Synthesis of Five-Membered exo-Glycals from Six-Membered 2-Iodo-endo-glycals.

Five-membered exo-glycals were synthesized from six-membered 2-iodo-endo-glycals by a metal/halogen exchange/ring-opening sequence followed by a cyclization catalyzed by Ag2CO3.

The prognostic value of quality of life in atrial fibrillation on patient value.

BACKGROUND: In this study, the prognostic value of AF-related quality of life (AFEQT) at baseline on Major Adverse Cardiovascular Events (MACE) and improvement of perceived symptoms (EHRA) was assessed. Furthermore, the relationship between QoL and AF-related hospitalizations was assessed. METHODS: A cohort of AF-patients diagnosed between November 2014 and October 2019 in four hospitals embedded within the Netherlands Heart Network were prospectively followed for 12 months. MACE was defined as stroke, myocardial infarction, heart failure and/or mortality. Subsequently, MACE, EHRA score improvement and AF-related hospitalizations between baseline and 12 months of follow-up were recorded. RESULTS: In total, 970 AF-patients were available for analysis. In analyses with patients with complete information on the confounder subset 36/687 (5.2%) AF-patients developed MACE, 190/432 (44.0%) improved in EHRA score and 189/510(37.1%) were hospitalized during 12 months of follow-up. Patients with a low AFEQT score at baseline more often developed MACE (OR(95%CI): 2.42(1.16-5.06)), more often improved in EHRA score (OR(95%CI): 4.55(2.45-8.44) and were more often hospitalized (OR(95%CI): 4.04(2.22-7.01)) during 12 months post diagnosis, compared to patients with a high AFEQT score at baseline. CONCLUSIONS: AF-patients with a lower quality of life at diagnosis more often develop MACE, more often improve on their symptoms and also were more often hospitalized, compared to AF-patients with a higher quality of life. This study highlights that the integration of patient-reported outcomes, such as quality of life, has the potential to be used as a prognostic indicator of the expected disease course for AF.

Incorporation of a cyclobutyl substituent in molecules by transition metal-catalyzed cross-coupling reactions.

In this review, the incorporation of a cyclobutyl substituent in molecules, by transition metal-catalyzed cross-coupling, is described by only considering the formation of C-C bonds. Three main strategies are used to introduce a cyclobutyl substituent in molecules by involving either electrophilic or nucleophilic cyclobutane derivatives.

Ni-Catalyzed Cross-Coupling of 2-Iodoglycals and 2-Iodoribals with Grignard Reagents: A Route to 2-C-Glycosides and 2'-C-Nucleosides.

The synthesis of 2-C-glycals and 2-C-ribals was achieved in good yields using a nickel-catalyzed cross-coupling between 2-iodoglycals and 2-iodoribal respectively and Grignard reagents. The prepared 2-C-glycals and ribals were then transformed into 2-C-2-deoxyglycosides, 2-C-diglycosides and 2'-C-2'-deoxynucleosides. The developed method was applied to the synthesis of a 2-chloroadenine 2'-deoxyribonucleoside - a structural analogue of cladribine (Mavenclad®, Leustatin®) and clofarabine (Clolar®, Evoltra®), two compounds used in the treatment of relapsing-remitting multiple sclerosis and hairy cell leukemia.

Age-dependency of EHRA improvement based on quality of life at diagnosis of atrial fibrillation.

