Pulmonary artery pressure monitoring in chronic heart failure: effects across clinically relevant subgroups in the MONITOR-HF trial.

BACKGROUND AND AIMS: In patients with chronic heart failure (HF), the MONITOR-HF trial demonstrated the efficacy of pulmonary artery (PA)-guided HF therapy over standard of care in improving quality of life and reducing HF hospitalizations and mean PA pressure. This study aimed to evaluate the consistency of these benefits in relation to clinically relevant subgroups. METHODS: The effect of PA-guided HF therapy was evaluated in the MONITOR-HF trial among predefined subgroups based on age, sex, atrial fibrillation, diabetes mellitus, left ventricular ejection fraction, HF aetiology, cardiac resynchronisation therapy, and implantable cardioverter defibrillator. Outcome measures were based upon significance in the main trial and included quality of life, clinical, and PA pressure endpoints, and were assessed for each subgroup. Differential effects in relation to the subgroups were assessed with interaction terms. Both unadjusted and multiple testing adjusted interaction terms were presented. RESULTS: The effects of PA monitoring on quality of life, clinical events, and PA pressure were consistent in the predefined subgroups, without any clinically relevant heterogeneity within or across all endpoint categories (all adjusted interaction P-values were nonsignificant). In the unadjusted analysis of the primary endpoint quality-of-life change, weak trends towards a less pronounced effect in older patients (Pinteraction = 0.03; adjusted Pinteraction = 0.33) and diabetics (Pinteraction = 0.01; adjusted Pinteraction = 0.06) were observed. However, these interaction effects did not persist after adjusting for multiple testing. CONCLUSIONS: This subgroup analysis confirmed the consistent benefits of PA-guided HF therapy observed in the MONITOR-HF trial across clinically relevant subgroups, highlighting its efficacy in improving quality of life, clinical, and PA pressure endpoints in chronic HF patients.

Longitudinal Changes in Circulating Ketone Body Levels in Patients With Acute Heart Failure: A Post Hoc Analysis of the EMPA-Response-AHF Trial.

BACKGROUND: Ketone bodies are endogenous fuels produced by the liver under conditions of metabolic or neurohormonal stress. Circulating ketone bodies are increased in patients with chronic heart failure (HF), yet little is known about the effect of acute HF on ketosis. We tested the hypothesis that ketogenesis is increased in patients with acute decompensated HF. METHODS AND RESULTS: This was a post hoc analysis of 79 patients with acute HF included in the EMPA-RESPONSE-AHF trial, which compared sodium-dependent glucose-cotransporter protein 2 inhibitor treatment with empagliflozin for 30 days with placebo in patients with acute HF [NCT03200860]. Plasma concentrations of ketone bodies acetone, ß-hydroxybutyrate, and acetoacetate were measured at baseline and 5 different timepoints. Changes in ketone bodies over time were monitored using repeated measures analysis of variance. In the total cohort, median total ketone body concentration was 251 µmol/L (interquartile range, 178-377 µmol/L) at baseline, which gradually decreased to 202 µmol/L (interquartile range, 156-240 µmol/L) at day 30 (P = .041). Acetone decreased from 60 µmol/L (interquartile range, 34-94 µmol/L) at baseline to 30 µmol/L (interquartile range, 21-42 µmol/L) ( P < .001), whereas ß-hydroxybutyrate and acetoacetate remained stable over time. Higher acetone concentrations were correlated with higher N-terminal pro brain natriuretic peptide levels (r = 0.234; P = .039). Circulating ketone bodies did not differ between patients treated with empagliflozin or placebo throughout the study period. A higher acetone concentration at baseline was univariately associated with a greater risk of the composite end point, including in-hospital worsening HF, HF rehospitalizations, and all-cause mortality after 30 days. However, after adjustment for age and sex, acetone did not remain an independent predictor for the combined end point. CONCLUSIONS: Circulating ketone body concentrations, and acetone in particular, were significantly higher during an episode of acute decompensated HF compared with after stabilization. Treatment with empagliflozin did not affect ketone body concentrations in patients with acute HF.

