Non-severe aortic regurgitation increases short-term mortality in acute heart failure with preserved ejection fraction.

Mild or moderate aortic regurgitation (AR) has only little effect on cardiovascular outcome in people with normal left ventricular ejection fraction (EF); therefore, it is not perceived as a major clinical problem. This study investigates whether mild or moderate AR is associated with increased short-term mortality in patients hospitalized for treatment of acute heart failure (AHF) and whether mild or moderate AR impacts differently on short-term mortality in AHF patients with reduced EF (AHFrEF), mid-range EF (AHFmrEF), or preserved EF (AHFpEF). This mono-centric study included 505 consecutive adult patients hospitalized for de novo or worsening chronic HF not related to acute ischaemia or severe valvular pathology in the echocardiogram at index hospitalization. Cox regression analysis studied the impact of AR on all-cause mortality (ACM) over the 150 days' study period. Mild or moderate AR was associated with increased ACM (HR 1.75 [95% CI: 1.1-2.7]; P = 0.009). The prevalence of mild or moderate AR in the study population was 42% and not significantly different between AHFpEF (n = 227), AHFmrEF (n = 86), and AHFrEF (n = 192) study participants (37.9% vs. 50.0% vs. 42.7%; P = 0.144). In AHFpEF patients, the age-adjusted hazard for ACM was increased in patients with AR compared with patients without AR (HR 2.17 [95% CI: 1.1-4.2]; P = 0.002). The age-adjusted hazard for ACM was increased by a trend in AHFmrEF with AR (HR 7.11, [95% CI: 0.9-57.8]; P = 0.067) and not different between the AHFrEF groups (HR 0.95 [95% CI: 0.5-1.8]; P = 0.875). Mild or moderate AR increased ACM only in AHFpEF patients, highlighting a distinct clinical relevance

Already low drug dose antagonism of the renin-angiotensin aldosterone system decreases 1-year mortality and rehospitalization in old heart failure patients

Hospitalization for heart failure treatment (HHF) is an incisive event in the course of HF. Today, the large majority of HHF patients is ≥ 65 years and discharge HF drugs are most often not applied at dose levels acknowledged to provide prognostic benefit. This study therefore aims to investigate the treatment effect size of discharge HF drugs in old HHF patients. Drugs are analyzed according to pharmacological class. Individual discharge HF drug dose is reported as percentage of guidelines-recommended target dose. Primary endpoint was 1-year all-cause mortality (ACM) after discharge; the secondary endpoint combined 1-year ACM and first cardiovascular hospitalization within 1 year after discharge. Comparison between 65-80 years and > 80 years old study participants tested the relative treatment effect size as a function of respective age group. The 875 consecutive HHF patients had a median age of 82 years [76-87 years]; 48.6 % were females. Betablocker and diuretic treatment did not change the incidence of endpoints. Inhibition of the renin-angiotensin system (RASi), when compared to no treatment, decreased the incidence of endpoints both at the 1-25 % and the > 25 % target dose level. Antagonists of the mineralocorticoid receptor (MRA), when compared to no treatment, decreased the secondary endpoint at the 1-25 % target dose level but not at the > 25 % target dose level. The relative treatment effect size of RASi or MRA corresponded between the age strata for both endpoints. Low-dose RASi and MRA had beneficial effects in these old HHF patients

Has the profile of heart transplantation recipients changed within the last three decades?

