Expected Event Rate Research Articles

Impacts of Black-hole-forming Supernova Explosions on the Diffuse Neutrino Background

The flux spectrum, event rate, and experimental sensitivity are investigated for the diffuse supernova (SN) neutrino background (DSNB), which originates from past stellar collapses and is also known as a supernova relic neutrino background. For this purpose, the contribution of collapses that lead to successful supernova explosion and black hole (BH) formation simultaneously, which are suggested to be a nonnegligible population from the perspective of Galactic chemical evolution, is taken into account. If the BH-forming SNe involve matter fallback onto the protoneutron star for the long term, their total emitted neutrino energy becomes much larger than that of ordinary SNe and failed SNe (BH formation without explosion). Then, in the case of the normal mass hierarchy in neutrino oscillations and with half of all core-collapse SNe being BH-forming SNe, the expected event rate according to the current DSNB model is enhanced by up to a factor of 2 due to the BH-forming SNe. While substantial uncertainties exist regarding the duration of the matter fallback, which determines the total amount of emitted neutrinos, and the fraction of BH-forming SNe, the operation time required to detect the DSNB at Hyper-Kamiokande would be reduced by such contribution in any case.

Potential to Identify the Neutrino Mass Ordering with Reactor Antineutrinos in JUNO

Abstract The Jiangmen Underground Neutrino Observatory (JUNO) is a multi-purpose neutrino experiment under construction in South of China. This paper presents an updated estimate of JUNO's sensitivity to the neutrino mass ordering using the reactor antineutrinos emitted from eight nuclear reactor cores in the Taishan and Yangjiang nuclear power plants. This measurement is planned by studying the fine interference pattern caused by quasi-vacuum oscillations in the oscillated antineutrino spectrum at a baseline of 52.5~km and is completely independent of the CP violating phase and the neutrino mixing angle θ23. The sensitivity is obtained through a joint analysis of JUNO and TAO detectors utilizing the best available knowledge to date about the location and overburden of the JUNO experimental site, the local and global nuclear reactors, the JUNO and TAO detectors responses, the expected event rates and spectra of signal and backgrounds, and the systematic uncertainties of the analysis inputs. It is found that a 3σ median sensitivity to reject the wrong mass ordering hypothesis can be reached with an exposure of about 6.5 years × 26.6~GW thermal power.Content from this work may be used under the terms of the Creative Commons Attribution 3.0 licence. Any further distribution of this work must maintain attribution to the author(s) and the title of the work, journal citation and DOI. Article funded by SCOAP3 and published under licence by Chinese Physical Society and the Institute of High Energy Physics of the Chinese Academy of Science and the Institute of Modern Physics of the Chinese Academy of Sciences and IOP Publishing Ltd.

Fully ab-initio all-electron calculation of dark matter-electron scattering in crystals with evaluation of systematic uncertainties

We calculate target-material responses for dark matter–electron scattering at the all-electron level using atom-centered Gaussian basis sets. The all-electron effects enhance the material response at high momentum transfers from dark matter to electrons, q≳O(10αme), compared to calculations using conventional plane wave methods, including those used in ; this enhances the expected event rates at energy transfers E≳10 eV, especially when scattering through heavy mediators. We carefully test a range of systematic uncertainties in the theory calculation, including those arising from the choice of basis set, exchange-correlation functional, number of unit cells in the Bloch sum, k-mesh, and neglect of scatters with very high momentum transfers. We provide state-of-the-art crystal form factors, focusing on silicon and germanium. Our code and results are made publicly available as a new tool, called (“”). Published by the American Physical Society 2024

Abstract PO5-19-01: The HER2-RADiCAL study (Response ADaptive CAre pLan) – Tailoring treatment for HER2 positive early breast cancer