Search for Λ[over ¯]-Λ Baryon-Number-Violating Oscillations in the Decay J/ψ→pK

We report on the first search for Λ[over ¯]-Λ oscillations in the decay J/ψ→pK^{-}Λ[over ¯]+c.c. by analyzing 1.31×10^{9} J/ψ events accumulated with the BESIII detector at the BEPCII collider. The J/ψ events are produced using e^{+}e^{-} collisions at a center of mass energy sqrt[s]=3.097 GeV. No evidence for hyperon oscillations is observed. The upper limit for the oscillation rate of Λ[over ¯] to Λ hyperons is determined to be P(Λ)=[B(J/ψ→pK^{-}Λ+c.c.)/B(J/ψ→pK^{-}Λ[over ¯]+c.c.)]<4.4×10^{-6} corresponding to an oscillation parameter δm_{ΛΛ[over ¯]} of less than 3.8×10^{-18} GeV at the 90% confidence level.

Observation of the Singly Cabibbo Suppressed Decay Λ_{c}

The singly Cabibbo-suppressed decay Λ_{c}^{+}→nπ^{+} is observed for the first time with a statistical significance of 7.3σ by using 3.9 fb^{-1} of e^{+}e^{-} collision data collected at center-of-mass energies between 4.612 and 4.699 GeV with the BESIII detector at BEPCII. The branching fraction of Λ_{c}^{+}→nπ^{+} is measured to be (6.6±1.2_{stat}±0.4_{syst})×10^{-4}. By taking the upper limit of branching fractions of Λ_{c}^{+}→pπ^{0} from the Belle experiment, the ratio of branching fractions between Λ_{c}^{+}→nπ^{+} and Λ_{c}^{+}→pπ^{0} is calculated to be larger than 7.2 at the 90% confidence level, which disagrees with most predictions of the available phenomenological models. In addition, the branching fractions of the Cabibbo-favored decays Λ_{c}^{+}→Λπ^{+} and Λ_{c}^{+}→Σ^{0}π^{+} are measured to be (1.31±0.08_{stat}±0.05_{syst})×10^{-2} and (1.22±0.08_{stat}±0.07_{syst})×10^{-2}, respectively, which are consistent with previous results.

Observation of J/ψ Electromagnetic Dalitz Decays to X(1835), X(2120), and X(2370).

Using a sample of about 10^{10} J/ψ events collected at a center-of-mass energy sqrt[s]=3.097 GeV with the BESIII detector, the electromagnetic Dalitz decays J/ψ→e^{+}e^{-}π^{+}π^{-}η^{'}, with η^{'}→γπ^{+}π^{-} and η^{'}→π^{+}π^{-}η, have been studied. The decay J/ψ→e^{+}e^{-}X(1835) is observed with a significance of 15σ, and also an e^{+}e^{-} invariant-mass dependent transition form factor of J/ψ→e^{+}e^{-}X(1835) is presented for the first time. The intermediate states X(2120) and X(2370) are also observed in the π^{+}π^{-}η^{'} invariant-mass spectrum with significances of 5.3σ and 7.3σ. The corresponding product branching fractions for J/ψ→e^{+}e^{-}X, X→π^{+}π^{-}η^{'} [X=X(1835), X(2120), and X(2370)] are reported.

Measurement of the Cross Section for e

Based on electron-positron collision data collected with the BESIII detector operating at the Beijing Electron-Positron Collider II storage rings, the value of R≡σ(e^{+}e^{-}→hadrons)/σ(e^{+}e^{-}→µ^{+}µ^{-}) is measured at 14 center-of-mass energies from 2.2324 to 3.6710 GeV. The resulting uncertainties are less than 3.0% and are dominated by systematic uncertainties.

