Spatial variations in aromatic hydrocarbon emission in a dust-rich galaxy.

Dust grains absorb half of the radiation emitted by stars throughout the history of the universe, re-emitting this energy at infrared wavelengths1-3. Polycyclic aromatic hydrocarbons (PAHs) are large organic molecules that trace millimetre-size dust grains and regulate the cooling of interstellar gas within galaxies4,5. Observations of PAH features in very distant galaxies have been difficult owing to the limited sensitivity and wavelength coverage of previous infrared telescopes6,7. Here we present James Webb Space Telescope observations that detect the 3.3 µm PAH feature in a galaxy observed less than 1.5 billion years after the Big Bang. The high equivalent width of the PAH feature indicates that star formation, rather than black hole accretion, dominates infrared emission throughout the galaxy. The light from PAH molecules, hot dust and large dust grains and stars are spatially distinct from one another, leading to order-of-magnitude variations in PAH equivalent width and ratio of PAH to total infrared luminosity across the galaxy. The spatial variations we observe suggest either a physical offset between PAHs and large dust grains or wide variations in the local ultraviolet radiation field. Our observations demonstrate that differences in emission from PAH molecules and large dust grains are a complex result of localized processes within early galaxies.

Frailty and transcatheter valve intervention: A narrative review.

Frailty is a common clinical syndrome that portends poor peri-procedural outcomes and increased mortality following transcatheter valve interventions. We reviewed frailty assessment tools in transcatheter intervention cohorts to recommend a pathway for preprocedural frailty assessment in patients referred for transcatheter valve procedures, and evaluated current evidence for frailty interventions and their efficacy in transcatheter intervention. We recommend the use of a frailty screening instrument to identify patients as frail, with subsequent referral for comprehensive geriatric assessment in these patients, to assist in selecting appropriate patients and then optimizing them for transcatheter valve interventions. Interventions to reduce preprocedural frailty are not well defined, however, data from limited cohort studies support exercise-based interventions to increase functional capacity and reduce frailty in parallel with preprocedural medical optimization.

Using pulsatility responses to breath-hold maneuvers to predict readmission rates in continuous-flow left ventricular assist device patients.

BACKGROUND: Dynamic respiratory maneuvers induce heterogenous changes to flow-pulsatility in continuous-flow left ventricular assist device patients. We evaluated the association of these pulsatility responses with patient hemodynamics and outcomes. METHODS: Responses obtained from HVAD (Medtronic) outpatients during successive weekly clinics were categorized into three ordinal groups according to the percentage reduction in flow-waveform pulsatility (peak-trough flow) upon inspiratory-breath-hold, (%∆P): (1) minimal change (%∆P ≤ 50), (2) reduced pulsatility (%∆P > 50 but <100), (3) flatline (%∆P = 100). Same-day echocardiography and right-heart-catheterization were performed. Readmissions were compared between patients with ≥1 flatline response (F-group) and those without (NF-group). RESULTS: Overall, 712 responses were obtained from 55 patients (82% male, age 56.4 ± 11.5). When compared to minimal change, reduced pulsatility and flatline responses were associated with lower central venous pressure (14.2 vs. 11.4 vs. 9.0 mm Hg, p = 0.08) and pulmonary capillary wedge pressure (19.8 vs. 14.3 vs. 13.0 mm Hg, p = 0.03), lower rates of ≥moderate mitral regurgitation (48% vs. 13% vs. 10%, p = 0.01), lower rates of ≥moderate right ventricular impairment (62% vs. 25% vs. 27%, p = 0.03), and increased rates of aortic valve opening (32% vs. 50% vs. 75%, p = 0.03). The F-group (n = 28) experienced numerically lower all-cause readmissions (1.51 vs. 2.79 events-per-patient-year [EPPY], hazard-ratio [HR] = 0.67, p = 0.12), reduced heart failure readmissions (0.07 vs. 0.57 EPPY, HR = 0.15, p = 0.008), and superior readmission-free survival (HR = 0.47, log-rank p = 0.04). Syncopal readmissions occurred exclusively in the F-group (0.20 vs. 0 EPPY, p = 0.01). CONCLUSION: Responses to inspiratory-breath-hold predicted hemodynamics and readmission risk. The impact of inspiratory-breath-hold on pulsatility can non-invasively guide hemodynamic management decisions, patient optimization, and readmission risk stratification.