Heart transplantation remains the most durable treatment for patients with end-stage heart failure refractory to medical treatment. Central elements of the listing criteria for heart transplantation have remained largely unchanged in the last three decades whereas treatment of heart failure has significantly increased survival and reduced disease-related symptoms. It remains unknown whether the improvement of heart failure therapy changed the profile of heart transplantation candidates or affected post-transplant survival. The study investigated a total of 323 heart transplant recipients of the Lausanne University Hospital with 328 transplant operations between 1987 and 2018. Patients were separated into three groups on the basis of availability of heart failure therapy: period 1 (1987-1998; n = 115) when renin-angiotensin system blockade and diuretic treatment were available; period 2 (1999-2010; n = 106) marked by the addition of beta-blocker and mineralocorticoid receptor antagonist treatment in severe heart failure, and the establishment of cardiac defibrillator and resynchronisation therapy; period 3 (2011-2018; n = 107) characterised by the increasing use of ventricular assist devices for bridge to transplantation. The patient characteristics age (all: 53.4 years), male sex (all: 79%) and body mass index (all: 24.5 kg/m2) did not differ between periods. History of arterial hypertension was less prevalent in period 2 (period 1 vs 2 vs 3: 44 vs 28 vs 43%, p = 0.04) whereas other cardiovascular risk factors were equally distributed. Left ventricular ejection fraction, VO2max, and pulmonary vascular resistance were not different between the three periods. The prevalence of ischaemic cardiomyopathy was higher in periods 1 and 3; dilated non-ischaemic cardiomyopathy was more frequent in period 2. Post-transplant 1-year survival was highest in period 3 (1 vs 2 vs 3: 87.2 ± 3.2% vs 70.8 ± 4.4% vs 93.0 ± 2.6%, p always ≤0.02), and the Kaplan-Meier estimates of survivors of the first year post-transplant were not different between the three periods. In descriptive analysis, early mortality was not associated with acknowledged pretransplant predictors of post-transplant mortality. Availability of different medical heart failure treatments did not result in greatly different pretransplant characteristics of heart transplantation recipients across the three periods. This suggests that the maintained central criteria of listing for heart transplantation still identify end-stage heart failure patients with a similar profile. This finding can explain the unchanged overall mortality on condition of 1-year survival across the three periods, since pretransplant characteristics are relevant for long-term survival after heart transplantation

Decongestion improving right heart function ameliorates prognosis after an acute heart failure episode.

The prognostic role of decongestion-related change of cardiac morphology and in particular right heart function has not been investigated comprehensively in AHF patients. This prospective observational single-centre study included consecutive patients hospitalized for treatment of AHF with reduced, mildly-reduced or preserved left ventricular ejection fraction (LVEF). Comprehensive transthoracic echocardiography at admission and discharge assessed decongestion-related change of cardiac function and morphology. The combined endpoint of 1 year all-cause mortality and cardiovascular rehospitalization explored the prognostic importance of decongestion-related change. The 176 study participants were 83 years old [74-87] and 54% were men. Fifty one (29%) had rLVEF, 65 (37%) mrLVEF, and 60 (34%) pLVEF. The proportion of de novo or worsening chronic HF was not different between LVEF groups. HF aetiology and cardiovascular risk factors were equally distributed across all groups except for a higher BMI in the pLVEF group. Decongestion equally reduced body weight, heart rate, systolic and diastolic blood pressure, tricuspid regurgitation gradient, and inferior vena cava diameter across all groups (P < 0.004 for all). Decongestion-related increase in TAPSE independent of the LVEF was associated with improvement of right-ventricular-pulmonary artery coupling and a lower incidence of the combined outcome in the Cox proportional hazard risk analysis (unadjusted HR 0.50 95% CI 0.33-0.78, P = 0.002; adjusted HR 0.46 95% CI: 0.33-0.78, P = 0.001). Decongestion-related increase in TAPSE and recovery of RV/pulmonary artery coupling was observed across all LVEF groups and associated with a risk reduction for the combined endpoint highlighting the important prognostic role of right heart recovery after an AHF episode

DNA topoisomerases participate in fragility of the oncogene RET

Fragile site breakage was previously shown to result in rearrangement of the RET oncogene, resembling the rearrangements found in thyroid cancer. Common fragile sites are specific regions of the genome with a high susceptibility to DNA breakage under conditions that partially inhibit DNA replication, and often coincide with genes deleted, amplified, or rearranged in cancer. While a substantial amount of work has been performed investigating DNA repair and cell cycle checkpoint proteins vital for maintaining stability at fragile sites, little is known about the initial events leading to DNA breakage at these sites. The purpose of this study was to investigate these initial events through the detection of aphidicolin (APH)-induced DNA breakage within the RET oncogene, in which 144 APHinduced DNA breakpoints were mapped on the nucleotide level in human thyroid cells within intron 11 of RET, the breakpoint cluster region found in patients. These breakpoints were located at or near DNA topoisomerase I and/or II predicted cleavage sites, as well as at DNA secondary structural features recognized and preferentially cleaved by DNA topoisomerases I and II. Co-treatment of thyroid cells with APH and the topoisomerase catalytic inhibitors, betulinic acid and merbarone, significantly decreased APH-induced fragile site breakage within RET intron 11 and within the common fragile site FRA3B. These data demonstrate that DNA topoisomerases I and II are involved in initiating APH-induced common fragile site breakage at RET, and may engage the recognition of DNA secondary structures formed during perturbed DNA replication

