Search

Background: This study investigated oxygen handling of human hearts donated after circulatory death (DCD) on normothermic ex-situ heart perfusion (ESHP) and evaluated oxygen handling markers as adjuncts to cardiac viability assessment. Methods: This single-center retrospective study included human DCD heart transplantation procedures using ESHP. Lactate concentrations, blood gas, myocardial oxygen consumption (MVO2), delivery (MDO2), and extraction (MEO2), coronary blood flow (CBF), coronary vascular resistance (CVR), and adenosine infusion were reported over time. Correlation between parameters was assessed, and statistical testing compared patients who did and did not require extracorporeal membrane oxygenation (ECMO) support after transplantation. Results: Lactate concentrations decreased during ESHP in all transplanted hearts (n = 25) and increased in 1 rejected heart. Arterial partial pressure of oxygen (PO2) was 75.2 ± 2.9 kPa, with an arteriovenous ΔPO2 of 44.8 ± 10.4 kPa. Oxygen saturation was 100% in most arterial and venous samples. Average MVO2 was 2.7 ± 0.6 ml/min/100 g myocardium, MDO2 98.5 ± 20.4 ml/min, and MEO2 8.6 ± 1.8%. Average CVR was 0.025 ± 0.006 mm Hg min/ml/100 g and increased over time. ΔPO2 correlated strongly with MVO2 (R = 0.797, p

Abstract Boolean networks (BNs) have been extensively used to model gene regulatory networks (GRNs). The dynamics of BNs depend on the network architecture and regulatory logic rules (Boolean functions (BFs)) associated with nodes. Nested canalyzing functions (NCFs) have been shown to be enriched among the BFs in the large-scale studies of reconstructed Boolean models. The central question we address here is whether that enrichment is due to certain sub-types of NCFs. We build on one sub-type of NCFs, the chain functions (or chain-0 functions) proposed by Gat-Viks and Shamir. First, we propose two other sub-types of NCFs, namely, the class of chain-1 functions and generalized chain functions, the union of the chain-0 and chain-1 types. Next, we find that the fraction of NCFs that are chain-0 (also holds for chain-1) functions decreases exponentially with the number of inputs. We provide analytical treatment for this and other observations on BFs. Then, by analyzing three different datasets of reconstructed Boolean models we find that generalized chain functions are significantly enriched within the NCFs. Lastly we illustrate that upon imposing the constraints of generalized chain functions on three different GRNs we are able to obtain biologically viable Boolean models.

Abstract Aims Current heart failure (HF) guidelines recommend to prescribe four drug classes in patients with HF with reduced ejection fraction (HFrEF). A clear challenge exists to adequately implement guideline‐directed medical therapy (GDMT) regarding the sequencing of drugs and timely reaching target dose. It is largely unknown how the paradigm shift from a serial and sequential approach for drug therapy to early parallel application of the four drug classes will be executed in daily clinical practice, as well as the reason clinicians may not adhere to new guidelines. We present the design and rationale for the real‐world TITRATE‐HF study, which aims to assess sequencing strategies for GDMT initiation, dose titration patterns (order and speed), intolerance for GDMT, barriers for implementation, and long‐term outcomes in patients with de novo, chronic, and worsening HF. Methods and results A total of 4000 patients with HFrEF, HF with mildly reduced ejection fraction, and HF with improved ejection fraction will be enrolled in >40 Dutch centres with a follow‐up of at least 3 years. Data collection will include demographics, physical examination and vital parameters, electrocardiogram, laboratory measurements, echocardiogram, medication, and quality of life. Detailed information on titration steps will be collected for the four GDMT drug classes. Information will include date, primary reason for change, and potential intolerances. The primary clinical endpoints are HF‐related hospitalizations, HF‐related urgent visits with a need for intravenous diuretics, all‐cause mortality, and cardiovascular mortality. Conclusions TITRATE‐HF is a real‐world multicentre longitudinal registry that will provide unique information on contemporary GDMT implementation, sequencing strategies (order and speed), and prognosis in de novo, worsening, and chronic HF patients.

With remarkable advancements in the development of connected and autonomous vehicles (CAVs), the integration of teleoperation has become crucial for improving safety and operational efficiency. However, teleoperation faces substantial challenges, with network latency being a critical factor influencing its performance. This survey paper explores the impact of network latency along with state-of-the-art mitigation/compensation approaches. It examines cascading effects on teleoperation communication links (i.e., uplink and downlink) and how delays in data transmission affect the real-time perception and decision-making of operators. By elucidating the challenges and available mitigation strategies, the paper offers valuable insights for researchers, engineers, and practitioners working towards the seamless integration of teleoperation in the evolving landscape of CAVs.

Abstract Aims Heart failure (HF) is a progressive disease in which periods of clinical stability are interrupted by episodes of clinical deterioration known as worsening heart failure (WHF). Patients who develop WHF are at high risk of subsequent death, rehospitalization, and excessive healthcare costs. As such, WHF could be seen as a separate disease stage and precursor of advanced HF. Whether WHF has a substantial health, societal, and economic impact evidence regarding its multifactorial nature and the specific barriers in treatment, including advanced HF therapies, remains scarce. The CHAIN‐HF registry aims to describe the incidence, characteristics, current treatment, and outcomes of WHF. Additionally, it will promote structured regional collaboration and educate on increasing awareness for WHF and describe the implementation of guideline directed medical therapy and utilization of advanced HF therapies in a collaborative network. Methods and results The CHAIN‐HF registry is a prospective, observational, and multicentre study from the collaborating hospitals (Rijnmond HF Network) in the Rotterdam area. Unselected and consecutive patients (irrespective of ejection fraction) with a WHF event will be included. Comprehensive data including demographics, co‐morbidities, treatment, and in‐hospital and post‐discharge outcomes will be collected. Notably, data on socio‐economic status, treatment decisions, and referral for advanced HF therapies will be included. Conclusions CHAIN‐HF will be the first prospective, dedicated WHF registry in a collaborative network of hospitals that will provide robust real‐world evidence on the incidence, characteristics, and outcomes of WHF. Moreover, it will provide information on of the value of regional collaboration to improve awareness and outcomes of WHF.

