Spectroscopy of short-lived radioactive molecules.

Molecular spectroscopy offers opportunities for the exploration of the fundamental laws of nature and the search for new particle physics beyond the standard model1-4. Radioactive molecules-in which one or more of the atoms possesses a radioactive nucleus-can contain heavy and deformed nuclei, offering high sensitivity for investigating parity- and time-reversal-violation effects5,6. Radium monofluoride, RaF, is of particular interest because it is predicted to have an electronic structure appropriate for laser cooling6, thus paving the way for its use in high-precision spectroscopic studies. Furthermore, the effects of symmetry-violating nuclear moments are strongly enhanced5,7-9 in molecules containing octupole-deformed radium isotopes10,11. However, the study of RaF has been impeded by the lack of stable isotopes of radium. Here we present an experimental approach to studying short-lived radioactive molecules, which allows us to measure molecules with lifetimes of just tens of milliseconds. Energetically low-lying electronic states were measured for different isotopically pure RaF molecules using collinear resonance ionisation at the ISOLDE ion-beam facility at CERN. Our results provide evidence of the existence of a suitable laser-cooling scheme for these molecules and represent a key step towards high-precision studies in these systems. Our findings will enable further studies of short-lived radioactive molecules for fundamental physics research.

Positronium Laser Cooling via the 1

We report on laser cooling of a large fraction of positronium (Ps) in free flight by strongly saturating the 1^{3}S-2^{3}P transition with a broadband, long-pulsed 243 nm alexandrite laser. The ground state Ps cloud is produced in a magnetic and electric field-free environment. We observe two different laser-induced effects. The first effect is an increase in the number of atoms in the ground state after the time Ps has spent in the long-lived 2^{3}P states. The second effect is one-dimensional Doppler cooling of Ps, reducing the cloud's temperature from 380(20) to 170(20) K. We demonstrate a 58(9)% increase in the fraction of Ps atoms with v_{1D}<3.7×10^{4} ms^{-1}.

Stroke outcomes following durable left ventricular assist device implant in patients bridged with micro-axial flow pump: Insights from a large registry.

BACKGROUND: Stroke after durable left ventricular assist device (d-LVAD) implantation portends high mortality. The incidence of ischemic and hemorrhagic stroke and the impact on stroke outcomes of temporary mechanical circulatory support (tMCS) management among patients requiring bridge to d-LVAD with micro-axial flow-pump (mAFP, Abiomed) is unsettled. METHODS: Consecutive patients, who underwent d-LVAD implantation after being bridged with mAFP at 19 institutions, were retrospectively included. The incidence of early ischemic and hemorrhagic stroke after d-LVAD implantation (<60 days) and association of pre-d-LVAD characteristics and peri-procedural management with a specific focus on tMCS strategies were studied. RESULTS: Among 341 patients, who underwent d-LVAD implantation after mAFP implantation (male gender 83.6%, age 58 [48-65] years, mAFP 5.0/5.5 72.4%), the early ischemic stroke incidence was 10.8% and early hemorrhagic stroke 2.9%. The tMCS characteristics (type of mAFP device and access, support duration, upgrade from intra-aortic balloon pump, ECMELLA, ECMELLA at d-LVAD implantation, hemolysis, and bleeding) were not associated with ischemic stroke after d-LVAD implant. Conversely, the device model (mAFP 2.5/CP vs. mAFP 5.0/5.5: HR 5.6, 95%CI 1.4-22.7, p = 0.015), hemolysis on mAFP support (HR 10.5, 95% CI 1.3-85.3, p = 0.028) and ECMELLA at d-LVAD implantation (HR 5.0, 95% CI 1.4-18.7, p = 0.016) were associated with increased risk of hemorrhagic stroke after d-LVAD implantation. Both early ischemic (HR 2.7, 95% CI 1.9-4.5, p < 0.001) and hemorrhagic (HR 3.43, 95% CI 1.49-7.88, p = 0.004) stroke were associated with increased 1-year mortality. CONCLUSIONS: Among patients undergoing d-LVAD implantation following mAFP support, tMCS characteristics do not impact ischemic stroke occurrence, while several factors are associated with hemorrhagic stroke suggesting a proactive treatment target to reduce this complication.

Measurements of Strong-Interaction Effects in Kaonic-Helium Isotopes at Sub-eV Precision with X-Ray Microcalorimeters.