DNA replication and the GINS complex: localization on extended chromatin fibers

<p>Abstract</p> <p>Background</p> <p>The GINS complex is thought to be essential for the processes of initiation and elongation of DNA replication. This complex contains four subunits, one of which (Psf1) is proposed to bind to both chromatin and DNA replication-associated proteins. To date there have been no microscopic analyses to evaluate the chromatin distribution of this complex. Here, we show the organization of GINS complexes on extended chromatin fibers in relation to sites of DNA replication and replication-associated proteins.</p> <p>Results</p> <p>Using immunofluorescence microscopy we were able to visualize ORC1, ORC2, PCNA, and GINS complex proteins Psf1 and Psf2 bound to extended chromatin fibers. We were also able to detect these proteins concurrently with the visualization of tracks of recently replicated DNA where EdU, a thymidine analog, was incorporated. This allowed us to assess the chromatin association of proteins of interest in relation to the process of DNA replication. ORC and GINS proteins were found on chromatin fibers before replication could be detected. These proteins were also associated with newly replicated DNA in bead-like structures. Additionally, GINS proteins co-localized with PCNA at sites of active replication.</p> <p>Conclusion</p> <p>In agreement with its proposed role in the initiation of DNA replication, GINS proteins associated with chromatin near sites of ORC binding that were devoid of EdU (absence of DNA replication). The association of GINS proteins with PCNA was consistent with a role in the process of elongation. Additionally, the large size of our chromatin fibers (up to approximately 7 Mb) allowed for a more expansive analysis of the distance between active replicons than previously reported.</p

First Results from HERA Phase I: Upper Limits on the Epoch of Reionization 21 cm Power Spectrum

We report upper limits on the Epoch of Reionization 21 cm power spectrum at redshifts 7.9 and 10.4 with 18 nights of data (∼36 hr of integration) from Phase I of the Hydrogen Epoch of Reionization Array (HERA). The Phase I data show evidence for systematics that can be largely suppressed with systematic models down to a dynamic range of ∼109 with respect to the peak foreground power. This yields a 95% confidence upper limit on the 21 cm power spectrum of 212≤(30.76)2mK2 at k = 0.192 h Mpc-1 at z = 7.9, and also 212≤(95.74)2mK2 at k = 0.256 h Mpc-1 at z = 10.4. At z = 7.9, these limits are the most sensitive to date by over an order of magnitude. While we find evidence for residual systematics at low line-of-sight Fourier k π modes, at high k π modes we find our data to be largely consistent with thermal noise, an indicator that the system could benefit from deeper integrations. The observed systematics could be due to radio frequency interference, cable subreflections, or residual instrumental cross-coupling, and warrant further study. This analysis emphasizes algorithms that have minimal inherent signal loss, although we do perform a careful accounting in a companion paper of the small forms of loss or bias associated with the pipeline. Overall, these results are a promising first step in the development of a tuned, instrument-specific analysis pipeline for HERA, particularly as Phase II construction is completed en route to reaching the full sensitivity of the experiment

Measuring HERA's Primary Beam in Situ: Methodology and First Results

The central challenge in 21 cm cosmology is isolating the cosmological signal from bright foregrounds. Many separation techniques rely on the accurate knowledge of the sky and the instrumental response, including the antenna primary beam. For drift-scan telescopes, such as the Hydrogen Epoch of Reionization Array (HERA), that do not move, primary beam characterization is particularly challenging because standard beam-calibration routines do not apply (Cornwell et al.) and current techniques require accurate source catalogs at the telescope resolution. We present an extension of the method from Pober et al. where they use beam symmetries to create a network of overlapping source tracks that break the degeneracy between source flux density and beam response and allow their simultaneous estimation. We fit the beam response of our instrument using early HERA observations and find that our results agree well with electromagnetic simulations down to a -20 dB level in power relative to peak gain for sources with high signal-to-noise ratio. In addition, we construct a source catalog with 90 sources down to a flux density of 1.4 Jy at 151 MHz.The central challenge in 21 cm cosmology is isolating the cosmological signal from bright foregrounds. Many separation techniques rely on the accurate knowledge of the sky and the instrumental response, including the antenna primary beam. For drift-scan telescopes, such as the Hydrogen Epoch of Reionization Array (HERA), that do not move, primary beam characterization is particularly challenging because standard beam-calibration routines do not apply (Cornwell et al.) and current techniques require accurate source catalogs at the telescope resolution. We present an extension of the method from Pober et al. where they use beam symmetries to create a network of overlapping source tracks that break the degeneracy between source flux density and beam response and allow their simultaneous estimation. We fit the beam response of our instrument using early HERA observations and find that our results agree well with electromagnetic simulations down to a -20 dB level in power relative to peak gain for sources with high signal-to-noise ratio. In addition, we construct a source catalog with 90 sources down to a flux density of 1.4 Jy at 151 MHz

