgical aortic valve replacement in the Netherlands.

OBJECTIVE: We sought to investigate real-world outcomes of patients with degenerated biological aortic valve prostheses who had undergone valve-in-valve transcatheter aortic valve implantation (ViV-TAVI) or reoperative surgical aortic valve replacement (redo-SAVR) in the Netherlands. METHODS: Patients who had undergone ViV-TAVI or redo-SAVR for a degenerated biological aortic valve prosthesis in the Netherlands between January 2014 and December 2018 were eligible for this retrospective study. Patients with a prior homograft, active endocarditis or mechanical aortic valve prosthesis were excluded. Patients were matched using the propensity score. The primary endpoint was a composite of 30-day all-cause mortality and in-hospital postoperative stroke. Secondary endpoints were all-cause mortality at different time points, in-hospital postoperative stroke, pacemaker implantation and redo procedures within one year. Baseline characteristics and outcome data were collected from the Netherlands Heart Registration. RESULTS: From 16 cardiac centres, 653 patients were included in the study (374 ViV-TAVI and 279 redo-SAVR). European System for Cardiac Operative Risk Evaluation I (EuroSCORE I) was higher in ViV-TAVI patients (19.4, interquartile range (IQR) 13.3-27.9 vs 13.8, IQR 8.3-21.9, p < 0.01). After propensity score matching, 165 patients were matched with acceptable covariate balance. In the matched cohorts, the primary endpoint was not significantly different for ViV-TAVI and redo-SAVR patients (odds ratio 1.30, 95% confidence interval 0.57-3.02). Procedural, 30-day and 1­year all-cause mortality rates, incidence of in-hospital postoperative stroke, pacemaker implantation and redo procedures within one year were also similar between cohorts. CONCLUSION: Patients with degenerated aortic bioprostheses treated with ViV-TAVI or redo-SAVR have similar mortality and morbidity.

The health potential of neighborhoods: A population-wide study in the Netherlands.

BACKGROUND: While differences in population health across neighborhoods with different socioeconomic characteristics are well documented, health disparities across neighborhoods with similar socioeconomic characteristics are less well understood. We aimed to estimate population health inequalities, both within and between neighborhoods with similar socioeconomic status, and assessed the association of neighborhood characteristics and socioeconomic spillover effects from adjacent neighborhoods. METHODS: Based on Dutch whole-population data we determined the percentage of inhabitants with good or very good self-assessed health (SAH) and the percentage of inhabitants with at least one chronic disease (CD) in 11,504 neighborhoods. Neighborhoods were classified by quintiles of a composite neighborhoods socioeconomic status score (NSES). A set of spatial models was estimated accounting for spatial effects in the dependent, independent, and error components of the model. RESULTS: Substantial population health disparities in SAH and CD both within and between neighborhoods NSES quintiles were observed, with the largest SAH variance in the lowest NSES group. Neighborhoods adjacent to higher SES neighborhoods showed a higher SAH and a lower prevalence of CD. Projected impacts from the spatial regressions indicate how modest changes in NSES among the lowest socioeconomic neighborhoods can contribute to population health in both low- and high-SES neighborhoods. CONCLUSION: Population health differs substantially among neighborhoods with similar socioeconomic characteristics, which can partially be explained by a spatial socio-economic spillover effect.

Management of cryptoglandular fistula-in-ano among gastrointestinal surgeons in the Netherlands.