First Measurement of Polarizations in the Decay D

Using a data sample corresponding to an integrated luminosity of 2.93 fb^{-1} collected at a center-of-mass energy sqrt[s]=3.773 GeV by the BESIII detector, the decay D^{0}→ωϕ is observed for the first time. The branching fraction is measured to be (6.48±0.96±0.40)×10^{-4} with a significance of 6.3σ, where the first and second uncertainties are statistical and systematic, respectively. An angular analysis reveals that the ϕ and ω mesons from the D^{0}→ωϕ decay are transversely polarized. The 95% confidence level upper limit on longitudinal polarization fraction is set to be less than 0.24, which is inconsistent with current theoretical expectations and challenges our understanding of the underlying dynamics in charm meson decays.

Diagnostic role of echocardiography for patients with heart failure symptoms and preserved left ventricular ejection fraction.

The syndrome heart failure with preserved ejection fraction (HFpEF) represents patients with different comorbidities and specific etiologies, but with a key and common alteration: an elevation in left ventricular (LV) filling pressure or pulmonary capillary wedge pressure (PCWP). Expert consensuses, society guidelines, and diagnostic scores have been stated to diagnose HFpEF syndrome based mainly on the determination of elevated LV filling pressure or PCWP by transthoracic echocardiography (TTE). Echocardiographic parameters such as early (E) and late diastolic mitral inflow velocity (mitral E/A ratio), septal and lateral mitral annular early diastolic velocity (E'), ratio of the early diastolic mitral inflow and annular velocity (E/E'-ratio), maximal left atrial volume index (LAVImax), and tricuspid regurgitation peak velocity (VTR) constitute the pivotal parameters for determining elevated LV filling pressure or PCWP in patients with suspected HFpEF symptoms. Notwithstanding this, taking into consideration the heterogeneity of patients with HFpEF symptoms, the term "HFpEF" should be considered as a syndrome rather than an entity since HFpEF results from different pathological entities that should and can be characterized by echocardiography and multimodality imaging. Comprehensive TTE might help diagnose specific diseases and etiologies by characterization of specific cardiac phenotypes.

Immune checkpoint inhibitor-associated myocarditis : Case reports and a review of the literature.

Immune checkpoint inhibitors (ICIs) are increasingly recognised to effectuate long-lasting therapeutic responses in solid tumours. However, ICI therapy can also result in various immune-related adverse events, such as ICI-associated myocarditis, a rare but serious complication. The clinical spectrum is wide and includes asymptomatic patients and patients with fulminant heart failure, making it challenging to diagnose this condition. Furthermore, the optimal diagnostic algorithm and treatment of ICI-associated myocarditis is unknown. In this review, we describe two cases on both ends of the spectrum and discuss the challenges in recognising, diagnosing and treating ICI-associated myocarditis.

Rationale and design of the PHOspholamban RElated CArdiomyopathy intervention STudy (i-PHORECAST).

BACKGROUND: The p.Arg14del (c.40_42delAGA) phospholamban (PLN) pathogenic variant is a founder mutation that causes dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM). Carriers are at increased risk of malignant ventricular arrhythmias and heart failure, which has been ascribed to cardiac fibrosis. Importantly, cardiac fibrosis appears to be an early feature of the disease, occurring in many presymptomatic carriers before the onset of overt disease. As with most monogenic cardiomyopathies, no evidence-based treatment is available for presymptomatic carriers. AIMS: The PHOspholamban RElated CArdiomyopathy intervention STudy (iPHORECAST) is designed to demonstrate that pre-emptive treatment of presymptomatic PLN p.Arg14del carriers using eplerenone, a mineralocorticoid receptor antagonist with established antifibrotic effects, can reduce disease progression and postpone the onset of overt disease. METHODS: iPHORECAST has a multicentre, prospective, randomised, open-label, blinded endpoint (PROBE) design. Presymptomatic PLN p.Arg14del carriers are randomised to receive either 50 mg eplerenone once daily or no treatment. The primary endpoint of the study is a multiparametric assessment of disease progression including cardiac magnetic resonance parameters (left and right ventricular volumes, systolic function and fibrosis), electrocardiographic parameters (QRS voltage, ventricular ectopy), signs and/or symptoms related to DCM and ACM, and cardiovascular death. The follow-up duration is set at 3 years. BASELINE RESULTS: A total of 84 presymptomatic PLN p.Arg14del carriers (n = 42 per group) were included. By design, at baseline, all participants were in New York Heart Association (NHYA) class I and had a left ventricular ejection fraction > 45% and < 2500 ventricular premature contractions during 24-hour Holter monitoring. There were no statistically significant differences between the two groups in any of the baseline characteristics. The study is currently well underway, with the last participants expected to finish in 2021. CONCLUSION: iPHORECAST is a multicentre, prospective randomised controlled trial designed to address whether pre-emptive treatment of PLN p.Arg14del carriers with eplerenone can prevent or delay the onset of cardiomyopathy. iPHORECAST has been registered in the clinicaltrials.gov-register (number: NCT01857856).

