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Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): PSIDER (ZOn-MW) PREDICT2 (Hartstichting) Background: The PLN p.Arg14del risk model is a mutation-specific risk model developed to predict individual malignant ventricular arrhythmia (VA) risk to inform decision-making for primary prevention implantable cardioverter defibrillator (ICD) implantation. While the risk model has proven to be valid, two main points of criticisms remain to be discussed: first, the risk model is only validated at baseline and second, appropriate ICD therapy and sustained ventricular tachycardia (VT) Purpose: To evaluate the diagnostic performance of the PLN p.Arg14del risk model longitudinal at 3 year follow-up and to reevaluate the predictors regarding SCD. Methods: Clinical data of 278 PLN p.Arg14del mutation carriers with no history of malignant VA at both baseline and 3 year follow-up were collected. During a median follow-up of 4 years (Interquartile range (IQR) 1.8-6.5), 31 (11%) carriers experienced malignant VA, defined as sustained VA, appropriate ICD intervention, or (aborted) SCD. The reevaluation of the predictors with the 3 year follow up data revealed hazard ratio’s (HR) that were similar to the baseline PLN p.Arg14del risk model for left ventricular ejection fraction (HR 1.10 [95% CI, 1.06-1.12], p To reevaluate the predictive performance of the PLN p.Arg14del risk model for a more strict surrogate of SCD we redefined the outcome as VT >250 beats per minute sustained (lasting ≥30 seconds) or terminated by ICD, ventricular fibrillation, aborted SCD and SCD. We included 669 PLN p.Arg14del carriers with no presentation or history of sustained VA or (aborted) SCD. During a median follow-up of 4.75 years (IQR 1.9-7.9), 33 (5%) carriers experienced the outcome. Results of the univariable analysis are shown in table 1. The PLN p.Arg14del risk model yielded a C-statistic of 0.75 (95% CI 0.70-0.80). Adding risk factors sex, age and sustained VT Conclusion: The PLN p.Arg14del risk model was validated longitudinal at 3 year follow-up and it held its performance with a more strict definition of SCD.

Aims In patients with Brugada syndrome (BrS) but without spontaneous Type-1 electrocardiogram, several electrocardiographic characteristics have been studied, including the β-angle. Previous studies suggested that the β-angle might be useful in distinguishing BrS-patients from patients with only suggestive repolarization patterns without performing sodium channel blocker provocation testing. In this study, we aimed to determine the diagnostic value of the β-angle in patients suspected of BrS. Methods and results A large cohort (n = 1430) of consecutive patients who underwent provocation testing was evaluated. β-angles were measured in leads V1, V2, and their corresponding positions over the second and third intercostal space. Receiver-operating characteristic curves were constructed and the diagnostic accuracy of previously reported β-angle cut-offs were calculated and evaluated. The importance of the β-angle for predicting the provocation test outcome was determined using a prediction model constructed with logistic regression. The optimum β-angle cut-off in our cohort for ruling out a positive provocation test was 15°; sensitivities were 80–98% and negative predictive values were 79–96% among the right precordial leads. Previously reported β-angle cut-offs performed less well, indicated by lower Youden indices. In the optimism-corrected prediction model [C-statistic: 0.78 (95% CI: 0.75–0.81)], the β-angle had large value (Z-score: 2.1–10.3) and aided construction of a nomogram to predict test outcome. Conclusion To predict the outcome of provocation testing for BrS, the β-angle alone does not demonstrate strong diagnostic characteristics. However, the β-angle is an important variable to predict provocation test outcome and thus has added value.

Background/Introduction Recently, a variant-specific prediction model for PLN p.Arg14del variant carriers was developed to predict individual malignant ventricular arrhythmia (VA) risk to inform decision-making for primary prevention implantable cardioverter defibrillator (ICD) implantation. This model predicts malignant VA risk from data at diagnosis, but iterative evaluation of malignant VA risk may be warranted considering that the risk factors for malignant VA are progressive. Purpose To evaluate the diagnostic performance of the PLN p.Arg14del risk model. Methods/Results Date were collected of 278 PLN p.Arg14del variant carriers at 3 year follow-up. This was considered the new baseline for the survival analysis. Patients with history of malignant VA at both baseline and during the first 3 years after baseline were excluded. At 3 year patients were aged 40.1±18.0 year and 40.7% was male. Median left ventricular ejection fraction (LVEF) was 53% and percentage with microvoltages was 10.3. During a median follow-up of 4 years (Interquartile range 1.8–6.5) 31 (11%) carriers experienced malignant VA, defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. Reevaluation of the predictors with the 3 year follow-up data revealed hazard rates that were similar to those in the original PLN p.Arg14del risk model; LVEF per 1% decrease (hazard ratio (HR) 1.10 [95% confidence interval (CI), 1.06–1.12]; p Conclusion The PLN p.Arg14del risk model is valid at 3 year follow-up in PLN p.Arg14del variant carriers with no history of malignant VA and can therefore be used to inform decision-making for primary prevention ICD implantation not merely at diagnosis, but also during follow-up and can be seen as a type of validation in a cohort where no other large cohort is present to perform external validation. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): 1. PSIDER: From pluripotent stem cells to prime editing gene therapy for inheritedcardiomyopathies. ZOn-MW.2. PREDICT2: Predicting sudden cardiac arrest. The Dutch Heart Foundation.

Objectives This study aimed to explore echocardiographic characteristics of phospholamban (PLN) p.Arg14del mutation carriers to investigate whether structural and/or functional abnormalities could be identified before onset of symptoms. Background Carriers of the genetic PLN p.Arg14del mutation may develop arrhythmogenic and/or dilated cardiomyopathy. Overt disease is preceded by a pre-symptomatic phase of variable length in which disease expression seems to be absent. Methods PLN p.Arg14del mutation carriers with an available echocardiogram were included. Mutation carriers were classified as pre-symptomatic if they had no history of ventricular arrhythmias (VAs), a premature ventricular complex count of Results The final study population consisted of 281 PLN p.Arg14del mutation carriers, 139 of whom were classified as pre-symptomatic. In comparison to control subjects, pre-symptomatic mutation carriers had lower global longitudinal strain and higher LV mechanical dispersion (both p Conclusions Global and regional LV mechanical alterations in PLN p.Arg14del mutation carriers precede arrhythmic symptoms and overt structural disease. Pre-symptomatic mutation carriers with normal deformation patterns in the apex are at low risk of developing VA within 3 years, whereas mutation carriers with apical PSS appear to be at higher risk.