Abstract Background The presence or absence of residual disease following neoadjuvant systemic anti-cancer therapy (neoSACT) for HER2-positive early breast cancer (HER2+ EBC) provides powerful prognostic information. Pathological complete response (pCR) following neoSACT, particularly in patients with earlier clinical TNM stage at diagnosis, identifies a population with excellent survival outcomes in whom the balance of toxicity associated with the current treatment pathway may be disproportionate to absolute clinical benefit. Aims >HER2-RADiCAL seeks to reduce the treatment burden and healthcare costs of treating HER2+ EBC by testing the hypothesis that pCR can be used as a functional response biomarker to select patients who can safely receive less systemic therapy with minimal/no loss of efficacy. Trial design and eligibility criteria HER2-RADiCAL is a response-directed interventional cohort/threshold-crossing design study embedded within a real-world data-driven clinical pathway model. Patients with ER-positive or negative HER2+ EBC with cT1N1 or cT2N0-1 stage at diagnosis are eligible after completion of standard of care neoSACT and locally determined pCR (ypT0/Tis ypN0). Patients with pathological features consistent with previous malignant involvement in >4 nodes are not eligible. Adjuvant trastuzumab +/- pertuzumab may have continued prior to study entry provided no more than 9 cycles of trastuzumab are received. After registration all participants receive a total of 9 cycles of trastuzumab including those administered prior to study entry. Participants receive no further pertuzumab and no adjuvant chemotherapy. Adjuvant endocrine therapy and radiotherapy are given as per standard of care. Central pathology review of pCR status will be conducted in a subset of cases. A Study Within a Trial (SWAT) will explore identification of factors influencing patient decision-making for participation in studies of response-adapted treatment. Statistical methods The primary endpoint is relapse-free interval. Recruitment of 720 participants over 3.5 years will provide 90% power to exclude an event rate >6.5% at 3 years (expected event rate ≤4%). Secondary endpoints include relapse-free survival, invasive breast cancer-free survival, invasive disease-free survival, distant recurrence-free interval, breast cancer-free interval, overall survival, treatment pathway adherence and cost-effectiveness. An interventional cohort is preferred to a randomised non-inferiority trial based on the known event rate in this population which is sufficiently low such that any deviation from this expected event rate would indicate failure of the reduced therapy strategy. Real-world data driven clinical pathway model Health economic modelling will compare the protocol-driven study cohort with two comparator pathways: a non-response adapted maximum therapy pathway (the standard clinical pathway prior to the study) and a real-world representative pathway derived from anonymised data for all patients treated for HER2+ EBC within the UK NHS. Patient and public involvement Our PPI partners continue to shape this research, holding key roles as trial management group members, overseeing progress of the study, contributing to protocol amendment development, and design and implementation of the SWAT. Current status The first patient was enrolled in December 2021. At 10th July 2023, 25 research sites have opened with 39 participants recruited. Site opening continues with a minimum target of 40. Responding to continued use of anthracycline-based regimens in UK practice, eligibility criteria have recently been extended to permit entry of patients who have received anthracycline-containing neoSACT. For further information contact her2radical-icrctsu@icr.ac.uk. Citation Format: Iain Macpherson, Stuart McIntosh, Lucy Kilburn, Holly Tovey, Laura Moretti, Katie Goddard, Indrani Bhattacharya, Clinton Boyd, Cliona Kirwan, Ciara O'Brien, Duncan Wheatley, Jennifer Glendenning, Mairead MacKenzie, Hilary Stobart, Claire Snowdon, Andrew Wardley, Abeer Shaaban, Peter Hall, David Cameron, Judith Bliss. The HER2-RADiCAL study (Response ADaptive CAre pLan) – Tailoring treatment for HER2 positive early breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-19-01.

Randomized comparison of TAVI valves: The Compare-TAVI trial

Based on technical advancements and clinical evidence, transcatheter aortic valve implantation (TAVI) has been widely adopted. New generation TAVI valve platforms are continually being developed. Ideally, new valves should be superior or at least non-inferior regarding efficacy and safety, when compared to best-in-practice contemporary TAVI valves. The Compare-TAVI trial (ClinicalTrials.gov NCT04443023) was launched in 2020, to perform a 1:1 randomized comparison of new vs contemporary TAVI valves, preferably in all comers. Consecutive cohorts will be launched with sample sizes depending on the choice of interim analyses, expected event rates, and chosen superiority or non-inferiority margins. Enrollment has just been finalized in cohort B, comparing the Sapien 3/Sapien 3 Ultra Transcatheter Heart Valve (THV) series (Edwards Lifesciences, Irvine, California, USA) and the Myval/Myval Octacor THV series (Meril Life Sciences Pvt. Ltd., Vapi, Gujarat, India) balloon expandable valves. This non-inferiority study was aimed to include 1062 patients. The 1-year composite safety and efficacy endpoint comprises death, stroke, moderate-severe aortic regurgitation, and moderate-severe valve deterioration. Patients will be followed until withdrawal of consent, death, or completion of 10-year follow-up, whichever comes first. Secondary endpoints will be monitored at 30 days, 1, 3, 5, and 10 years. The Compare-TAVI organization will launch consecutive cohorts wherein patients scheduled for TAVI are randomized to one of two valves. The aim is to ensure that the short- and long-term performance and safety of new valves being introduced is benchmarked against what achieved by best-in-practice contemporary valves.