Hypertrophic cardiomyopathy (HCM) is the most common inherited myocardial disorder of the heart, but effective treatment options remain limited. Mavacamten, a direct myosin modulator, has been presented as novel pharmacological therapy for HCM. The aim of this study was to analyze the biomechanical response of HCM tissue to Mavacamten using living myocardial slices (LMS). LMS (n = 58) from patients with HCM (n = 10) were cultured under electromechanical stimulation, and Verapamil and Mavacamten were administered on consecutive days to evaluate their effects on cardiac biomechanics. Mavacamten and Verapamil reduced contractile force and dF/dt and increased time-to-relaxation in a similar manner. Yet, the time-to-peak of the cardiac contraction was prolonged after administration of Mavacamten (221.0 ms (208.8 – 236.3) vs. 237.7 (221.0 – 254.7), p = 0.004). In addition, Mavacamten prolonged the functional refractory period (FRP) (330 ms (304 − 351) vs. 355 ms (313 − 370), p = 0.023) and better preserved twitch force with increasing stimulation frequencies, compared to Verapamil. As such, Mavacamten reduced (hyper-)contractility and prolonged contraction duration of HCM LMS, suggesting a reduction in cardiac wall stress. Also, Mavacamten might protect against the development of ventricular tachyarrhythmias due to prolongation of the FRP, and improve toleration of tachycardia due to better preservation of twitch force at tachycardiac stimulation frequencies.

Background. Bacterial colonization (BC) of the lower airways is common in lung transplant recipients (LTRs) and increases the risk of chronic lung allograft dysfunction. Diagnosis often requires bronchoscopy. Exhaled breath analysis using electronic nose (eNose) technology may noninvasively detect BC in LTRs. Therefore, we aimed to assess the diagnostic accuracy of an eNose to detect BC in LTRs. Methods. We performed a cross-sectional analysis within a prospective, single-center cohort study assessing the diagnostic accuracy of detecting BC using eNose technology in LTRs. In the outpatient clinic, consecutive LTR eNose measurements were collected. We assessed and classified the eNose measurements for the presence of BC. Using supervised machine learning, the diagnostic accuracy of eNose for BC was assessed in a random training and validation set. Model performance was evaluated using receiver operating characteristic analysis. Results. In total, 161 LTRs were included with 80 exclusions because of various reasons. Of the remaining 81 patients, 16 (20%) were classified as BC and 65 (80%) as non-BC. eNose-based classification of patients with and without BC provided an area under the curve of 0.82 in the training set and 0.97 in the validation set. Conclusions. Exhaled breath analysis using eNose technology has the potential to noninvasively detect BC.

Heart failure (HF) is a rapidly growing pandemic while medical treatment options remain limited. Omecamtiv mecarbil (OM) is a novel HF drug that directly targets the myosin heads of the cardiac muscle. This study used living myocardial slices (LMS) from patients with HF to evaluate the direct biomechanical effects of OM as compared to dobutamine. LMS were produced from patients with end-stage HF undergoing cardiac transplantation or left ventricular assist device implantation and cultured under electromechanical stimulation (diastolic preload: ca. 1 mN, stimulation frequency: 0.5 Hz). Dobutamine and omecamtiv mecarbil (OM) were administered on consecutive days and biomechanical effects were continuously recorded with dedicated force transducers. OM and dobutamine significantly increased contractile force to a similar maximum force, but OM also increased median time-to-peak with 48 % (p = 0.046) and time-to-relaxation with 68 % (p = 0.045). OM administration led to impaired relaxation of HF LMS with increasing stimulation frequencies, which was not observed with dobutamine. Furthermore, the functional refractory period was significantly shorter after administration of OM compared to dobutamine (235 ms (200–265) vs. 270 ms (259–283), p = 0.035). In conclusion, OM increased contractile force and systolic duration of HF LMS, indicating an improvement in cardiac function and normalization of systolic time intervals in patients with HF. Conversely, OM slowed relaxation, which could lead to diastolic filling abnormalities. As such, OM showed benefits on systolic function on one hand but potential hindrances of diastolic function on the other hand.

Abstract Background Genotyping and sequencing technologies produce increasingly large numbers of genetic markers with potentially high rates of missing or erroneous data. Therefore, the construction of linkage maps is more and more complex. Moreover, the size of segregating populations remains constrained by cost issues and is less and less commensurate with the numbers of SNPs available. Thus, guaranteeing a statistically robust marker order requires that maps include only a carefully selected subset of SNPs. Results In this context, the SeSAM software allows automatic genetic map construction using seriation and placement approaches, to produce (1) a high-robustness framework map which includes as many markers as possible while keeping the order robustness beyond a given statistical threshold, and (2) a high-density total map including the framework plus almost all polymorphic markers. During this process, care is taken to limit the impact of genotyping errors and of missing data on mapping quality. SeSAM can be used with a wide range of biparental populations including from outcrossing species for which phases are inferred on-the-fly by maximum-likelihood during map elongation. The package also includes functions to simulate data sets, convert data formats, detect putative genotyping errors, visualize data and map quality (including graphical genotypes), and merge several maps into a consensus. SeSAM is also suitable for interactive map construction, by providing lower-level functions for 2-point and multipoint EM analyses. The software is implemented in a R package including functions in C++. Conclusions SeSAM is a fully automatic linkage mapping software designed to (1) produce a framework map as robust as desired by optimizing the selection of a subset of markers, and (2) produce a high-density map including almost all polymorphic markers. The software can be used with a wide range of biparental mapping populations including cases from outcrossing. SeSAM is freely available under a GNU GPL v3 license and works on Linux, Windows, and macOS platforms. It can be downloaded together with its user-manual and quick-start tutorial from ForgeMIA (SeSAM project) at https://forgemia.inra.fr/gqe-acep/sesam/-/releases