Implantation of an implantable cardioverter defibrillator (ICD) is standard care for primary prevention of sudden cardiac death. However, ICD-related complications are increasing as the population of ICD recipients grows.ICD-related complications in a national DO-IT Registry cohort of 1442 primary prevention ICD patients were assessed in terms of additional use of hospital care resources and costs.During a median follow-up of 28.7 months (IQR 25.2-33.7) one or more complications occurred in 13.5% of patients. A complication resulted in a surgical intervention in 53% of cases and required on average 3.65 additional hospital days. The additional hospital costs were €6,876 per complication or €8,110 per patient, to which clinical re-interventions and additional hospital days contributed most. Per category of complications, infections required most hospital utilisation and were most expensive at an average of €22,892. The mean costs were €5,800 for lead-related complications, €2,291 for pocket-related complications and €5,619 for complications due to other causes. We estimate that the total yearly incidence-based costs in the Netherlands for hospital management of ICD-related complications following ICD implantation for primary prevention are €2.7 million.Complications following ICD implantation are related to a substantial additional need for hospital resources. When performing cost-effectiveness analyses of ICD implantation, including the costs associated with complications, one should be aware that real-world complication rates may deviate from trial data. Considering the economic implications, strategies to reduce the incidence of complications are encouraged.

Primary prophylactic implantable cardioverter-defibrillators (ICDs) in patients with non-ischaemic cardiomyopathy (NICMP) remains controversial. This study sought to assess the benefit of ICD therapy with or without cardiac resynchronisation therapy (CRT) in patients with NICMP. In addition, data were compared with real-world clinical data to perform a risk/benefit analysis.Relevant randomised clinical trials (RCTs) published in meta-analyses since DANISH, and in PubMed, EMBASE and Cochrane databases from 2016 to 2020 were identified. The benefit of ICD therapy stratified by CRT use was assessed using random effects meta-analysis techniques.Six RCTs were included in the meta-analysis. Among patients without CRT, ICD use was associated with a 24% reduction in mortality (hazard ratio [HR]: 0.76; 95% confidence interval [CI]: 0.62-0.93; P = 0.008). In contrast, among patients with CRT, a CRT-defibrillator was not associated with reduced mortality (HR: 0.74, 95% CI 0.47-1.16; P = 0.19). For ICD therapy without CRT, absolute risk reduction at 3‑years follow-up was 3.7% yielding a number needed to treat of 27.ICD use significantly improved survival among patients with NICMP who are not eligible for CRT. Considering CRT, the addition of defibrillator therapy was not significantly associated with mortality benefit compared with CRT pacemaker.

INTRODUCTION AND OBJECTIVES: Recent observations suggest that patients with a previous failed catheter ablation have an increased risk of atrial fibrillation (AF) recurrence after subsequent thoracoscopic AF ablation. We assessed the risk of AF recurrence in patients with a previous failed catheter ablation undergoing thoracoscopic ablation.METHODS: We included patients from 3 medical centers. To correct for potential heterogeneity, we performed propensity matching to compare AF freedom (freedom from any atrial tachyarrhythmia > 30 s during a 1-year follow-up). Left atrial appendage tissue was analyzed for collagen distribution.RESULTS: A total of 705 patients were included, and 183 had a previous failed catheter ablation. These patients had fewer risk factors for AF recurrence than ablation naïve controls: smaller indexed left atrial volume (40.9 ± 12.5 vs 43.0 ± 12.5 mL/m2, P = .048), less congestive heart failure (1.5% vs 8.9%, P = .001), and less persistent AF (52.2% vs 60.3%, P = .067). However, AF history duration was longer in patients with a previous failed catheter ablation (6.5 [4-10.5] vs 4 [2-8] years; P CONCLUSIONS: Patients with a prior failed catheter ablation had fewer risk factors for AF recurrence but more frequently had AF recurrence after thoracoscopic AF ablation than ablation naïve patients. This may in part be explained by more progressed, subclinical, atrial fibrosis formation.

The yield of 18 ion beams of radioactive gold nuclei produced in the thick uranium target at ISOLDE (CERN) by 1.4-GeV protons was measured. The production-efficiency dependence on the half-life (efficiency curve) was derived using the in-target production calculations by the FLUKA-CERN code. The irregularities in the efficiency curve for long-lived high-spin gold isomers (Aum) were found. Three release models were tested for the efficiency-curve description.

Background: Pathogenic variants in phospholamban (PLN, like p. Arg14del), are found in patients diagnosed with arrhythmogenic (ACM) and dilated cardiomyopathy (DCM). Fibrosis formation in the heart is one of the hallmarks in PLN p.Arg14del carriers. During collagen synthesis and breakdown, propeptides are released into the circulation, such as procollagen type I carboxy-terminal propeptide (PICP) and C-terminal telopeptide collagen type I (ICTP).Aim: To investigate if PICP/ICTP levels in blood are correlative biomarkers for clinical disease severity and outcome in PLN p.Arg14del variant carriers.Methods: Serum and EDTA blood samples were collected from 72 PLN p.Arg14del carriers (age 50.5 years, 63% female) diagnosed with ACM (n = 12), DCM (n = 14), and preclinical variant carriers (n = 46). PICP levels were measured with an enzyme-linked immune sorbent assay and ICTP with a radio immuno-assay. Increased PICP/ICTP ratios suggest a higher collagen deposition. Clinical data including electrocardiographic, and imaging results were adjudicated from medical records.Results: No correlation between PICP/ICTP ratios and late gadolinium enhancement (LGE) was found. Moderate correlations were found between the PICP/ICTP ratio and end-diastolic/systolic volume (both rs = 0.40, n = 23, p = 0.06). PICP/ICTP ratio was significantly higher in patients with T wave inversion (TWI), especially in leads V4–V6, II, III, and aVF (p < 0.022) and in patients with premature ventricular contractions (PVCs) during an exercise tolerance test (p = 0.007).Conclusion: High PICP/ICTP ratios correlated with clinical parameters, such as TWI and PVCs. Given the limited size and heterogeneity of the patient group, additional studies are required to substantiate the incremental prognostic value of these fibrosis biomarkers in PLN p.Arg14del patients.