Resonant spin-flavor precession of sterile neutrinos

We analyze the impact of resonant conversions mediated by non-vanishing magnetic moments between active neutrinos and a heavy sterile neutrino on the supernova neutrino flux. We present the level-crossing scheme for such a scenario and derive the neutrino fluxes after conversion, paying particular attention to the order in which the resonances occur. We then compute the expected event rates from the neutronization burst of a future supernova at DUNE and Hyper-Kamiokande to derive new constraints on the neutrino magnetic moment. With this, we find a sensitivity down to a few 10-15 μB for a sterile neutrino in the O(eV) mass range.

Accuracy of Event Rate and Effect Size Estimation in Major Cardiovascular Trials

For the design of a randomized clinical trial (RCT), estimation of the expected event rate and effect size of an intervention is needed to calculate the sample size. Overestimation may lead to an underpowered trial. To evaluate the accuracy of published estimates of event rate and effect size in contemporary cardiovascular RCTs. A systematic search was conducted in MEDLINE for multicenter cardiovascular RCTs associated with MeSH (Medical Subject Headings) terms for cardiovascular diseases published in the New England Journal of Medicine, JAMA, or the Lancet between January 1, 2010, and December 31, 2019. Identified trials underwent abstract review; eligible trials then underwent full review, and those with insufficiently reported data were excluded. Data were extracted from the original publication or the study protocol, and a random-effects model was used for data pooling. This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline. The primary outcome was the accuracy of event rate and effect size estimation. Accuracy was determined by comparing the observed event rate in the control group and the effect size with their hypothesized values. Linear regression was used to determine the association between estimation accuracy and trial characteristics. Of the 873 RCTs identified, 374 underwent full review and 30 were subsequently excluded, resulting in 344 trials for analysis. The median observed event rate was 9.0% (IQR, 4.3% to 21.4%), which was significantly lower than the estimated event rate of 11.0% (IQR, 6.0% to 25.0%) with a median deviation of -12.3% (95% CI, -16.4% to -5.6%; P < .001). More than half of the trials (196 [61.1%]) overestimated the expected event rate. Accuracy of event rate estimation was associated with a higher likelihood of refuting the null hypothesis (0.13 [95% CI, 0.01 to 0.25]; P = .03). The median observed effect size in superiority trials was 0.91 (IQR, 0.74 to 0.99), which was significantly lower than the estimated effect size of 0.72 (IQR, 0.60 to 0.80), indicating a median overestimation of 23.1% (95% CI, 17.9% to 28.3%). A total of 216 trials (82.1%) overestimated the effect size. In this systematic review of contemporary cardiovascular RCTs, event rates of the primary end point and effect sizes of an intervention were frequently overestimated. This overestimation may have contributed to the inability to adequately test the trial hypothesis.

Ticagrelor alone versus ticagrelor plus aspirin from month 1 to month 12 after percutaneous coronary intervention in patients with acute coronary syndromes (ULTIMATE-DAPT): a randomised, placebo-controlled, double-blind clinical trial

