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BACKGROUND: Heart failure (HF) is a chronic condition in which the heart does not pump enough blood to meet the bodys demands. Diffusing capacity of the lung for nitric oxide (DLNO) and carbon monoxide (DLCO) may be used to classify patients with HF, as DLNO and DLCO are lung function measurements that reflect pulmonary gas exchange. Our objectives were to determine 1) if DLNO added to DLCO testing predicts HF better than DLCO alone and 2) whether the binary classification of HF is better when DLNO z-scores are combined with DLCO z-scores than using DLCO z-scores alone. METHODS: This was a retrospective secondary data analysis in 140 New York Heart Association Class II HF patients (ejection fraction

Abstract Background Long-COVID symptoms remain incompletely defined due to a large heterogeneity in the populations studied, case definitions, and settings of care. The aim of this study was to assess, in patients accessing care for Long-COVID, the profile of symptoms reported, the possible clustering of symptoms and cases, the functional status compared to pre-infection, and the impact on working activity. Methods Multicentre cohort study with a collection of both retrospective and prospective data. Demographics, comorbidities, severity and timing of acute COVID, subjective functional status, working activity and presence of 30 different symptoms were collected using a shortened version of the WHO Post COVID-19 Case Report Form. The impact on working activity was assessed in multivariable logistic regression models. Clustering of symptoms was analysed by hierarchical clustering and the clustering of cases by two-step automatic clustering. Results The study evaluated 1297 individuals (51.5% women) from 30 clinical centres. Men and women had different profiles in terms of comorbidities, vaccination status, severity and timing of acute SARS-CoV-2 infection. Fatigue (55.9%) and dyspnea (47.2%) were the most frequent symptoms. Women reported more symptoms (3.6 vs. 3.1, p

Abstract Background Some chromatinopathies may present with common clinical findings (intellectual disability, brain and limb malformation, facial dysmorphism). Furthermore, one of their cardinal shared features is growth dysregulation.We aimed to assess and deepen this resemblance in three specific conditions, namely Wiedemann-Steiner (WDSTS), Kleefstra (KLEFS1) and Coffin-Siris syndrome (CSS1), with a particular focus on possible metabolic roots. Methods Eleven patients were enrolled, three with WDSTS, five with KLEFS1 and three with CSS1, referring to Fondazione IRCCS Ca’ Granda Ospedale Maggiore, Milan, Italy. We performed both a physical examination with detailed anthropometric measurements and an evaluation of the patients’ REE (rest energy expenditure) by indirect calorimetry, comparing the results with age- and sex-matched healthy controls. Results We observed new clinical features and overlap between these conditions suggesting that different disturbances of epigenetic machinery genes can converge on a common effect, leading to overlapping clinical phenotypes. The REE was not distinguishable between the three conditions and healthy controls. Conclusions Epigenetic machinery plays an essential role both in growth regulation and in neurodevelopment; we recommend evaluating skeletal [craniovertebral junction abnormalities (CVJ) polydactyly], otolaryngological [obstructive sleep apnea syndrome (OSAs), recurrent otitis media], dental [tooth agenesis, talon cusps], and central nervous system (CNS) [olfactory bulbs and cerebellum anomalies] features. These features could be included in monitoring guidelines. Further studies are needed to deepen the knowledge about energy metabolism.

Abstract Introduction Multiple sclerosis (MS) is a chronic neurodegenerative disease that leads to impaired cognitive function and accumulation of disability, with significant socioeconomic burden. Serious unmet need in the context of managing MS has given rise to ongoing research efforts, leading to the launch of new drugs planned for the near future, and subsequent concerns about the sustainability of healthcare systems. This study assessed the changes in the Italian MS market and their impact on the expenditures of the Italian National Healthcare Service between 2023 and 2028. Methods A horizon-scanning model was developed to estimate annual expenditure from 2023 to 2028. Annual expenditure for MS was calculated by combining the number of patients treated with each product (clinical inputs) and the yearly costs of therapy (economic inputs). Baseline inputs (2020–2022) were collected from IQVIA® real-world data, while input estimation for the 5-year forecast was integrated with analog analyses and the insights of clinicians and former payers. Results The number of equivalent patients treated in 2028 in Italy was estimated at around 67,000, with an increase of 10% versus 2022. In terms of treatment pattern evolution, first-line treatments are expected to reduce their shares from 47% in 2022 to 27% in 2028, and Bruton tyrosine kinase inhibitors are expected to reach 23% of patient shares. Overall, expenditure for MS is estimated to decrease from €721 million in 2022 to €551 million in 2028, mainly due to losses of exclusivity and renegotiation of drug prices. Conclusion Despite the increase in the number of patients treated for MS and the launch of new molecules that will reach high market penetration, the model confirmed sustainability for the Italian National Healthcare Service.