Cost-Effectiveness of Cardiovascular Magnetic Resonance for Rejection Surveillance After Cardiac Transplantation in the Australian Health Care System.

BACKGROUND: Heart transplantation is an effective treatment for end-stage congestive heart failure, however, achieving the right balance of immunosuppression to maintain graft function while minimising adverse effects is challenging. Serial endomyocardial biopsies (EMBs) are currently the standard for rejection surveillance, despite being invasive. Replacing EMB-based surveillance with cardiac magnetic resonance (CMR)-based surveillance for acute cardiac allograft rejection has shown feasibility. This study aimed to assess the cost-effectiveness of CMR-based surveillance in the first year after heart transplantation. METHOD: A prospective clinical trial was conducted with 40 orthotopic heart transplant (OHT) recipients. Participants were randomly allocated into two surveillance groups: EMB-based, and CMR-based. The trial included economic evaluations, comparing the frequency and cost of surveillance modalities in relation to quality-adjusted life years (QALYs) within the first year post-transplantation. Sensitivity analysis encompassed modelled data from observed EMB and CMR arms, integrating two hypothetical models of expedited CMR-based surveillance. RESULTS: In the CMR cohort, 238 CMR scans and 15 EMBs were conducted, versus (vs) 235 EMBs in the EMB group. CMR surveillance yielded comparable rejection rates (CMR 74 vs EMB 94 events, p=0.10) and did not increase hospitalisation risk (CMR 32 vs EMB 46 events, p=0.031). It significantly reduced the necessity for invasive EMBs by 94%, lowered costs by an average of AUD$32,878.61, and enhanced cumulative QALY by 0.588 compared with EMB. Sensitivity analysis showed that increased surveillance with expedited CMR Models 1 and 2 were more cost-effective than EMB (all p<0.01), with CMR Model 1 achieving the greatest cost savings (AUD$34,091.12±AUD$23,271.86 less) and utility increase (+0.62±1.49 QALYs, p=0.011), signifying an optimal cost-utility ratio. Model 2 showed comparable utility to the base CMR model (p=0.900) while offering the benefit of heightened surveillance frequency during periods of elevated rejection risk. CONCLUSIONS: CMR-based rejection surveillance in orthotopic heart transplant recipients provides a cost-effective alternative to EMB-based surveillance. Furthermore, it reduces the need for invasive procedures, without increased risk of rejection or hospitalisation for patients, and can be incorporated economically for expedited surveillance. These findings have important implications for improving patient care and optimising resource allocation in post-transplant management.

Cardiovascular Magnetic Resonance for Rejection Surveillance After Cardiac Transplantation.

BACKGROUND: Endomyocardial biopsy (EMB) is the gold standard method for surveillance of acute cardiac allograft rejection (ACAR) despite its invasive nature. Cardiovascular magnetic resonance (CMR)-based myocardial tissue characterization allows detection of myocarditis. The feasibility of CMR-based surveillance for ACAR-induced myocarditis in the first year after heart transplantation is currently undescribed. METHODS: CMR-based multiparametric mapping was initially assessed in a prospective cross-sectional fashion to establish agreement between CMR- and EMB-based ACAR and to determine CMR cutoff values between rejection grades. A prospective randomized noninferiority pilot study was then undertaken in adult orthotopic heart transplant recipients who were randomized at 4 weeks after orthotopic heart transplantation to either CMR- or EMB-based rejection surveillance. Clinical end points were assessed at 52 weeks. RESULTS: Four hundred one CMR studies and 354 EMB procedures were performed in 106 participants. Forty heart transplant recipients were randomized. CMR-based multiparametric assessment was highly reproducible and reliable at detecting ACAR (area under the curve, 0.92; sensitivity, 93%; specificity, 92%; negative predictive value, 99%) with greater specificity and negative predictive value than either T1 or T2 parametric CMR mapping alone. High-grade rejection occurred in similar numbers of patients in each randomized group (CMR, n=7; EMB, n=8; P=0.74). Despite similarities in immunosuppression requirements, kidney function, and mortality between groups, the rates of hospitalization (9 of 20 [45%] versus 18 of 20 [90%]; odds ratio, 0.091; P=0.006) and infection (7 of 20 [35%] versus 14 of 20 [70%]; odds ratio, 0.192; P=0,019) were lower in the CMR group. On 15 occasions (6%), patients who were randomized to the CMR arm underwent EMB for clarification or logistic reasons, representing a 94% reduction in the requirement for EMB-based surveillance. CONCLUSIONS: A noninvasive CMR-based surveillance strategy for ACAR in the first year after orthotopic heart transplantation is feasible compared with EMB-based surveillance. REGISTRATION: HREC/13/SVH/66 and HREC/17/SVH/80. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY: ACTRN12618000672257.