BACKGROUND: Management of cryptoglandular fistula-in-ano (FIA) can be challenging. Despite Dutch and international guidelines determining optimal therapy is still quite difficult. The aim of this study was to report current practices in the management of cryptoglandular FIA among gastrointestinal surgeons in the Netherlands. METHODS: Dutch surgeons and residents who are treating FIA regularly were sent a survey invitation by email. The survey was available online from September 19 to December 1 2019. The questionnaire consisted of 28 questions concerning diagnostic and surgical techniques in the treatment of intersphincteric and transsphincteric FIA. RESULTS: In total, 147 (43%) surgeons responded and completed the survey. Magnetic resonance imaging was the preferred diagnostic imaging modality (97%) followed by the endo-anal ultrasound (12%). In case of a high FIA, 86% used a non-cutting seton. Most respondents removed a seton between 6 weeks and 3 months (n = 84, 58%). Fistulotomy was the procedure of preference in low transsphincteric (86%) and low intersphincteric FIA (92%). Mucosal advancement flap (MAF) and ligation of intersphincteric fistula tract (LIFT), with 78% and 46%, respectively, were the procedures that were applied most often in high transsphincteric FIA. In high intersphincteric FIA 67% performed a MAF and 33% a fistulotomy. Thirty-three percent of all respondents stated that they habitually closed the internal fistula opening, half of them used a Z-plasty. For debridement of the fistula tract the preferred method was curettage (78%). CONCLUSIONS: Dutch gastrointestinal surgeons use various techniques in the management of FIA. Novel promising techniques should be investigated adequately in sufficient large trials to increase consensus. A core outcome measurement and a prospective international database would help in comparing results. Until then, treatment should be adjusted to the individual patient, governed by fistula characteristics and patient choice.

Rubber band ligation versus haemorrhoidectomy for the treatment of grade II-III haemorrhoids: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: The aim of this study was to review clinical outcome of haemorrhoidectomy and rubber band ligation in grade II-III haemorrhoids. METHODS: A systematic review was conducted. Medline, Embase, Cochrane Library, Clinicaltrials.gov, and the WHO International Trial Registry Platform were searched, from inception until May 2018, to identify randomised clinical trials comparing rubber band ligation with haemorrhoidectomy for grade II-III haemorrhoids. The primary outcome was control of symptoms. Secondary outcomes included postoperative pain, postoperative complications, anal continence, patient satisfaction, quality of life and healthcare costs were assessed. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. RESULTS: Three hundred and twenty-four studies were identified. Eight trials met the inclusion criteria. All trials were of moderate methodological quality. Outcome measures were diverse and not clearly defined. Control of symptoms was better following haemorrhoidectomy. Patients had less pain after rubber band ligation. There were more complications (bleeding, urinary retention, anal incontinence/stenosis) in the haemorrhoidectomy group. Patient satisfaction was equal in both groups. There were no data on quality of life and healthcare costs except that in one study patients resumed work more early after rubber band ligation. CONCLUSIONS: Haemorrhoidectomy seems to provide better symptom control but at the cost of more pain and complications. However, due to the poor quality of the studies analysed/it is not possible to determine which of the two procedures provides the best treatment for grade II-III haemorrhoids. Further studies focusing on clearly defined outcome measurements taking patients perspective and economic impact into consideration are required.

Better survival after transcatheter aortic valve replacement by process improvements.

OBJECTIVE: The aim of this study is to assess the effects on procedural, 30-day, and 1­year all-cause mortality by a newly introduced quality improvement strategy in patients after transcatheter aortic valve replacement (TAVR). METHODS: In October 2015, a coherent set of quality improving interventions with respect to patient geriatric screening, general diagnostic examination and safety of the procedure was implemented at a single centre in the Netherlands. Patients undergoing TAVR in 2013-2018 were included for retrospective analysis. Mortality was assessed in the pre-quality improvement strategy cohort (January 2013 to October 2015; cohort A) and in the post-quality improvement strategy cohort (November 2015 to December 2018; cohort B). Logistic regression analysis was used to estimate the influence of patient and procedural characteristics on the results of the quality improvement strategy in terms of procedural, 30-day, and 1­year all-cause mortality. RESULTS: In total, 806 patients were analysed with 274 patients in cohort A and 532 patients in cohort B. After introduction of the quality improvement strategy, procedural (4.4% to 1.3%, p < 0.01), 30-day (8.4% to 2.7%, p < 0.01) and 1­year (16.4% to 8.5%, p < 0.01) all-cause mortality significantly decreased. Multivariate regression analysis showed that the quality improvement strategy also significantly reduced 30-day (odds ratio [OR] 0.19, 95% confidence interval [CI] 0.09-0.42) and 1­year (OR 0.38, 95% CI 0.24-0.61) all-cause mortality if corrected for patient characteristics. CONCLUSION: Structural meetings on evaluation of outcomes highlight potential areas for improvement and subsequent outcome-based quality improvement initiatives can result in lower procedural, 30-day, and 1­year all-cause mortality.