We have measured the 3d→2p transition x rays of kaonic ^{3}He and ^{4}He atoms using superconducting transition-edge-sensor microcalorimeters with an energy resolution better than 6 eV (FWHM). We determined the energies to be 6224.5±0.4(stat)±0.2(syst) eV and 6463.7±0.3(stat)±0.1(syst) eV, and widths to be 2.5±1.0(stat)±0.4(syst) eV and 1.0±0.6(stat)±0.3(stat) eV, for kaonic ^{3}He and ^{4}He, respectively. These values are nearly 10 times more precise than in previous measurements. Our results exclude the large strong-interaction shifts and widths that are suggested by a coupled-channel approach and agree with calculations based on optical-potential models.

Isotope Shifts of Radium Monofluoride Molecules.

Isotope shifts of ^{223-226,228}Ra^{19}F were measured for different vibrational levels in the electronic transition A^{2}Π_{1/2}←X^{2}Σ^{+}. The observed isotope shifts demonstrate the particularly high sensitivity of radium monofluoride to nuclear size effects, offering a stringent test of models describing the electronic density within the radium nucleus. Ab initio quantum chemical calculations are in excellent agreement with experimental observations. These results highlight some of the unique opportunities that short-lived molecules could offer in nuclear structure and in fundamental symmetry studies.

Hemodynamic Response to Rapid Saline Infusion Compared with Exercise in Healthy Participants Aged 20-80 Years.

BACKGROUND AND OBJECTIVE: Rapid saline infusion and exercise has been proposed as methods to unmask cardiovascular disease. However, the normal hemodynamic response to rapid saline infusion has not been compared to exercise nor is it known whether the responses are age-dependent.We assessed the hemodynamic response to rapid saline infusion in healthy participants over a wide age-range and compared it to exercise in the same participants. METHODS AND RESULTS: Fifty healthy participants (young <40 years, n = 16, middle-aged 40-59 years, n = 15, elderly 60-80 years, n = 19) underwent right heart catheterization at rest, during semisupine ergometer exercise at three exercise levels (25%, 50%, and 75% of peak VO2) and after rapid saline infusion (10 ml/kg at a rate of 150 ml/min). Rapid saline infusion significantly increased pulmonary capillary wedge pressure (PCWP) similarly across all age groups (∆PCWP 6 ±â€¯2; 7 ±â€¯2; 6 ±â€¯4 mmHg for the young, middle-aged and elderly respectively) with no correlation between age and ∆PCWP (r = 0.05; p = 0.74). However, there was a negative correlation between age and ∆stroke volume (SV) as elderly participants had a lower increase in SV following rapid saline infusion (r = 0.44; p = 0.002). On the contrary, exercise-induced significantly larger and age-dependent increases in PCWP (r = 0.58; p < 0.0001). Exercise also caused a larger increase in SV compared with rapid fluid loading (p = 0.0003) CONCLUSION: Unlike exercise, rapid saline infusion caused an age-independent increase in PCWP in healthy adults. Suggesting that age-related impairments beyond passive stiffness have a greater impact on exercise-induced increase in PCWP. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT01974557.

Subsequent reproductive outcome among women with peripartum cardiomyopathy: a nationwide study.

OBJECTIVE: To describe the subsequent reproductive outcome for a Danish nationwide cohort of women with peripartum cardiomyopathy (PPCM). DESIGN: Nationwide historic cohort study. SETTING: Secondary and tertiary centres across Denmark. SAMPLE: Women with PPCM. METHODS: Sixty-one women with PPCM during 2005-2014 were identified in a nationwide, registry-based study and the diagnosis was validated through audit of patient records. A new search for subsequent reproductive outcome in this cohort from 2005-2016 was conducted in the Danish National Birth Registry and the Danish National Patient Registry. Detailed clinical data were obtained from patient records. MAIN OUTCOME MEASURES: Sterilisations and subsequent reproductive outcomes after PPCM, including all pregnancies, miscarriages, terminations and deliveries. RESULTS: Of 61 women with PPCM, 13 (21%) had a total of 16 subsequent pregnancies resulting in one miscarriage, seven early terminations, one ectopic pregnancy and seven liveborn children. There were no maternal deaths or significant cardiac events during pregnancy, but one woman, who gave birth to a liveborn child, had a relapse of PPCM 7 weeks postpartum. None of the six women who had a first trimester termination, experienced relapse of PPCM. Of the 13 women with a subsequent pregnancy, 62% had prior to this been advised against a new pregnancy due to the risk of recurrent PPCM. A total of four women (6.6%) were sterilised. CONCLUSION: Peripartum cardiomyopathy affects women's reproduction with few subsequent pregnancies resulting in a liveborn child. The finding of a 1/7 relapse among women with recovered LVEF is in accordance with most previous studies. TWEETABLE ABSTRACT: Outcome in pregnancies after peripartum cardiomyopathy: results from the first nationwide study.