Combining laser spectroscopy in a Versatile Arc Discharge and Laser Ion Source, with Penning-trap mass spectrometry at the CERN-ISOLDE facility, this work reports on mean-square charge radii of neutron-rich mercury isotopes across the $N = 126$ shell closure, the electromagnetic moments of $^{207}$Hg and more precise mass values of $^{206-208}$Hg. The odd-even staggering (OES) of the mean square charge radii and the kink at $N = 126$ are analyzed within the framework of covariant density functional theory (CDFT), with comparisons between different functionals to investigate the dependence of the results on the underlying single-particle structure. The observed features are defined predominantly in the particle-hole channel in CDFT, since both are present in the calculations without pairing. However, the magnitude of the kink is still affected by the occupation of the $1i_{11/2}$ and $2g_{9/2}$ orbitals with a dependence on the relative energies as well as pairing., 20 pages, 12 figures, Phys. Rev. C in press

The in-gas-jet laser spectroscopy method relies on the production of uniform and low-temperature gas jets to fully resolve the atomic hyperfine structure and efficiently determine fundamental nuclear properties of short-lived isotopes from, e.g., the hardly accessible actinide and transactinide elements. In this article we present the studies devoted to designing, producing, and characterizing the flow properties of a convergent-divergent (de Laval) hypersonic nozzle with a superior performance for laser spectroscopy applications. A novel flow mapping technique, based on resonance ionization spectroscopy (RIS), has been employed to characterize the local flow properties of an argon gas jet formed by this nozzle, revealing a 61.5-mm long, highly collimated atomic jet at a uniform low temperature of 16.6(5) K [Mach 8.11(12)] that will enable laser spectroscopy experiments on heavy-exotic nuclei with an unprecedented spectral resolution and a high efficiency. These results have been compared with those obtained by planar laser induced fluorescence spectroscopy (PLIFS) studies and show a good agreement between the two techniques and a significant improvement in efficiency of the RIS mapping method with respect to PLIFS. The data are compared to state-of-the-art fluid-dynamics calculations that were carried out to obtain the nozzle contour and simulate its performance, as well as to explain the observation of a possible onset of argon nucleation.

© 2019 Elsevier B.V. Radio-frequency (RF) ion guides, also known as Linear Paul Traps, are powerful devices to efficiently transport ion beams from high to low pressure regions while keeping good ion optical properties. A set of ion guides comprising three different RF quadrupole (RFQ) structures has been designed using ion-trajectory simulations to improve the performance of the In-Gas Laser Ionizations and Spectroscopy (IGLIS) technique currently under development at KU Leuven. Results of the commissioning tests for the total transport efficiency and transient time through the ion guides as well as the longitudinal energy spread and transverse emittance are found to be in agreement with ion trajectory simulations considering a realistic ion-atom interaction potential. ispartof: Nuclear Instruments and Methods in Physics Research, Section B: Beam Interactions with Materials and Atoms vol:463 pages:148-153 ispartof: location:SWITZERLAND, CERN, Geneva status: published

A new automated control system is developed for the In-Gas Laser Ionization and Spectroscopy (IGLIS) laboratory at KU Leuven. The IGLIS Control System is capable of stabilizing a narrowband single-mode tunable diode laser with a standard deviation of 1.14 MHz. Furthermore, the system controls and synchronizes all data acquisition for multiple techniques from resonant laser spectroscopy in gas cell or in gas jet to atomic Planar-Laser Induced Fluorescence (PLIF) spectroscopy of copper atoms seeded in a supersonic gas jet. The IGLIS Control System is validated by measuring the hyperfine splitting parameters of the ground state transition at 327 nm in 63Cu. A new automated control system is developed for the In-Gas Laser Ionization and Spectroscopy (IGLIS) laboratory at KU Leuven. The IGLIS Control System is capable of stabilizing a narrowband single-mode tunable diode laser with a standard deviation of 1.14 MHz. Furthermore, the system controls and synchronizes all data acquisition for multiple techniques from resonant laser spectroscopy in gas cell or in gas jet to atomic Planar-Laser Induced Fluorescence (PLIF) spectroscopy of copper atoms seeded in a supersonic gas jet. The IGLIS Control System is validated by measuring the hyperfine splitting parameters of the ground state transition at 327 nm in 63Cu. ispartof: Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms vol:463 pages:297-301 ispartof: location:SWITZERLAND, CERN, Geneva status: published

A study of the laser-ionized and mass-separated neutron-deficient isotopes Au 176 , 177 , 179 was performed using the Resonance Ionization Laser Ion Source and the Windmill detection setup at ISOLDE, CERN. New and improved data on complex fine-structure α decays of the three isotopes were deduced, providing insight into the low-lying levels in the daughter nuclei Ir 172 , 173 , 175 . New information on the properties of β -decay daughter products Pt 177 , 179 was also obtained. From the first in-source laser spectroscopy measurements of the hyperfine structure in the atomic 267.6-nm transition of Au 176 , the nuclear magnetic moments for both high- and low-spin α -decaying states were deduced. Together with the values determined from the additivity relations, they were used to propose the most probable spins and configurations for both states. The α -decay branching ratios were determined as b α ( Au ls 176 ) = 58 ( 5 ) % and b α ( Au hs 176 ) = 29 ( 5 ) % .

IntroductionSudden cardiac death (SCD) is the leading cause of death in patients with myocardial infarction (MI) and can be prevented by the implantable cardioverter defibrillator (ICD). Currently, risk stratification for SCD and decision on ICD implantation are based solely on impaired left ventricular ejection fraction (LVEF). However, this strategy leads to over- and under-treatment of patients because LVEF alone is insufficient for accurate assessment of prognosis. Thus, there is a need for better risk stratification. This is the study protocol for developing and validating a prediction model for risk of SCD in patients with prior MI.Methods and AnalysisThe EU funded PROFID project will analyse 23 datasets from Europe, Israel and the US (∼225,000 observations). The datasets include patients with prior MI or ischemic cardiomyopathy with reduced LVEFEthics and disseminationLocal ethical approval was obtained. The final model will be disseminated through scientific publications and a web-calculator. Statistical code will be published through open-source repositories.

