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Sacubitril/valsartan (Sac/Val) improves left ventricular ejection fraction (LVEF) in heart failure (HF) with reduced ejection fraction regardless of previous treatments. Improvements in LVEF may change eligibility for primary implantable cardioverter-defibrillator (ICD) placement. Awaiting LVEF improvement may expose patients to potential risks for arrhythmic complications.The authors sought to develop a model predicting LVEF change after Sac/Val therapy.A total of 416 persons with HF and LVEF of 35% were included in this analysis. Following initiation of Sac/Val, echocardiographic parameters were measured serially for 1 year. A machine learning algorithm was implemented to develop a risk model for predicting the persistence of LVEF of 35% after 1 year and was validated in a separate group of study participants.Baseline LVEF, left ventricular mass index, HF duration, age, N-terminal pro-B-type natriuretic peptide concentration at baseline and change by day 14, and body mass index were the most significant factors for identifying lack of LVEF improvement to ≥35% after 1 year. In the training and validation cohorts, the areas under the model curve for predicting lack of LVEF improvement were 0.92 and 0.86, respectively. Three categories of likelihood for LVEF of 35% after 1 year of Sac/Val treatment were developed based on the model predictions: 3.8%, 30.1%, and 83.7%. During follow-up, arrhythmia event rates were 0.9%, 2.9%, and 6.7% in these groups, respectively.Many persons with HF with reduced ejection fraction eligible for ICD insertion experience an increase in LVEF to ≥35% after treatment with Sac/Val. Early identification of those less likely to improve their LVEF might allow for more refined selection of primary ICD candidates. (Effects of Sacubitril/Valsartan Therapy on biomarkers, Myocardial Remodeling, and Outcomes [PROVE-HF]; NCT02887183).

Although sacubitril/valsartan (Sac/Val) is indicated for the treatment of heart failure with reduced ejection fraction (HFrEF), gaps in care continue to exist for those with newer onset HFrEF vs those with longer durations of disease.We categorized 794 persons with HFrEF (EF of ≤40%) according to a HF duration of less than 12 months, 12-24 months, 24-60 months, and more than60 months. After the initiation of Sac/Val, concentrations of N-terminal pro-B type natriuretic peptide, high sensitivity cardiac troponin T, and soluble ST2 were measured, and Kansas City Cardiomyopathy Questionnaire 23 scores were obtained serially from baseline to 12 months. The left ventricular ejection fraction was measured by echocardiography. Significant decreases in the concentrations of N-terminal pro-B type natriuretic peptide, high sensitivity cardiac troponin T, and soluble ST2 were observed regardless of HF duration (P.001). Comparable gains in Kansas City Cardiomyopathy Questionnaire 23 scores were achieved in all HF duration categories. Moreover, consistent reverse cardiac remodeling in all HF duration categories occurred, with the absolute left ventricular ejection fraction improvement by 12 months across HF duration groups of 12.2%, 6.9%, 8.5%, and 8.6% for HF duration of less than 12 months, 12-24 months, 24-60 months, and more than 60 months, respectively.The initiation of Sac/Val decreases prognostic biomarkers, improves health status, and reverses cardiac remodeling processes, regardless of HF duration.We categorized 794 persons with heart failure owing to a low ejection fraction according to disease duration into 4 groups: less than 12 months, 12-24 months, 24-60 months, and more than 60 months. After the initiation of sacubitril/valsartan (Entresto), we found that regardless of the duration of heart failure significant improvements occurred in cardiac biomarkers, patients felt better with improved health status and on testing with cardiac ultrasound examination, improvement in heart size, and function occurred. These results suggest that, regardless of heart failure duration, patients with a reduced ejection fraction would benefit from use of sacubitril/valsartan for their care.