Abstract Boolean networks have been widely used to model gene networks. However, such models are coarse-grained to an extent that they abstract away molecular specificities of gene regulation. Alternatively, bipartite Boolean network models of gene regulation explicitly distinguish genes from transcription factors (TFs). In such bipartite models, multiple TFs may simultaneously contribute to gene regulation by forming heteromeric complexes, thus giving rise to composition structures. Since bipartite Boolean models are relatively recent, an empirical investigation of their biological plausibility is lacking. Here, we estimate the prevalence of composition structures arising through heteromeric complexes. Moreover, we present an additional mechanism where composition structures may arise as a result of multiple TFs binding to cis-regulatory regions and provide empirical support for this mechanism. Next, we compare the restriction in BFs imposed by composition structures and by biologically meaningful properties. We find that though composition structures can severely restrict the number of Boolean functions (BFs) driving a gene, the two types of minimally complex BFs, namely nested canalyzing functions (NCFs) and read-once functions (RoFs), are comparatively more restrictive. Finally, we find that composition structures are highly enriched in real networks, but this enrichment most likely comes from NCFs and RoFs.

Abstract In June 2021, the Pacific Northwest experienced a heatwave that broke all previous records. Estimated return levels based on observations up to the year before the event suggested that reaching such high temperatures is not possible in today's climate. We here assess the suitability of the prevalent statistical approach by analyzing extreme temperature events in climate model large ensemble and synthetic extreme value data. We demonstrate that the method is subject to biases, as high return levels are generally underestimated and, correspondingly, the return period of low‐likelihood heatwave events is overestimated, if the underlying extreme value distribution is derived from a short historical record. These biases have even increased in recent decades due to the emergence of a pronounced climate change signal. Furthermore, if the analysis is triggered by an extreme event, the implicit selection bias affects the likelihood assessment depending on whether the event is included in the modeling.

AimsChronic kidney disease (CKD) pre-heart transplantation (HTx) has been proposed as a risk factor for malignancy risk post-HTx. Using multicenter registry data, our aim was to calculate the death-adjusted annual incidence of malignancies post-HTx, corroborate the association between CKD pre-HTx and malignancy risk post-HTx, and determine other risk factors for post-HTx malignancies.Methods and materialsWe used data from patients transplanted in North American HTx centers between January 2000 and June 2017 and registered in the International Society for Heart and Lung Transplantation Thoracic Organ Transplant Registry. We excluded recipients with missing data on post-HTx malignancies, heterotopic heart transplant, retransplantation, multi-organ transplantation, and patients with a total artificial heart pre-HTx.ResultsOverall, 34,873 patients were included to determine the annual incidence of malignancies, 33,345 patients were included in the risk analyses. The incidence of any malignancy, solid-organ malignancy, post-transplant lymphoproliferative disease (PTLD), and skin cancer adjusted for death 15 years post-HTx, was 26.6%, 10.9%, 3.6%, and 15.8% respectively. Besides widely acknowledged risk factors, CKD stage ≥4 pre-HTx was associated with the development of all malignancies post-HTx (HR 1.17 compared to CKD stage 1, p = 0.023), as well as solid-organ malignancies (HR 1.35, p = 0.01), but not for PTLD (HR 0.73, p = 0.057), and skin cancer (HR 1.06, p = 0.59).ConclusionRisk of malignancy post-HTx remains high. CKD stages ≥4 pre-HTx was associated with an increased risk for any malignancy and solid-organ malignancy post-HTx. Strategies to mitigate the impact of pre-HTx patient factors on the risk of post-HTx malignancy are needed.

Abstract Aims The need for permanent pacemakers (PMs) after heart transplantation (HT) is increasing. The aim was to determine the influence of cardiac allograft vasculopathy (CAV), donor age, and other risk factors on PM implantations early and late after HT and its effect on survival. Methods and results A retrospective, single‐centre study was performed including HTs from 1984 to July 2018. Early PM was defined as PM implantation ≤90 days and late PM as PM > 90 days. Risk factors for PM and survival after PM were determined with (time‐dependent) multivariable Cox regression. Out of 720 HTs performed, 62 were excluded (55 mortalities ≤30 days and 7 retransplantations). Of the remaining 658 patients, 95 (14%) needed a PM: 38 (6%) early and 57 (9%) late during follow‐up (median 9.3 years). Early PM risk factors were donor age [hazard ratio (HR) 1.06, P

Background: Right ventricular failure (RVF) is a significant cause of morbidity and mortality in patients with a left ventricular assist device (LVAD). This study is aimed to investigate the influence of a pectus excavatum on early and late outcomes, specifically RVF, following LVAD implantation. Methods: A retrospective study was performed, that included patients with a HeartMate 3 LVAD at our tertiary referral center. The Haller index (HI) was calculated using computed tomography (CT) scan to evaluate the chest-wall dimensions. Results: In total, 80 patients (median age 57 years) were included. Two cohorts were identified: 28 patients (35%) with a normal chest wall (HI 30 days) recurrent readmission for RVF occurred more often in patients with pectus excavatum (p = 0.008). The onset of late RVF started around 18 months after implantation and increased thereafter in the overall study cohort. Conclusions: Pectus excavatum is observed frequently in patients with a LVAD implantation. These patients have an increased rate of readmissions and late RVF. Further investigation is required to explore the extent and severity of chest-wall abnormalities on the risk of RVF.