Aims This study was performed to develop and externally validate prediction models for appropriate implantable cardioverter-defibrillator (ICD) shock and mortality to identify subgroups with insufficient benefit from ICD implantation. Methods and results We recruited patients scheduled for primary prevention ICD implantation and reduced left ventricular function. Bootstrapping-based Cox proportional hazards and Fine and Gray competing risk models with likely candidate predictors were developed for all-cause mortality and appropriate ICD shock, respectively. Between 2014 and 2018, we included 1441 consecutive patients in the development and 1450 patients in the validation cohort. During a median follow-up of 2.4 (IQR 2.1–2.8) years, 109 (7.6%) patients received appropriate ICD shock and 193 (13.4%) died in the development cohort. During a median follow-up of 2.7 (IQR 2.0–3.4) years, 105 (7.2%) received appropriate ICD shock and 223 (15.4%) died in the validation cohort. Selected predictors of appropriate ICD shock were gender, NSVT, ACE/ARB use, atrial fibrillation history, Aldosterone-antagonist use, Digoxin use, eGFR, (N)OAC use, and peripheral vascular disease. Selected predictors of all-cause mortality were age, diuretic use, sodium, NT-pro-BNP, and ACE/ARB use. C-statistic was 0.61 and 0.60 at respectively internal and external validation for appropriate ICD shock and 0.74 at both internal and external validation for mortality. Conclusion Although this cohort study was specifically designed to develop prediction models, risk stratification still remains challenging and no large group with insufficient benefit of ICD implantation was found. However, the prediction models have some clinical utility as we present several scenarios where ICD implantation might be postponed.

Aims Phospholamban (PLN) p.Arg14del mutation carriers are at risk of developing malignant ventricular arrhythmias (VAs) and/or heart failure. Currently, left ventricular ejection fraction (LVEF) plays an important role in risk assessment for VA in these individuals. We aimed to study the incremental prognostic value of left ventricular mechanical dispersion (LVMD) by echocardiographic deformation imaging for prediction of sustained VA in PLN p.Arg14del mutation carriers. Methods and results We included 243 PLN p.Arg14del mutation carriers, which were classified into three groups according to the ‘45/45’ rule: (i) normal left ventricular (LV) function, defined as preserved LVEF ≥45% with normal LVMD ≤45 ms (n = 139), (ii) mechanical LV dysfunction, defined as preserved LVEF ≥45% with abnormal LVMD >45 ms (n = 63), and (iii) overt LV dysfunction, defined as reduced LVEF Conclusion LVMD has incremental prognostic value on top of LVEF in PLN p.Arg14del mutation carriers, particularly in those with preserved LVEF. The ‘45/45’ rule is a practical approach to echocardiographic risk stratification in this challenging group of patients. This approach may also have added value in other diseases where LVEF deterioration is a relative late marker of myocardial dysfunction.

Background One third of primary prevention implantable cardioverter‐defibrillator patients receive appropriate therapy, but all remain at risk of defibrillator complications. Information on these complications in contemporary cohorts is limited. This study assessed complications and their risk factors after defibrillator implantation in a Dutch nationwide prospective registry cohort and forecasts the potential reduction in complications under distinct scenarios of updated indication criteria. Methods and Results Complications in a prospective multicenter registry cohort of 1442 primary implantable cardioverter‐defibrillator implant patients were classified as major or minor. The potential for reducing complications was derived from a newly developed prediction model of appropriate therapy to identify patients with a low probability of benefitting from the implantable cardioverter‐defibrillator. During a follow‐up of 2.2 years (interquartile range, 2.0–2.6 years), 228 complications occurred in 195 patients (13.6%), with 113 patients (7.8%) experiencing at least one major complication. Most common ones were lead related (n=93) and infection (n=18). Minor complications occurred in 6.8% of patients, with lead‐related (n=47) and pocket‐related (n=40) complications as the most prevailing ones. A surgical reintervention or additional hospitalization was required in 53% or 61% of complications, respectively. Complications were strongly associated with device type. Application of stricter implant indication results in a comparable proportional reduction of (major) complications. Conclusions One in 13 patients experiences at least one major implantable cardioverter‐defibrillator–related complication, and many patients undergo a surgical reintervention. Complications are related to defibrillator implantations, and these should be discussed with the patient. Stricter implant indication criteria and careful selection of device type implanted may have significant clinical and financial benefits.

The pathogenic mutation p.Arg14del in the gene encoding Phospholamban (PLN) is known to cause cardiomyopathy and leads to increased risk of sudden cardiac death. Automatic tools might improve the detection of patients with this rare disease. Deep learning is currently the state-of-the-art in signal processing but requires large amounts of data to train the algorithms. In situations with relatively small amounts of data, like PLN, transfer learning may improve accuracy. We propose an ECG-based detection of the PLN mutation using transfer learning from a model originally trained for sex identification. The sex identification model was trained with 256,278 ECGs and subsequently finetuned for PLN detection (155 ECGs of patients with PLN) with two control groups: a balanced age/sex matched group and a randomly selected imbalanced population. The data was split in 10 folds and 20% of the training data was used for validation and early stopping. The models were evaluated with the area under the receiver operating characteristic curve (AUROC) of the testing data. We used gradient activation for explanation of the prediction models. The models trained with transfer learning outperformed the models trained from scratch for both the balanced (AUROC 0.87 vs AUROC 0.71) and imbalanced (AUROC 0.0.90 vs AUROC 0.65) population. The proposed approach was able to improve the accuracy of a rare disease detection model by transfer learning information from a non-manual annotated and abundant label with only limited data available.

The mean-square charge radii of $^{207,208}$Hg ($Z=80, N=127,128$) have been studied for the first time and those of $^{202,203,206}$Hg ($N=122,123,126$) remeasured by the application of in-source resonance-ionization laser spectroscopy at ISOLDE (CERN). The characteristic \textit{kink} in the charge radii at the $N=126$ neutron shell closure has been revealed, providing the first information on its behavior below the $Z=82$ proton shell closure. A theoretical analysis has been performed within relativistic Hartree-Bogoliubov and non-relativistic Hartree-Fock-Bogoliubov approaches, considering both the new mercury results and existing lead data. Contrary to previous interpretations, it is demonstrated that both the kink at $N=126$ and the odd-even staggering (OES) in its vicinity can be described predominately at the mean-field level, and that pairing does not need to play a crucial role in their origin. A new OES mechanism is suggested, related to the staggering in the occupation of the different neutron orbitals in odd- and even-$A$ nuclei, facilitated by particle-vibration coupling for odd-$A$ nuclei.