Doses of sacubitril/valsartan (Sac/Val) achieved in clinical trials of heart failure with reduced ejection fraction (HFrEF) are often not reached in clinical practice.The purpose of this study was to investigate associations among Sac/Val doses and changes in prognostic biomarkers, health status, and cardiac remodeling among individuals with HFrEF through 12 months of treatment with Sac/Val administered per usual care.A total of 794 persons with HFrEF (ejection fraction [EF] ≤40%) were categorized according to average daily doses of Sac/Val divided into tertiles. Change from baseline to 12 months in biomarkers (N-terminal pro-B-type natriuretic peptide, high-sensitivity cardiac troponin T, soluble ST2, atrial natriuretic peptide, urinary cyclic guanosine monophosphate), Kansas City Cardiomyopathy Questionnaire-23 scores, and parameters of cardiac reverse remodeling (left ventricular EF, indexed left atrial and ventricular volumes, and E/e') were assessed.The average daily dose was 112 mg in Tertile 1 (low dose), 342 mg in Tertile 2 (moderate dose), and 379 mg in Tertile 3 (high dose). Similar changes in prognostic biomarkers were observed in all dose tertiles. Gains in Kansas City Cardiomyopathy Questionnaire-23 scores were comparable regardless of dose category. Consistent reverse cardiac remodeling in all dose categories occurred; the median absolute left ventricular EF improvement across HF dose groups was 9.3%, 8.7%, and 10.2%, for low, moderate, and high doses, respectively; similar improvements in left atrial and ventricular volumes and E/e' were also observed across dose categories.Among patients with HFrEF, similar improvement in prognostic biomarkers, health status, and cardiac remodeling were observed across various Sac/Val doses. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183.

Here two D–A3 regioisomers, comprising three dibenzothiophene-S,S-dioxide acceptor units attached to a central triazatruxene core, are studied. Both molecules show thermally activated delayed fluorescence (TADF), however, the efficiency of the TADF mechanism is strongly affected by the D–A substitution position. The meta- substituted emitter (1 b) shows a slightly higher-lying singlet charge transfer state and a lower-lying triplet state than that observed in the para- substituted emitter (1 a), resulting in a larger singlet–triplet splitting (ΔEST) of 0.28 eV compared to only 0.01 eV found in 1 a. As expected, this ΔEST difference strongly impacts the reverse intersystem crossing (rISC) rates and the para- isomer 1 a exhibits a much faster delayed fluorescence emission. Calculations show that the triplet energy difference between the two isomers is due to steric hindrance variances along the donor–acceptor rotation axis in these molecules: as 1 b is less restricted, rotation of its acceptor unit leads to a lower T1 energy, further away from the region of high density of states (the region where larger vibronic coupling is found, favouring rISC). Therefore, our results show how the substitution pattern has a marked effect on triplet state energies and character, verifying the key structural designs for highly efficient TADF materials.

Background Several different B-type natriuretic peptide (BNP) assays are used clinically for diagnostic and prognostic evaluation of heart failure (HF). BNP binds weakly to neprilysin and is cleaved in multiple areas adjacent to the binding sites for the antibodies used in these immunoassays. We assessed the changes in BNP following neprilysin inhibition as measured by 3 immunoassays that recognize different epitopes. Methods Among 130 participants with HF with reduced ejection fraction, blood was collected prior to treatment with sacubitril/valsartan (sac/val) and then repeatedly measured through 52 weeks of treatment. BNP concentrations were measured with 3 widely used BNP assays (Siemens, Abbott, and Quidel). Results Study participants had a mean age of 65 ± 13 years and 76% were men. The median BNP concentration at baseline was 133 ng/L by the Siemens assay, 127 ng/L by the Abbott assay, and 141 ng/L by the Quidel assay. Following initiation of sac/val, there were significantly greater declines in BNP measured by Quidel and Abbott (P = 0.009 and P < 0.001), respectively (both with N-terminal capture antibodies), compared to Siemens (with C-terminal capture antibodies). The difference from baseline was not statistically significant until after week 12 (mean –10.1% for Quidel and –14.3% for Abbott) compared to non-significant differences before 12 weeks (mean –4.5% for Quidel and –6.0% for Abbott). Conclusions Following initiation of sac/val, BNP measurements may modestly differ depending on the assay method used, particularly after a few months of treatment. Whether these differences relate to neprilysin-mediated degradation of antibody binding sites deserves further study. Study registration PROVE-HF ClinicalTrials.gov Identifier: NCT02887183.