The safe use of metformin in heart failure patients both with and without T2DM: A cross-sectional and longitudinal study.

AIMS: This study investigated the safe use of metformin in patients with (1) type 2 diabetes mellitus (T2DM) and heart failure on metformin, and (2) heart failure without T2DM and metformin naïve. METHODS: Two prospective studies on heart failure patients were undertaken. The first was a cross-sectional study with two patient cohorts, one with T2DM on metformin (n = 44) and one without T2DM metformin naive (n = 47). The second was a 12-week interventional study of patients without T2DM (n = 27) where metformin (500 mg immediate release, twice daily) was prescribed. Plasma metformin and lactate concentrations were monitored. Individual pharmacokinetics were compared between cohorts. Univariable and multivariable analysis analysed the effects of variables on plasma lactate concentrations. RESULTS: Plasma metformin and lactate concentrations mostly (99.9%) remained below safety thresholds (5 mg/L and 5 mmol/L, respectively). Metformin concentration had no significant relationship with lactic acidosis safety markers. In the interventional study, New York Heart Association (NYHA) II (P < .03) and III (P < .001) grading was associated with higher plasma lactate concentrations, whereas male sex was associated with 47% higher plasma lactate concentrations (P < .05). The pharmacokinetics of heart failure patients with and without T2DM were similar. CONCLUSIONS: We observed no unsafe plasma lactate concentrations in patients with heart failure treated with metformin. Metformin exposure did not influence plasma lactate concentrations, but NYHA class and sex did. The pharmacokinetics of metformin in heart failure patients are similar irrespective of T2DM. These findings may support the safe use of metformin in heart failure patients with and without T2DM.

Comparing left ventricular assist device inflow cannula angle between median sternotomy and thoracotomy using 3D reconstructions.

BACKGROUND: Left ventricular assist device (LVAD) implantation via thoracotomy has many potential advantages compared to conventional sternotomy, including improved inflow cannula (IFC) positioning. We compared the difference in IFC angles, postoperative, and long-term outcomes for patients with LVADs implanted via thoracotomy and sternotomy. METHODS: A single-center, retrospective analysis of 14 patients who underwent thoracotomy implantation was performed and matched with 28 patients who underwent sternotomy LVAD implantations for a total of 42 patients. Inclusion required a minimum LVAD support duration of 30 days and excluded concomitant procedures. A postoperative CT-chest was used to measure the angle the between the IFC and mitral valve in two-dimensions and results were compared with three-dimensional reconstruction using the same CT chest. Outcome data were extracted from medical records. RESULTS: There was no significant difference in gender, INTERMACS score, BMI, or age between the two groups. Median cardiopulmonary bypass time was longer in the thoracotomy group compared to the sternotomy group, 107 min (86-122) versus 76 min (56-93), p < 0.01. 3D reconstructions revealed less deviation of the IFC away from the mitral valve in devices implanted via thoracotomy compared to sternotomy, median (IQR) angle 16.3° (13.9°-21.0°) versus 23.2° (17.9°-26.4°), p < 0.01. Rates of pump thrombosis, stroke, and gastrointestinal bleeding were not significantly different. CONCLUSIONS: Devices implanted via thoracotomy demonstrated less deviation away from mitral valve. However, there was no difference in morbidity between the two approaches. 3D reconstruction of the heart is an innovative technique to measure angulation and is clinically advantageous when compared to 2D imaging.

Ten-year retrospective cohort analysis of ventricular assist device infections.