Measurement of the Absolute Branching Fraction of D_{s}

Using a dataset of 6.32 fb^{-1} of e^{+}e^{-} annihilation data collected with the BESIII detector at center-of-mass energies between 4178 and 4226 MeV, we have measured the absolute branching fraction of the leptonic decay D_{s}^{+}→τ^{+}ν_{τ} via τ^{+}→e^{+}ν_{e}ν[over ¯]_{τ}, and find B_{D_{s}^{+}→τ^{+}ν_{τ}}=(5.27±0.10±0.12)×10^{-2}, where the first uncertainty is statistical and the second is systematic. The precision is improved by a factor of 2 compared to the previous best measurement. Combining with f_{D_{s}^{+}} from lattice quantum chromodynamics calculations or the |V_{cs}| from the CKMfitter group, we extract |V_{cs}|=0.978±0.009±0.012 and f_{D_{s}^{+}}=(251.1±2.4±3.0) MeV, respectively. Combining our result with the world averages of B_{D_{s}^{+}→τ^{+}ν_{τ}} and B_{D_{s}^{+}→µ^{+}ν_{µ}}, we obtain the ratio of the branching fractions B_{D_{s}^{+}→τ^{+}ν_{τ}}/B_{D_{s}^{+}→µ^{+}ν_{µ}}=9.72±0.37, which is consistent with the standard model prediction of lepton flavor universality.

Model-Independent Determination of the Spin of the Ω

We present an analysis of the process ψ(3686)→Ω^{-}Ω[over ¯]^{+} (Ω^{-}→K^{-}Λ, Ω[over ¯]^{+}→K^{+}Λ[over ¯], Λ→pπ^{-}, Λ[over ¯]→p[over ¯]π^{+}) based on a dataset of 448×10^{6} ψ(3686) decays collected with the BESIII detector at the BEPCII electron-positron collider. The helicity amplitudes for the process ψ(3686)→Ω^{-}Ω[over ¯]^{+} and the decay parameters of the subsequent decay Ω^{-}→K^{-}Λ (Ω[over ¯]^{+}→K^{+}Λ[over ¯]) are measured for the first time by a fit to the angular distribution of the complete decay chain, and the spin of the Ω^{-} is determined to be 3/2 for the first time since its discovery more than 50 years ago.

First Measurement of the Absolute Branching Fraction of Λ→pµ

The absolute branching fraction of Λ→pµ^{-}ν[over ¯]_{µ} is reported for the first time based on an e^{+}e^{-} annihilation sample of 10×10^{9} J/ψ events collected with the BESIII detector at sqrt[s]=3.097 GeV. The branching fraction is determined to be B(Λ→pµ^{-}ν[over ¯]_{µ})=[1.48±0.21(stat)±0.08(syst)]×10^{-4}, which is improved by about 30% in precision over the previous indirect measurements. Combining this result with the world average of B(Λ→pe^{-}ν[over ¯]_{e}), we obtain the ratio {[Γ(Λ→pµ^{-}ν[over ¯]_{µ})]/[Γ(Λ→pe^{-}ν[over ¯]_{e})]} to be 0.178±0.028, which agrees with the standard model prediction assuming lepton flavor universality. The asymmetry of the branching fractions of Λ→pµ^{-}ν[over ¯]_{µ} and Λ[over ¯]→p[over ¯]µ^{+}ν_{µ} is also determined, and no evidence for CP violation is found.