The synthetic methodology to covalently link donors to form cyclophane-based thermally activated delayed fluorescence (TADF) molecules is presented. These are the first reported examples of TADF cyclophanes with “electronically innocent” bridges between the donor units. Using a phenothiazine-dibenzothiophene-S,S-dioxide donor–acceptor–donor (D–A–D) system, the two phenothiazine (PTZ) donor units were linked by three different strategies: (i) ester condensation, (ii) ether synthesis, and (iii) ring closing metathesis. Detailed X-ray crystallographic, photophysical and computational analyses show that the cyclophane molecular architecture alters the conformational distribution of the PTZ units, while retaining a certain degree of rotational freedom of the intersegmental D–A axes that is crucial for efficient TADF. Despite their different structures, the cyclophanes and their nonbridged precursors have similar photophysical properties since they emit through similar excited states resulting from the presence of the equatorial conformation of their PTZ donor segments. In particular, the axial–axial conformations, known to be detrimental to the TADF process, are suppressed by linking the PTZ units to form a cyclophane. The work establishes a versatile linking strategy that could be used in further functionalization while retaining the excellent photophysical properties of the parent D–A–D system.

Directional coupling of light in nanophotonic circuits has recently attracted increasing interest, with numerous experimental realizations based on broken rotational or mirror symmetries of the light-matter system. The most prominent underlying effect is the spin-orbit interaction of light in subwavelength structures. Unfortunately, coupling of light to such structures is, in general, very inefficient. In this work, we experimentally demonstrate an order of magnitude enhancement of the directional coupling between two nanowaveguides by means of a whispering gallery microcavity. We also show that both transversmagnetic and transverse electric modes can be used for the enhancement., 3 figures

This work shows that trifluoromethyl (CF3) substituents can be used to increase the rate of thermally activated delayed fluorescence (TADF) in conjugated organic molecules by tuning the excitonic character of the singlet and triplet excited states. The synthesis and detailed photophysical characterization of four new functionalized donor–acceptor–donor (D–A–D) compounds using CF3-substituted-thioxanthene-S,S-dioxide and dimethylacridine units are presented. Several compounds are reported to exhibit rapid blue/green thermally activated delayed fluorescence with major delayed fluorescence lifetime components of ≈1–2 μs. Changes in the orbital character of singlet and triplet states (local vs. charge transfer) result in significant changes in rates of delayed fluorescence, despite similar ΔEST values. The change in orbital character is well supported by TD-DFT calculations. Electrochemical measurements reveal strong shifts in redox potentials that can be induced by σ-electron withdrawing CF3 substituents. Trifluoromethyl substituted compounds with a wider ΔEST also perform more efficiently than might be expected due to the demonstrated changes in excited state character. This study reveals important photophysical and molecular design implications for the future development of TADF emitters.