Background: Acute mediastinitis is rarely caused by haematogenous spread of a remote infection. In this respect, since the only medical therapy is usually unsuccessful, treating acute mediastinitis with no source of infection detected is very challenging and management not standardized. In this case report, we describe non-surgical management experience of acute mediastinitis caused by methicillin-sensitive Staphylococcus aureus. Case presentation: In a 79-year-old man judged not eligible for cardiac surgery, we attempted the infection source control through vacuum-assisted closure therapy, together with antimicrobial therapy. We observed gradual clinical, laboratory and radiologic improvements: reduced swelling and normalization of the white blood cell count and C-reactive protein level were associated with reduction in size of a periaortic abscess. Conclusion: We managed a clinical condition with high mortality risk with chronic antimicrobial therapy alone, a strategy that is rarely considered. With this medical strategy we achieved an optimal response to a clinical picture that does not allow any other approach.

Abstract Background Reviews on Down syndrome do not or only marginally address the issue of kidney and urogenital tract abnormalities, and lower urinary tract dysfunctions. Hence, we performed a meta-analysis of the literature. Methods A literature search was undertaken in the Library of Medicine, Web of Science and Excerpta Medica. The search algorithm combined various keywords: (Down syndrome OR trisomy 21 OR mongolism) AND (kidney OR urinary tract OR bladder) AND (malformation OR dysfunction OR anomaly OR abnormality OR size). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement was used. Results Eight case-control studies were retained for the final analysis. Three studies addressed the prevalence of kidney and urogenital tract abnormalities: an increased pooled relative risk of 5.49 (95%-CI: 1.78–16.93) was observed in Down syndrome. Penile malformations, obstructive malformations (including urethral valves), dilated urinary tract system, and kidney hypodysplasia were especially common. Three reports addressed the prevalence of lower urinary tract dysfunction: an increased pooled relative risk of 2.95 (95%-CI: 1.15–7.56) was observed. Finally, an autoptic study and an ultrasound study disclosed a reduced kidney size in Down syndrome. Conclusions This meta-analysis indicates that abnormalities of the kidney and urogenital tract, lower urinary tract dysfunctions, and a reduced kidney size present with an increased frequency in individuals with Down syndrome.

Abstract Aims Although cardiopulmonary exercise testing (CPET) is the gold standard to assess exercise capacity, simpler tests (i.e., 6‐min walk test, 6MWT) are also commonly used. The aim of this study was to evaluate the relationship between cardiorespiratory parameters during CPET and 6MWT in a large, multicentre, heterogeneous population. Methods We included athletes, healthy subjects, and heart failure (HF) patients of different severity, including left ventricular assist device (LVAD) carriers, who underwent both CPET and 6MWT with oxygen consumption measurement. Results We enrolled 186 subjects (16 athletes, 40 healthy, 115 non‐LVAD HF patients, and 15 LVAD carriers). CPET‐peakV̇O2 was 41.0 [35.0–45.8], 26.2 [23.1–31.0], 12.8 [11.1–15.3], and 15.2 [13.6–15.6] ml/Kg/min in athletes, healthy, HF patients, and LVAD carriers, respectively (P