Abstract Background Accurately predicting which patients with chronic heart failure (CHF) are particularly vulnerable for adverse outcomes is of crucial importance to support clinical decision making. The goal of the current study was to examine the predictive value on long term heart failure (HF) hospitalisation and all-cause mortality in CHF patients, by exploring and exploiting machine learning (ML) and traditional statistical techniques on a Dutch health insurance claims database. Methods Our study population consisted of 25,776 patients with a CHF diagnosis code between 2012 and 2014 and one year and three years follow-up HF hospitalisation (1446 and 3220 patients respectively) and all-cause mortality (2434 and 7882 patients respectively) were measured from 2015 to 2018. The area under the receiver operating characteristic (ROC) curve (AUC) was calculated after modelling the data using Logistic Regression, Random Forest, Elastic Net regression and Neural Networks. Results AUC rates ranged from 0.710 to 0.732 for 1-year HF hospitalisation, 0.705–0.733 for 3-years HF hospitalisation, 0.765–0.787 for 1-year mortality and 0.764–0.791 for 3-years mortality. Elastic Net performed best for all endpoints. Differences between techniques were small and only statistically significant between Elastic Net and Logistic Regression compared with Random Forest for 3-years HF hospitalisation. Conclusion In this study based on a health insurance claims database we found clear predictive value for predicting long-term HF hospitalisation and mortality of CHF patients by using ML techniques compared to traditional statistics.

Abstract Aims Lifestyle changes, such as increasing physical activity (PA), are a cornerstone of treatment of patients with chronic heart failure (HF). However, improving PA in HF patients is challenging, and low participation rates for cardiac rehabilitation (CR) as well as relapse to low PA levels after CR are major issues. We designed a randomized controlled trial to investigate if PA monitoring with motivational feedback before and after centre‐based CR in HF patients with reduced ejection fraction (HFrEF) will lead to a clinically meaningful increase in physical fitness. Methods and results A randomized controlled trial will be conducted in a sample of 180 HFrEF patients (New York Heart Association Class II/III) who are referred to 12‐week standard CR. Patients will be randomized (2:1) to (1) standard of care (SoC) plus wearing a PA monitoring device (Fitbit Charge 3) with personalized step goals, feedback and motivation or (2) SoC only. The intervention lasts ±7 months: 4–5 weeks before CR, 12 weeks during CR and 12 weeks after CR. Measurements will take place at three time points. The primary endpoint is the change in the distance in 6‐min walking test (6MWT) over the entire study period. Other endpoints include step count, grip strength, quality of life and all‐cause mortality or hospitalization. Conclusions HF‐aPProACH will provide novel information on the effectiveness of remote PA stimulation and feedback before, during and after standard CR using a commercially available device to improve physical fitness in HFrEF patients.

Solid organ transplant recipients (SOTRs) are at high risk of human herpesvirus (HHV)-related morbidity and mortality due to the use of immunosuppressive therapy. We aim to increase awareness and understanding of HHV disease burden in SOTRs by providing an overview of current prevention and management strategies as described in the literature and guidelines. We discuss challenges in both prevention and treatment as well as future perspectives.

Abstract Aims This study aimed to investigate the left ventricular (LV) remodelling and long‐term prognosis of patients with new‐onset acute heart failure (HF) with reduced ejection fraction who were pharmacologically managed and survived until hospital discharge. We compared patients with ischaemic and non‐ischaemic aetiology. Methods and results This cohort study consisted of 111 patients admitted with new‐onset acute HF in the period 2008–2016 [62% non‐ischaemic aetiology, 48% supported by inotropes, vasopressors, or short‐term mechanical circulatory devices, and left ventricular ejection fraction (LVEF) at discharge 28% (interquartile range 22–34)]. LV dimensions, LVEF, and mitral valve regurgitation were used as markers for LV remodelling during up to 3 years of follow‐up. Both patients with non‐ischaemic and ischaemic HF had significant improvement in LVEF (P

Abstract Aims Recent reports demonstrated that patients with heart failure (HF) might have an increased risk to develop malignancies. This is also seen in patients with chronic kidney disease (CKD). Immunosuppression in heart transplantation (HT) recipients additionally increases the risk of malignancies. The aim of this study was to determine the relation between HF duration and CKD pre‐HT and the risk of malignancy development post‐HT. Methods and results We included all adult HT recipients transplanted between January 2000 and November 2017 in our centre. Patients were excluded if they died or were retransplanted within 3 months post‐HT. Clinical characteristics were retrospectively collected. Sixty out of 250 patients (24%) developed a malignancy after a median of 66 months [interquartile range 33–108] post‐HT. In multivariable Cox regression analysis, HF duration was not a risk factor for all malignancies or solid organ malignancies post‐HT [hazard ratio (HR) 1.033 (0.974–1.096), P = 0.281 and HR 1.036 (0.958–1.120), P = 0.376, respectively]. Age [HR 1.051 (1.016–1.086), P = 0.004] and CKD pre‐HT [HR 2.173 (1.236–3.822), P = 0.007] were independent risk factors for all malignancies. CKD pre‐HT [HR 2.542 (1.142–5.661), P = 0.022] increased the risk for solid organ malignancies. Exclusion of patients with durable mechanical circulatory support in the analysis did not alter the significance of these risk factors. Conclusions Duration of HF pre‐HT was not associated with malignancy risk post‐HT. CKD was an independent risk factor for malignancies post‐HT. More studies are needed to investigate this association.

Abstract Background Introgression of a quantitative trait locus (QTL) by successive backcrosses is used to improve elite lines (recurrent parent) by introducing alleles from exotic material (donor parent). In the absence of selection, the proportion of the donor genome decreases by half at each generation. However, since selection is for the donor allele at the QTL, elimination of the donor genome around that QTL will be much slower than in the rest of the genome (i.e. linkage drag). Using markers to monitor the genome around the QTL and in the genetic background can accelerate the return to the recurrent parent genome. Successful introgression of a locus depends partly on the occurrence of crossovers at favorable positions. However, the number of crossovers per generation is limited and their distribution along the genome is heterogeneous. Recently, techniques have been developed to modify these two recombination parameters. Results In this paper, we assess, by simulations in the context of Brassicaceae, the effect of increased recombination on the efficiency of introgression programs by studying the decrease in linkage drag and the recovery of the recurrent genome. The simulated selection schemes begin by two generations of foreground selection and continue with one or more generations of background selection. Our results show that, when the QTL is in a region that initially lacked crossovers, an increase in recombination rate can decrease linkage drag by nearly ten-fold after the foreground selection and improves the return to the recurrent parent. However, if the QTL is in a region that is already rich in crossovers, an increase in recombination rate is detrimental. Conclusions Depending on the recombination rate in the region targeted for introgression, increasing it can be beneficial or detrimental. Thus, the simulations analysed in this paper help us understand how an increase in recombination rate can be beneficial. They also highlight the best methods that can be used to increase recombination rate, depending on the situation.