Following percutaneous coronary intervention with stent placement to treat acute coronary syndromes, international clinical guidelines generally recommend dual antiplatelet therapy with aspirin plus a P2Y12 receptor inhibitor for 12 months to prevent myocardial infarction and stent thrombosis. However, data on single antiplatelet therapy with a potent P2Y12 inhibitor earlier than 12 months after percutaneous coronary intervention for patients with an acute coronary syndrome are scarce. The aim of this trial was to assess whether the use of ticagrelor alone, compared with ticagrelor plus aspirin, could reduce the incidence of clinically relevant bleeding events without an accompanying increase in major adverse cardiovascular or cerebrovascular events (MACCE). In this randomised, placebo-controlled, double-blind clinical trial, patients aged 18 years or older with an acute coronary syndrome who completed the IVUS-ACS study and who had no major ischaemic or bleeding events after 1-month treatment with dual antiplatelet therapy were randomly assigned to receive oral ticagrelor (90 mg twice daily) plus oral aspirin (100 mg once daily) or oral ticagrelor (90 mg twice daily) plus a matching oral placebo, beginning 1 month and ending at 12 months after percutaneous coronary intervention (11 months in total). Recruitment took place at 58 centres in China, Italy, Pakistan, and the UK. Patients were required to remain event-free for 1 month on dual antiplatelet therapy following percutaneous coronary intervention with contemporary drug-eluting stents. Randomisation was done using a web-based system, stratified by acute coronary syndrome type, diabetes, IVUS-ACS randomisation, and site, using dynamic minimisation. The primary superiority endpoint was clinically relevant bleeding (Bleeding Academic Research Consortium [known as BARC] types 2, 3, or 5). The primary non-inferiority endpoint was MACCE (defined as the composite of cardiac death, myocardial infarction, ischaemic stroke, definite stent thrombosis, or clinically driven target vessel revascularisation), with an expected event rate of 6·2% in the ticagrelor plus aspirin group and an absolute non-inferiority margin of 2·5 percentage points between 1 month and 12 months after percutaneous coronary intervention. The two co-primary endpoints were tested sequentially; the primary superiority endpoint had to be met for hypothesis testing of the MACCE outcome to proceed. All principal analyses were assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03971500, and is completed. Between Sept 21, 2019, and Oct 27, 2022, 3400 (97·0%) of the 3505 participants in the IVUS-ACS study were randomly assigned (1700 patients to ticagrelor plus aspirin and 1700 patients to ticagrelor plus placebo). 12-month follow-up was completed by 3399 (>99·9%) patients. Between month 1 and month 12 after percutaneous coronary intervention, clinically relevant bleeding occurred in 35 patients (2·1%) in the ticagrelor plus placebo group and in 78 patients (4·6%) in the ticagrelor plus aspirin group (hazard ratio [HR] 0·45 [95% CI 0·30 to 0·66]; p<0·0001). MACCE occurred in 61 patients (3·6%) in the ticagrelor plus placebo group and in 63 patients (3·7%) in the ticagrelor plus aspirin group (absolute difference -0·1% [95% CI -1·4% to 1·2%]; HR 0·98 [95% CI 0·69 to 1·39]; pnon-inferiority<0·0001, psuperiority=0·89). In patients with an acute coronary syndrome who had percutaneous coronary intervention with contemporary drug-eluting stents and remained event-free for 1 month on dual antiplatelet therapy, treatment with ticagrelor alone between month 1 and month 12 after the intervention resulted in a lower rate of clinically relevant bleeding and a similar rate of MACCE compared with ticagrelor plus aspirin. Along with the results from previous studies, these findings show that most patients in this population can benefit from superior clinical outcomes with aspirin discontinuation and maintenance on ticagrelor monotherapy after 1 month of dual antiplatelet therapy. The Chinese Society of Cardiology, the National Natural Scientific Foundation of China, and the Jiangsu Provincial & Nanjing Municipal Clinical Trial Project. For the Mandarin translation of the abstract see Supplementary Materials section.

GSpyNetTree: a signal-vs-glitch classifier for gravitational-wave event candidates

Despite achieving sensitivities capable of detecting the extremely small amplitude of gravitational waves (GWs), LIGO and Virgo detector data contain frequent bursts of non-Gaussian transient noise, commonly known as ‘glitches’. Glitches come in various time-frequency morphologies, and they are particularly challenging when they mimic the form of real GWs. Given the higher expected event rate in the next observing run (O4), LIGO-Virgo GW event candidate validation will require increased levels of automation. Gravity Spy, a machine learning tool that successfully classified common types of LIGO and Virgo glitches in previous observing runs, has the potential to be restructured as a compact binary coalescence (CBC) signal-vs-glitch classifier to accurately distinguish between glitches and GW signals. A CBC signal-vs-glitch classifier used for automation must be robust and compatible with a broad array of background noise, new sources of glitches, and the likely occurrence of overlapping glitches and GWs. We present GSpyNetTree, the Gravity Spy Convolutional Neural Network Decision Tree: a multi-CNN classifier using CNNs in a decision tree sorted via total GW candidate mass tested under these realistic O4-era scenarios.

Searching for supermassive charged gravitinos in underground experiments

We examine possible experimental signatures that may be exploited to search for stable supermassive particles with electric charges of O(1)\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${{\\mathcal {O}}}(1)$$\\end{document} in future underground experiments, and the upcoming JUNO experiment in particular. The telltale signal providing a unique signature of such particles, would be a correlated sequence of three or more nuclear recoils along a straight line, corresponding to the motion of a non-relativistic (β≲10-2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\beta \\lesssim 10^{-2}$$\\end{document}) particle that could enter the detector from any direction. We provide some preliminary estimates for the expected event rates.