Observation of D

Using 2.93 fb^{-1} of e^{+}e^{-} collision data taken with the BESIII detector at a center-of-mass energy of 3.773 GeV, the observation of the D^{0}→K_{1}(1270)^{-}e^{+}ν_{e} semileptonic decay is presented. The statistical significance of the decay D^{0}→K_{1}(1270)^{-}e^{+}ν_{e} is greater than 10σ. The branching fraction of D^{0}→K_{1}(1270)^{-}e^{+}ν_{e} is measured to be (1.09±0.13_{-0.16}^{+0.09}±0.12)×10^{-3}. Here, the first uncertainty is statistical, the second is systematic, and the third originates from the assumed branching fraction of K_{1}(1270)^{-}→K^{-}π^{+}π^{-}. The fraction of longitudinal polarization in D^{0}→K_{1}(1270)^{-}e^{+}ν_{e} is determined for the first time to be 0.50±0.19_{stat}±0.08_{syst}.

Direct Measurement of the Branching Fractions B(ψ(3686)→J/ψX) and B(ψ(3770)→J/ψX), and Observation of the State R(3760) in e

We report a measurement of the observed cross sections of e^{+}e^{-}→J/ψX based on 3.21 fb^{-1} of data accumulated at energies from 3.645 to 3.891 GeV with the BESIII detector operated at the BEPCII collider. In analysis of the cross sections, we measured the decay branching fractions of B(ψ(3686)→J/ψX)=(64.4±0.6±1.6)% and B(ψ(3770)→J/ψX)=(0.5±0.2±0.1)% for the first time. The energy-dependent line shape of these cross sections cannot be well described by two Breit-Wigner (BW) amplitudes of the expected decays ψ(3686)→J/ψX and ψ(3770)→J/ψX. Instead, it can be better described with one more BW amplitude of the decay R(3760)→J/ψX. Under this assumption, we extracted the R(3760) mass M_{R(3760)}=3766.2±3.8±0.4 MeV/c^{2} , total width Γ_{R(3760)}^{tot}=22.2±5.9±1.4 MeV, and product of leptonic width and decay branching fraction Γ_{R(3760)}^{ee}B[R(3760)→J/ψX]=(79.4±85.5±11.7) eV. The significance of the R(3760) is 5.3σ. The first uncertainties of these measured quantities are from fits to the cross sections and second systematic.

Observation of a Near-Threshold Structure in the K

We report a study of the processes of e^{+}e^{-}→K^{+}D_{s}^{-}D^{*0} and K^{+}D_{s}^{*-}D^{0} based on e^{+}e^{-} annihilation samples collected with the BESIII detector operating at BEPCII at five center-of-mass energies ranging from 4.628 to 4.698 GeV with a total integrated luminosity of 3.7 fb^{-1}. An excess of events over the known contributions of the conventional charmed mesons is observed near the D_{s}^{-}D^{*0} and D_{s}^{*-}D^{0} mass thresholds in the K^{+} recoil-mass spectrum for events collected at sqrt[s]=4.681 GeV. The structure matches a mass-dependent-width Breit-Wigner line shape, whose pole mass and width are determined as (3982.5_{-2.6}^{+1.8}±2.1) MeV/c^{2} and (12.8_{-4.4}^{+5.3}±3.0) MeV, respectively. The first uncertainties are statistical and the second are systematic. The significance of the resonance hypothesis is estimated to be 5.3 σ over the contributions only from the conventional charmed mesons. This is the first candidate for a charged hidden-charm tetraquark with strangeness, decaying into D_{s}^{-}D^{*0} and D_{s}^{*-}D^{0}. However, the properties of the excess need further exploration with more statistics.

