PLD3 and PLD4 are single-stranded acid exonucleases that regulate endosomal nucleic-acid sensing.

The sensing of microbial genetic material by leukocytes often elicits beneficial pro-inflammatory cytokines, but dysregulated responses can cause severe pathogenesis. Genome-wide association studies have linked the gene encoding phospholipase D3 (PLD3) to Alzheimer's disease and have linked PLD4 to rheumatoid arthritis and systemic sclerosis. PLD3 and PLD4 are endolysosomal proteins whose functions are obscure. Here, PLD4-deficient mice were found to have an inflammatory disease, marked by elevated levels of interferon-γ (IFN-γ) and splenomegaly. These phenotypes were traced to altered responsiveness of PLD4-deficient dendritic cells to ligands of the single-stranded DNA sensor TLR9. Macrophages from PLD3-deficient mice also had exaggerated TLR9 responses. Although PLD4 and PLD3 were presumed to be phospholipases, we found that they are 5' exonucleases, probably identical to spleen phosphodiesterase, that break down TLR9 ligands. Mice deficient in both PLD3 and PLD4 developed lethal liver inflammation in early life, which indicates that both enzymes are needed to regulate inflammatory cytokine responses via the degradation of nucleic acids.

An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma.

Treating patients who have cancer with vaccines that stimulate a targeted immune response is conceptually appealing, but cancer vaccine trials have not been successful in late-stage patients with treatment-refractory tumours1,2. We are testing melanoma FixVac (BNT111)-an intravenously administered liposomal RNA (RNA-LPX) vaccine, which targets four non-mutated, tumour-associated antigens that are prevalent in melanoma-in an ongoing, first-in-human, dose-escalation phase I trial in patients with advanced melanoma (Lipo-MERIT trial, ClinicalTrials.gov identifier NCT02410733). We report here data from an exploratory interim analysis that show that melanoma FixVac, alone or in combination with blockade of the checkpoint inhibitor PD1, mediates durable objective responses in checkpoint-inhibitor (CPI)-experienced patients with unresectable melanoma. Clinical responses are accompanied by the induction of strong CD4+ and CD8+ T cell immunity against the vaccine antigens. The antigen-specific cytotoxic T-cell responses in some responders reach magnitudes typically reported for adoptive T-cell therapy, and are durable. Our findings indicate that RNA-LPX vaccination is a potent immunotherapy in patients with CPI-experienced melanoma, and suggest the general utility of non-mutant shared tumour antigens as targets for cancer vaccination.

Competition and moral behavior: A meta-analysis of forty-five crowd-sourced experimental designs.

Does competition affect moral behavior? This fundamental question has been debated among leading scholars for centuries, and more recently, it has been tested in experimental studies yielding a body of rather inconclusive empirical evidence. A potential source of ambivalent empirical results on the same hypothesis is design heterogeneity-variation in true effect sizes across various reasonable experimental research protocols. To provide further evidence on whether competition affects moral behavior and to examine whether the generalizability of a single experimental study is jeopardized by design heterogeneity, we invited independent research teams to contribute experimental designs to a crowd-sourced project. In a large-scale online data collection, 18,123 experimental participants were randomly allocated to 45 randomly selected experimental designs out of 95 submitted designs. We find a small adverse effect of competition on moral behavior in a meta-analysis of the pooled data. The crowd-sourced design of our study allows for a clean identification and estimation of the variation in effect sizes above and beyond what could be expected due to sampling variance. We find substantial design heterogeneity-estimated to be about 1.6 times as large as the average standard error of effect size estimates of the 45 research designs-indicating that the informativeness and generalizability of results based on a single experimental design are limited. Drawing strong conclusions about the underlying hypotheses in the presence of substantive design heterogeneity requires moving toward much larger data collections on various experimental designs testing the same hypothesis.

Assessment of Hydrophilicity/Hydrophobicity in Mesoporous Silica by Combining Adsorption, Liquid Intrusion, and Solid-State NMR Spectroscopy.