Levosimendan in Acute and Advanced Heart Failure: an Expert Perspective on Posology and Therapeutic Application.

Levosimendan, a calcium sensitizer and potassium channel-opener, is widely appreciated by many specialist heart failure practitioners for its effects on systemic and pulmonary hemodynamics and for the relief of symptoms of acute heart failure. The drug's impact on mortality in large randomized controlled trials has been inconsistent or inconclusive but, in contrast to conventional inotropes, there have been no indications of worsened survival and some signals of improved heart failure-related quality of life. For this reason, levosimendan has been proposed as a safer inodilator option than traditional agents in settings, such as advanced heart failure. Positive effects of levosimendan on renal function have also been described. At the HEART FAILURE 2018 congress of the Heart Failure Association of the European Society of Cardiology, safe and effective use levosimendan in acute and advanced heart failure was examined in a series of expert tutorials. The proceedings of those tutorials are summarized in this review, with special reference to advanced heart failure and heart failure with concomitant renal dysfunction. Meta-analysis of clinical trials data is supportive of a renal-protective effect of levosimendan, while physiological observations suggest that this effect is exerted at least in part via organ-specific effects that may include selective vasodilation of glomerular afferent arterioles and increased renal blood flow, with no compromise of renal oxygenation. These lines of evidence require further investigation and their clinical significance needs to be evaluated in specifically designed prospective trials.

The clinical utility of FDG PET/CT among solid organ transplant recipients suspected of malignancy or infection.

PURPOSE: Solid organ transplant (SOT) recipients are at high risk of developing infections and malignancies. 18F-FDG PET/CT may enable timely detection of these diseases and help to ensure early intervention. We aimed to describe the clinical utility of FDG PET/CT in consecutive, diagnostic unresolved SOT recipients transplanted from January 2004 to May 2015. METHODS: Recipients with a post-transplant FDG PET/CT performed as part of diagnostic work-up were included. Detailed chart reviews were done to extract relevant clinical information and determine the final diagnosis related to the FDG PET/CT. Based on á priori defined criteria and the final diagnosis, results from each scan were classified as true or false, and diagnostic values determined. RESULTS: Among the 1,814 recipients in the cohort, 145 had an FDG PET/CT performed; 122 under the indication of diagnostically unresolved symptoms with a suspicion of malignancy or infection. The remaining (N = 23) had an FDG PET/CT to follow-up on a known disease or to stage a known malignancy. The 122 recipients underwent a total of 133 FDG PET/CT scans performed for a suspected malignancy (66 %) or an infection (34 %). Sensitivity, specificity, and positive and negative predictive values of the FDG PET/CT in diagnosing these conditions were 97, 84, 87, and 96 %, respectively. CONCLUSION: FDG PET/CT is an accurate diagnostic tool for the work-up of diagnostic unresolved SOT recipients suspected of malignancy or infection. The high sensitivity and NPV underlines the potential usefulness of PET/CT for excluding malignancy or focal infections in this often complex clinical situation.

Risk of infectious diseases among first-degree relatives of transplant recipients who develop CMV infection: is the infectious phenotype inheritable?

Transplant recipients are at high risk of cytomegalovirus (CMV) infection. Mechanisms explaining the variation in risk of infections are far from fully elucidated. We hypothesised that host genetics explains part of the variation in risk of infection and examined if relatives of recipients with CMV infection have higher rates of severe infections compared to relatives of recipients without this infectious phenotype. In a register-based study, we included first-degree relatives of transplant recipients and examined the risk of hospitalisation due to overall infection or viral infection and risk of death among relatives of recipients who developed CMV infection within the first year of transplantation compared to relatives of recipients without CMV. Analyses were adjusted for sex, age and calendar year. We included 4470 relatives who were followed for 103,786 person-years, median follow-up 24 years [interquartile range (IQR) 12-36]. There were a total of 1360 infection-related hospitalisations in the follow-up period, incidence rate (IR) 13.1/1000 person-years [95% confidence interval (CI), 12.4; 13.8]. 206 relatives were hospitalised with viral infection, IR 1.8/1000 person-years (95% CI, 1.6; 2.0). There was no increased risk of hospitalisation due to infections, IR ratio (IRR) 0.99 (95% CI, 0.88; 1.12), nor specifically viral infections, IRR 0.87 (95% CI, 0.63; 1.19), in relatives of recipients with CMV compared to relatives of recipients without CMV. Also, no difference was seen in analyses stratified by transplant type, family relation and CMV serostatus. The risk of hospitalisation due to infection is not increased among first-degree relatives of transplant recipients with CMV infection compared to relatives of recipients without CMV.