Background: In the last decade, the kynurenine pathway (KP) has gained attention in the pathogenesis of cognitive impairment in schizophrenia being at the croassroad between neuroinflammation and glutamatergic and cholinergic neurotransmission. However, clinical findings are scarse and conflicting, and the specific contributions of these two systems to the neurobiology of cognitive symptoms are far from being elucidated. Furthermore, little is known about the molecular underpinnings of non-pharmacological interventions for cognitive improvement, including rehabilitation strategies. Methods: The current study examined 72 patients with schizophrenia, divided in two clusters depending on the severity of the cognitive impairment, with the aim to evaluate the impact of inflammatory biomarkers and KP metabolites depending on cognitive functioning. Moreover, we studied their possible link to the cognitive outcome in relation to sessions of cognitive remediation therapy (CRT) and aerobic exercise (AE) in a longitudinal arm of 42 patients. Results: Neuroinflammation appeared to exert a more pronounced influence on cognition in patients exhibiting a higher cognitive functioning, contrasting with the activation of the KP, which had a greater impact on individuals with a lower cognitive profile. Cognitive improvements after the treatments were negatively predicted by levels of TNF-α and positively predicted by the 3-hydroxykynurenine (3−HK)/kynurenine (KYN) ratio, an index of the kynurenine-3-monooxygenase (KMO) enzyme activity. Conclusion: Overall, these findings add novel evidence on the biological underpinnings of cognitive impairment in schizophrenia pointing at a differential role of neuroinflammation and KP metabolites in inducing cognitive deficits depending on the cognitive reserve and predicting outcomes after rehabilitation.

BackgroundA sex-based evaluation of prognosis in heart failure (HF) is lacking.Methods and resultsWe analyzed the Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score registry, which includes HF with reduced ejection fraction (HFrEF) patients. A cross-validation procedure was performed to estimate weights separately for men and women of all MECKI score parameters: left ventricular ejection fraction (LVEF), hemoglobin, kidney function assessed by Modification of Diet in Renal Disease, blood sodium level, ventilation vs. carbon dioxide production slope, and peak oxygen consumption (peakVO2). The primary outcomes were the composite of all-cause mortality, urgent heart transplant, and implant of a left ventricle assist device. The difference in predictive ability between the native and sex recalibrated MECKI (S-MECKI) was calculated using a receiver operating characteristic (ROC) curve at 2 years and a calibration plot. We retrospectively analyzed 7,900 HFrEF patients included in the MECKI score registry (mean age 61 ± 13 years, 6,456 men/1,444 women, mean LVEF 33% ± 10%, mean peakVO2 56.2% ± 17.6% of predicted) with a median follow-up of 4.05 years (range 1.72–7.47). Our results revealed an unadjusted risk of events that was doubled in men compared to women (9.7 vs. 4.1) and a significant difference in weight between the sexes of most of the parameters included in the MECKI score. S-MECKI showed improved risk classification and accuracy (area under the ROC curve: 0.7893 vs. 0.7799, p = 0.02) due to prognostication improvement in the high-risk settings in both sexes (MECKI score >10 in men and >5 in women).ConclusionsS-MECKI, i.e., the recalibrated MECKI according to sex-specific differences, constitutes a further step in the prognostic assessment of patients with severe HFrEF.

Background and AimsPhysical performance is a major contributor of mobility and independence during older life. Despite a progressive decline in musculoskeletal function starts from middle age, several factors acting during the life-course can negatively influence musculoskeletal functional capacities. Lifestyle interventions incorporating nutrition and physical exercise can help maximizing the muscle functional capacities in early life as well as preserving them later in life. Among various dietary compounds, omega-3 polyunsaturated fatty acids (PUFAs) are gaining growing attention for their potential effects on muscle membrane composition and muscle function. Indeed, several pathways are enhanced, such as an attenuation of pro-inflammatory oxidative stress, mitochondrial function, activation of the mammalian target of rapamycin (mTOR) signaling and reduction of insulin resistance.MethodsWe performed a narrative review to explore the existing literature on the relationship between omega-3 PUFAs and physical performance across the life-course.ResultsGrowing evidence from randomized controlled trials (RCTs) suggests beneficial effects of omega-3 PUFAs on muscle function, including physical performance parameters in mid to later life. On the other hand, despite a direct association in early life is not available in literature, some mechanisms by which omega-3 PUFAs may contribute to improved adult physical performance could be hypothesized.ConclusionOmega-3 PUFAs are gaining growing attention for their positive effect on muscle function parameters. The integration of physical function measures in future studies would be of great interest to explore whether omega-3 PUFAs could contribute to improved muscle function, starting from early life and extending throughout the lifespan. However, larger and high-quality RCTs are needed to fully elucidate the beneficial effects of omega-3 PUFAs supplementation on muscle mass and function.