Abstract 66: Optimal Delay Time to Initiate Anticoagulation After Ischemic Stroke in Atrial Fibrillation: Primary Results of the START Trial

Introduction: Clinical practice guidelines recommend initiation of anticoagulation within 2 weeks after stroke due to atrial fibrillation (AF). It is unknown whether there is an optimal day within that 14-day period that balances the risks of recurrent embolic vs serious hemorrhagic events. Methodology: The Lone Start Stroke START trial is a pragmatic, prospective, multi-center, response-adaptive randomized Phase 2 study of 200 patients prescribed a direct oral anticoagulant (DOAC) for secondary prevention of stroke due to AF. Patients were randomized into one of 4 Arms: Day 3-4 from stroke onset, Day 6, Day 10, or Day 14. The primary outcome was an ischemic (stroke or systemic embolus) or hemorrhagic (ICH or major systemic hemorrhage) event observed within 30 days from the index stroke time of onset. Posterior probabilities that each arm was the best were calculated at predefined intervals and randomization allocations were adjusted to favor the Arms with higher probabilities. Results: The median age was 75 (IQR 65-81), median NIHSS at presentation was 7 (IQR 4-14), median lesion diameter was 3.1 cm (IQR 2.0-4.4) at the time of randomization. The sample was 50% female, 17.5% non-white, and 16.5% Hispanic. Apixaban was the prescribed DOAC in 89% of the patients. No ischemic events were observed for Arm 1, and no hemorrhage events were observed for Arm 4. Arm 1 (3-4 days) had a posterior 41.1% probability of being the best among the four, with probabilities of 26.4%, 17.1%, and 15.4 % respectively, for the other arms. Response adapted randomization was feasible and favored the earlier two arms. Expected event rates for each arm are presented in the Table. The timing and severity of the outcome events will be presented at the conference. Conclusion: Although the START trial did not identify a clearly superior day to initiate DOAC for secondary stroke prevention in AF, the evidence suggests that initiating DOAC early is better than at later times within the first 2 weeks after stroke onset.

Updated Observing Scenarios and Multimessenger Implications for the International Gravitational-wave Networks O4 and O5

An advanced LIGO and Virgo’s third observing run brought another binary neutron star merger (BNS) and the first neutron-star black hole mergers. While no confirmed kilonovae were identified in conjunction with any of these events, continued improvements of analyses surrounding GW170817 allow us to project constraints on the Hubble Constant (H 0), the Galactic enrichment from r-process nucleosynthesis, and ultra-dense matter possible from forthcoming events. Here, we describe the expected constraints based on the latest expected event rates from the international gravitational-wave network and analyses of GW170817. We show the expected detection rate of gravitational waves and their counterparts, as well as how sensitive potential constraints are to the observed numbers of counterparts. We intend this analysis as support for the community when creating scientifically driven electromagnetic follow-up proposals. During the next observing run O4, we predict an annual detection rate of electromagnetic counterparts from BNS of () for the Zwicky Transient Facility (Rubin Observatory).

Left atrial appendage occlusion indicated by increased thrombotic risk versus increased bleeding risk: a comparison of the stroke despite anticoagulation (STR-OAC) and EWOLUTION cohorts