Everolimus Initiation With Early Calcineurin Inhibitor Withdrawal in De Novo Heart Transplant Recipients: Three-Year Results From the Randomized SCHEDULE Study.

In a randomized, open-label trial, de novo heart transplant recipients were randomized to everolimus (3-6 ng/mL) with reduced-exposure calcineurin inhibitor (CNI; cyclosporine) to weeks 7-11 after transplant, followed by increased everolimus exposure (target 6-10 ng/mL) with cyclosporine withdrawal or standard-exposure cyclosporine. All patients received mycophenolate mofetil and corticosteroids. A total of 110 of 115 patients completed the 12-month study, and 102 attended a follow-up visit at month 36. Mean measured GFR (mGFR) at month 36 was 77.4 mL/min (standard deviation [SD] 20.2 mL/min) versus 59.2 mL/min (SD 17.4 mL/min) in the everolimus and CNI groups, respectively, a difference of 18.3 mL/min (95% CI 11.1-25.6 mL/min; p < 0.001) in the intention to treat population. Multivariate analysis showed treatment to be an independent determinant of mGFR at month 36. Coronary intravascular ultrasound at 36 months revealed significantly reduced progression of allograft vasculopathy in the everolimus group compared with the CNI group. Biopsy-proven acute rejection grade ≥2R occurred in 10.2% and 5.9% of everolimus- and CNI-treated patients, respectively, during months 12-36. Serious adverse events occurred in 37.3% and 19.6% of everolimus- and CNI-treated patients, respectively (p = 0.078). These results suggest that early CNI withdrawal after heart transplantation supported by everolimus, mycophenolic acid and steroids with lymphocyte-depleting induction is safe at intermediate follow-up. This regimen, used selectively, may offer adequate immunosuppressive potency with a sustained renal advantage.

The Effect of Everolimus Initiation and Calcineurin Inhibitor Elimination on Cardiac Allograft Vasculopathy in De Novo Recipients: One-Year Results of a Scandinavian Randomized Trial.

Early initiation of everolimus with calcineurin inhibitor therapy has been shown to reduce the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant recipients. The effect of de novo everolimus therapy and early total elimination of calcineurin inhibitor therapy has, however, not been investigated and is relevant given the morbidity and lack of efficacy of current protocols in preventing CAV. This 12-month multicenter Scandinavian trial randomized 115 de novo heart transplant recipients to everolimus with complete calcineurin inhibitor elimination 7-11 weeks after HTx or standard cyclosporine immunosuppression. Ninety-five (83%) patients had matched intravascular ultrasound examinations at baseline and 12 months. Mean (± SD) recipient age was 49.9 ± 13.1 years. The everolimus group (n = 47) demonstrated significantly reduced CAV progression as compared to the calcineurin inhibitor group (n = 48) (ΔMaximal Intimal Thickness 0.03 ± 0.06 and 0.08 ± 0.12 mm, ΔPercent Atheroma Volume 1.3 ± 2.3 and 4.2 ± 5.0%, ΔTotal Atheroma Volume 1.1 ± 19.2 mm(3) and 13.8 ± 28.0 mm(3) [all p-values ≤ 0.01]). Everolimus patients also had a significantly greater decline in levels of soluble tumor necrosis factor receptor-1 as compared to the calcineurin inhibitor group (p = 0.02). These preliminary results suggest that an everolimus-based CNI-free can potentially be considered in suitable de novo HTx recipients.

High-resolution X-ray emission spectroscopy with transition-edge sensors: present performance and future potential.