BACKGROUND: The number of patients treated by ventricular assist devices (VAD) and the duration of VAD treatment is increasing. One of the main complications in terms of morbidity and mortality for VAD patients are microbial infections. With this study, we aimed to investigate the epidemiology and microbiological characteristics of infections occurring in a VAD population to identify modifiable factors. METHODS: We retrospectively analyzed patient characteristics, treatments and outcomes of VAD-specific/related infections. All patients implanted in our institution with a continuous flow VAD between January 2009 and January 2019 were included. Risk factors for VAD infection were assessed using simple and multiple linear regressions. RESULTS: Of the 104 patients screened, 99 were included in the analysis, the majority of which were men (78%). At implantation, the mean age was 56 years and the median time on VAD support was 541 days. The overall infection rate per year per patient was 1.4. Forty-seven patients (60%) suffered from VAD-specific/related infection. Half of all infection episodes occurred in the first 4 months but the proportion of VAD-specific/related infection was higher after the first 4 months (74% of all infection). Using regression models, no patient specific risk factors were associated with VAD-specific/related infections. CONCLUSION: No predictive factors for infection during VAD support were identified in this study. By extension, diabetes, renal insufficiency, age or high BMI are not sufficient to deny a patient access to ventricular support.

Metabolic Sequelae of Everolimus Treatment After Cardiac Transplant: A Hypothesis-Generating Study.

BACKGROUND: Although modern immunosuppressants improve survival post-transplant, they are associated with long-term metabolic complications, such as post-transplant diabetes mellitus (PTDM). Calcineurin inhibitor-sparing regimens using everolimus attenuate some complications such as left ventricular hypertrophy. However, the metabolic effects of everolimus following transplant are less clear. METHODS: Post-hoc analysis to compare PTDM and other metabolic outcomes in participants of a randomised open-label clinical trial of low-dose everolimus and tacrolimus versus standard-dose tacrolimus in heart transplant recipients (RADTAC1 study). RESULTS: There were 39 participants in the trial; mean follow-up was 6.4±1.5 years. There was a high rate of pre-existing diabetes (26%) and newly diagnosed PTDM (36%) during follow-up. Half the patients who developed PTDM in the everolimus-tacrolimus group (n=4/8) ceased diabetes medications during follow-up, which was not observed in patients on standard tacrolimus (n=0/6). In the first 12 months there was a higher use of non-insulin treatment for diabetes in the everolimus-tacrolimus group compared to the standard tacrolimus group. CONCLUSIONS: This study suggests that treatment with everolimus may be associated with improved glycaemic control of PTDM relative to treatment with standard doses of calcineurin inhibitor. These findings should be further studied in prospective randomised trials.

Importance of electromagnetic interactions between ICD and VAD devices-Mechanistic assessment.

BACKGROUND: Implanted cardioverter defibrillators (ICDs) and left ventricular assist devices (LVADs) are established interventions that prolong life in advanced heart failure, but their combination has not been demonstrated as beneficial. Electromagnetic interference (EMI) produced by a LVAD can preclude ICD interrogation with external programmers. We undertook a systematic evaluation of the LVAD-ICD interaction "in-vitro" to clarify the extent of this interaction. METHODS: Using explanted ICDs and VADs in a mock physiological rig, we assessed interrogation and reprogramming of ICD devices in the presence of a running LVAD. When connectivity between the ICD programmer and the ICD failed, we attempted three different techniques to re-establish connectivity: (1) Electromagnetic shielding of the ICD with a pseudo-faraday cage; (2) altering the LVAD speed; and (3) increasing the distance between the VAD and the ICD. RESULTS: We tested a total of 24 ICDs from different manufacturers in the presence of the Heartware (HW) and HeartMate 3 (HM3) LVADs. With HW, we only observed interaction with Biotronik ICD devices at very close range (0-6 cm). With HM3, only Medtronic ICD devices showed no interaction. Interactions could be mitigated by increasing the VAD-ICD distance. CONCLUSIONS: LVADs, notably the HM3, produce EMI that interferes with the communication between an ICD and its respective programmer. This may need to be considered when choosing the type of VAD to implant in patients with a previously implanted left-sided ICD. The only safe way to regain connectivity is to increase the distance between the VAD and the ICD, with patients raising their arm above their head.

Anatomical human fitting of the BiVACOR total artificial heart.