Background: Exercise is recommended for patients with chronic heart failure (CHF) and its intensity is usually set as a percentage of the maximal work rate (MWR) during cardiopulmonary exercise testing (CPX) or a symptom-limited incremental test (SLIT). As these tests are not always available in cardiac rehabilitation due to logistic/cost constraints, we aimed to develop a predictive model to estimate MWR at CPX (estMWR@CPX) in CHF patients using anthropometric and clinical measures and the 6-min walk test (6 MWT), the most widely used exercise field test. Methods: This is a multicentre cross-sectional retrospective study in a cardiac rehabilitation setting. Six hundred patients with HF in New York Heart Association (NYHA) functional class I-III underwent both CPX and 6 MWT and, through multivariable linear regression analysis, we defined several predictive models to define estMWR@CPX. Results: The best model included 6 MWT, sex, age, weight, NYHA class, left ventricular ejection fraction (LVEF), smoking status and chronic obstructive pulmonary disease COPD (adjusted R2 = 0.55; 95% LoA −39 to 33 W). When LVEF was excluded as a predictor, the resulting model performed only slightly worse (adjusted R2 = 0.54; 95% LoA −42 to 34 W). Only in 34% of cases was the percentage difference between estMWR@CPX and real MWR@CPX

Abstract Background Post COVID-19 syndrome is characterized by several cardiorespiratory symptoms but the origin of patients’ reported symptomatology is still unclear. Methods Consecutive post COVID-19 patients were included. Patients underwent full clinical evaluation, symptoms dedicated questionnaires, blood tests, echocardiography, thoracic computer tomography (CT), spirometry including alveolar capillary membrane diffusion (DM) and capillary volume (Vcap) assessment by combined carbon dioxide and nitric oxide lung diffusion (DLCO/DLNO) and cardiopulmonary exercise test. We measured surfactant derive protein B (immature form) as blood marker of alveolar cell function. Results We evaluated 204 consecutive post COVID-19 patients (56.5 ± 14.5 years, 89 females) 171 ± 85 days after the end of acute COVID-19 infection. We measured: forced expiratory volume (FEV1) 99 ± 17%pred, FVC 99 ± 17%pred, DLCO 82 ± 19%, DM 47.6 ± 14.8 mL/min/mmHg, Vcap 59 ± 17 mL, residual parenchymal damage at CT 7.2 ± 3.2% of lung tissue, peakVO2 84 ± 18%pred, VE/VCO2 slope 112 [102–123]%pred. Major reported symptoms were: dyspnea 45% of cases, tiredness 60% and fatigability 77%. Low FEV1, Vcap and high VE/VCO2 slope were associated with persistence of dyspnea. Tiredness was associated with high VE/VCO2 slope and low PeakVO2 and FEV1 while fatigability with high VE/VCO2 slope. SPB was fivefold higher in post COVID-19 than in normal subjects, but not associated to any of the referred symptoms. SPB was negatively associated to Vcap. Conclusions In patients with post COVID-19, cardiorespiratory symptoms are linked to VE/VCO2 slope. In these patients the alveolar cells are dysregulated as shown by the very high SPB. The Vcap is low likely due to post COVID-19 pulmonary endothelial/vasculature damage but DLCO is only minimally impaired being DM preserved.

Abstract Background Japanese Kawasaki disease (KD) risk scores cannot be adopted in non-Japanese patients. In North American populations a baseline coronary artery Z-score > 2 and the Son score are associated with coronary artery aneurysms (CAAs) at 4 and 8 weeks from disease onset. In European populations, the Kawanet and Kawanet-echo scores are associated with intravenous immunoglobulin resistance. This study aims to evaluate the association between KD risk scores and baseline coronary artery Z-scores with CAAs at one, two, and six months in a European population. Methods Historical cohort study of all the children diagnosed with KD in a tertiary care hospital in Milan, Italy, between 1st January 2015 and 31st May 2021. Univariate and multivariate (adjusting for age and corticosteroid therapy) logistic regression analyses were used to study the association between the risk scores, a baseline Z-score ≥ 2 and ≥ 2.5 with CAAs. Results Eighty-nine patients were diagnosed with KD at our Centre, and 12 were excluded based on the exclusion criteria. We included 77 patients, 51 (66%) males, and 26 (34%) females, with a median age at presentation of 27 months (IQR 13–46). A baseline Z-score ≥ 2 was correlated with CAAs at one and two-month follow-ups (odds ratio (OR) 10, 95% confidence interval (CI) 2–72, and OR 18, CI 3-357) but not at six-month follow-up. The Son score showed an association with one and two-month follow-up CAAs (OR 3, CI 1.3-7, and OR 3, CI 1.3-8) but not with a six-month follow-up. Conclusions Patients with a baseline Z-score ≥ 2 are at higher risk for CAAs in the long term. The Son score should be tested in larger European samples. Further studies should keep the observational periods longer than 8 weeks from KD onset.