X-ray emission spectroscopy (XES) is a powerful element-selective tool to analyze the oxidation states of atoms in complex compounds, determine their electronic configuration, and identify unknown compounds in challenging environments. Until now the low efficiency of wavelength-dispersive X-ray spectrometer technology has limited the use of XES, especially in combination with weaker laboratory X-ray sources. More efficient energy-dispersive detectors have either insufficient energy resolution because of the statistical limits described by Fano or too low counting rates to be of practical use. This paper updates an approach to high-resolution X-ray emission spectroscopy that uses a microcalorimeter detector array of superconducting transition-edge sensors (TESs). TES arrays are discussed and compared with conventional methods, and shown under which circumstances they are superior. It is also shown that a TES array can be integrated into a table-top time-resolved X-ray source and a soft X-ray synchrotron beamline to perform emission spectroscopy with good chemical sensitivity over a very wide range of energies.

Hyponatraemia at hospital admission is a predictor of overall mortality.

BACKGROUND: Hyponatraemia is a prognostic marker of increased mortality and morbidity in selected groups of hospitalised patients. The aim of the present study was to examine the prevalence and prognostic significance of hyponatraemia at hospital admission in an unselected population with a broad spectrum of medical and surgical diagnoses. METHODS: Consecutive patients >40 years of age admitted to a general district hospital in Greater Copenhagen between 1 April 1998 and 31 March 1999. Median follow-up time was 5.16 years (range 0-4372 days). Plasma sodium measurements were available in 2960 patients, and hyponatraemia defined as P-Na(+) <137 mmol/L at hospital admission was present in 1105 (37.3 %) patients. RESULTS: One-year mortality was higher for hyponatraemic patients than for normonatraemic patients: 27.5% versus 17.7%. Moreover, hyponatraemia was an independent predictor of short and long-term all-cause mortality after 1 year and after the entire observation period respectively: hazard ratio (HR) 1.6 (95 % confidence interval (CI) 1.4-1.9, P < 0.0001) and HR 1.4 (95 % CI 1.3-1.6, P < 0.0001). Patients with hyponatraemia had longer hospitalisations than patients with normonatraemia: 7.6 (±0.38) days vs 5.6 (±0.21) days, P < 0.001. There was no interaction between hyponatraemia at admission and any admission diagnoses (P > 0.05 for all interaction analyses). CONCLUSION: Hyponatraemia is associated with increased all-cause mortality and longer admission length independently of diagnosis and clinical variables.

Effect of high-intensity training versus moderate training on peak oxygen uptake and chronotropic response in heart transplant recipients: a randomized crossover trial.

In heart transplant (HTx) recipients, there has been reluctance to recommend high-intensity interval training (HIIT) due to denervation and chronotropic impairment of the heart. We compared the effects of 12 weeks' HIIT versus continued moderate exercise (CON) on exercise capacity and chronotropic response in stable HTx recipients >12 months after transplantation in a randomized crossover trial. The study was completed by 16 HTx recipients (mean age 52 years, 75% males). Baseline peak oxygen uptake (VO2peak ) was 22.9 mL/kg/min. HIIT increased VO2peak by 4.9 ± 2.7 mL/min/kg (17%) and CON by 2.6 ± 2.2 mL/kg/min (10%) (significantly higher in HIIT; p < 0.001). During HIIT, systolic blood pressure decreased significantly (p = 0.037) with no significant change in CON (p = 0.241; between group difference p = 0.027). Peak heart rate (HRpeak ) increased significantly by 4.3 beats per minute (p = 0.014) after HIIT with no significant change in CON (p = 0.34; between group difference p = 0.027). Heart rate recovery (HRrecovery ) improved in both groups with a trend toward greater improvement after HIIT. The 5-month washout showed a significant loss of improvement. HIIT was well tolerated, had a superior effect on oxygen uptake, and led to an unexpected increase in HRpeak accompanied by a faster HRrecovery . This indicates that the benefits of HIIT are partly a result of improved chronotropic response.

Everolimus initiation and early calcineurin inhibitor withdrawal in heart transplant recipients: a randomized trial.