Abstract Aims Health insurance claims (HIC) databases in the Netherlands capture unselected patient populations, which makes them suitable for epidemiological research on sex differences. Based on a HIC database, we aimed to reveal sex differences in heart failure (HF) outcomes, with particular focus on co‐morbidities and medication. Methods and results The Achmea HIC database included 14 517 men and 11 259 (45%) women with a diagnosis treatment code for chronic HF by January 2015. We related their sex, co‐morbidities, and medication adherence (medication possession rate >0.8) with the primary endpoint (PE) of all‐cause mortality or HF admission during a median follow‐up of 3.3 years, using Cox regression. Median age of men and women was 72 and 76 years, respectively. Prevalence of co‐morbidities and use of disease‐modifying drugs was higher in men; however, medication adherence was similar. At the end of follow‐up, 35.1% men and 31.8% women had reached the PE. The adjusted hazard ratio for men was 1.25 (95% confidence interval: 1.19–1.30). A broad range of co‐morbidities was associated with the PE. Overall, these associations were stronger in women than in men, particularly for renal insufficiency, chronic obstructive pulmonary disease/asthma, and diabetes. Non‐adherence to disease‐modifying drugs was related with a higher incidence of the PE, with similar effects between sexes. Conclusions In a representative sample of the Dutch population, as captured in a HIC database, men with chronic HF had a 25% higher incidence of death or HF admission than women. The impact of co‐morbidities on the outcome was sex dependent, while medication adherence was not.

PurposeBecause of the current lack of evidence-based antimicrobial treatment guidelines, Left Ventricular Assist Device (LVAD) infections are often treated according to local insights. Here, we propose a flowchart for protocolized treatment, in order to improve outcome.MethodsThe flowchart was composed based on literature, consensus and expert opinion statements. It includes choice, dosage and duration of antibiotics, and indications for suppressive therapy, with particular focus on Staphylococcus aureus (SA) (Figure 1). The preliminary treatment results of 28 patients (2 from start cephalexin suppressive therapy) after implementation in July 2018 are described.ResultsCumulative incidence for first episode of infection in a 3-year time period was 27% (26 of 96 patients with an LVAD). Twenty-one of 23 (91%) first episodes of driveline infection (10 superficial and 13 deep; nine of 13 caused by SA) were successfully treated with antibiotics according to flowchart with complete resolution of clinical signs and symptoms. For two patients with deep driveline infections, surgery was needed in addition. There were no relapses of deep driveline infections, and only 2 SA deep driveline re-infections after 6 months. Nine patients received cephalexin of whom four patients (44%) developed a breakthrough infection with cephalexin-resistant gram-negative bacteria.ConclusionsThe first results of this protocolized treatment approach of LVAD infections are promising. Yet, initiation of cephalexin suppressive therapy should be carefully considered given the occurrence of infections with resistant micro-organisms. The long-term outcome of this approach needs to be established in a larger number of patients, preferably in a multi-center setting.

This report describes the first heart transplantation recipient with acute biventricular heart failure symptoms caused by a post-myocarditis state, late after a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. No other viral pathogens could be detected. Computed tomography angiography did not show cardiac allograft vasculopathy, and myocardial biopsy demonstrated no clinically relevant rejection. Subsequent cardiovascular magnetic resonance imaging revealed extensive epicardial delayed enhancement without myocardial edema. Heart failure medication was initiated and an implantable cardioverter defibrillator was implanted (due to non-sustained ventricular tachycardias), leading to a partial recovery of the ejection fraction. Further studies are needed to investigate the number of heart transplant recipients with myocardial damage after a SARS-CoV-2 infection.

Abstract Data on the risk of aortic root thrombosis in patients with aortic valve replacement (AVR) and left ventricular assist device (LVAD) surgery are scarce. Two out of nine patients receiving AVR concomitant with LVAD surgery and two out of two patients receiving AVR on LVAD support, at our centre, developed an aortic root thrombus, all diagnosed with computed tomography (CT) angiography. These results demonstrate that patients with concomitant AVR and LVAD surgery, or AVR on LVAD support, have an increased risk of aortic root thrombosis. Therefore, early anti‐thrombotic therapy and vigilant diagnostic follow‐up, using CT scans, are warranted to prevent thromboembolic events.

Abstract Background There is no consensus on the optimal treatment for displaced midshaft clavicle fractures. Several studies indicate superior patient satisfaction in favour of operative reconstruction. It is unknown what drives superior satisfaction in this treatment group. The aim of this study was to explore patient satisfaction and identify contributors to patient satisfaction after operative and nonoperative treatment for displaced midshaft clavicle fractures in adults using a focus group approach. Methods Four face-to-face and two web-based focus groups were hosted. A total of 24 participants who were treated nonoperatively (n = 14) or operatively (n = 10) agreed to participate. Participants were selected using purposive sampling, ensuring variation in gender, age, treatment complications and outcomes. A question script was developed to systematically explore patient expectations, attitudes and satisfaction with different dimensions of care. All focus groups were voice-recorded and transcribed at verbatim. Thematic analysis was conducted on all face-to-face and web-based transcripts. Results The main emerging themes across treatment groups were; need for more information, functional recovery, speed of recovery and patient-doctor interaction. There was no difference in themes observed between operative and nonoperative focus groups. The lack of information was the most important complaint in dissatisfied patients. Conclusion Our study shows that informing patients about their injury, treatment options and expectations for recovery is paramount for overall patient satisfaction after treatment for a displaced midshaft clavicle fracture. Level of evidence Level III, focus group study.