We have developed a comprehensive strategy for quantitatively assessing the hydrophilicity/hydrophobicity of nanoporous materials by combining advanced adsorption studies, novel liquid intrusion techniques, and solid-state NMR spectroscopy. For this, we have chosen a well-defined system of model materials, i.e., the highly ordered mesoporous silica molecular sieve SBA-15 in its pristine state and functionalized with different amounts of trimethylsilyl (TMS) groups, allowing one to accurately tailor the surface chemistry while maintaining the well-defined pore structure. For an absolute quantification of the trimethylsilyl group density, quantitative 1H solid-state NMR spectroscopy under magic angle spinning was employed. A full textural characterization of the materials was obtained by high-resolution argon 87 K adsorption, coupled with the application of dedicated methods based on nonlocal-density functional theory (NLDFT). Based on the known texture of the model materials, we developed a novel methodology allowing one to determine the effective contact angle of water adsorbed on the pore surfaces from complete wetting to nonwetting, constituting a powerful parameter for the characterization of the surface chemistry inside porous materials. The surface chemistry was found to vary from hydrophilic to hydrophobic as the TMS functionalization content was increased. For wetting and partially wetting surfaces, pore condensation of water is observed at pressures P smaller than the bulk saturation pressure p0 (i.e., at p/p0 < 1) and the effective contact angle of water on the pore walls could be derived from the water sorption isotherms. However, for nonwetting surfaces, pore condensation occurs at pressures above the saturation pressure (i.e., at p/p0 > 1). In this case, we investigated the pore filling of water (i.e., the vapor-liquid phase transition) by the application of a novel, liquid water intrusion/extrusion methodology, allowing one to derive the effective contact angle of water on the pore walls even in the case of nonwetting. Complementary molecular simulations provide density profiles of water on pristine and TMS-grafted silica surfaces (mimicking the tailored, functionalized experimental silica surfaces), which allow for a molecular view on the water adsorbate structure. Summarizing, we present a comprehensive and reliable methodology for quantitatively assessing the hydrophilicity/hydrophobicity of siliceous nanoporous materials, which has the potential to optimize applications in heterogeneous catalysis and separation (e.g., chromatography).

[Mechanical management of refractory form of heart failure]. / Prise en charge mécanique de l'insuffisance cardiaque avancée.

Although the initial management of heart failure is essentially pharmacological, the use of mechanical circulatory support may become necessary in advanced forms. In cardiogenic shock, temporary mechanical circulatory support should be considered, while in more stable forms of advanced heart failure, implantation of a long-term left ventricular assist device (LVAD) can prolong survival and improve patient's quality of life. Recent improvements in LVAD technology have reduced post-implant complications, but the procedure is not without risk and requires close clinical follow-up.

Bien que la prise en charge initiale de l'insuffisance cardiaque soit essentiellement pharmacologique, le recours à des assistances circulatoires mécaniques peut devenir nécessaire dans les formes dites avancées. Dans le choc cardiogénique, l'utilisation d'assistances circulatoires mécaniques temporaires est à considérer alors que pour les formes d'insuffisance cardiaque avancée mieux stabilisées, l'implantation d'une assistance ventriculaire gauche de longue durée (Left Ventricular Assist Device - LVAD) permet de prolonger la survie et d'améliorer la qualité de vie des patients. Les améliorations technologiques récentes des LVAD ont permis de diminuer les complications, mais cette intervention n'est pas sans risque et nécessite un suivi clinique rapproché.

The P4-type ATPase ATP11C is essential for B lymphopoiesis in adult bone marrow.

B lymphopoiesis begins in the fetal liver, switching after birth to the bone marrow, where it persists for life. The unique developmental outcomes of each phase are well documented, yet their molecular requirements are not. Here we describe two allelic X-linked mutations in mice that caused cell-intrinsic arrest of adult B lymphopoiesis. Mutant fetal liver progenitors generated B cells in situ but not in irradiated adult bone marrow, which emphasizes a necessity for the affected pathway only in the context of adult bone marrow. The causative mutations were ascribed to Atp11c, which encodes a P4-type ATPase with no previously described function. Our data establish an essential, cell-autonomous and context-sensitive function for ATP11C, a putative aminophospholipid flippase, in B cell development.

Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer.