BACKGROUND: In this study, the relationship between AF-related quality of life (AFEQT) at baseline in AF-patients and the improvement on perceived symptoms and general state of health (EHRA, European Heart Rhythm Association score) at 12 months was assessed across predefined age categories. METHODS: Between November 2014 and October 2019 patients diagnosed with AF de novo in four hospitals embedded within the Netherlands Heart Network were prospectively followed for 12 months. These AF-patients were categorized into quartiles based on their AFEQT score at diagnosis and EHRA score was measured at diagnosis and 12 months of follow-up. Stratified analyses were performed using age categories (<65 vs. ≥65 years; <75 vs. ≥75 years). RESULTS: In total, 203/483 (42.0%) AF-patients improved in EHRA score after 12 months of follow-up. AF-patients in the lowest AFEQT quartile were more likely to improve, compared to patients in the highest AFEQT quartile (OR [95%CI]:4.73 [2.63-8.50]). Furthermore, patients ≥65 years and patients <75 years at diagnosis with lower AFEQT scores at baseline were most likely to improve in EHRA score after 12 months, compared to similarly aged patients with higher AFEQT scores at baseline. CONCLUSION: The present study indicates that AF-patients with a lower quality of life at diagnosis were most likely to improve their EHRA score after 12 months. This effect was most prominent in patients ≥65 years of age and patients <75 years of age, compared to patients >65 and ≥75 years, respectively. Future research should focus on further defining characteristics of these age groups to enable the implementation of age-tailored treatment.

Regional implementation of atrial fibrillation screening: benefits and pitfalls.

Aims: Despite general awareness that screening for atrial fibrillation (AF) could reduce health hazards, large-scale implementation is lagging behind technological developments. As the successful implementation of a screening programme remains challenging, this study aims to identify facilitating and inhibiting factors from healthcare providers' perspectives. Methods and results: A mixed-methods approach was used to gather data among practice nurses in primary care in the southern region of the Netherlands to evaluate the implementation of an ongoing single-lead electrocardiogram (ECG)-based AF screening programme. Potential facilitating and inhibiting factors were evaluated using online questionnaires (N = 74/75%) and 14 (of 24) semi-structured in-depth interviews (58.3%). All analyses were performed using SPSS 26.0. In total, 16 682 screenings were performed on an eligible population of 64 000, and 100 new AF cases were detected. Facilitating factors included 'receiving clear instructions' (mean ± SD; 4.12 ± 1.05), 'easy use of the ECG-based device' (4.58 ± 0.68), and 'patient satisfaction' (4.22 ± 0.65). Inhibiting factors were 'time availability' (3.20 ± 1.10), 'insufficient feedback to the practice nurse' (2.15 ± 0.89), 'absence of coordination' (54%), and the 'lack of fitting policy' (32%). Conclusion: Large-scale regional implementation of an AF screening programme in primary care resulted in a low participation of all eligible patients. Based on the perceived barriers by healthcare providers, future AF screening programmes should create preconditions to fit the intervention into daily routines, appointing an overall project lead and a General Practitioner (GP) as a coordinator within every GP practice.

Mechanical properties of 3-D printed polyvinyl alcohol matrix for detection of respiratory pathogens.

Polyvinyl alcohol is used to 3D print (fused deposition modelling) sampling matrices for bacterial detection. A specific configuration was designed using Computer-Aided Design software. The mechanical properties of the printed samples were studied using uniaxial tensile testing, and compared to those of the original Polyvinyl alcohol filament, with and without heat treatment. The effects of different factors such as UV treatment, printing speed, infill density and printing direction on the mechanical properties of the printed samples including strength, strain and modulus of elasticity were studied. The results show that the effect of the fused deposition modelling process on the mechanical properties of the printed Polyvinyl alcohol cannot be explained by its exposure to heat. UV treatment reduced the strength, characteristic strains and Young's modulus. It makes Polyvinyl alcohol samples brittle. The effects of printing speed and the infill density on the mechanical properties of printed samples can be no linear. An unexpected relation between printing direction and mechanical properties was demonstrated by the studied specimens that needs further theoretical understanding. There is a huge scatter in strength of PVA samples compared with typical engineering materials, and in the fracture strain of original PVA filament, the 3D printing process can reduce the scatter but only by a limited extent. To summarise, there is a sophisticated relation between printing parameters and the mechanical properties of the printed Polyvinyl alcohol.

Design and rationale of DUTCH-AF: a prospective nationwide registry programme and observational study on long-term oral antithrombotic treatment in patients with atrial fibrillation.