Abstract Aims Many heart transplant recipients will develop end‐stage renal disease in the post‐operative course. The aim of this study was to identify the long‐term incidence of end‐stage renal disease, determine its risk factors, and investigate what subsequent therapy was associated with the best survival. Methods and results A retrospective, single‐centre study was performed in all adult heart transplant patients from 1984 to 2016. Risk factors for end‐stage renal disease were analysed by means of multivariable regression analysis and survival by means of Kaplan–Meier. Of 685 heart transplant recipients, 71 were excluded: 64 were under 18 years of age and seven were re‐transplantations. During a median follow‐up of 8.6 years, 121 (19.7%) patients developed end‐stage renal disease: 22 received conservative therapy, 80 were treated with dialysis (46 haemodialysis and 34 peritoneal dialysis), and 19 received a kidney transplant. Development of end‐stage renal disease (examined as a time‐dependent variable) inferred a hazard ratio of 6.45 (95% confidence interval 4.87–8.54, P < 0.001) for mortality. Tacrolimus‐based therapy decreased, and acute kidney injury requiring renal replacement therapy increased the risk for end‐stage renal disease development (hazard ratio 0.40, 95% confidence interval 0.26–0.62, P < 0.001, and hazard ratio 4.18, 95% confidence interval 2.30–7.59, P < 0.001, respectively). Kidney transplantation was associated with the best median survival compared with dialysis or conservative therapy: 6.4 vs. 2.2 vs. 0.3 years (P < 0.0001), respectively, after end‐stage renal disease development. Conclusions End‐stage renal disease is a frequent complication after heart transplant and is associated with poor survival. Kidney transplantation resulted in the longest survival of patients with end‐stage renal disease.

Purpose: We report our single-institution stereotactic body radiation therapy (SBRT) experience on stage I renal cancer with prospectively collected toxicity and efficacy data. Methods and Materials: A total of 21 patients with solitary renal tumors, including 14 surgical candidates who refused surgery (66%), were treated with SBRT. Histologic confirmation was obtained on all patients before treatment; 2 had transitional cell carcinoma and 19 had renal cell carcinoma. The median age was 71 years (range, 58-88). Nearly all patients received 48 Gy in 3 fractions. Results: The median follow-up was 78 months (range, 5-107). At 5 years post treatment, the local tumor control rate was 100%. Tumor size decreased by a median value of 5.3% at 1 year post treatment, 15.6% at 2 years post treatment, and 15.4% at 5 years post treatment. Glomerular filtration rate had decreased by a median value of 1.5% at 1 year post treatment, 7.0% at 2 years post treatment, and 14.2% at 5 years post treatment. Three patients experienced grade 1 toxicity; no other treatment-related adverse effects were reported. Conclusions: SBRT is a promising noninvasive treatment in the management of primary renal cell carcinoma, with evolving clinical evidence demonstrating encouraging results with respect to local control and toxicity.

In, essentially, all species where meiotic crossovers (COs) have been studied, they occur preferentially in open chromatin, typically near gene promoters and to a lesser extent, at the end of genes. Here, in the case of Arabidopsis thaliana, we unveil further trends arising when one considers contextual information, namely summarised epigenetic status, gene or intergenic region size, and degree of divergence between homologs. For instance, we find that intergenic recombination rate is reduced if those regions are less than 1.5 kb in size. Furthermore, we propose that the presence of single nucleotide polymorphisms enhances the rate of CO formation compared to when homologous sequences are identical, in agreement with previous works comparing rates in adjacent homozygous and heterozygous blocks. Lastly, by integrating these different effects, we produce a quantitative and predictive model of the recombination landscape that reproduces much of the experimental variation.

Meiotic recombination generates genetic diversity but in most species the number of crossovers per meiosis is limited. Previous modeling studies showed that increasing recombination can enhance response to selection. However, such studies did not assume a specific method of modifying recombination. Our objective was to test whether two methods used to increase recombination in plants could increase genetic gain in a population undergoing recurrent selection such as in genomic selection programs. The first method, in Oryza sativa, used a mutant of anti-crossover genes, increasing global recombination without affecting the recombination landscape shape. The second one used the ploidy level of a cross between Brassica rapa and Brassica napus, increasing recombination especially in pericentromeric regions. Our modeling framework used these recombination landscapes and sampled quantitative trait loci positions from the actual gene distributions. We simulated selection programs with initially a cross between two inbred lines, for two species. Increased recombination enhanced the response to selection. The amount of enhancement in the cumulative gain largely depended on the species and the number of quantitative trait loci (2, 10, 20, 50, 200 or 1000 per chromosome). Genetic gains were increased up to 30% after 20 generations. Furthermore, increasing recombination in cold regions was the most effective: the gain was larger by 25% with the first method and 34% with the second one in B. rapa, and 12% compared to 16% in O. sativa. In summary, increased recombination enhances the genetic gain in long-term selection programs, with visible effects after four to five generations.

Abstract Pulmonary hypertension (PH) type II (classified by the World Health Organization) is a common complication in chronic left‐sided heart failure. In advanced heart failure therapy, fixed PH is an absolute contraindication for heart transplantation after which a left ventricular assist device (LVAD) is the only remaining option. With remote monitoring, we can now continuously evaluate the pulmonary artery pressures during long‐term LV unloading by the LVAD. In this case, we demonstrate that fixed PH can be reversed with LVAD implantation, whereby previous thoughts of this concept should be redefined in the era of assist devices.