Abstract Background Left atrial appendage occlusion (LAAO) provides mechanical cardioembolic protection, especially attractive for atrial fibrillation (AF) patients that cannot use oral anticoagulation therapy (OAC). Patients with prior stroke despite OAC are at high risk for recurrence and may also benefit from LAAO as (adjunctive) therapy. Purpose To investigate the efficacy of LAAO in AF patients with prior stroke on OAC compared to LAAO in AF patients with a contra-indication to OAC. Methods The STR-OAC LAAO is an international collaboration combining patients that underwent successful percutaneous LAAO because of a thrombo-embolic event or LAA thrombus on OAC from multiple LAAO registries (n=439). This cohort was compared to patients from the previously published EWOLUTION registry comprising of patients that successfully underwent LAAO because of a contra-indication for long-term OAC (n=1005). Thrombotic endpoints were prespecified and (non-procedural) major bleeding was defined as BARC score&amp;gt;2. Annualized event rates were calculated and compared to historical data based on individual patient risk scores. Results Both cohorts were comparable in terms of age and sex (Table 1). CHA2DS2-VASc and HAS-BLED scores were higher in the STR-OAC cohort. After LAAO indicated by a thrombotic event despite OAC, 33% of patients had a planned lifelong hybrid strategy approach of concomitant LAAO and OAC. Consequently, STR-OAC patients often continued OAC (with or without antiplatelet therapy), whereas EWOLUTION patients were more frequently discharged with antiplatelet therapy only. The annualized event rate (AER) for composite thrombotic events was slightly higher in the STROAC-LAAO compared to the EWOLUTION patients (4.2% versus 2.0%), possibly due to the higher thrombotic risk of this population. Major bleeding occurred more frequently in the EWOLUTION compared to STROAC-LAAO patients (AER 2.6% versus 1.1%, Table 2). In comparison to historically expected event rates, relative risk reduction (RRR) for thrombo-embolic events was 65% in the STR-OAC cohort, and 80% in the EWOLUTION cohort (Fig. 1). Annualized major bleeding rates were reduced with 81% and 46% in the STR-OAC-LAAO and EWOLUTION cohorts, respectively. Conclusions LAAO in AF patients with a thrombotic event despite OAC provides ischemic stroke protection similar to a guideline-recommended population with high bleeding risk. RRR for thrombotic events was more pronounced in the population contra-indicated for long-term OAC, while RRR for major bleeding was more pronounced in the patients that experienced a thrombotic event on OAC. Randomized trial data could endorse thrombotic event despite OAC as an indication for LAAO.Table 1&amp;2Figure 1

Atmospheric muons at PeV energies in radio neutrino detectors

Experiments seeking to detect radio emission stemming from neutrino interactions will soon reach sensitivities that bring a detection within reach. Since experiments like RNO-G or the future IceCube-Gen2 target more than an order of magnitude more effective volume than existing experiments, the renewed and detailed study of rare backgrounds is needed. In this paper, we study the potential background from energy losses of highly energetic atmospheric muons. Due to both limited experimental measurements and limited modeling in hadronic interaction models, the expected event rate is subject to large uncertainties. Here, we estimate rate predictions and their uncertainties for different models and instrumental parameters. We also study possible routes towards mitigation of the muon background, such as parent air shower detection, and illustrate what is needed to make the first measurement of the prompt muon flux at energies above 10 PeV.

Long-term outcomes of successful left atrial appendage occlusion with focus on stroke prevention: 10-year follow-up of a single-center registry.

Percutaneous left atrial appendage occlusion (LAAO) is an alternative to anticoagulation in the prevention of stroke in patients with nonvalvular atrial fibrillation, especially in patients with a contraindication for oral anticoagulation therapy (OAT). The study sought to obtain long-term patient outcomes after successful LAAO in everyday clinical practice. In this single-center registry spanning over 10 years, data of all consecutive patients that underwent percutaneous LAAO were collected. Observed thromboembolic and major bleeding event rates after successful LAAO during follow-up were compared with expected event rates based on CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism, vascular disease, age 65-74 years, sex category) and HAS-BLED (hypertension, abnormal renal or liver function, stroke, bleeding, labile international normalized ratio, elderly, drugs or alcohol) scores. Furthermore, anticoagulation and antiplatelet use during follow-up was evaluated. Of 230 patients scheduled for LAAO (38% women, 69.5 ± 8.2 years of age, CHA2DS2-VASc score 3.9 ± 1.6, HAS-BLED score 2.9 ± 1.0), 218 patients had a successful implantation (95%) with a follow-up duration of 5.2 ± 3.1 years. The procedure was combined with catheter ablation in 52% of the patients. Fifty thromboembolic complications (24 ischemic stroke, 26 transient ischemic attack) were observed during follow-up in 40 (18%) of 218 patients. Ischemic strokes occurred with a rate of 2.1 per 100 patient-years, accounting for a 66% relative risk reduction compared with the CHA2DS2-VASc predicted event rate. Device-related thrombus was observed in 5 (2%) patients. Sixty-five nonprocedural major bleeding complications occurred in 24 (11%) of 218 patients with a rate of 5.7 per 100-patient years, which is comparable to estimated HAS-BLED-bleeding rates under OAT use. At end of follow-up 71% of all patients were on single antiplatelet or no antiplatelet or anticoagulation treatment, while 29% were on OAT. Thromboembolic event rates during long-term follow-up after successful LAAO remained consistently lower than expected supporting the efficacy of LAAO.