A study of the ground states of the laser-ionized and mass-separated odd-odd isotopes 180,182Au was performed using the Resonance Ionization Laser Ion Source, Windmill detection setup and ISOLTRAP Multi-Reflection Time-of-Flight Mass Spectrometer at ISOLDE, CERN. A complex fine-structure α-decay pattern of 180Au was deduced, providing insight into the low-lying levels in the daughter nucleus 176Ir. An α-decay branching ratio of bα(180Au)=0.58(10)% and a half-life of T1/2=7.2(5) s have also been derived, allowing for the calculation of the reduced α-decay widths and determining the degree of hindrance of respective α-decay branches. From complementary first in-source laser spectroscopy measurements of the hyperfine structure in atomic transitions of 180,182Au, the nuclear magnetic moments of μ(180Au)=−0.83(9)μN and μ(182Au)=1.66(9)μN were extracted with an inclusion of a correction for the hyperfine anomaly. Based on the observed hyperfine structure patterns, and on the comparison of the measured and calculated μ values, a preferred ground-state spin and parity Iπ(180Augs)=(1+) is proposed, and the earlier assignment of Iπ(182Augs)=(2+) is confirmed. For 180Au, the most probable proton-neutron Nilsson configuration of π3/2−[532]⊗ν5/2−[512] suggests the same proton state as in the heavier deformed odd-odd nuclei 182,184Au.

This study aimed to explore echocardiographic characteristics of phospholamban (PLN) p.Arg14del mutation carriers to investigate whether structural and/or functional abnormalities could be identified before onset of symptoms.Carriers of the genetic PLN p.Arg14del mutation may develop arrhythmogenic and/or dilated cardiomyopathy. Overt disease is preceded by a pre-symptomatic phase of variable length in which disease expression seems to be absent.PLN p.Arg14del mutation carriers with an available echocardiogram were included. Mutation carriers were classified as pre-symptomatic if they had no history of ventricular arrhythmias (VAs), a premature ventricular complex count of 500/24 h, and a left ventricular (LV) ejection fraction of ≥45%. In addition, we included 70 control subjects with similar age and sex distribution as the pre-symptomatic mutation carriers. Comprehensive echocardiographic analysis (including deformation imaging) was performed.The final study population consisted of 281 PLN p.Arg14del mutation carriers, 139 of whom were classified as pre-symptomatic. In comparison to control subjects, pre-symptomatic mutation carriers had lower global longitudinal strain and higher LV mechanical dispersion (both p 0.001). In addition, post-systolic shortening (PSS) in the LV apex was observed in 43 pre-symptomatic mutation carriers (31%) and in none of the control subjects. During a median follow-up of 3.2 years (interquartile range: 2.1 to 5.6 years) in 104 pre-symptomatic mutation carriers, nonsustained VA occurred in 13 (13%). Presence of apical PSS was the strongest echocardiographic predictor of VA (multivariable hazards ratio: 5.11; 95% confidence interval [CI]: 1.37 to 19.08; p = 0.015), which resulted in a negative predictive value of 96% (95% CI: 89% to 98%) and a positive predictive value of 29% (95% CI: 21% to 40%).Global and regional LV mechanical alterations in PLN p.Arg14del mutation carriers precede arrhythmic symptoms and overt structural disease. Pre-symptomatic mutation carriers with normal deformation patterns in the apex are at low risk of developing VA within 3 years, whereas mutation carriers with apical PSS appear to be at higher risk.

Background Phospholamban (PLN) p.Arg14del mutation carriers are known to develop dilated and/or arrhythmogenic cardiomyopathy, and typical electrocardiographic (ECG) features have been identified for diagnosis. Machine learning is a powerful tool used in ECG analysis and has shown to outperform cardiologists. Objectives We aimed to develop machine learning and deep learning models to diagnose PLN p.Arg14del cardiomyopathy using ECGs and evaluate their accuracy compared to an expert cardiologist. Methods We included 155 adult PLN mutation carriers and 155 age- and sex-matched control subjects. Twenty-one PLN mutation carriers (13.4%) were classified as symptomatic (symptoms of heart failure or malignant ventricular arrhythmias). The data set was split into training and testing sets using 4-fold cross-validation. Multiple models were developed to discriminate between PLN mutation carriers and control subjects. For comparison, expert cardiologists classified the same data set. The best performing models were validated using an external PLN p.Arg14del mutation carrier data set from Murcia, Spain (n = 50). We applied occlusion maps to visualize the most contributing ECG regions. Results In terms of specificity, expert cardiologists (0.99) outperformed all models (range 0.53–0.81). In terms of accuracy and sensitivity, experts (0.28 and 0.64) were outperformed by all models (sensitivity range 0.65–0.81). T-wave morphology was most important for classification of PLN p.Arg14del carriers. External validation showed comparable results, with the best model outperforming experts. Conclusion This study shows that machine learning can outperform experienced cardiologists in the diagnosis of PLN p.Arg14del cardiomyopathy and suggests that the shape of the T wave is of added importance to this diagnosis.

Hyperfine-structure constants for the 6s2S1/2 and 6p2P1/2 atomic states of the Iπ=11/2− gold isomers Aum177,191,193,195 have been measured at CERN-ISOLDE, using the in-source laser resonance-ionization spectroscopy technique. From the measured hyperfine constants the differences between hyperfine anomalies for these atomic states have been deduced. These differential hyperfine anomaly values have been used to determine the 6s-state hyperfine anomaly relative to the stable Au197 with advanced atomic calculations. Magnetic dipole moments for the gold isomers in question have been deduced, taking into account the corresponding relative hyperfine-anomaly values. It has been shown that the commonly used prescription for the extraction of the magnetic moment values for the gold isotopes should be reconsidered. The magnetic moments calculated by this prescription have been reevaluated by properly accounting for the hyperfine anomaly, which is as large as 10% for several gold isotopes.