In a randomized, open-label trial, everolimus was compared to cyclosporine in 115 de novo heart transplant recipients. Patients were assigned within 5 days posttransplant to low-exposure everolimus (3­6 ng/mL) with reduced-exposure cyclosporine (n = 56), or standard-exposure cyclosporine (n = 59), with both mycophenolate mofetil and corticosteroids. In the everolimus group, cyclosporine was withdrawn after 7­11 weeks and everolimus exposure increased (6­10 ng/mL). The primary efficacy end point, measured GFR at 12 months posttransplant, was significantly higher with everolimus versus cyclosporine (mean ± SD: 79.8 ± 17.7 mL/min/1.73 m2 vs. 61.5 ± 19.6 mL/min/1.73 m2; p < 0.001). Coronary intravascular ultrasound showed that the mean increase in maximal intimal thickness was smaller (0.03 mm [95% CI 0.01, 0.05 mm] vs. 0.08 mm [95% CI 0.05, 0.12 mm], p = 0.03), and the incidence of cardiac allograft vasculopathy (CAV) was lower (50.0% vs. 64.6%, p = 0.003), with everolimus versus cyclosporine at month 12. Biopsy-proven acute rejection after weeks 7­11 was more frequent with everolimus (p = 0.03). Left ventricular function was not inferior with everolimus versus cyclosporine. Cytomegalovirus infection was less common with everolimus (5.4% vs. 30.5%, p < 0.001); the incidence of bacterial infection was similar. In conclusion, everolimus-based immunosuppression with early elimination of cyclosporine markedly improved renal function after heart transplantation. Since postoperative safety was not jeopardized and development of CAV was attenuated, this strategy may benefit long-term outcome.

Influence of implant strategy on the transition from temporary left ventricular assist device to durable mechanical circulatory support.

OBJECTIVES: Bridging from a temporary microaxial left ventricular assist device (tLVAD) to a durable left ventricular assist device (dLVAD) is playing an increasing role in the treatment of terminally ill patients with heart failure. Scant data exist about the best implant strategy. The goal of this study was to analyse differences in the dLVAD implant technique and effects on patient outcomes. METHODS: Data from 341 patients (19 European centres) who underwent a bridge-to-bridge implant from tLVAD to dLVAD between January 2017 and October 2022 were retrospectively analysed. The outcomes of the different implant techniques with the patient on cardiopulmonary bypass, extracorporeal life support or tLVAD were compared. RESULTS: A durable LVAD implant was performed employing cardiopulmonary bypass in 70% of cases (n = 238, group 1), extracorporeal life support in 11% (n = 38, group 2) and tLVAD in 19% (n = 65, group 3). Baseline characteristics showed no significant differences in age (P = 0.140), body mass index (P = 0.388), creatinine level (P = 0.659), the Model for End-Stage Liver Disease (MELD) score (P = 0.190) and rate of dialysis (P = 0.110). Group 3 had significantly fewer patients with preoperatively invasive ventilation and cardiopulmonary resuscitation before the tLVAD was implanted (P = 0.009 and P < 0.001 respectively). Concomitant procedures were performed more often in groups 1 and 2 compared to group 3 (24%, 37% and 5%, respectively, P < 0.001). The 30-day mortality data showed significantly better survival after an inverse probability of treatment weighting in group 3, but the 1-year mortality showed no significant differences among the groups (P = 0.012 and 0.581, respectively). Postoperative complications like the rate of right ventricular assist device (RVAD) implants or re-thoracotomy due to bleeding, postoperative respiratory failure and renal replacement therapy showed no significant differences among the groups. Freedom from the first adverse event like stroke, driveline infection or pump thrombosis during follow-up was not significantly different among the groups. Postoperative blood transfusions within 24 h were significantly higher in groups 1 and 2 compared to surgery on tLVAD support (P < 0.001 and P = 0.003, respectively). CONCLUSIONS: In our analysis, the transition from tLVAD to dLVAD without further circulatory support did not show a difference in postoperative long-term survival, but a better 30-day survival was reported. The implant using only tLVAD showed a reduction in postoperative transfusion rates, without increasing the risk of postoperative stroke or pump thrombosis. In this small cohort study, our data support the hypothesis that a dLVAD implant on a tLVAD is a safe and feasible technique in selected patients.

The time course of development and impact from viral resistance against ganciclovir in cytomegalovirus infection.