T cells directed against mutant neo-epitopes drive cancer immunity. However, spontaneous immune recognition of mutations is inefficient. We recently introduced the concept of individualized mutanome vaccines and implemented an RNA-based poly-neo-epitope approach to mobilize immunity against a spectrum of cancer mutations. Here we report the first-in-human application of this concept in melanoma. We set up a process comprising comprehensive identification of individual mutations, computational prediction of neo-epitopes, and design and manufacturing of a vaccine unique for each patient. All patients developed T cell responses against multiple vaccine neo-epitopes at up to high single-digit percentages. Vaccine-induced T cell infiltration and neo-epitope-specific killing of autologous tumour cells were shown in post-vaccination resected metastases from two patients. The cumulative rate of metastatic events was highly significantly reduced after the start of vaccination, resulting in a sustained progression-free survival. Two of the five patients with metastatic disease experienced vaccine-related objective responses. One of these patients had a late relapse owing to outgrowth of ß2-microglobulin-deficient melanoma cells as an acquired resistance mechanism. A third patient developed a complete response to vaccination in combination with PD-1 blockade therapy. Our study demonstrates that individual mutations can be exploited, thereby opening a path to personalized immunotherapy for patients with cancer.

Strategic Distractor Suppression Improves Selective Control in Human Vision.

Our visual environment is complicated, and our cognitive capacity is limited. As a result, we must strategically ignore some stimuli to prioritize others. Common sense suggests that foreknowledge of distractor characteristics, like location or color, might help us ignore these objects. But empirical studies have provided mixed evidence, often showing that knowing about a distractor before it appears counterintuitively leads to its attentional selection. What has looked like strategic distractor suppression in the past is now commonly explained as a product of prior experience and implicit statistical learning, and the long-standing notion the distractor suppression is reflected in α band oscillatory brain activity has been challenged by results appearing to link α to target resolution. Can we strategically, proactively suppress distractors? And, if so, does this involve α? Here, we use the concurrent recording of human EEG and eye movements in optimized experimental designs to identify behavior and brain activity associated with proactive distractor suppression. Results from three experiments show that knowing about distractors before they appear causes a reduction in electrophysiological indices of covert attentional selection of these objects and a reduction in the overt deployment of the eyes to the location of the objects. This control is established before the distractor appears and is predicted by the power of cue-elicited α activity over the visual cortex. Foreknowledge of distractor characteristics therefore leads to improved selective control, and α oscillations in visual cortex reflect the implementation of this strategic, proactive mechanism.SIGNIFICANCE STATEMENT To behave adaptively and achieve goals we often need to ignore visual distraction. Is it easier to ignore distracting objects when we know more about them? We recorded eye movements and electrical brain activity to determine whether foreknowledge of distractor characteristics can be used to limit processing of these objects. Results show that knowing the location or color of a distractor stops us from attentionally selecting it. A neural signature of this inhibition emerges in oscillatory alpha band brain activity, and when this signal is strong, selective processing of the distractor decreases. Knowing about the characteristics of task-irrelevant distractors therefore increases our ability to focus on task-relevant information, in this way gating information processing in the brain.

Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy.

Lymphoid organs, in which antigen presenting cells (APCs) are in close proximity to T cells, are the ideal microenvironment for efficient priming and amplification of T-cell responses. However, the systemic delivery of vaccine antigens into dendritic cells (DCs) is hampered by various technical challenges. Here we show that DCs can be targeted precisely and effectively in vivo using intravenously administered RNA-lipoplexes (RNA-LPX) based on well-known lipid carriers by optimally adjusting net charge, without the need for functionalization of particles with molecular ligands. The LPX protects RNA from extracellular ribonucleases and mediates its efficient uptake and expression of the encoded antigen by DC populations and macrophages in various lymphoid compartments. RNA-LPX triggers interferon-α (IFNα) release by plasmacytoid DCs and macrophages. Consequently, DC maturation in situ and inflammatory immune mechanisms reminiscent of those in the early systemic phase of viral infection are activated. We show that RNA-LPX encoding viral or mutant neo-antigens or endogenous self-antigens induce strong effector and memory T-cell responses, and mediate potent IFNα-dependent rejection of progressive tumours. A phase I dose-escalation trial testing RNA-LPX that encode shared tumour antigens is ongoing. In the first three melanoma patients treated at a low-dose level, IFNα and strong antigen-specific T-cell responses were induced, supporting the identified mode of action and potency. As any polypeptide-based antigen can be encoded as RNA, RNA-LPX represent a universally applicable vaccine class for systemic DC targeting and synchronized induction of both highly potent adaptive as well as type-I-IFN-mediated innate immune mechanisms for cancer immunotherapy.

[Cardiac surgery in the time of COVID19 - A narrative of three very unusual cases and lessons learned]. / Chirurgie cardiaque au temps du Covid-19 - Récit de trois cas très inhabituels et leçons retenues.