Sacubitril/valsartan (Sac/Val) improves outcomes in patients with heart failure with reduced ejection fraction (HFrEF).In this study, the authors sought to explore age differences in effects of Sac/Val on biomarkers, Kansas City Cardiomyopathy Questionnaire (KCCQ)-23 scores and cardiac remodeling.After initiation and titration of Sac/Val, concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-cTnT), and soluble suppressor of tumorigenicity 2 (sST2) were measured and KCCQ-23 scores obtained from baseline to 12 months. Left ventricular ejection fraction (LVEF), and indexed left ventricular end-systolic (LVESVi) and indexed left ventricular end-diastolic (LVEDVi) and left atrial volume index (LAVi) volumes were measured with the use of echocardiography. Safety end points were assessed. Age-stratified analysis was performed for groups aged 65, 65-74, and ≥75 years.Among 794 participants with HFrEF (mean age 65.1 years, 28.5% women), compared with patients aged 65 years (n = 369), 65-74 years (n = 237), and those aged ≥75 years (n = 188), had similar reductions in hs-cTnT and sST2, but less NT-proBNP reduction (-45.6% vs -40.2% vs -30.5%, respectively; P = 0.02). Gains in KCCQ-23 were smaller (+11.8 vs +11.4 vs +6.0 points; P = 0.03) in patients aged ≥75 years, although similar proportions of each age group achieved ≥10-point and ≥20-point increases in KCCQ-23 by month 12. Improvements in LVEF, LVEDVi, LVESVi, and LAVi were similar among age groups. Incidence of safety end points was also similar.Sac/Val resulted in significant improvements in prognostic biomarkers and measures of cardiac remodeling and health status from baseline to month 12 across age categories. Older study participants showed somewhat blunted reduction in NT-proBNP and less improvement in KCCQ-23 overall summary scores. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling, and Outcomes [PROVE-HF]; NCT02887183).

Commonly-used data assimilation methods are being adapted for use with agent-based models with the aim of allowing optimisation in response to new data in real-time. However, existing methods face difficulties working with categorical parameters, which are common in agent-based models. This paper presents a new method, the RJUKF, that combines the Unscented Kalman Filter (UKF) data assimilation algorithm with elements of the Reversible Jump (RJ) Markov chain Monte Carlo method. The proposed method is able to conduct data assimilation on both continuous and categorical parameters simultaneously. Compared to similar techniques for mixed state estimation, the RJUKF has the advantage of being efficient enough for online (i.e. real-time) application. The new method is demonstrated on the simulation of a crowd of people traversing a train station and is able to estimate both their current position (a continuous, Gaussian variable) and their chosen destination (a categorical parameter). This method makes a valuable contribution towards the use of agent-based models as tools for the management of crowds in busy places such as public transport hubs, shopping centres, or high streets.

We were asked by Innovation Embassy to work with a large dataset centred around gambling investment, with the task of making a predictive function for computing Customer Lifetime Value (CLV), and also to see if there are ways of detecting fraudulent financial practices and addictive gambling patterns. We had moderate success with the data as it stands, but we were partly held back for two main reasons: the ability to discern a solid definition of CLV due to highly inconsistent data and data that contained many large and incomputable gaps. Different machine learning algorithms were used to find CLV functions based on key variables. We also describe a short and explicit list of ways where the base data can be improved to support effective calculation of CLV. Our key findings suggest that the average customer's CLV is 1035 and ~80% of revenue is brought in from ~10% of the clients.

This paper explores the use of a particle filter—a data assimilation method—to incorporate real-time data into an agent-based model. We apply the method to a simulation of real pedestrians moving through the concourse of Grand Central Terminal in New York City (USA). The results show that the particle filter does not perform well due to (i) the unpredictable behaviour of some pedestrians and (ii) because the filter does not optimise the categorical agent parameters that are characteristic of this type of model. This problem only arises because the experiments use real-world pedestrian movement data, rather than simulated, hypothetical data, as is more common. We point to a potential solution that involves resampling some of the variables in a particle, such as the locations of the agents in space, but keeps other variables such as the agents’ choice of destination. This research illustrates the importance of including real-world data and provides a proof of concept for the application of an improved particle filter to an agent-based model. The obstacles and solutions discussed have important implications for future work that is focused on building large-scale real-time agent-based models.