INTRODUCTION: Anticoagulation therapy is pivotal in the management of stroke prevention in atrial fibrillation (AF). Prospective registries, containing longitudinal data are lacking with detailed information on anticoagulant therapy, treatment adherence and AF-related adverse events in practice-based patient cohorts, in particular for non-vitamin K oral anticoagulants (NOAC). With the creation of DUTCH-AF, a nationwide longitudinal AF registry, we aim to provide clinical data and answer questions on the (anticoagulant) management over time and of the clinical course of patients with newly diagnosed AF in routine clinical care. Within DUTCH-AF, our current aim is to assess the effect of non-adherence and non-persistence of anticoagulation therapy on clinical adverse events (eg, bleeding and stroke), to determine predictors for such inadequate anticoagulant treatment, and to validate and refine bleeding prediction models. With DUTCH-AF, we provide the basis for a continuing nationwide AF registry, which will facilitate subsequent research, including future registry-based clinical trials. METHODS AND ANALYSIS: The DUTCH-AF registry is a nationwide, prospective registry of patients with newly diagnosed 'non-valvular' AF. Patients will be enrolled from primary, secondary and tertiary care practices across the Netherlands. A target of 6000 patients for this initial cohort will be followed for at least 2 years. Data on thromboembolic and bleeding events, changes in antithrombotic therapy and hospital admissions will be registered. Pharmacy-dispensing data will be obtained to calculate parameters of adherence and persistence to anticoagulant treatment, which will be linked to AF-related outcomes such as ischaemic stroke and major bleeding. In a subset of patients, anticoagulation adherence and beliefs about drugs will be assessed by questionnaire. ETHICS AND DISSEMINATION: This study protocol was approved as exempt for formal review according to Dutch law by the Medical Ethics Committee of the Leiden University Medical Centre, Leiden, the Netherlands. Results will be disseminated by publications in peer-reviewed journals and presentations at scientific congresses. TRIAL REGISTRATION NUMBER: Trial NL7467, NTR7706 (https://www.trialregister.nl/trial/7464).

Formal Transition-Metal-Catalyzed Phosphole C-H Activation for the Synthesis of Pentasubstituted Phospholes.

Unprecedented formal transition-metal-catalyzed phosphole C-H functionalization is described in this paper. Pentasubstituted phospholes were prepared via the copper-catalyzed reaction of 1,3,4-trisubstituted phosphole with aryl iodides or bromides under distinct conditions. The developed methodology is able to accommodate a wide variety of substituents, including aryl, heteroaryl, and alkenyl.

Indolylboronic Acids: Preparation and Applications.

Indole derivatives are associated with a variety of both biological activities and applications in the field of material chemistry. A number of different strategies for synthesizing substituted indoles by means of the reactions of indolylboronic acids with electrophilic compounds are considered the methods of choice for modifying indoles because indolylboronic acids are easily available, stable, non-toxic and new reactions using indolylboronic acids have been described in the literature. Thus, the aim of this review is to summarize the methods available for the preparation of indolylboronic acids as well as their chemical transformations. The review covers the period 2010-2019.

Regional collaboration to improve atrial fibrillation care: Preliminary data from the Netherlands heart network.

BACKGROUND: Guideline non-adherence and variations in therapeutic and diagnostic trajectories result in suboptimal atrial fibrillation (AF) treatments. Large academic and referral hospitals demonstrated positive effects of dedicated outpatient AF clinics. Although similar results have not been indicated in (small) non-academic hospitals yet, ample opportunities are present when collaboration is initiated on a regional level. Therefore, this study assesses the effectiveness of outpatient AF clinics in a collaborative region in the Netherlands. METHODS: For this study baseline and 6 months follow-up data of a prospective cohort including newly or recently diagnosed AF-patients of 4 hospitals involved in the Netherlands Heart Network are used. From January'15 to March'16 patient relevant outcome measures (ie EHRA score, stroke, major bleedings, hospitalizations, serious adverse effects of medication, and mortality) are gathered. Descriptive and regression analyses are performed to assess the effectiveness of outpatient AF clinics. RESULTS: In the analyses 448 AF-patients were included. After 6 months, significant improvements regarding EHRA score (P < 0.01), hypertension (P < 0.01), and type of AF (P < 0.01) were indicated. Results of the patient relevant outcomes showed that AF-patients were hospitalized 23 times, no major bleedings and 2 strokes occurred. Furthermore, 0 AF-patients reported serious adverse effects of medication and no AF-patients deceased. CONCLUSIONS: Collaboration between cardiologists in a regional setting permits further improvement of AF care. Therefore, such quality targets are not exclusively reserved to large academic or referral hospitals. Although promising, future research should put effort in measuring the effectiveness of the outpatient AF clinics also on the long run.