© 2019 Elsevier B.V. Laser spectroscopy enables the determination of fundamental atomic and nuclear properties with high precision. In view of the low production rates of the heaviest elements, a high total efficiency is a crucial requirement for any experimental setup to be used in on-line experiments. The setup requires the use of gas stopping techniques to slow down the radionuclides of interest. In previous studies laser spectroscopy was performed inside a gas-filled stopping cell with a limited spectral resolution of a few GHz. Collisional broadening inside stopping cells ultimately limits the precision of laser spectroscopic studies and hampers in particular hyperfine spectroscopy. The spectral linewidth is reduced by an order of magnitude when the laser spectroscopy is performed in a well-collimated gas jet formed by the exit nozzle of a gas stopping cell. In addition, the exposure of the jet to high-repetition rate laser light which saturates the optical transitions allows maintaining a high total efficiency. Here, we present a new setup dedicated to laser spectroscopy of the heaviest elements with an improved resolution, which is presently under construction. This setup combines the efficient filament neutralization demonstrated for nobelium with the improved resolution of in-gas-jet spectroscopy. ispartof: Nuclear Instruments and Methods in Physics Research, Section B: Beam Interactions with Materials and Atoms vol:463 pages:272-276 ispartof: location:SWITZERLAND, CERN, Geneva status: published

A comprehensive study of the isotope 178Au has been made at the CERN-ISOLDE facility, using resonance laser ionization. Two long-lived states in 178Au were identified—a low-spin ground state and a high-spin isomer—each of which were produced as pure beams. Using the ISOLTRAP precision Penning trap, the excitation energy of the isomeric state in 178Au was determined to be E∗=189(14)keV. The α-decay fine structure patterns of the two states were studied using the Windmill decay station, providing information on the low-lying states in the daughter nucleus 174Ir. Nuclear spin assignments of I(178Aug)=(2,3) and I(178Aum)=(7,8) are made based on the observed β-decay feeding and hyperfine structure intensity patterns. These spin assignments are used for fitting the hyperfine structures of the two states from which values for the magnetic dipole moments are extracted. The extracted moments are compared with calculations using additivity relations to establish the most probable configurations for 178Aug,m.

In-source resonance ionization spectroscopy of the neutron-rich actinium isotopes $^{225\ensuremath{-}229}\mathrm{Ac}$ has been performed at the ISAC facility in TRIUMF, probing a $^{2}D_{3/2}\ensuremath{\rightarrow}^{4}P_{5/2}^{\ensuremath{\circ}}$ atomic transition. New data on the magnetic dipole moments and changes in mean-square charge radii $\ensuremath{\delta}\ensuremath{\langle}{r}^{2}\ensuremath{\rangle}$ of $^{226,228,229}\mathrm{Ac}$ have been obtained. The comparison of the measured isotope shifts and magnetic dipole coupling constants $a(^{4}P_{5/2}^{\ensuremath{\circ}})$ of $^{225,227}\mathrm{Ac}$ with a high-resolution data set is used to identify systematic uncertainties on the deduced $\ensuremath{\delta}{\ensuremath{\langle}{r}^{2}\ensuremath{\rangle}}^{A,215}$ and magnetic dipole moment values. The charge radii odd-even staggering is evaluated for the odd-$N$ isotopes, showing that $^{226}\mathrm{Ac}$ has an inverted odd-even staggering that might be linked with a reflection-asymmetric shape. Comparison of the magnetic dipole moments of $^{225,227,229}\mathrm{Ac}$ with Nilsson-model estimates supports the assumption of octupole deformation in isotopes $^{225,227}\mathrm{Ac}$ and its gradual decrease toward isotope $^{229}\mathrm{Ac}$. The changes in mean-square charge radii are compared to self-consistent calculations employing multiple modern energy density functionals: SLy5s1, BSk31, and DD-MEB1. For SLy5s1 in particular, self-consistent time-reversal breaking calculations of odd-odd nuclei incorporating finite octupole deformation are reported for the first time. For these calculations, the overall best agreement is obtained when the octupole degree of freedom is taken into account.

Introduction The p.Arg14del founder mutation in the gene encoding phospholamban (PLN) is associated with an increased risk of malignant ventricular arrhythmia and heart failure. Ejection fraction (EF) is the gold standard of systolic left ventricular (LV) function, however new technics using global longitudinal strain (GLS) are able to detect LV dysfunction early, e.g. in patients with chemotherapy. Moreover, strain analysis on post systolic shortening (PSS) can show distinct pattern in various diseases, e.g. patients with myocardial fibrosis and amyloid. The goal of this study was to investigate whether speckle tracking (GLS and PSS) of the LV can detect LV dysfunction in patients with PLN mutations and whether these patients have a specific PSS pattern. Method 72 Patients (49 female, mean age 32 years) diagnosed with the genetic PLN mutation p.Arg14del and 21 controls (10 female, mean age 27 years) underwent complete Echocardiographic exam including LVEF, GLS and PSI of all LV segments. LVEF Results Pearson correlation is in PLN patients between PSI apex and EF 0.677 (P PLN patients appeared to have a typical pattern with a high PSI in the apical segments. An apical PSI >20 was the strongest diagnostic parameter indicating LV dysfunction. Apical PSI >20 and LVEF Diagnostic characteristics PLN Controls P-value LVEF, % 55.2 59.3 0.033 GLS, % 15.5 17.3 0.163 PSI basal 8.5 10.1 0.326 PSI mid 5.6 2.9 0.070 PSI apical 15.6 2.1 0.01 LVEF, left ventricular ejection fraction; GLS, Global longitudinal strain; PSI, post systolic index. PSI Conclusion PLN patients have a typical pattern of high PSI in the apex of the left ventricular which can be used as a diagnostic test to detect LV dysfunction.