COVID19 altered and impacted medical and surgical practice around the world. Standard of care and routine procedures are disrupted. Majors shift in personnel, and ad hoc new team as well as delocalization and working with new infrastructures are further challenges to be dealt with. This review of three very unusual scenarios illustrates pitfalls and dangers harbored in the re-shaped landscape of COVID19 exemplifying the narrow path bridging from the medical and surgical comfort zone to uncharted territory and eventually leading to collateral damage.

Le Covid-19 a profondément modifié et sévèrement impacté les pratiques médicales et chirurgicales à long terme. Les standards de prise en charge et les procédures de routine sont altérés, voire perturbés. Des mutations majeures au niveau du personnel et des équipes de même que la délocalisation ou le travail avec de nouvelles infrastructures sont autant de défis à relever, encore aujourd'hui. Trois scénarios inhabituels illustrent les pièges et les dangers qui se cachent dans le paysage marqué par le Covid-19. Ces exemples démontrent la marge étroite entre la zone de confort médicale et chirurgicale classique et l'appréhension d'une situation inhabituelle qui risque d'entraîner des dommages collatéraux pour les patients.

Mutant MHC class II epitopes drive therapeutic immune responses to cancer.

Tumour-specific mutations are ideal targets for cancer immunotherapy as they lack expression in healthy tissues and can potentially be recognized as neo-antigens by the mature T-cell repertoire. Their systematic targeting by vaccine approaches, however, has been hampered by the fact that every patient's tumour possesses a unique set of mutations ('the mutanome') that must first be identified. Recently, we proposed a personalized immunotherapy approach to target the full spectrum of a patient's individual tumour-specific mutations. Here we show in three independent murine tumour models that a considerable fraction of non-synonymous cancer mutations is immunogenic and that, unexpectedly, the majority of the immunogenic mutanome is recognized by CD4(+) T cells. Vaccination with such CD4(+) immunogenic mutations confers strong antitumour activity. Encouraged by these findings, we established a process by which mutations identified by exome sequencing could be selected as vaccine targets solely through bioinformatic prioritization on the basis of their expression levels and major histocompatibility complex (MHC) class II-binding capacity for rapid production as synthetic poly-neo-epitope messenger RNA vaccines. We show that vaccination with such polytope mRNA vaccines induces potent tumour control and complete rejection of established aggressively growing tumours in mice. Moreover, we demonstrate that CD4(+) T cell neo-epitope vaccination reshapes the tumour microenvironment and induces cytotoxic T lymphocyte responses against an independent immunodominant antigen in mice, indicating orchestration of antigen spread. Finally, we demonstrate an abundance of mutations predicted to bind to MHC class II in human cancers as well by employing the same predictive algorithm on corresponding human cancer types. Thus, the tailored immunotherapy approach introduced here may be regarded as a universally applicable blueprint for comprehensive exploitation of the substantial neo-epitope target repertoire of cancers, enabling the effective targeting of every patient's tumour with vaccines produced 'just in time'.

The extrafoveal preview paradigm as a measure of predictive, active sampling in visual perception.

A key feature of visual processing in humans is the use of saccadic eye movements to look around the environment. Saccades are typically used to bring relevant information, which is glimpsed with extrafoveal vision, into the high-resolution fovea for further processing. With the exception of some unusual circumstances, such as the first fixation when walking into a room, our saccades are mainly guided based on this extrafoveal preview. In contrast, the majority of experimental studies in vision science have investigated "passive" behavioral and neural responses to suddenly appearing and often temporally or spatially unpredictable stimuli. As reviewed here, a growing number of studies have investigated visual processing of objects under more natural viewing conditions in which observers move their eyes to a stationary stimulus, visible previously in extrafoveal vision, during each trial. These studies demonstrate that the extrafoveal preview has a profound influence on visual processing of objects, both for behavior and neural activity. Starting from the preview effect in reading research we follow subsequent developments in vision research more generally and finally argue that taking such evidence seriously leads to a reconceptualization of the nature of human visual perception that incorporates the strong influence of prediction and action on sensory processing. We review theoretical perspectives on visual perception under naturalistic viewing conditions, including theories of active vision, active sensing, and sampling. Although the extrafoveal preview paradigm has already provided useful information about the timing of, and potential mechanisms for, the close interaction of the oculomotor and visual systems while reading and in natural scenes, the findings thus far also raise many new questions for future research.