BACKGROUND: BiVACOR is a novel total artificial heart (TAH) utilizing a single centrifugal magnetically levitated rotor with the ability to modulate pulsatile flow. The device has been successfully tested in a bovine model. We undertook a multicenter anatomical and virtual fitting study of the BiVACOR in patients undergoing heart transplantation. METHODS: 10 patients were recruited across two heart transplant centers. A sterilized 1:1 titanium model of the device was inserted into the patient's chest post heart explant, prior to implantation of the donor heart. Measurements were recorded in situ. The device was then removed. Following this, retrospective 3D reconstructions were created from computed tomography chest scans to simulate a virtual fitting. RESULTS: Mean age was 53 years (range 38-67). Mean BMI was 28 (range 20-37). Heart failure etiology was varied-with ischemic cardiomyopathy being the most common. Mean spine-to-sternum distance at the tenth thoracic vertebrae (T10) was 14 cm (range 11-18). Mean aorta to aortic Port distance was 0.2 cm (range 0-0.5). Mean pulmonary artery to pulmonary artery port distance was 4.2 cm (range 1-7). The device fitted suitably in all patients without gross distortion to the geometry between native vessel/chamber and port. CONCLUSIONS: This study described the anatomical and virtual fitting of the BiVACOR TAH. The device fit well within the chest cavities of all 10 patients, who represented a variety of body morphologies and heart failure etiology.

Clinical characteristics and prognosis of cardiac amyloidosis defined by mass spectrometry-based proteomics in an Australian cohort.

BACKGROUND: Cardiac amyloidosis has a very poor prognosis, but it is the nature of the involved precursor protein that ultimately dictates treatment and survival. AIM: Definitively characterise the amyloid subtype by mass spectrometry (MS) in an Australian cohort of patients with cardiac amyloidosis. METHODS: We report the clinical characteristics and survival of 47 cardiac amyloid patients across two Australian centres including 39 patients evaluated for definitive amyloid subtype utilising laser microdissection and tandem mass spectrometry. RESULTS: A quarter (n = 12) of patients were classified as wild-type transthyretin amyloidosis (ATTRwt), 33 patients as light or heavy chain amyloidosis (AL or AH) and two as hereditary mutant transthyretin amyloidosis. Greater left ventricular hypertrophy (interventricular septum 22 vs 15 mm; P = 0.005) and history of cardiac arrhythmia (75% vs 31%; P = 0.016) were significantly associated with ATTRwt patients compared with AL/AH patients. AL patients demonstrated significantly shorter median survival compared with ATTRwt patients (3.5 vs 37 months; P = 0.007). New York Heart Association class III-IV symptoms or plasma cells ≥10% at diagnosis, were the only independent predictors of worse survival in AL patients on multivariate analysis. CONCLUSIONS: AL amyloidosis accounted for 68% of our cohort of patients with cardiac amyloidosis while ATTR accounted for 26%. In the era of novel therapies for both AL amyloid and ATTR, identification of the correct amyloid subtype is essential in making therapeutic decisions and providing accurate prognostic information to patients. Laser microdissection and tandem mass spectrometry plays an important role in identifying amyloid subtype, particularly in complex cases.

Vasoplegia in patients following ventricular assist device explant and heart transplantation.

BACKGROUND: Vasoplegia has been shown to be associated with increased morbidity and mortality in patients undergoing cardiac surgery. It has been previously stated that low pulsatile states as seen with current left ventricular assist devices (LVADs) may contribute to vasoplegia post LVAD-explant and heart transplant. We sought to examine the literature regarding vasoplegia in the post-operative setting for patients undergoing LVAD explant and heart transplant. METHOD: A literature review was conducted to firstly define vasoplegia in the setting of LVAD patients, and secondly to better understand the relationship between vasoplegia and LVAD explantation in the postoperative heart transplant patient cohort. A keyword search of 'vasoplegia' OR 'vasoplegic' AND 'transplant' was used. Search engines used were PubMed, Cochrane Library, ClinicalTrials.gov, Ovid, Scopus and grey literature. RESULTS: 17 studies met the selection criteria for review. Three key themes emerged from the literature. Firstly, there is limited consensus regarding the definition of vasoplegia. Secondly, patients with LVADs experienced higher rates of vasoplegia following heart transplant than their counterparts and thirdly, increased cardiopulmonary bypass time was associated with a higher rate of vasoplegia. CONCLUSION: Vasoplegia is not clearly defined in the literature as it pertains to the LVAD patient cohort. Patients bridged with LVADs appear to have higher rates of vasoplegia, however the aetiology of this is unclear and may be associated with continuous flow physiology or prolonged cardiopulmonary bypass time. A universal definition will aid in risk stratification, early recognition and management.

Transapical Transcatheter Mitral Valve Implantation in Heart Failure: Haemodynamic Challenges for a New Frontier.