This study assessed changes in B-type natriuretic peptide (BNP) among patients with heart failure with reduced ejection fraction (HFrEF) treated with sacubitril/valsartan (Sac/Val) according to standard prescribing information.Through inhibition of neprilysin, Sac/Val may increase BNP concentrations.In an individual patient analysis from the EVALUATE-HF (Study of Effects of Sacubitril/Valsartan vs. Enalapril on Aortic Stiffness in Patients With Mild to Moderate HF With Reduced Ejection Fraction) (n = 221) and the PROVE-HF (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes) (n = 146) studies, we examined changes in BNP, N-terminal pro-BNP (NT-proBNP), and urinary cyclic guanosine monophosphate (ucGMP) from baseline to week 4 and week 12.Median (IQRs) concentration of BNP at baseline, week 4, and week 12 were 145 [IQR: 55-329], 136 [IQR: 50-338], and 135 [IQR: 51-299] ng/L, respectively. There was no significant change from baseline to week 4 (0% [-30% to +41%]; P = 0.36) or week 12 (+1% [-36% to +50%]; P = 0.97). By week 12, one-half of the study participants had a BNP decline. There was no association between Sac/Val dose and BNP changes. Change in BNP was directly associated with change in NT-proBNP (rho: = 0.81; P 0.001), which decreased by -30% (-50% to -8%) and -32% (-54% to -1%) to weeks 4 and 12 (P 0.001 for both). In contrast, change in BNP was only weakly associated with change in ucGMP (rho: = 0.19; P 0.001). Increases in ucGMP were observed regardless of whether BNP was decreased (+11% [-34% to +115%]), unchanged (+34% [-15% to +205%]), or increased (+57% [-12% to +14%]).In this pooled analysis of patients with HFrEF with standard indications for Sac/Val treatment, there was no significant overall increase in BNP concentrations, and patients demonstrated increase in ucGMP regardless of the trajectory of BNP change. (Study of Effects of Sacubitril/Valsartan vs. Enalapril on Aortic Stiffness in Patients With Mild to Moderate HF With Reduced Ejection Fraction [EVALUATE-HF]; NCT02874794) (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183).

We derive explicit formulae to quantify the Markov chain state-space compression, or lumping, that can be achieved in a broad range of dynamical processes on real-world networks, including models of epidemics and voting behaviour, by exploiting redundancies due to symmetries. These formulae are applied in a large-scale study of such symmetry-induced lumping in real-world networks, from which we identify specific networks for which lumping enables exact analysis that could not have been done on the full state-space. For most networks, lumping gives a state-space compression ratio of up to 10 7 , but the largest compression ratio identified is nearly 10 12 . Many of the highest compression ratios occur in animal social networks. We also present examples of types of symmetry found in real-world networks that have not been previously reported.

In this work, we present a packaged whispering gallery mode (WGM) device based on an optical nanoantenna as the coupler and a glass microsphere as the resonator. The microspheres were fabricated from either SiO2 fiber or Er3+-doped fiber, the latter creating a WGM laser with a threshold of 93 µW at 1531 nm. The coupler-resonator WGM device was packaged in a glass capillary. The performance of the packaged microlaser was characterized, with lasing emission both excited in and collected from the WGM cavity via the nanoantenna. The packaged system provides isolation from environmental contamination, a small size, and unidirectional coupling while maintaining a high quality (Q-) factor (∼108).

Interactions between laser beams and plasma are widely studied, mostly with short pulses [1] . Here, we use an experimental setup where the most important instrument is a CW whispering-gallery mode micro-cavity with plasma inside. As one can see in figure 1 , the plasma is electrically ignited between two electrodes inside a bubble resonator [2] - [4] filled with low-pressure argon while the evanescent field of the resonating light ( Fig. 1 c) overlaps with the plasma.