IMPROV-ED trial: eHealth programme for faster recovery and reduced healthcare utilisation after CABG.

BACKGROUND: After coronary artery bypass grafting (CABG), healthcare utilisation is high and is partly unplanned. eHealth applications have been proposed to reduce healthcare consumption and to enable patients to get actively involved in their recovery. This way, healthcare expenses can be reduced and the quality of care can be improved. OBJECTIVES: We aim to evaluate whether the use of an eHealth programme can reduce unplanned healthcare utilisation and improve mental and physical health in the first 6 weeks after discharge in patients who underwent CABG. In addition, patient satisfaction and use of the eHealth programme will be evaluated. METHODS: For this single-centre randomised controlled trial, at least 280 patients referred for CABG will be included at the preoperative outpatient clinic and randomised to an intervention or control group. The intervention group will have access to an eHealth programme, which consists of online educational videos developed by the Dutch Heart Foundation and postoperative video consultations with a physician. The control group will receive standard care and will not have access to the eHealth programme. The primary endpoint is healthcare utilisation; other endpoints include anxiety, duration of recovery, quality of life and patient satisfaction. Participants will complete several questionnaires at 6 time points during the study. RESULTS: Patient enrolment started in February 2020 and completion of the follow-up period is expected in August 2021. CONCLUSION: This randomised trial was initiated to test the hypothesis that patients who are partaking in our eHealth programme use less unplanned care and experience a better quality of life, less anxiety and a faster recovery than controls.

Heart rate variability in hypertensive pregnancy disorders: A systematic review.

BACKGROUND: Hypertensive pregnancy disorders (HPD) are associated with dysfunction of the autonomic nervous system. Cardiac autonomic functions can be assessed by heart rate variability (HRV) measurements. OBJECTIVE: To study whether HRV detects differences in the function of the autonomic nervous system between pregnant women with HPD compared to normotensive pregnant women and between women with a history of a pregnancy complicated by HPD compared to women with a history of an uncomplicated pregnancy. METHODS: A systematic search was performed in Medline, EMBASE, and CENTRAL to identify studies comparing HRV between pregnant women with HPD or women with a history of HPD to women with (a history of) normotensive pregnancies. RESULTS: The search identified 523 articles of which 24 were included in this review, including 850 women with (a history of) HPD and 1205 normotensive controls. The included studies showed a large heterogenicity. A decrease in overall HRV was found in preeclampsia (PE), compared to normotensive pregnant controls. A trend is seen towards increased low frequency/high frequency-ratio in women with PE compared to normotensive pregnant controls. CONCLUSION: Our systematic review supports the hypothesis a sympathetic overdrive is found in HPD which is associated with a parasympathetic withdrawal. However, the included studies in our review showed a large diversity in the methods applied and their results.

Review on Factors Influencing Physician Guideline Adherence in Cardiology.

Cardiovascular disease is the most common cause of death in Western countries. Physician adherence to guidelines is often suboptimal, resulting in impaired patient outcome and prognosis. Multiple studies have been conducted to evaluate patterns and the influencing factors of patient adherence, but little is known about factors influencing physician guideline adherence. This review aims to identify factors influencing physician guideline adherence relevant to cardiology and to provide insights and suggestions for future improvement. Physician adherence was measured as adherence to standard local medical practice and applicable guidelines. Female gender and older age had a negative effect on physician guideline adherence. In addition, independent of the type of heart disease, physicians without cardiologic specialization were linked to physician noncompliance. Also, guideline adherence in primary care centers was at a lower level compared with secondary or tertiary care centers. The importance of guideline adherence increases as patients age, and complex diseases and comorbidity arise. Appropriate resources and interventions, taking important factors for nonadherence in account, are necessary to improve guideline adoption and adherence in every level of the chain. This in turn should improve patient outcome.