Secondary mitral regurgitation (MR) and heart failure are mutually dependent. Secondary MR occurs as a consequence of heart failure in patients with impaired left ventricular (LV) function, decreasing cardiac efficiency, accelerating a decline in contractility and worsening the already dismal prognosis of these patients. Advances in transcatheter techniques have now given promise to improved survival, outcomes, and quality of life for patients with advanced heart failure and secondary MR. Although transcatheter edge-to-edge repair is well established, transapical transcatheter mitral valve implantation (TMVI) may represent a more durable solution for correction of secondary MR without the need for cardiopulmonary bypass. Correction of MR, however, is thought to acutely increase LV afterload due to the elimination of low afterload regurgitant flow. In high-risk patients, this may cause acute decompensated heart failure. Off-pump TMVI on a beating heart poses a number of unique challenges, but also the opportunity to study invasive haemodynamic indices in high-risk heart failure patients for the first time. In the following discussion, we review the acute haemodynamic changes during off-pump TMVI in patients with heart failure in order to better guide optimal patient selection and management.

Phenotyping of Stable Left Ventricular Assist Device Patients Using Noninvasive Pump Flow Responses to Acute Loading Transients.

BACKGROUND: Although it has been established that continuous flow left ventricular assist devices are sensitive to loading conditions, the effect of acute load and postural changes on pump flow have not been explored systematically. METHODS AND RESULTS: Fifteen stable outpatients were studied. Patients sequentially transitioned from the seated position to supine, passive leg raise, and standing with transition effects documented. A modified Valsalva maneuver, consisting of a forced expiration with an open glottis, was performed in each position. A sustained, 2-handed handgrip was performed in the supine position. The pump flow waveform was recorded continuously and left ventricular end-diastolic diameter measured during each stage using transthoracic echocardiography. Transitioning from seated to supine posture produced a significant increase in the flow and the ventricular end-diastolic diameter, consistent with an increased preload. The transition from supine to standing produced a transient increase in the mean flow and decreased the flow pulsatility index. At steady state, these changes were reversed with a decrease in the mean and trough flow and increased pulsatility index, consistent with venous redistribution and possible baroreflex compensation. Four distinct patterns of standing-induced flow waveform effects were identified, reflecting varying preload, afterload, and individual compensatory effects. A sustained handgrip produced a significant decrease in flow and increase in flow pulsatility across all patients, reflecting an increased afterload pressure. A modified Valsalva maneuver produced a decrease in the flow pulsatility while seated, supine, and standing, but not during leg raise. Five patterns of pulsatility effect during Valsalva were observed: (1) minimal change, (2) pulsatility recovery, (3) rapid flatline, (4) slow flatline with delayed flow recovery, and (5) primary suction. CONCLUSIONS: Acute disturbances in loading conditions produce heterogeneous pump flow responses reflecting their complex interactions with pump and ventricular function as well as reflex compensatory mechanisms. Differences in responses and individual variabilities have significant implications for automated pump control algorithms.

Colonic malakoplakia in a dual stem cell and cardiac transplant recipient: A case report and literature review.

We describe the first published case of malakoplakia in a dual stem cell and cardiac transplant recipient. In the 2 months following cardiac transplantation, our patient developed persistent diarrhea and recurrent E coli bacteremia. Biopsies obtained from areas of colonic thickening revealed malakoplakia. Despite improvement in symptoms with prolonged antimicrobial therapy and reduction of his immunosuppression, he eventually died from sepsis. Our case highlights not only the importance of the timely diagnosis of this rare disorder, but also the difficulty in determining optimal treatment duration, particularly where excision of involved areas is not possible, as data on this disease are lacking. Here we describe our case and review the available literature published on malakoplakia in the cardiac transplant population.

The formation of submillimetre-bright galaxies from gas infall over a billion years.

Submillimetre-bright galaxies at high redshift are the most luminous, heavily star-forming galaxies in the Universe and are characterized by prodigious emission in the far-infrared, with a flux of at least five millijanskys at a wavelength of 850 micrometres. They reside in haloes with masses about 10(13) times that of the Sun, have low gas fractions compared to main-sequence disks at a comparable redshift, trace complex environments and are not easily observable at optical wavelengths. Their physical origin remains unclear. Simulations have been able to form galaxies with the requisite luminosities, but have otherwise been unable to simultaneously match the stellar masses, star formation rates, gas fractions and environments. Here we report a cosmological hydrodynamic galaxy formation simulation that is able to form a submillimetre galaxy that simultaneously satisfies the broad range of observed physical constraints. We find that groups of galaxies residing in massive dark matter haloes have increasing rates of star formation that peak at collective rates of about 500-1,000 solar masses per year at redshifts of two to three, by which time the interstellar medium is sufficiently enriched with metals that the region may be observed as a submillimetre-selected system. The intense star formation rates are fuelled in part by the infall of a reservoir gas supply enabled by stellar feedback at earlier times, not through major mergers. With a lifetime of nearly a billion years, our simulations show that the submillimetre-bright phase of high-redshift galaxies is prolonged and associated with significant mass buildup in early-Universe proto-clusters, and that many submillimetre-bright galaxies are composed of numerous unresolved components (for which there is some observational evidence).