Abstract Background The European Union (EU) approved the placement on European market of insect-based novel foods. Those foods were defined safe for the consumption for all European population, including children. Main body The nutrition committee of the Italian society of Paediatric Hepatology and Nutrition (SIGENP) performed literature research to understand benefits and risk of those use of those NF for Italian children. A special attention was reserved to the European Food Safety Agency (EFSA) reports upon which those novel insect-based were approved. Conclusions Based on the current knowledge, despite a possible ecological advantage, the group of expert suggests additional researches before pronouncing on a possible use for children diet, because of insufficient evidence on nutritional benefits and possible food allergies.

Background. In high-income countries, shopping for non-prescription multivitamin–multimineral supplements has tremendously increased. Objective and Methods. The purpose of this labeling analysis is to inform on the daily elemental iron (with or without vitamin C) supply provided by multivitamin–multimineral supplements sold online by Amazon in Western and Southern Europe (amazon.es®, amazon.de®, amazon.it®, and amazon.fr®). Results. We identified 298 iron-containing multivitamin–multimineral preparations sold by Amazon marketplaces: 153 preparations sourced from amazon.de®, 68 from amazon.fr®, 54 from amazon.it®, and 23 from amazon.es®. The daily iron dose provided by these preparations was 14 [5–14] mg (median and interquartile range), with no differences among the marketplaces. Approximately 90% (n = 265) of the preparations contained ferrous iron. Moreover, 85% (n = 253) of the preparations were fortified with vitamin C in a dose of 80 [40–100] mg daily. Conclusions. The median supply of iron (about 14 mg) and vitamin C (80 mg) in iron-containing multivitamin–multimineral preparations offered on Amazon platforms in Western and Southern Europe falls below that currently recommended for iron deficiency in review articles, namely 100 mg of iron and 500 mg of vitamin C per day. The iron supply of iron-containing multivitamin–multimineral preparations falls also below the dose of 30–60 mg advocated to prevent iron deficiency in menstruating women.

Febrile seizures (FS) can be frightening for parents, even though they are usually harmless. Various questionnaires have been used to assess parental reactions and awareness about FS, revealing insufficient knowledge. Studies have shown that educational interventions significantly reduce parental concerns, improve knowledge, and promote better first-aid measures. Providing clear information and emotional support to parents is important to reduce their concerns and improve FS management. Healthcare providers should give comprehensive information about FS, including the risk of recurrence, and provide clear instructions on their management. The economic impact of FS includes direct and indirect costs. Studies have shown a decrease of hospitalizations and associated costs due to improved clinical adherence to guidelines, which also reduces the inappropriate use of healthcare resources. This systematic review provides a comprehensive overview of the existing literature on parental anxiety and education about FS, as well as their economic impact, aiming at identifying areas for improvement in the management of FS and providing valuable insights for healthcare providers and policymakers to better address the non-clinical burden of this condition.

Juvenile Systemic Connective Tissue Diseases (JSCTD) are a heterogeneous group of chronic autoimmune diseases, associated with dyslipidemia and increased cardiovascular risk are related. Studies from the last 10 years, from 2013 to 2022, on lipid profiles in JSCTD were collected. Different studies on lipid profiles in children affected by JSCTD were selected, because the aim is to analyze the cardiovascular risk and the possibility of atherosclerosis in these patients in whom, sometimes, corticosteroid therapies and immunosuppressants increase the state of dyslipidemia. Several studies have shown that autoimmune diseases with an inflammatory substrate also share abnormalities in lipid profile and increased cardiovascular risk. Specifically, associations have been found between Juvenile Systemic Connective Tissue Diseases and elevated triglycerides, TC-C (Total Cholesterol), LDL-C (Low-Density Lipoprotein), low HDL-C (High-Density Lipoprotein), and increased risk of developing diseases such as myocardial infarction, peripheral vascular disease, pulmonary and arterial hypertension, and atrial fibrillation. Supplementation with alpha-linolenic acid (ALA) on the other hand has also been analyzed with positive results in reducing inflammatory parameters, such as IL-6 (Interleukin-6), CRP (C-reactive protein), and fasting glucose, in subjects with dyslipidemia. These observations suggest that supplementation with ALA, an omega-3 precursor, may positively modulate both the inflammatory status and dyslipidemic conditions in patients with autoimmune disorders.