Market shocks and professionals' investment behavior - Evidence from the COVID-19 crash.

We investigate how the experience of extreme events, such as the COVID-19 market crash, influence risk-taking behavior. To isolate changes in risk-taking from other factors, we ran controlled experiments with finance professionals in December 2019 and March 2020. We observe that their investments in the experiment were 12 percent lower in March 2020 than in December 2019, although their price expectations had not changed, and although they considered the experimental asset less risky during the crash than before. This lower perceived risk is likely due to adaptive normalization, as volatility during the shock is compared to volatility experienced in real markets (which was low in December 2019, but very high in March 2020). Lower investments during the crash can be supported by higher risk aversion, not by changes in beliefs.

The peripheral preview effect with faces: Combined EEG and eye-tracking suggests multiple stages of trans-saccadic predictive and non-predictive processing.

The world appears stable despite saccadic eye-movements. One possible explanation for this phenomenon is that the visual system predicts upcoming input across saccadic eye-movements based on peripheral preview of the saccadic target. We tested this idea using concurrent electroencephalography (EEG) and eye-tracking. Participants made cued saccades to peripheral upright or inverted face stimuli that changed orientation (invalid preview) or maintained orientation (valid preview) while the saccade was completed. Experiment 1 demonstrated better discrimination performance and a reduced fixation-locked N170 component (fN170) with valid than with invalid preview, demonstrating integration of pre- and post-saccadic information. Moreover, the early fixation-related potentials (FRP) showed a preview face inversion effect suggesting that some pre-saccadic input was represented in the brain until around 170 ms post fixation-onset. Experiment 2 replicated Experiment 1 and manipulated the proportion of valid and invalid trials to test whether the preview effect reflects context-based prediction across trials. A whole-scalp Bayes factor analysis showed that this manipulation did not alter the fN170 preview effect but did influence the face inversion effect before the saccade. The pre-saccadic inversion effect declined earlier in the mostly invalid block than in the mostly valid block, which is consistent with the notion of pre-saccadic expectations. In addition, in both studies, we found strong evidence for an interaction between the pre-saccadic preview stimulus and the post-saccadic target as early as 50 ms (Experiment 2) or 90 ms (Experiment 1) into the new fixation. These findings suggest that visual stability may involve three temporal stages: prediction about the saccadic target, integration of pre-saccadic and post-saccadic information at around 50-90 ms post fixation onset, and post-saccadic facilitation of rapid categorization.

External Iliac Artery Endofibrosis in a Female Cyclist: A Case Report.

External iliac artery endofibrosis is a rare disease described mainly in male endurance athletes. It presents as claudication of the lower limb during near-maximum effort. The patients lack the usual risk factors for atherosclerosis, which makes diagnosis challenging. We present a case of external iliac artery endofibrosis in a female competitive cyclist. The initial surgical management was complicated by early recurrence due to intimal hyperplasia. After secondary drug-eluting balloon angioplasty, the patient was able to resume competition. As such, it is important to maintain a high index of suspicion when evaluating a patient presenting with claudication symptoms in this setting. Primary treatment is surgical, and in cases of early recurrence angioplasty may be indicated. Most patients can return to full activity after healing is complete.

Rescue of a Failing Endovascular Infrarenal Aortic Repair Using an Off-The-Shelf Branched Endograft.

BACKGROUND: Proximal aortic dilation following open and endovascular aortic repair (EVAR) is a well-known phenomenon. If severe enough, it may lead to late onset of type Ia endoleak that jeopardizes the proximal seal. METHODS: We report the case of a patient previously treated by EVAR for an infrarenal aneurysm who developed a type Ia endoleak after proximal aortic dilation. His aneurysms enlarged to 10 cm mandating a rapid repair without the delay for a custom-made device. RESULTS: We successfully used the off-the-shelf thoracic t-Branch graft (Cook, Bloomington, IN) with its 4 branches to treat the dilated aorta and seal the endoleak. CONCLUSION: The off-the-shelf t-Branch is a useful option in patient with previous EVAR presenting with proximal aortic dilation and endoleak who cannot wait for a custom-made device.

The effect of preexisting anti-carrier immunity on subsequent responses to CRM197 or Qb-VLP conjugate vaccines.