Cardiac structure and function before and after bariatric surgery: a clinical overview.

Obesity, defined as a body mass index of ≥30 kg/m2 , is the most common chronic metabolic disease worldwide and its prevalence has been strongly increasing. Obesity has deleterious effects on cardiac function. The purpose of this review is to evaluate the effects of obesity and excessive weight loss due to bariatric surgery on cardiac function, structural changes and haemodynamic responses of both the left and right ventricle.

Catheter ablation of symptomatic idiopathic ventricular arrhythmias : A five-year single-centre experience.

AIMS: This study was designed to gain insight into the patient characteristics, results and possible complications of ablation procedures for symptomatic idiopathic premature ventricular complexes (PVC) and idiopathic ventricular tachycardia (VT). METHODS: Data were collected from all patients who underwent radiofrequency catheter ablation for symptomatic PVCs and idiopathic VT in the Catharina Hospital between 1 January 2011 and 31 December 2015. The procedural endpoint was elimination or non-inducibility of the clinical arrhythmia. Successful sustained ablation was defined as the persistent elimination of at least 80% of the PVCs or the absence of VTs at follow-up. In case of suspected PVC-induced cardiomyopathy, the systolic left ventricular function was reassessed 3 months post procedure. RESULTS: Our cohort consisted of 131 patients who underwent one or more ablation procedures; 99 because of symptomatic premature ventricular complexes, 32 because of idiopathic VT. In total 147 procedures were performed. The procedural ablation success rate was 89%. Successful sustained ablation rate was 82%. Eighteen (13.2%) patients had suspected PVC-induced cardiomyopathy. In 15 of them (83%), successful sustained ablation was achieved and the left ventricular ejection fraction improved from a mean of 39% (±8.8) to 55.4% (±8.1). Most arrhythmias originated from the right ventricular outflow tract (60%) or aortic cusps (13%). Complications included three tamponades. CONCLUSION: Catheter ablation therapy for idiopathic ventricular arrhythmias is very effective with a sustained success rate of 82%. In patients with PVC-induced cardiomyopathy, it leads to improvement of systolic left ventricular function. However, risk for complications is not negligible, even in experienced hands.

Assessment of the protein interaction between coagulation factor XII and corn trypsin inhibitor by molecular docking and biochemical validation.

Essentials Corn Trypsin Inhibitor (CTI) is a selective inhibitor of coagulation Factor XII (FXII). Molecular modelling of the CTI-FXIIa complex suggested a canonical inhibitor binding mode. Mutagenesis revealed the CTI inhibitory loop and helices α1 and α2 mediate the interaction. This confirms that CTI inhibits FXII in canonical fashion and validates the molecular model. SUMMARY: Background Corn trypsin inhibitor (CTI) has selectivity for the serine proteases coagulation factor XII and trypsin. CTI is in widespread use as a reagent that specifically inhibits the intrinsic pathway of blood coagulation but not the extrinsic pathway. Objectives To investigate the molecular basis of FXII inhibition by CTI. Methods We performed molecular docking of CTI, using its known crystal structure, with a model of the activated FXII (FXIIa) protease domain. The interaction model was verified by use of a panel of recombinant CTI variants tested for their ability to inhibit FXIIa enzymatic activity in a substrate cleavage assay. Results The docking predicted that: (i) the CTI central inhibitory loop P1 Arg34 side chain forms a salt bridge with the FXIIa S1 pocket Asp189 side chain; (ii) Trp22 from CTI helix α1 interacts with the FXIIa S3 pocket; and (iii) Arg43 from CTI helix α2 forms a salt bridge with FXIIa H1 pocket Asp60A. CTI amino acid substitution R34A negated all inhibitory activity, whereas the G32W, L35A, W22A and R42A/R43A substitutions reduced activity by large degrees of 108-fold, 41-fold, 158-fold, and 100-fold, respectively; the R27A, W37A, W39A and R42A substitutions had no effect. Synthetic peptides spanning CTI residues 20-44 had inhibitory activity that was three-fold to 4000-fold less than that of full-length CTI. Conclusions The data confirm the validity of a canonical model of the FXIIa-CTI interaction, with helix α1 (Trp22), central inhibitory loop (Arg34) and helix α2 (Arg43) of CTI being required for effective binding by contacting the S1, S3 and H1 pockets of FXIIa, respectively.