IntroductionWe assessed clinical and laboratory parameters associated with early recurrence of febrile seizure in patients presenting at the Emergency Department with a first episode.MethodsCase series of patients admitted to the emergency department with the first episode of febrile seizure for ten consecutive years. Exclusion criteria were focal features and prolonged duration (>15 min).ResultsWe included 693 patients, 284 (41%) female. Median age of 20 (IQR 15–27) months. Fifty-two (8%) patients had a recurrence within 24 h. At univariate analysis, patients with recurrent seizures had higher use of antipyretics (88% vs. 74%, P = 0.03, OR 2.6, 95% CI: 1.1–7.7), higher median maximal body temperature (39.3 °C, IQR 38.9–39.9, vs. 38.9, IQR 38.4–39.3, P

Feeding/behavior problems are highly prevalent in autistic children. This study aimed to explore the interplay between autistic features, sensory processing patterns, emotional/behavioral difficulties, and feeding problems in children with a clinical diagnosis of autism spectrum disorder. Ninety-nine children aged 1.5-5 years were assessed using the Children's Eating Behavior Inventory (CEBI), the Child Behavior Checklist, the Revised Sensory Profile--Second Edition (SP-2), and the Food Frequency Questionnaire. The sample was divided into two subgroups based on the presence of feeding behavior problems as rated by parents on the CEBI. Children with feeding problems showed more severe internalizing symptoms and were more reactive to sensory stimuli than children without feeding problems. We also found a significant relationship between higher levels of autistic features and greater feeding behavior problems. A mediation analysis model indicated that this relationship was mediated by sensory processing, as reflected by SP-2 quadrants scores. Although preliminary, these findings suggest that children with higher levels of autistic features could be at greater risk of developing feeding behavior problems only if they also have a higher sensory sensitivity to environmental stimuli.

Abstract Background and objective N-terminal pro-B-type natriuretic peptide (NT-proBNP) and soluble interleukin 1 receptor-like 1 ST2 (sST2) are biomarkers used to grade heart failure with reduced ejection fraction (HFrEF) severity. Both are potential targets of HFrEF treatment, but the first is associated with the patient’s hemodynamic status, while the second is more indicative of the inflammatory status and of myocardial fibrosis. The aim of this study was to assess the kinetics of these biomarkers after treatment with sacubitril/valsartan in HFrEF. Methods We analyzed blood samples of patients with HFrEF at baseline (before sacubitril/valsartan treatment), after 1, 2, and 3 months (respectively, after a month taking the 24/26 – 49/51 – 97/103 mg twice daily, or b.i.d., doses), and 6 months after the maximum-tolerated dose was reached (end study). Results We obtained samples from 72 patients with HFrEF (age 64.0 ± 10.5 years, 83% males). NT-proBNP and sST2 values progressively and significantly reduced to 37% and 16%, respectively, with a greater reduction for NT-proBNP (p < 0.001). Specifically, NT-proBNP reduced from 1144 [593–2586] pg/mL to 743 [358–1524] pg/mL and sST2 from 27.3 [20.5–35.0] ng/mL to 23.1 [15.9–30.7] ng/mL, p for trend < 0.001 in both cases. The reduction of the two biomarkers over time occurred with statistically significant different kinetics: deferred for sST2 and faster for NT-proBNP. No significant changes in renal function and potassium levels were recorded. Conclusion These findings suggest that, in patients with HF, sacubitril/valsartan effects on the cardiovascular system share a double pathway: a first, hemodynamic, faster pathway and a second, non-hemodynamic anti-fibrotic, delayed one. Both likely contribute to the sacubitril/valsartan benefits in HFrEF.