Background/Introduction The founder mutation p.Arg14del in the gene encoding phospholamban (PLN) is a known cause of arrhythmogenic cardiomyopathy (ACM) with distinct clinical features, such as microvoltages on the ECG and right or left ventricular dysfunction or both. At present, risk stratification for ICD implantation in carriers of this mutation is based on left ventricular ejection fraction and previous ventricular arrhythmia's, which are not specific risk factors for the PLN p.Arg14del cardiomyopathy. Purpose Our goal is to develop a mutation specific prediction model for incident malignant ventricular arrhythmia to guide ICD implantation. Methods Data were collected from p.Arg14del carriers with no history of malignant VA at baseline, identified between September 2009 and June 2018 in three Dutch university hospitals. Genetic analysis of PLN was performed in a clinical setting in index patients with clinical signs of DCM/ACM, or in family members of p.Arg14del carriers. We collected clinical data from the first cardiac evaluation and follow-ups. Malignant VAs were defined as sustained VA, appropriate ICD intervention or (aborted) sudden cardiac death. A prediction model was developed using Cox Proportional Hazard regression. Candidate baseline predictors were pre specified based on literature and clinical expertise. Age, sex, proband status, sudden cardiac death (SCD) in 1st degree relative, repolarization abnormalities, microvoltages, premature ventricular complexes (PVC) burden on 24hrs Holter monitoring, LVEF and non-sustained ventricular arrhythmias (NSVT) were considered. The multivariable model was fitted using stepwise backward selection based on Akaike's Information Criterion. Results We included 440 p.Arg14del carriers with a mean age of 41±18 years and 41% males. During a median follow-up of 4.7 years (IQR 1.7–7.3), 44 incident malignant VA occurred, 20 sustained VAs and 24 appropriate ICD therapies. The multivariable HR's of selected predictors were: 2.2 for minor and 4.5 for major repolarization abnormalities vs no abnormalities (p value respectively 0.06 and 0.01), 2.2 for LVEF 500PVC/24hrs (p value 0.003). Carriers with and without events could be accurately distinguished with this model, with an optimism corrected C-statistic of 0.81. The model calibrated well, with agreement of observed and predicted 5 year malignant VA risk. Risk groups were split into quintiles of predicted risk, figure 1 shows the Kaplan Meier curve of incident malignant VA per risk group. The 5 year risk of incident malignant VA in the lowest 3 quintiles was 0%, 9% in the 4th quintile and 25.2% in the highest quintile. Conclusion We created a PLN p.Arg14del mutation specific prediction model to estimate risk of incident malignant VA. With this model a clear distinction between high risk and low risk patients can be made and can be used to guide ICD implantation for primary prevention.

The In-Gas-jet Laser Ionization and Spectroscopy (IGLIS) technique relies on narrow-bandwidth, high-peak-power, short-pulse-length (≈10 ns), and high-repetition-rate laser pulses to probe, precisely and efficiently, the hyperfine structure of medium-heavy and heavy isotopes, embedded in a supersonic jet. The power and repetition rate requirements of the laser system are met by combining ≈100 W, 8 ns pulse width, 10 kHz commercial Nd:YAG pump lasers with a single-mode continuous wave seeded Pulsed Dye Amplifier (PDA). The common multi-longitudinal-mode operation of these Nd:YAG pump lasers causes, however, undesirable frequency sidebands in the output spectrum of the PDA system, hindering the attainable spectral resolution, a correct interpretation, and an accurate analysis of the hyperfine spectra. In this article, a new prototype Nd:YAG laser is presented, which combined with the PDA system is capable of providing quasi-transform-limited laser pulses at 10 kHz, with only limited losses in laser power. This system reduces any spectral sideband amplitude below a proven upper limit of 0.2% with one order of magnitude extra reduction expected based on simulations. A full characterization of both the Nd:YAG and PDA laser systems is done by studying the temporal and frequency behavior in detail. This study is finalized by a performance benchmark of this combined laser system in the hyperfine spectroscopy of copper isotopes, showcasing its applicability for future IGLIS studies.

Neutron-deficient Hg177-185 isotopes were studied using in-source laser resonance-ionization spectroscopy at the CERN-ISOLDE radioactive ion-beam facility in an experiment combining different detection methods tailored to the studied isotopes. These include either α-decay tagging or multireflection time-of-flight gating for isotope identification. The endpoint of the odd-even nuclear shape staggering in mercury was observed directly by measuring for the first time the isotope shifts and hyperfine structures of Hg177-180. Changes in the mean-square charge radii for all mentioned isotopes, magnetic dipole, and electric quadrupole moments of the odd-A isotopes and arguments in favor of I=7/2 spin assignment for Hg177,179 were deduced. Experimental results are compared with density functional theory (DFT) and Monte Carlo shell model (MCSM) calculations. DFT calculations using Skyrme parametrizations predict a jump in the charge radius around the neutron N=104 midshell, with an odd-even staggering pattern related to the coexistence of nearly degenerate oblate and prolate minima. This near-degeneracy is highly sensitive to many aspects of the effective interaction, a fact that renders perfect agreement with experiments out of reach for current functionals. Despite this inherent difficulty, the SLy5s1 and a modified UNEDF1SO parametrization predict a qualitatively correct staggering that is off by two neutron numbers. MCSM calculations of states with the experimental spins and parities show good agreement for both electromagnetic moments and the observed charge radii. A clear mechanism for the origin of shape staggering within this context is identified: A substantial change in occupancy of the proton πh9/2 and neutron νi13/2 orbitals., SCOPUS: ar.j, info:eu-repo/semantics/published

A new approach to observe the radiative decay of the $^{229}$Th nuclear isomer, and to determine its energy and radiative lifetime, is presented. Situated at a uniquely low excitation energy, this nuclear state might be a key ingredient for the development of a nuclear clock, a nuclear laser and the search for time variations of the fundamental constants. The isomer's $\gamma$ decay towards the ground state will be studied with a high-resolution VUV spectrometer after its production by the $\beta$ decay of $^{229}$Ac. The novel production method presents a number of advantages asserting its competitive nature with respect to the commonly used $^{233}$U $\alpha$-decay recoil source. In this paper, a feasibility analysis of this new concept, and an experimental investigation of its key ingredients, using a pure $^{229}$Ac ion beam produced at the ISOLDE radioactive beam facility, is reported., Comment: 11 pages, 5 figures, 2 tables

Background Gastrointestinal functional and motility disorders, like irritable bowel syndrome (IBS), have a high prevalence in the Western population and cause significant morbidity and loss of quality of life leading to considerable costs for health care. A decade ago, it has been demonstrated that interstitial cells of Cajal and intestinal smooth muscle cells, cells important for gastrointestinal motility, express the sodium channel alpha subunit Nav1.5. In the heart, aberrant variants in this sodium channel, encoded by SCN5A, are linked to inherited arrhythmia syndromes, like the long-QT syndrome type 3 and Brugada syndrome. Mounting data show a possible contribution of SCN5A mutants to gastrointestinal functional and motility disorders. Two percent of IBS patients harbor SCN5A mutations with electrophysiological evidence of loss- and gain-of-function. In addition, gastrointestinal symptoms are more prevalent in cardiac SCN5A-mutation positive patients. Purpose This review firstly describes the Nav1.5 channel and its physiological role in ventricular cardiomyocytes and gastrointestinal cells, then we focus on the involvement of mutant Nav1.5 in gastrointestinal functional and motility disorders. Future research might uncover novel mutation-specific treatment strategies for SCN5A-encoded gastrointestinal channelopathies.