Social inhibition and emotional distress in patients with coronary artery disease: The Type D personality construct.

We examined the validity of the social inhibition component of Type D, its distinctiveness from negative affectivity, and value regarding emotional distress as measured with the DS14 in 173 coronary artery disease patients. In dimensional analysis, social inhibition and negative affectivity emerged as distinct traits. Analysis of continuous negative affectivity and social inhibition measures showed main effects for several emotional and inhibition markers and an interaction effect for social anxiety. Categorical analysis indicated that Type D patients reported more depression, negative mood, social anxiety, and less positive mood. Social inhibition is not a redundant trait, but has additional conceptual value.

Dearomatization Strategy for the Synthesis of Arylated 2H-Pyrroles and 2,3,5-Trisubstituted 1H-Pyrroles.

The first high-yielding route to arylated 2H-pyrroles was developed. The methodology utilizes 2,5-disubstituted pyrroles that are metalated, and the aryl substituents are introduced by a palladium-catalyzed cross-coupling reaction. The prepared pyrroles can be rearranged to 2,3,5-trisubstituted pyrroles under acidic conditions. Attempts to convert the 2,3,5-trisubstituted pyrroles to 2,3,4,5-tetrasubstituted pyrroles by the dearomatization rearrangement strategy were unsuccessful.

The synthesis of polysubstituted indoles from 3-bromo-2-indolyl phosphates.

A novel methodology for the synthesis of functionalised indoles based on the cross-coupling reactions of 3-bromo-2-indolyl phosphates is described. The preparation involves the conversion of easily available 2-oxindoles to 3,3-dibromo-2-oxindoles followed by the Perkow reaction affording 3-bromo-2-indolyl phosphates. Then bromine atom is substituted regioselectively by the Suzuki coupling reaction. We observed that aluminum chloride promoted the reaction of 3-substituted-2-indolyl phosphates with organozinc reagents furnishing 2,3-disubstituted indoles as final products. The overall diversity and efficiency of the methodology was demonstrated by the synthesis of bioactive molecule from easily available substances.

Does the Use of a Decision Aid Improve Decision Making in Prosthetic Heart Valve Selection? A Multicenter Randomized Trial.

BACKGROUND: A Dutch online patient decision aid to support prosthetic heart valve selection was recently developed. A multicenter randomized controlled trial was conducted to assess whether use of the patient decision aid results in optimization of shared decision making in prosthetic heart valve selection. METHODS AND RESULTS: In a 5-center randomized controlled trial, patients were allocated to receive either standard preoperative care (control group) or additional access to the patient decision aid (intervention group). Legally capable adult patients accepted for elective isolated or combined aortic and mitral valve replacement were included. Primary outcome was preoperative decisional conflict (Decisional Conflict Scale); secondary outcomes included patient knowledge, involvement in valve selection, anxiety and depression, (valve-specific) quality of life, and regret. Out of 306 eligible patients, 155 were randomized (78 control and 77 intervention). Preoperative decisional conflict did not differ between the groups (34% versus 33%; P=0.834). Intervention patients felt better informed (median Decisional Conflict Scale informed subscore: 8 versus 17; P=0.046) and had a better knowledge of prosthetic valves (85% versus 68%; P=0.004). Intervention patients experienced less anxiety and depression (median Hospital Anxiety and Depression Scale score: 6 versus 9; P=0.015) and better mental well-being (mean Short Form Health Survey score: 54 versus 50; P=0.032). Three months postoperatively, valve-specific quality of life and regret did not differ between the groups. CONCLUSIONS: A patient decision aid to support shared decision making in prosthetic heart valve selection does not lower decisional conflict. It does result in more knowledgeable, better informed, and less anxious and depressed patients, with a better mental well-being. CLINICAL TRIAL REGISTRATION: http://www.trialregister.nl. Unique identifier: NTR4350.