Large and growing data resources on the diversity, distribution, and properties of minerals are ushering in a new era of data-driven discovery in mineralogy. The most comprehensive international mineral database is the IMA database, which includes information on more than 5400 approved mineral species and their properties, and the mindat.org data source, which contains more than 1 million species/locality data on minerals found at more than 300 000 localities. Analysis and visualization of these data with diverse techniques—including chord diagrams, cluster diagrams, Klee diagrams, skyline diagrams, and varied methods of network analysis—are leading to a greater understanding of the co-evolving geosphere and biosphere. New data-driven approaches include mineral evolution, mineral ecology, and mineral network analysis—methods that collectively consider the distribution and diversity of minerals through space and time. These strategies are fostering a deeper understanding of mineral co-occurrences and, for the first time, facilitating predictions of mineral species that occur on Earth but have yet to be discovered and described. Keywords: Mineral evolution, Mineral ecology, Skyline diagrams, Network analysis, Cluster analysis, Chord diagrams, Klee diagrams

Abstract Background Achilles tendon rupture (ATR) is a common sports injury, with a rising incidence and significant impairments. Due to the lack of treatment guidelines, there is no consensus about diagnostic methods, primary treatment (non-surgical or surgical) and rehabilitation. It is hypothesized that this lack of consensus and guidelines leads to sub-optimal recovery and higher societal costs. The primary aim of this study is to give a broad insight into the recovery after ATR. Secondarily this study aims to explore factors contributing to recovery and gain insight into the cost-effectiveness of ATR management. Methods This multicenter prospective cohort study will include all adult (≥ 18 years) patients with an ATR treated at the three main hospitals in the Northern Netherlands: University Medical Center Groningen, Martini Hospital Groningen and Medical Center Leeuwarden. All subjects will be invited for three visits at 3, 6 and 12 months post-injury. The following data will be collected: patient-reported outcome measures (PROMs), physical tests, imaging and economic questionnaires. At 3 months post-injury personal, injury, and treatment data will be collected through a baseline questionnaire and assessment of the medical file. The PROMs concern the Dutch version of the Achilles Tendon Total Rupture Score, EQ-5D-5 L, Oslo Sport Trauma Research Center Overuse Injury Questionnaire, Injury Psychological Readiness Return to Sport Scale, Tampa Scale of Kinesiophobia, Expectations, Motivation and Satisfaction questionnaire and a ranking of reasons for not returning to sport. The administered physical tests are the heel-rise test, standing dorsiflexion range of motion, resting tendon length and single leg hop for distance. Ultrasound Tissue Characterization will be used for imaging. Finally, economic data will be collected using the Productivity Cost Questionnaire and Medical Consumption Questionnaire. Discussion This prospective cohort study will contribute to optimal decision making in the primary treatment and rehabilitation of ATRs by providing insight into (1) ATR recovery (2) novel imaging for monitoring recovery (3) (barriers to) return to sport and (4) cost-effectiveness of management. The analysis of these data strives to give a broad insight into the recovery after ATR as well as provide data on novel imaging and costs, contributing to individualized ATR management. Trial registration Trialregister.nl. NTR6484. 20/06/2017. 20/07/2017.

BackgroundStudies on herpes zoster (HZ) incidence in solid organ transplant (SOT) recipients report widely varying numbers. We investigated HZ incidence, severity, and risk factors in recipients of four different SOTs, with a follow-up time of 6–14 years.MethodsRecords of 1,033 transplant recipients after first heart (HTx: n = 211), lung (LuTx: n = 121), liver (LiTx: n = 258) and kidney (KTx: n = 443) transplantation between 2000 and 2014 were analyzed for VZV-PCR, clinical signs of HZ, and complications.ResultsHZ was diagnosed in 108 of 1,033 patients (10.5%): 36 HTx, 17 LuTx, 15 LiTx, and 40 KTx recipients. Overall HZ incidence rate after HTx (30.7 cases/1,000 person–years (PY)), LuTx (38.8 cases/1,000 PY), LiTx (22.7 cases/1,000 PY) and KTx (14.5 cases/1,000 PY) was significantly higher than in the general 50–70 year population. Multivariable analysis demonstrated age ≥50 years at transplantation (p = 0.038, RR 1.536), type of organ transplant (overall p = 0.002; LuTx p = 0.393; RR 1.314; LiTx p = 0.011, RR 0.444; KTx p = 0.034, RR 0.575), CMV prophylaxis (p = 0.043, RR 0.631) and type of anti-rejection therapy (overall p = 0.020; methylprednisolone p = 0.008, RR 0.475; r-ATG p = 0.64, RR1.194) as significant risk factors. Complications occurred in 33 of 108 (31%) patients (39% of HTx, 47% of LuTx, 20% of LiTx, 20% of KTx): post-herpetic neuralgia, disseminated disease, and cranial nerve involvement.ConclusionHZ incidence and severity in SOT recipients are most pronounced after heart and lung transplantation, in older patients, and when CMV prophylaxis is lacking.

Recombinant Inbred Lines (RILs) are obtained through successive generations of inbreeding. In 1931 Haldane and Waddington published a landmark paper where they provided the probabilities of achieving any combination of alleles in 2-way RILs for 2 and 3 loci. In the case of sibling RILs where sisters and brothers are crossed at each generation, there has been no progress in treating 4 or more loci, a limitation we overcome here without much increase in complexity. In the general situation of L loci, the task is to determine 2L probabilities, but we find that it is necessary to first calculate the 4L “identical by descent” (IBD) probabilities that a RIL inherits at each locus its DNA from one of the four originating chromosomes. We show that these 4L probabilities satisfy a system of linear equations that follow from self-consistency. In the absence of genetic interference—crossovers arising independently—the associated matrix can be written explicitly in terms of the recombination rates between the different loci. We provide the matrices for L up to 4 and also include a computer program to automatically generate the matrices for higher values of L. Furthermore, our framework can be generalized to recombination rates that are different in female and male meiosis which allows us to show that the Haldane and Waddington 2-locus formula is valid in that more subtle case if the meiotic recombination rate is taken as the average rate across female and male. Once the 4L IBD probabilities are determined, the 2L probabilities of RIL genotypes are obtained via summations of these quantities. In fine, our computer program allows to determine the probabilities of all the multilocus genotypes produced in such sibling-based RILs for L