BIO FOr CARE: biomarkers of hypertrophic cardiomyopathy development and progression in carriers of Dutch founder truncating MYBPC3 variants-design and status.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most prevalent monogenic heart disease, commonly caused by truncating variants in the MYBPC3 gene. HCM is an important cause of sudden cardiac death; however, overall prognosis is good and penetrance in genotype-positive individuals is incomplete. The underlying mechanisms are poorly understood and risk stratification remains limited. AIM: To create a nationwide cohort of carriers of truncating MYBPC3 variants for identification of predictive biomarkers for HCM development and progression. METHODS: In the multicentre, observational BIO FOr CARe (Identification of BIOmarkers of hypertrophic cardiomyopathy development and progression in Dutch MYBPC3 FOunder variant CARriers) cohort, carriers of the c.2373dupG, c.2827C > T, c.2864_2865delCT and c.3776delA MYBPC3 variants are included and prospectively undergo longitudinal blood collection. Clinical data are collected from first presentation onwards. The primary outcome constitutes a composite endpoint of HCM progression (maximum wall thickness ≥ 20 mm, septal reduction therapy, heart failure occurrence, sustained ventricular arrhythmia and sudden cardiac death). RESULTS: So far, 250 subjects (median age 54.9 years (interquartile range 43.3, 66.6), 54.8% male) have been included. HCM was diagnosed in 169 subjects and dilated cardiomyopathy in 4. The primary outcome was met in 115 subjects. Blood samples were collected from 131 subjects. CONCLUSION: BIO FOr CARe is a genetically homogeneous, phenotypically heterogeneous cohort incorporating a clinical data registry and longitudinal blood collection. This provides a unique opportunity to study biomarkers for HCM development and prognosis. The established infrastructure can be extended to study other genetic variants. Other centres are invited to join our consortium.

Improvement in left ventricular ejection fraction after pharmacological up-titration in new-onset heart failure with reduced ejection fraction.

OBJECTIVE: Recent studies have reported suboptimal up-titration of heart failure (HF) therapies in patients with heart failure and a reduced ejection fraction (HFrEF). Here, we report on the achieved doses after nurse-led up-titration, reasons for not achieving the target dose, subsequent changes in left ventricular ejection fraction (LVEF), and mortality. METHODS: From 2012 to 2018, 378 HFrEF patients with a recent (< 3 months) diagnosis of HF were referred to a specialised HF-nurse led clinic for protocolised up-titration of guideline-directed medical therapy (GDMT). The achieved doses of GDMT at 9 months were recorded, as well as reasons for not achieving the optimal dose in all patients. Echocardiography was performed at baseline and after up-titration in 278 patients. RESULTS: Of 345 HFrEF patients with a follow-up visit after 9 months, 69% reached ≥ 50% of the recommended dose of renin-angiotensin-system (RAS) inhibitors, 73% reached ≥ 50% of the recommended dose of beta-blockers and 77% reached ≥ 50% of the recommended dose of mineralocorticoid receptor antagonists. The main reasons for not reaching the target dose were hypotension (RAS inhibitors and beta-blockers), bradycardia (beta-blockers) and renal dysfunction (RAS inhibitors). During a median follow-up of 9 months, mean LVEF increased from 27.6% at baseline to 38.8% at follow-up. Each 5% increase in LVEF was associated with an adjusted hazard ratio of 0.84 (0.75-0.94, p = 0.002) for mortality and 0.85 (0.78-0.94, p = 0.001) for the combined endpoint of mortality and/or HF hospitalisation after a mean follow-up of 3.3 years. CONCLUSIONS: This study shows that protocolised up-titration in a nurse-led HF clinic leads to high doses of GDMT and improvement of LVEF in patients with new-onset HFrEF.