Coronary artery disease in congenital single coronary artery in adults: A Dutch case series.

AIM: To assess the current diagnostic and therapeutic management and the clinical implications of congenital single coronary artery (SCA) in adults. METHODS: We identified 15 patients with a SCA detected from four Dutch angiography centers in the period between 2010 and 2013. Symptomatic patients who underwent routine diagnostic coronary angiography (CAG) for suspected coronary artery disease and who incidentally were found to have isolated SCA were analyzed. RESULTS: Fifteen (7 females) with a mean age of 58.5 ± 13.78 years (range 43-86) had a SCA. Conventional CAG demonstrated congenital isolated SCA originating as a single ostium from the right sinus of Valsalva in 6 patients and originating from the left in 9 patients. Minimal to moderate coronary atherosclerotic changes were found in 4, and severe stenotic lesions in another 4 patients. Seven patients were free of coronary atherosclerosis. Runs of non-sustained ventricular tachycardia were documented in 2 patients, one of whom demonstrated transmural ischemic changes on presentation. Myocardial perfusion scintigraphic evidence of transmural myocardial ischemia was found in 1 patient due to kinking and squeezing of the SCA with an interarterial course between the aorta and pulmonary artery. Multi-slice computed tomography (MSCT) was helpful to delineate the course of the anomalous artery relative to the aorta and pulmonary artery. Percutaneous coronary intervention was successfully performed in 3 patients. Eight patients were managed medically. Arterial bypass graft was performed in 4 patients with the squeezed SCA. CONCLUSION: SCA may be associated with transient transmural myocardial ischemia and aborted sudden death in the absence of coronary atherosclerosis. The availability and sophistication of MSCT facilitates the delineation of the course of a SCA. We present a Dutch case series and review of the literature.

Biochemical analysis of neomycin-resistance in the methanoarchaeon Methanothermobacter thermautotrophicus and some implications for energetic processes in this strain.

Methanogenesis-driven ATP synthesis in a neomycin-resistant mutant of Methanothermobacter thermautotrophicus (formerly Methanobacterium thermoautotrophicum strain DeltaH) was strongly inhibited at both pH 6.8 and pH 8.5 by the uncoupler 3,3',4',5 -tetrachlorosalicylanilide (TCS) in the presence of either 1 or 10 mM NaCl. The generation of a membrane potential in the mutant cells at pH 6.8 was also strongly inhibited by TCS in the presence of 1 or 10 mM NaCl. On the other hand, at pH 8.5 in the presence of 10mM NaCl, a protonophore-resistant membrane potential of approximately 150 mV was found. These results indicate that in the mutant cells the process of energy transduction between methanogenesis and membrane potential generation is not impaired. In contrast to the wild-type strain, ATP synthesis in the mutant cells was driven by an electrochemical gradient of H(+) under alkaline conditions. Unlike wild-type cells, the mutant lacks the capacity to transduce an uncoupler-resistant membrane potential energy at pH 8.5 into ATP synthesis. Na(+)/H(+) exchange was comparable in the wild type and the mutant cells. Western blots of sub-cellular fractions with polyclonal antiserum reactive to the B-subunit of the halobacterial A-type H(+)-translocating ATPase confirmed the presence of A-type ATP synthase in the mutant cells. Furthermore, in the mutant cells a protein band of molecular mass about 45 kDa is absent but there was an abundant protein band at about 67 kDa. Based on the observed bioenergetic features of the mutant cells, neither the A(1)A(o) ATP synthase alone nor together with the Na(+)/H(+) antiporter seems to be responsible for ATP synthesis driven by sodium motive force. Rather, some other links between neomycin-resistance and failure of sodium motive force-dependent ATP synthesis in the neomycin resistant mutant are discussed.