CONTEXT: Certain antigens, such as haptens (small molecules), short peptides, and carbohydrates (e.g. bacterial polysaccharides) are non- or poorly immunogenic unless conjugated to a carrier molecule that provides a structural scaffold for antigen presentation as well as T cell help required for B-cell activation and maturation. However, the carriers themselves are immunogenic and resulting carrier-specific immune responses may impact the immunogenicity of other conjugate vaccines using the same carrier that are administered subsequently. OBJECTIVE: Herein, using two different carriers (cross-reactive material 197, CRM and Qb-VLP), we examined in mice the impact that preexisting anti-carrier antibodies (Ab) had on subsequent immune responses to conjugates with either the same or a different carrier. METHOD: For this purpose, we used two nicotine hapten conjugates (NIC7-CRM or NIC-Qb), two IgE peptide conjugates (Y-CRM or Y-Qb), and a pneumococcal polysaccharide conjugate (Prevnar 13(®)). RESULTS: Prior exposure to CRM or Qb-VLP significantly reduced subsequent responses to the conjugated antigen having the homologous carrier, with the exception of Prevnar 13® where anti-polysaccharide responses were similar to those in animals without preexisting anti-carrier Ab. CONCLUSION: Collectively, the data suggest that the relative sizes of the antigen and carrier, as well as the conjugation density for a given conjugate impact the extent of anti-carrier suppression. All animals developed anti-carrier responses with repeat vaccination and the differences in Ab titer between groups with and without preexisting anti-carrier responses became less apparent; however, anti-carrier effects were more durable for Ab function.

Nasotemporal ERP differences: evidence for increased inhibition of temporal distractors.

Previous research has demonstrated behavioral advantages for stimuli in the temporal relative to the nasal visual hemifield. To investigate whether this nasotemporal asymmetry reflects a genuinely attentional bias, we recorded event-related potentials in a task where participants identified a color-defined target digit in one visual hemifield that was accompanied by an irrelevant distractor in the opposite hemifield (experiment 1). To dissociate the processing of stimuli in nasal and temporal visual hemifields, an eye-patching procedure was used. Targets triggered N2pc components that marked their attentional selection. Unexpectedly, these N2pc components were larger and emerged earlier for nasal relative to temporal targets. Experiment 2 provided evidence that this nasotemporal asymmetry for the N2pc is linked to an increased attentional inhibition of temporal distractors. Relative to nasal distractors, temporal distractors elicited an increased inhibition-related contralateral positivity, resulting in more pronounced differences between contralateral and ipsilateral event-related potentials on trials with temporal distractors and nasal targets. These results provide novel evidence for a genuinely attentional contribution to nasotemporal asymmetries and suggest that such asymmetries are associated with top-down controlled distractor inhibition.

New Self-Expanding Transcatheter Valve for Off-Pump Transatrial Mitral Valve-In-Ring Implantation.

OBJECTIVES: To validate a self-expanding transcatheter valve for off-pump transatrial mitral valve-in-ring (VIR) implantation via a left thoracotomy. METHODS: Mitral valve annuloplasty was performed via sternotomy during cardiopulmonary bypass on 9 pigs. After successful weaning from extracorporal circulation, the custom-made, self-expanding transcatheter VIR device was deployed under fluoroscopic guidance within the annuloplasty ring via a left thoracotomy. Hemodynamic data before and after the implantation were recorded. Mitral annulus diameter and valve area were measured by echocardiography. Transvalvular and left-ventricular outflow-tract pressure gradient were measured invasively. RESULTS: Eight successful implantations were performed. Implantation failed in 1 pig because of difficulty with technical delivery of the sheath. Mean transatrial procedure time was 12.6 ± 1.7 min. Hemodynamic status during transatrial implantation was stable, and differences were not statistically significant. Mean mitral annulus diameter and mean mitral orifice area were 2.32 ± 0.2 and 3.84 ± 0.55 cm2, respectively. Mild regurgitation was detected in 7 animals and moderate regurgitation in 1. Mean gradients were 6.1 ± 5.0 mm Hg across the device. Postmortem examination confirmed adequate positioning of devices within the annuloplasty ring. CONCLUSIONS: This custom-made transcatheter device allows for safe and reproducible off-pump transatrial mitral VIR implantations. Transatrial access is a promising route to facilitate VIR implantations. Our custom-made stent-valve may be suitable for VIR procedures.