In rare cases, the removal of a single proton (Z) or neutron (N) from an atomic nucleus leads to a dramatic shape change. These instances are crucial for understanding the components of the nuclear interactions that drive deformation. The mercury isotopes (Z = 80) are a striking example1,2: their close neighbours, the lead isotopes (Z = 82), are spherical and steadily shrink with decreasing N. The even-mass (A = N + Z) mercury isotopes follow this trend. The odd-mass mercury isotopes 181,183,185Hg, however, exhibit noticeably larger charge radii. Due to the experimental difficulties of probing extremely neutron-deficient systems, and the computational complexity of modelling such heavy nuclides, the microscopic origin of this unique shape staggering has remained unclear. Here, by applying resonance ionization spectroscopy, mass spectrometry and nuclear spectroscopy as far as 177Hg, we determine 181Hg as the shape-staggering endpoint. By combining our experimental measurements with Monte Carlo shell model calculations, we conclude that this phenomenon results from the interplay between monopole and quadrupole interactions driving a quantum phase transition, for which we identify the participating orbitals. Although shape staggering in the mercury isotopes is a unique and localized feature in the nuclear chart, it nicely illustrates the concurrence of single-particle and collective degrees of freedom at play in atomic nuclei. In rare cases, the removal of a single proton (Z) or neutron (N) from an atomic nucleus leads to a dramatic shape change. These instances are crucial for understanding the components of the nuclear interactions that drive deformation. The mercury isotopes (Z = 80) are a striking example1,2: their close neighbours, the lead isotopes (Z = 82), are spherical and steadily shrink with decreasing N. The even-mass (A = N + Z) mercury isotopes follow this trend. The odd-mass mercury isotopes 181,183,185Hg, however, exhibit noticeably larger charge radii. Due to the experimental difficulties of probing extremely neutron-deficient systems, and the computational complexity of modelling such heavy nuclides, the microscopic origin of this unique shape staggering has remained unclear. Here, by applying resonance ionization spectroscopy, mass spectrometry and nuclear spectroscopy as far as 177Hg, we determine 181Hg as the shape-staggering endpoint. By combining our experimental measurements with Monte Carlo shell model calculations, we conclude that this phenomenon results from the interplay between monopole and quadrupole interactions driving a quantum phase transition, for which we identify the participating orbitals. Although shape staggering in the mercury isotopes is a unique and localized feature in the nuclear chart, it nicely illustrates the concurrence of single-particle and collective degrees of freedom at play in atomic nuclei. ispartof: Nature Physics vol:14 issue:12 status: published

© 2018 authors. Published by the American Physical Society. Published by the American Physical Society under the terms of the »https://creativecommons.org/licenses/by/4.0/» Creative Commons Attribution 4.0 International license. Further distribution of this work must maintain attribution to the author(s) and the published article's title, journal citation, and DOI. The method of laser spectroscopy in supersonic gas jets was proposed for high-resolution and high-efficiency in-gas laser ionization and spectroscopy studies of short-lived nuclei. The flow properties of such supersonic gas jets have been characterized under off-line conditions. Planar laser-induced fluorescence spectroscopy of seeded copper atoms has been applied to nonintrusively measure velocity, temperature, and relative density profiles of gas jets formed by different de Laval nozzles. For validation, planar laser-induced fluorescence spectroscopy was applied on supersonic free jets with well-known flow parameters. The performance of the in-gas-jet laser spectroscopy method is determined by the achievable spectral resolution, which requires an optimization and a precise manufacturing of the nozzle inner contour as well as a pressure matching of the background medium at the nozzle exit. Our studies now enable a thorough understanding and quantification of these requirements and a determination of the final performance of the in-gas-jet method. Additionally, a comparison between the experimental results and the numerical calculations was performed for the temperature, velocity, and Mach number profiles of underexpanded and quasiuniform jets formed by a de Laval nozzle. ispartof: Physical Review X vol:8 issue:4 pages:041008-041008 status: published

Aims This study aims to improve risk stratification for primary prevention implantable cardioverter defibrillator (ICD) implantation by developing a new mutation-specific prediction model for malignant ventricular arrhythmia (VA) in phospholamban (PLN) p.Arg14del mutation carriers. The proposed model is compared to an existing PLN risk model. Methods and results Data were collected from PLN p.Arg14del mutation carriers with no history of malignant VA at baseline, identified between 2009 and 2020. Malignant VA was defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. A prediction model was developed using Cox regression. The study cohort consisted of 679 PLN p.Arg14del mutation carriers, with a minority of index patients (17%) and male sex (43%), and a median age of 42 years [interquartile range (IQR) 27–55]. During a median follow-up of 4.3 years (IQR 1.7–7.4), 72 (10.6%) carriers experienced malignant VA. Significant predictors were left ventricular ejection fraction, premature ventricular contraction count/24 h, amount of negative T waves, and presence of low-voltage electrocardiogram. The multivariable model had an excellent discriminative ability {C-statistic 0.83 [95% confidence interval (CI) 0.78–0.88]}. Applying the existing PLN risk model to the complete cohort yielded a C-statistic of 0.68 (95% CI 0.61–0.75). Conclusion This new mutation-specific prediction model for individual VA risk in PLN p.Arg14del mutation carriers is superior to the existing PLN risk model, suggesting that risk prediction using mutation-specific phenotypic features can improve accuracy compared to a more generic approach.

Hyperfine-structure parameters and isotope shift of the 9/2$^−$ isomeric state in $^{187}$Au relative to $^{197}$Au for the 267.6-nm atomic transition have been measured for the first time using the in-source resonance-ionization spectroscopy technique. The magnetic dipole moment and change in the mean-square charge radius for this 9/2$^−$ isomer have been deduced. The observed large isomer shift relative to the 1/2$^+$ ground state in $^{187}$Au confirms the occurrence of the shape coexistence in $^{187}$Au proposed earlier from the analysis of the nuclear spectroscopic data and particle plus triaxial rotor calculations. The analysis of the magnetic moment supports the previously proposed 9/2$^−$, 1/2$^−$[541] assignment at moderate prolate deformation for $^{187}$Au$^m$.