Reduced number of cardiovascular events and increased cost-effectiveness by genotype-guided antiplatelet therapy in patients undergoing percutaneous coronary interventions in the Netherlands.

AIM: This study explores clinical outcome in cytochrome P450 2C19 (CYP2C19)-related poor metaboliser patients treated with either clopidogrel or prasugrel after percutaneous coronary intervention (PCI) and investigates whether this could be cost-effective. METHODS AND RESULTS: This single-centre, observational study included 3260 patients scheduled for elective PCI between October 2010 and June 2013 and followed for adverse cardiovascular events until October 2014. Post PCI, CYP2C19 poor metaboliser patients were treated with clopidogrel or prasugrel, in addition to aspirin. In total, 32 poor metabolisers were treated with clopidogrel and 41 with prasugrel. The number of adverse cardiovascular events, defined as death from cardiovascular cause, myocardial infarction, stent thrombosis, every second visit to the catheterisation room for re-PCI in the same artery, or stroke, within 1.5 years of PCI, was significantly higher in the CYP2C19 poor metaboliser group treated with clopidogrel (n = 10, 31 %) compared with the poor metaboliser group treated with prasugrel (n = 2, 5 %) (p = 0.003). Costs per gained quality-adjusted life years (QALY) were estimated, showing that genotype-guided post-PCI treatment with prasugrel could be cost-effective with less than € 10,000 per gained QALY. CONCLUSION: This study provides evidence that for CYP2C19-related poor metabolisers prasugrel may be more effective than clopidogrel to prevent major adverse cardiovascular events after PCI and this approach could be cost-effective.

Spatial distribution of electrical reconnection after pulmonary vein isolation in patients with recurrent paroxysmal atrial fibrillation.

INTRODUCTION: Recurrence of atrial fibrillation after pulmonary vein isolation (PVI) occurs frequently and may be associated with electrical reconnection of the pulmonary veins (PV). We investigated spatial distribution of electrical reconnection during re-do procedures in patients with paroxysmal atrial fibrillation who had previous successful acute electrical PVI with either single irrigated tip, antral ablation (s-RF; n = 38) or multi-electrode, duty-cycled ablation (PVAC; n = 48). METHODS AND RESULTS: EP navigator, mapping and irrigated tip ablation catheters were used in all re-do procedures. Sites of reconnection were assessed in a 12-segment model. Baseline clinical and demographic characteristics were similar in both groups. The number of PVs reconnected per patient was similar in both groups (2.9 ± 0.9 and 3.2 ± 0.7 (p = 0.193), s­RF and PVAC, respectively), and each PV was equally affected. However, the inferior quadrant of the right lower PV was significantly more vulnerable to reconnection after previous PVAC ablation, whereas the superior quadrant of the right upper PV showed significantly more reconnection in the s­RF group. CONCLUSION: The overall number of PVs reconnected was equally high in both groups, and each PV was affected equally. However, there were significant differences in the spatial distribution of electrical reconnection. Better understanding of predilection sites for reconnection might help to improve the long-term success rate of PVI.