Detection of cosmic structures using the bispectrum phase. II. First results from application to cosmic reionization using the Hydrogen Epoch of Reionization Array

Characterizing the epoch of reionization (EoR) at $z\gtrsim 6$ via the redshifted 21 cm line of neutral Hydrogen (HI) is critical to modern astrophysics and cosmology, and thus a key science goal of many current and planned low-frequency radio telescopes. The primary challenge to detecting this signal is the overwhelmingly bright foreground emission at these frequencies, placing stringent requirements on the knowledge of the instruments and inaccuracies in analyses. Results from these experiments have largely been limited not by thermal sensitivity but by systematics, particularly caused by the inability to calibrate the instrument to high accuracy. The interferometric bispectrum phase is immune to antenna-based calibration and errors therein, and presents an independent alternative to detect the EoR HI fluctuations while largely avoiding calibration systematics. Here, we provide a demonstration of this technique on a subset of data from the Hydrogen Epoch of Reionization Array (HERA) to place approximate constraints on the IGM brightness temperature. From this limited data, at $z=7.7$ we infer "$1\sigma$" upper limits on the IGM brightness temperature to be $\le 316$ "pseudo" mK at $\kappa_\parallel=0.33\,\textrm{"pseudo"}\,h$ Mpc$^{-1}$ (data-limited) and $\le 1000$ "pseudo" mK at $\kappa_\parallel=0.875\,\textrm{"pseudo"}\,h$ Mpc$^{-1}$ (noise-limited). The "pseudo" units denote only an approximate and not an exact correspondence to the actual distance scales and brightness temperatures. By propagating models in parallel to the data analysis, we confirm that the dynamic range required to separate the cosmic HI signal from the foregrounds is similar to that in standard approaches, and the power spectrum of the bispectrum phase is still data-limited (at $\gtrsim 10^6$ dynamic range) indicating scope for further improvement in sensitivity as the array build-out continues

Detection of cosmic structures using the bispectrum phase. II. First results from application to cosmic reionization using the Hydrogen Epoch of Reionization Array

Characterizing the epoch of reionization (EoR) at $z\gtrsim 6$ via the redshifted 21 cm line of neutral Hydrogen (HI) is critical to modern astrophysics and cosmology, and thus a key science goal of many current and planned low-frequency radio telescopes. The primary challenge to detecting this signal is the overwhelmingly bright foreground emission at these frequencies, placing stringent requirements on the knowledge of the instruments and inaccuracies in analyses. Results from these experiments have largely been limited not by thermal sensitivity but by systematics, particularly caused by the inability to calibrate the instrument to high accuracy. The interferometric bispectrum phase is immune to antenna-based calibration and errors therein, and presents an independent alternative to detect the EoR HI fluctuations while largely avoiding calibration systematics. Here, we provide a demonstration of this technique on a subset of data from the Hydrogen Epoch of Reionization Array (HERA) to place approximate constraints on the IGM brightness temperature. From this limited data, at $z=7.7$ we infer "$1\sigma$" upper limits on the IGM brightness temperature to be $\le 316$ "pseudo" mK at $\kappa_\parallel=0.33\,\textrm{"pseudo"}\,h$ Mpc$^{-1}$ (data-limited) and $\le 1000$ "pseudo" mK at $\kappa_\parallel=0.875\,\textrm{"pseudo"}\,h$ Mpc$^{-1}$ (noise-limited). The "pseudo" units denote only an approximate and not an exact correspondence to the actual distance scales and brightness temperatures. By propagating models in parallel to the data analysis, we confirm that the dynamic range required to separate the cosmic HI signal from the foregrounds is similar to that in standard approaches, and the power spectrum of the bispectrum phase is still data-limited (at $\gtrsim 10^6$ dynamic range) indicating scope for further improvement in sensitivity as the array build-out continues