The genus Mentha is taxonomically and phylogenetically challenging due to complex genomes, polyploidization and an extensive historical nomenclature, potentially hiding cryptic taxa. A straightforward interpretation of phylogenetic relationships within the section Mentha is further hindered by dominant but outdated concepts on historically identified hybrid taxa. Mentha spicata is traditionally considered to be of hybrid origin, but the evidence for this is weak. Here, we aim to understand the phylogenetic relationships within the section Mentha using large sample sizes and to revisit the hybrid status and identity of M. spicata. We show that two of three traditional species in the subsection Spicatae are polyphyletic, as is the subsection as a whole, while the real number of cryptic species was underestimated. Compared to previous studies we present a fundamentally different phylogeny, with a basal split between M. spicata s.s. and M. longifolia s.s. Cluster analyses of morphological and genotypic data demonstrate that there is a dissociation between morphologically and genotypically defined groups of samples. We did not find any evidence that M. spicata is of hybrid origin, and we conclude its taxonomic status should be revised. The combination of genetic and phenotypic information is essential when evaluating hyperdiverse taxonomic groups.

Jérémy B Coquart,1 Jean-Marie Grosbois,2,3 Cecile Olivier,4 Frederic Bart,2 Ingrid Castres,1 Benoit Wallaert4 1Faculté des Sciences du Sport, Université de Rouen, CETAPS, EA 3832, Mont Saint Aignan, 2Service de Pneumologie, Centre Hospitalier de Béthune, Beuvry, 3Formaction Santé, Perenchies, 4Service de Pneumologie et Immunoallergologie, Centre Hospitalier Universitaire de Lille, Hôpital Calmette, Université de Lille 2, France Background: This retrospective, observational study of a routine clinical practice reports the feasibility and efficiency of home-based pulmonary rehabilitation (PR), including transcutaneous neuromuscular electrical stimulation (NMES) or usual endurance physical exercise (UEPE), on exercise tolerance, anxiety/depression, and health-related quality of life (HRQoL) in patients with COPD.Methods: Seventy-one patients with COPD participated in home-based PR with NMES (Group NMES [GNMES]), while 117 patients participated in home-based PR with the UEPEs (Group UEPE [GUEPE]). NMES was applied for 30 minutes twice a day, every day. The endurance exercises in GUEPE began with a minimum 10-minute session at least 5 days a week, with the goal being 30–45 minutes per session. Three upper and lower limb muscle strengthening exercises lasting 10–15 minutes were also proposed to both the groups for daily practice. Moreover, PR in both the groups included a weekly 90-minute session based on an educational needs assessment. The sessions comprised endurance physical exercise for GUEPE, NMES for GNMES, resumption of physical daily living activities, therapeutic patient education, and psychosocial support to facilitate health behavior changes. Before and after PR, functional mobility and physical exercise capacity, anxiety, depression, and HRQoL were evaluated at home.Results: The study revealed that NMES significantly improved functional mobility (−18.8% in GNMES and −20.6% in GUEPE), exercise capacity (+20.8% in GNMES and +21.8% in GUEPE), depression (−15.8% in GNMES and −30.1% in GUEPE), and overall HRQoL (−7.0% in GNMES and −18.5% in GUEPE) in the patients with COPD, regardless of the group (GNMES or GUEPE) or severity of airflow obstruction. Moreover, no significant difference was observed between the groups with respect to these data (P>0.05).Conclusion: Home-based PR including self-monitored NMES seems feasible and effective for severely disabled COPD patients with severe exercise intolerance. Keywords: pulmonary rehabilitation, global management program, severity of airflow obstruction, chronic obstructive pulmonary disease, NMES

Meiotic recombination by crossovers (COs) is tightly regulated, limiting its key role in producing genetic diversity. However, while COs are usually restricted in number and not homogenously distributed along chromosomes, we show here how to disrupt these rules in Brassica species by using allotriploid hybrids (AAC, 2n = 3x = 29), resulting from the cross between the allotetraploid rapeseed (B. napus, AACC, 2n = 4x = 38) and one of its diploid progenitors (B. rapa, AA, 2n = 2x = 20). We produced mapping populations from different genotypes of both diploid AA and triploid AAC hybrids, used as female and/or as male. Each population revealed nearly 3,000 COs that we studied with SNP markers well distributed along the A genome (on average 1 SNP per 1.25 Mbp). Compared to the case of diploids, allotriploid hybrids showed 1.7 to 3.4 times more overall COs depending on the sex of meiosis and the genetic background. Most surprisingly, we found that such a rise was always associated with (i) dramatic changes in the shape of recombination landscapes and (ii) a strong decrease of CO interference. Hybrids carrying an additional C genome exhibited COs all along the A chromosomes, even in the vicinity of centromeres that are deprived of COs in diploids as well as in most studied species. Moreover, in male allotriploid hybrids we found that Class I COs are mostly responsible for the changes of CO rates, landscapes and interference. These results offer the opportunity for geneticists and plant breeders to dramatically enhance the generation of diversity in Brassica species by disrupting the linkage drag coming from limits on number and distribution of COs.

This paper proposes a comprehensive study of indoor intruder tracking using visible light communication (VLC). A realistic indoor VLC channel was developed, taking into consideration reflections, shadowing, and ambient noise. The intruder was considered smart and aiming to escape tracking. This was modelled by adding noise and disturbance to the intruder’s trajectory. We propose to extend the application of minimax filtering from state estimation in the radio frequency (RF) domain to intruder tracking using VLC. The performance of the proposed method was examined and compared with Kalman filter for both VLC and RF. The simulation results showed that the minimax filter provided marginally better tracking and was more robust to the adversary behavior of the intruder than Kalman filter, with less than 0.5 cm estimation error. In addition, minimax was significantly better than Kalman filter for RF tracking applications.