(Val)ganciclovir is used to treat cytomegalovirus (CMV) infection following solid organ (SOT) or hematopoietic stem cell (HSCT) transplantation. Treatment failures occur, but the contribution from 39 known ganciclovir-related mutations (GRMs) in the CMV-UL97 gene remains controversial. We propose a categorization of these GRMs potentially useful when interpreting sequence analyses in clinical settings. The UL97 gene was sequenced from first/recurrent CMV infections among consecutive SOT or HSCT recipients during 2004-2009. GRMs were categorized as: Signature GRM (sGRM) if in vitro ganciclovir IC(50) ratio for mutated versus wild-type virus >2 (n = 24); polymorphic GRM (pGRM) if ratio <2 (n = 15). (Val)ganciclovir treatment failure was defined as persistent viremia for 30 days or switch to foscarnet within this period. Of 99 (49 HSCT and 50 SOT) recipients with one CMV infection episode, 15 (13 HSCT and 2 SOT) experienced a total of 19 recurrent infection episodes. The prevalence of sGRM was 0% at start of first episode, whereas at start of recurrent episodes, prevalence was 37%. Only one sGRM was present at a time in individual patients. Patients with CMV containing an sGRM (vs. wild type)-but not with a pGRM-were at excess risk of treatment failure (odds ratio = 70.6 [95% CI:8.2-609.6]; p < 0.001). sGRMs emerged only following longer termed use of antiherpetic drugs and usually in recurrent CMV infection episodes. Risk of ganciclovir treatment failure was raised if an sGRM was detected.

Resting and exercise haemodynamic characteristics of patients with advanced heart failure and preserved ejection fraction.

AIMS: This study aimed to describe haemodynamic features of patients with advanced heart failure with preserved ejection fraction (HFpEF) as defined by the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). METHODS AND RESULTS: We used pooled data from two dedicated HFpEF studies with invasive exercise haemodynamic protocols, the REDUCE LAP-HF (Reduce Elevated Left Atrial Pressure in Patients with Heart Failure) trial and the REDUCE LAP-HF I trial, and categorized patients according to advanced heart failure (AdHF) criteria. The well-characterized HFpEF patients were considered advanced if they had persistent New York Heart Association classification of III-IV and heart failure (HF) hospitalization < 12 months and a 6 min walk test distance < 300 m. Twenty-four (22%) out of 108 patients met the AdHF criteria. On evaluation, clinical characteristics and resting haemodynamics were not different in the two groups. Patients with AdHF had lower work capacity compared with non-advanced patients (35 ± 16 vs. 45 ± 18 W, P = 0.021). Workload-corrected pulmonary capillary wedge pressure normalized to body weight (PCWL) was higher in AdHF patients compared with non-advanced (112 ± 55 vs. 86 ± 49 mmHg/W/kg, P = 0.04). Further, AdHF patients had a smaller increase in cardiac index during exercise (1.1 ± 0.7 vs. 1.6 ± 0.9 L/min/m2 , P = 0.028). CONCLUSIONS: A significantly higher PCWL and lower cardiac index reserve during exercise were observed in AdHF patients compared with non-advanced. These differences were not apparent at rest. Therapies targeting the haemodynamic compromise associated with advanced HFpEF are needed.

Effect of high intensity exercise on peak oxygen uptake and endothelial function in long-term heart transplant recipients.

Coronary allograft vasculopathy is a well-known long-term complication after cardiac transplantation. Endothelial dysfunction is involved and may be prevented by aerobic exercise. The purpose of this study was to examine whether high intensity aerobic exercise improves peak oxygen uptake (VO(2 peak) ) and endothelial function in heart transplant (HT) recipients. Twenty-seven long-term HT recipients were randomized to either 8-weeks high intensity aerobic exercise or no training. Flow mediated dilation of the brachial artery (FMD) was measured by ultrasound and VO(2 peak) by the analysis of expired air. Blood pressure and biomarkers were measured before and after 8 weeks. VO(2 peak) increased significantly in the exercise group (VO(2 peak) 23.9 ± 1.79 to 28.3 ± 1.63 mL/kg/min compared to controls (VO(2 peak) 24.6 ± 1.38 to 23.4 ± 1.58, p < 0.001 exercise vs. control).FMD increased in the exercise group compared to controls (8.3 ± 1.1% to 11.4 ± 1.2% vs. 5.6 ± 1.0% to 5.3 ± 1.7%, p = 0.024). No increase in nitroglycerin-induced vasodilation was observed. Systolic blood pressure fell in the exercise group (142 ±4.2 mmHg to127 ± 3.4 mmHg, p = 0.01) and was unchanged in controls (141 ± 4.2 mmHg to 142 ±6.4 mmHg, NS). High intensity aerobic exercise reduces systolic blood pressure and improves endothelial function in HT recipients.