Background: Sacubitril/valsartan (S/V) treatment is associated with reverse cardiac remodeling and reductions in biomarkers reflecting ventricular wall stress and myocardial injury, such as NT-proBNP (N-terminal pro-B-type natriuretic peptide), hs-cTnT (high-sensitivity cardiac troponin T), and soluble suppressor of tumorigenicity 2 (sST2). How longitudinal changes in these biomarkers analyzed collectively are associated with cardiac remodeling in patients with heart failure with reduced ejection fraction treated with S/V is uncertain. Methods: In a prospective study of S/V in patients with heart failure with reduced ejection fraction, this prespecified exploratory analysis included patients with serially collected biomarkers and echocardiographic measures of cardiac remodeling through 12 months of treatment. A multivariate latent growth curve model assessed associations between simultaneous changes in biomarkers and left ventricular ejection fraction and left atrial volume index. Results: Seven hundred fifteen out of 794 total study participants were included (mean age 65 years, 73% male). Mean baseline left ventricular ejection fraction and left atrial volume index were 29% and 40 mL/m 2 , respectively. Adjusted geometric mean baseline concentrations for biomarkers included NT-proBNP of 649 pg/mL, hs-cTnT of 15.9 ng/L, and sST2 of 24.7 ng/mL. Following initiation of S/V, circulating concentrations of NT-proBNP, hs-cTnT, and sST2 significantly decreased within 30 days and remained significantly different than baseline at all subsequent timepoints. From baseline to month 12, decreases in adjusted biomarker concentrations averaged −27.9% (95% CI, −35.1% to −20.7%; P P P Conclusions: Following initiation of S/V, NT-proBNP, hs-cTnT, and sST2 concentrations decreased significantly. Longitudinal changes in NT-proBNP and hs-cTnT together associated with left atrial and left ventricular reverse remodeling. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02887183.

We report the synthesis and structural and photophysical characterization of two series of molecules with functionalized azatriangulene electron donor cores and three pendant electron acceptor units. The presented donor and acceptor units are joined by C–C bonds, instead of the usual C–heteroatom bonds often found in thermally activated delayed fluorescence (TADF) emitters. The effects of the donor–acceptor strength and donor–acceptor dihedral angle on the emission properties are assessed. The data establish that the singlet–triplet energy gap is >0.3 eV and that delayed emission is present in only specific host matrices, irrespective of host polarity. Specific host behavior is atypical of many TADF materials, and we suggest the delayed emission in this work does not occur by a conventional vibronically coupled TADF mechanism, as the ΔEST value is too large. Detailed photophysical analysis and supporting density functional theory calculations suggest that some presented azatriangulene molecules emit via an upper-triplet state crossing mechanism. This work highlights that several different mechanisms can be responsible for delayed emission, often with highly similar photophysics. Detailed photophysical analysis is required to establish which delayed emission mechanism is occurring. Our results also highlight a clear future direction toward vibronically coupled C–C bonded TADF materials.

Biotinylated pharmaceuticals are of great interest due to the strong interactions between biotinyl-functionality and streptavidin/avidin, which opens up avenues for efficient targeting and localisation. Three new carbon monoxide-releasing molecules (CO-RMs) have been synthesised and characterised using chemical and biological analysis. An alkyne-containing CO-RM 2 was found to be toxic to RAW 264.7 murine macrophages; and thus therapeutically viable CO-RM 1 was employed as the alkyne precursor for [3 + 2] cycloaddition chemistry enabling a new acid-containing CO-RM 4 and biotin-bioconugate-CO-RM (BiotinCORM 5) to be prepared. CO-RM 4 showed significantly improved solubility and BiotinCORM 5 acts as a photo-CO-RM. We have found that an avidin-CORM adduct of 5 is a CO-releasing protein, releasing CO on irradiation with light (400 nm). The avidin-biotinCORM adduct of 5 was found to have a binding energy of 10 kcal mol-1.

This paper will critically assess the utility of conventional and novel data sources for building fine-scale spatio-temporal estimates of the ambient population. It begins with a review of data sources employed in existing studies of the ambient population, followed by preliminary analysis to further explore the utility of each dataset. The identification and critiquing of data sources which may be useful for building estimates of the ambient population are novel contributions to the literature. This paper will provide a framework of reference for researchers within urban analytics and other areas where an accurate measurement of the ambient population is required. This work has implications for national and international applications where accurate small area estimates of the ambient population are crucial in the planning and management of urban areas, the development of realistic models and informing policy. This research highlights workday population estimates, in conjunction with footfall camera and Wi-Fi sensors data as potentially valuable for building estimates of the ambient population.