Dynamic data-enabled stratified sampling for trial invitations with application in NHS-Galleri.

Participants of health research studies such as cancer screening trials usually have better health than the target population. Data-enabled recruitment strategies might be used to help minimise healthy volunteer effects on study power and improve equity. A computer algorithm was developed to help target trial invitations. It assumes participants are recruited from distinct sites (such as different physical locations or periods in time) that are served by clusters (such as general practitioners in England, or geographical areas), and the population may be split into defined groups (such as age and sex bands). The problem is to decide the number of people to invite from each group, such that all recruitment slots are filled, healthy volunteer effects are accounted for, and equity is achieved through representation in sufficient numbers of all major societal and ethnic groups. A linear programme was formulated for this problem. The optimisation problem was solved dynamically for invitations to the NHS-Galleri trial (ISRCTN91431511). This multi-cancer screening trial aimed to recruit 140,000 participants from areas in England over 10 months. Public data sources were used for objective function weights, and constraints. Invitations were sent by sampling according to lists generated by the algorithm. To help achieve equity the algorithm tilts the invitation sampling distribution towards groups that are less likely to join. To mitigate healthy volunteer effects, it requires a minimum expected event rate of the primary outcome in the trial. Our invitation algorithm is a novel data-enabled approach to recruitment that is designed to address healthy volunteer effects and inequity in health research studies. It could be adapted for use in other trials or research studies.

Neutrino predictions from choked Gamma-Ray Bursts and comparison with the observed cosmic diffuse neutrino flux

The strong constraints from the Fermi-LAT data on the isotropic gamma-ray background suggest that the neutrinos observed by IceCube might possibly come from sources that are hidden to gamma-ray observations. A possibility emerged in recent years is that neutrinos may come from jets of collapsing massive stars which fail to break out of the stellar envelope, and for this reason they are known as choked jets, or choked Gamma-Ray Bursts (GRBs). We here show our predictions of neutrino flux and spectrum expected from these sources, focusing on Type II SNe, through detailed calculations of pγ interactions and accounting for all the neutrino production channels and scattering angles. We provide predictions of expected event rates for ANTARES, IceCube, and the next generation neutrino telescope KM3NeT.We also compute the contribution of the choked GRB population to the diffuse astrophysical neutrino flux, thus providing constraints on the local rate of this source population as to reproduce the observed neutrino flux.

Rationale and design of the TUXEDO-2 India study: Ultra-Thin strUt Supraflex Cruz versus XiencE in a Diabetic pOpulation with multi-vessel disease–2

The role of percutaneous coronary interventions (PCI) in patients with diabetes mellitus and multi-vessel disease has been questioned by the results of the FREEDOM trial, which showed superiority of coronary artery bypass graft(CABG) over first generation drug-eluting stents (DES) including a reduction in mortality. In the light of safer and more efficacious stents and significantly better medical management, those results that date back to 2012 need to be revisited. TUXEDO-2 is a study designed to compare two contemporary stents in Indian diabetic patients with multi-vessel disease. The primary objective of the TUXEDO-2 study is to compare the clinical outcomes of PCI with ultra-thin Supraflex Cruz vs Xience when combined with contemporary optimal medical therapy (OMT) in diabetic patients with multi-vessel disease. The secondary objective is to compare clinical outcomes between a pooled cohort from both arms of the study (Supraflex Cruz+Xience; PCI arm) vs CABG based on a performance goal derived from the CABG arm of the FREEDOM trial (historical cohort). The tertiary objective is a randomized comparison of ticagrelor vs prasugrel in addition to aspirin for the composite of ischemic and bleeding events. In this prospective, open-label, multi-centre, 2×2 factorial, randomized, controlled study, 1,800 patients with diabetes mellitus and multi-vessel disease (inclusion criteria similar to FREEDOM trial) with indication for coronary revascularization will be randomly assigned to Supraflex Cruz or Xience stents and also to ticagrelor- or prasugrel- based antiplatelet strategies. All patients will receive guideline directed OMT and optimal PCI including image- and physiology-guided complete revascularization where feasible. The patients will be followed through five years to assess their clinical status and major clinical events. The primary endpoint is a non-inferiority comparison of target lesion failure at one-year for Supraflex Cruz vs Xience (primary objective) with an expected event rate of 11% and a non-inferiority margin of 4.5%. For PCI vs CABG (secondary objective), the primary endpoint is major adverse cardiac events (MACE), defined as a composite of all cause death, nonfatal myocardial infarction, or stroke at one-year and yearly up to five years, with a performance goal of 21.6%. For ticagrelor vs prasugrel (tertiary objective), the primary endpoint is composite of death, myocardial infarction, stroke, and major bleeding as per the Bleeding Academic Research Consortium (BARC) at one-year with expected event rate of 15% and a non-inferiority margin of 5%. The TUXEDO-2 study is a contemporary study involving state-of-the-art PCI combined with guideline directed OMT in a complex subset of patients with diabetes mellitus and multi-vessel disease. The trial will answer the question as to whether a biodegradable polymer coated ultra-thin Supraflex Cruz stent is an attractive option for PCI in diabetic patients with multi-vessel disease. It will also help address the question whether the results of FREEDOM trial would have been different in the current era of safer and more efficacious stents and modern medical therapy. In addition, the comparative efficacy and safety of ticagrelor vs prasugrel in addition to aspirin will be evaluated. (CTRI/2019/11/022088).