Safety and patient-reported outcomes of atezolizumab, carboplatin, and etoposide in extensive-stage small-cell lung cancer (IMpower133): a randomized phase I/III trial.

BACKGROUND: The addition of atezolizumab to carboplatin and etoposide (CP/ET) significantly improved progression-free and overall survival for patients with extensive-stage small-cell lung cancer (ES-SCLC) in the IMpower133 study (NCT02763579). We have evaluated adverse events (AEs) and patient-reported outcomes in IMpower133 to assess the benefit-risk profile of this regimen. PATIENTS AND METHODS: Patients received four 21-day cycles of CP/ET plus intravenous atezolizumab 1200 mg or placebo (induction phase), followed by atezolizumab or placebo (maintenance phase) until progression or loss of benefit. AEs were assessed and patient-reported outcomes were evaluated every 3 weeks during treatment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (QLQ-C30) and QLQ-LC13. RESULTS: Overall, 394 patients were assessable for safety in the induction phase and 318 in the maintenance phase. The frequency of AEs, grade 3-4 AEs, and serious AEs was similar between arms in both phases. Immune-related AEs were more frequent in the atezolizumab arm during both induction (28% versus 17%; leading to atezolizumab/placebo interruption 9% versus 5%, leading to withdrawal 4% versus 0%) and maintenance (26% versus 15%; leading to atezolizumab/placebo interruption, 3% versus 2%, leading to withdrawal 1% versus 1%), most commonly rash (induction 11% versus 9%, maintenance 14% versus 4%), and hypothyroidism (induction 4.0% versus 0%, maintenance 10% versus 1%). Changes in patient-reported treatment-related symptoms commonly associated with quality of life impairment were generally similar during induction and most of the maintenance phase. Patient-reported function and health-related quality of life (HRQoL) improved in both arms after initiating treatment, with more pronounced and persistent HRQoL improvements in the atezolizumab arm. CONCLUSIONS: In patients with ES-SCLC, atezolizumab plus CP/ET has a comparable safety profile to placebo plus CP/ET, and the addition of atezolizumab did not adversely impact patient-reported HRQoL. These data demonstrate the positive benefit-risk profile of first-line atezolizumab plus CP/ET in ES-SCLC and further support this regimen as a new standard of care in this setting. CLINICAL TRIALS NUMBER: NCT02763579.

Cardiac foetal reprogramming: a tool to exploit novel treatment targets for the failing heart.

As the heart matures during embryogenesis from its foetal stages, several structural and functional modifications take place to form the adult heart. This process of maturation is in large part due to an increased volume and work load of the heart to maintain proper circulation throughout the growing body. In recent years, it has been observed that these changes are reversed to some extent as a result of cardiac disease. The process by which this occurs has been characterized as cardiac foetal reprogramming and is defined as the suppression of adult and re-activation of a foetal genes profile in the diseased myocardium. The reasons as to why this process occurs in the diseased myocardium are unknown; however, it has been suggested to be an adaptive process to counteract deleterious events taking place during cardiac remodelling. Although still in its infancy, several studies have demonstrated that targeting foetal reprogramming in heart failure can lead to substantial improvement in cardiac functionality. This is highlighted by a recent study which found that by modulating the expression of 5-oxoprolinase (OPLAH, a novel cardiac foetal gene), cardiac function can be significantly improved in mice exposed to cardiac injury. Additionally, the utilization of angiotensin receptor neprilysin inhibitors (ARNI) has demonstrated clear benefits, providing important clinical proof that drugs that increase natriuretic peptide levels (part of the foetal gene programme) indeed improve heart failure outcomes. In this review, we will highlight the most important aspects of cardiac foetal reprogramming and will discuss whether this process is a cause or consequence of heart failure. Based on this, we will also explain how a deeper understanding of this process may result in the development of novel therapeutic strategies in heart failure.