Discrepancies between proxy estimates and patient reported, health related, quality of life: minding the gap between patient and clinician perceptions in heart failure.

PURPOSE: Health related quality of life (HRQoL) is rarely routinely measured in the clinical setting. In the absence of patient reported data, clinicians rely on proxy and informal estimates to support clinical decisions. This study compares clinician estimates (proxy) with patient reported HRQoL in patients with advanced heart failure and examines factors influencing discrepancies. METHODS: Seventy-five patients with heart failure, (22 females, 53 males) completed the EQ-5D-5L questionnaire. Thirty-nine clinicians (11 medical, 23 nursing, 5 allied health) completed the proxy version (V1) producing 194 dyads. Correlation was assessed using Spearman's rank tests, systematic bias was examined with Bland-Altman analyses. Inter-rater agreement at the domain level, was investigated using linear weighted Kappa statistics while factors influencing the IRG were explored using independent student t-tests, analysis of variance and regression. RESULTS: There was a moderate positive correlation between clinician HRQoL estimates and patient reported utility (r = 0.38; p < .0005). Mean clinician estimates were higher than patient reported utility (0.60 vs 0.54; p = 0.008), with significant underestimation of reported problems apparent in three of the five EQ-5D-5L domains. Patient sex (female), depressed mood and frailty were all associated with an increased inter-rater gap. CONCLUSION: Clinicians in this sample overestimated HRQoL. Factors affecting the inter-rater gap, including sex and depression, support formal HRQoL screening to enhance clinical conversations and decision making. The discrepancy also supports regulatory restriction on the use of expert opinion in the development of QALYs in health economic analysis.

The use of direct oral anticoagulants in patients with ventricular assist devices: Is there hope for Factor Xa inhibition?

The use of continuous-flow ventricular assist devices (cf-VAD) necessitates systemic anticoagulation, routinely with vitamin K antagonists (VKA). Newer direct oral anticoagulants (DOACs) have significant advantages over VKA in providing a predictable level of systemic anticoagulation without frequent monitoring or strict dietary surveillance. Despite randomized evidence demonstrating their usefulness in several conditions including atrial fibrillation, there is limited data pertaining to their use in cf-VAD patients. Early reports of adverse outcomes has resulted in a Class III recommendation, advising against DOACs generally in cf-VAD patients. Recent reports suggest there may be a role for certain DOACs; as such we present a systematic review identifying studies reporting DOAC uses in patients with a cf-VAD. We identified eight pertinent studies, including a single randomized controlled trial and seven case reports/series. Limited numbers and significant study heterogeneity limits interpretation; however, Factor Xa inhibitors appear to be feasible alternatives, favorable to direct thrombin inhibitors, although further research is required.

Ageing, Hypertension and Aortic Valve Stenosis: A Conscious Uncoupling.

Aortic valve stenosis (AS) is no longer considered to be a disease of fixed left ventricular (LV) afterload (due to an obstructive valve), but rather, functions as a series circuit with important contributions from both the valve and ageing vasculature. Patients with AS are frequently elderly, with hypertension and a markedly remodelled aorta. The arterial component is sizable, and yet, the contribution of ventricular afterload has been difficult to determine. Arterial stiffening increases the speed of propagation of the blood pressure wave along the central arteries (estimated as the pulse wave velocity), which results in an earlier return of reflected waves. The effect is to augment blood pressure in the proximal aorta during systole, increasing the central pulse pressure and, in turn, placing even greater afterload on the heart. Elevated global LV afterload is known to have adverse consequences on LV remodelling, function and survival in patients with AS. Consequently, there is renewed focus on methods to estimate the relative contributions of local versus global changes in arterial mechanics and valvular haemodynamics in patients with AS. We present a review on existing and upcoming methods to quantify valvulo-arterial impedance and thereby global LV load in patients with AS.