ATLAS toward the High Luminosity era: Challenges on electronic systems

In order to face the challenging experimental conditions at the HL-LHC, the ATLAS detector will be equipped with new sets of both front-end and off-detector electronics and a new trigger and data acquisition system able to cope with the expected event rates and pile-up levels. The large number of detector channels, huge volumes of input and output data, short time available to process and transmit data, harsh radiation environment and the need of low power consumption, all impose great challenges on the design and operation of the electronic systems.

Accuracy of event rate and effect size estimation in major cardiovascular trials

Abstract Background During the design of a randomized controlled trial (RCT), the estimation of the expected event rate (ER) and effect size (ES) of an intervention is an essential step to calculate the sample size, which determines the scope of the trial. Overestimation of ER and ES might lead to an underpowered trial design. Objective To evaluate the accuracy of the estimation of ER and ES in contemporary cardiovascular RCTs. Methods We searched “Medline” for cardiovascular RCTs published in the New England Journal of Medicine, The Journal of the American Medical Association, or The Lancet between 2010 and 2019. Only multicenter RCTs with a dichotomous primary endpoint and with not more than 2 study arms were included. Data were extracted from the original publication or the associated study protocol. For trials that tested superiority of an intervention, the effect size measurements hazard ratio, odds ratio, or risk ratio were summarized as the effect size ratio (ESR). To determine the accuracy of estimation, we compared the observed to the hypothesized ER and ESR, respectively. The association of the accuracy of estimation with trial characteristics was determined by linear regression. Results Of 875 identified publications, 374 underwent full review. After exclusion of trials with insufficiently reported data for this analysis, data from 344 trials were analyzed. 145 trials (42.2%) were industry sponsored, 122 (35.5%) were investigator-initiated with industry-co funding, and 77 (22.1%) with government or public funding. The majority (186; 54.1%) tested a drug as the intervention. 263 (76.5%) were designed to test for superiority of the intervention. The primary endpoint consisted of at least 2 components in 247 (71.8%) trials. The median estimated sample size was 2386 (interquartile range [IQR] 800, 6000). The median observed event rate was 9.0% (IQR 4.3, 21.4%) and was significantly lower compared with the estimated ER (11.0% [IQR 6.0, 25.0%]; median deviation from estimation −6.9% [95% confidence interval, CI −10.0, −3.7%]; p&amp;lt;0.001). 196 trials (61%) overestimated the event rate (Figure 1A). The overestimation was consistent across several subgroups (Figure 2A). The median observed ESR was 0.910 (IQR 0.740, 0.990) and was significantly higher compared with the estimated ESR (0.724 [IQR 0.600, 0.795]; median deviation from estimated effect size 26.0% [95% CI, 19.0, 33.0%]). 216 (82.1%) trials overestimated the effect size (Figure 1B). This overestimation was consistent across all analyzed subgroups (Figure 2B) and was less pronounced in trials with use of a composite primary outcome. Conclusion 6 of 10 contemporary cardiovascular RCTs overestimated the event rate for the primary endpoint and 8 of 10 trials overestimated the effect sizes of an intervention. Overestimation may lead to inability to answer the trial hypothesis. Funding Acknowledgement Type of funding sources: None.