Both asthma and chronic obstructive pulmonary disease (COPD) are inflammatory chronic respiratory conditions with high rates of morbidity and mortality worldwide. The objectives of this review are to briefly describe the pathophysiology and epidemiology of asthma and COPD, discuss guideline recommendations for uncontrolled disease, and review a new generic option for the treatment of asthma and COPD. Although mild forms of these diseases may be controlled with as-needed pharmacotherapy, uncontrolled or persistent asthma and moderate or severe COPD uncontrolled by bronchodilators with elevated eosinophilia or frequent exacerbations may require intervention with combination therapy with inhaled corticosteroids (ICS) and long-acting beta agonists (LABAs), according to international guidelines. Fixed-dose combinations of ICS/LABA are commonly prescribed for both conditions, with fluticasone propionate (FP) and salmeterol forming a cornerstone of many treatment plans. An oral inhalation powder containing the combination of FP and salmeterol has been available as Advair Diskus® in the United States for almost 20 years, and the first and only substitutable generic version of this product has recently been approved for use: Wixela™ Inhub™. Bioequivalence of Wixela Inhub and Advair Diskus has been established. Furthermore, the Inhub inhaler was shown to be robust and easy to use, suggesting that Wixela Inhub may provide an alternative option to Advair Diskus for patients with asthma or COPD requiring intervention with an ICS/LABA.

In this paper, we present a pricing mechanism that aligns incentives of agents who exchange resources on a decentralized ledger with the goal of maximizing transaction throughput. Subdividing a blockchain ledger into shards promises to greatly increase transaction throughput with minimal loss of security. However, the organization and type of the transactions also affects the ledger's efficiency, which is increased by wallet agents transacting in a single shard whenever possible while collectively distributing their transactions uniformly across the available shards. Since there is no central authority to enforce these properties, the only means of achieving them is to design the system such that it is in agents' interest to act in a way that benefits overall throughput. We show that our proposed pricing policy does exactly this by inducing a potential game for the agents, where the potential function relates directly to ledger throughput. Simulations demonstrate that this policy leads to near-optimal throughput under a variety of conditions.

Objective This study sought to determine whether patients with heart failure and reduced ejection fraction (HFrEF) with type 2 diabetes mellitus (T2DM) have similar reverse cardiac remodeling with sacubitril/valsartan as patients without T2DM. Background Sacubitril/valsartan promotes reverse cardiac remodeling and improves outcomes in patients with HFrEF. Patients with HFrEF with T2DM have worse prognosis than those without T2DM. Methods In this post hoc analysis of PROVE-HF (Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure), we examined changes in N-terminal pro–b-type natriuretic peptide (NT-proBNP), measures of cardiac remodeling, and Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) scores from baseline to 12 months following initiation of sacubitril/valsartan between patients with HFrEF with and without T2DM. Using latent growth curve modeling, we evaluated the longitudinal association between changes in NT-proBNP, left ventricular ejection fraction, and KCCQ-OS. Results Among 794 patients enrolled, 361 (45.5%) had T2DM. NT-proBNP concentrations were modestly higher at baseline among patients with T2DM but were reduced after initiation of sacubitril/valsartan. Cross-sectional improvement was observed in left ventricular ejection fraction (T2DM: 28.3% at baseline and 37% at 12 months vs. non-T2DM: 28.1% at baseline and 38.3% at 12 months) and KCCQ-OS (T2DM: 71 at baseline and 83 at 12 months vs. non-T2DM: 76 at baseline and 88 at 12 months). Similar changes were also observed for other echocardiographic measures. In longitudinal analyses, the average NT-proBNP change was similar in patients with T2DM (–5.6% vs. –7.1% per 90-day interval; p = 0.64), whereas improvements in KCCQ-OS scores were slightly smaller (2.1 vs. 3.46 per 90-day interval; p = 0.07). Conclusions Sacubitril/valsartan favorably affects natriuretic peptide levels, reverse cardiac remodeling, and health status in patients with HFrEF with and without T2DM. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183 )