DynaMight: estimating molecular motions with improved reconstruction from cryo-EM images.

How to deal with continuously flexing molecules is one of the biggest outstanding challenges in single-particle analysis of proteins from cryogenic-electron microscopy (cryo-EM) images. Here, we present DynaMight, a software tool that estimates a continuous space of conformations in a cryo-EM dataset by learning three-dimensional deformations of a Gaussian pseudo-atomic model of a consensus structure for every particle image. Inversion of the learned deformations is then used to obtain an improved reconstruction of the consensus structure. We illustrate the performance of DynaMight for several experimental cryo-EM datasets. We also show how error estimates on the deformations may be obtained by independently training two variational autoencoders on half sets of the cryo-EM data, and how regularization of the three-dimensional deformations through the use of atomic models may lead to important artifacts due to model bias. DynaMight is distributed as free, open-source software, as part of RELION-5.

Does an instructional video as a stand-alone tool promote the acquisition of practical clinical skills? A randomised simulation research trial of skills acquisition and short-term retention.

BACKGROUND: The effectiveness of instructional videos as a stand-alone tool for the acquisition of practical skills is yet unknown because instructional videos are usually didactically embedded. Therefore, we evaluated the acquisition of the skill of a humeral intraosseous access via video in comparison to that of a self-study with an additional retention test. METHODS: After ethical approval, we conducted two consecutive studies. Both were designed as randomised controlled two-armed trials with last-year medical students as independent samples at our institutional simulation centre of a tertiary university hospital centre. In Study 1, we randomly assigned 78 participants to two groups: Vid-Self participants watched an instructional video as an intervention, followed by a test, and after seven days did a self-study as a control, followed by a test. Self-Vid ran through the trial in reverse order. In Study 2, we investigated the influence of the sequence of the two teaching methods on learning success in a new sample of 60 participants: Vid-Self watched an instructional video and directly afterward did the self-study followed by a test, whereas Self-Vid ran through that trial in reverse order. In Studies 1 and 2, the primary outcome was the score (worst score = 0, best score = 20) of the test after intervention and control. The secondary outcome in Study 1 was the change in score after seven days. RESULTS: Study 1: The Vid-Self (Participants n = 42) was superior to the Self-Vid (n = 36) (mean score 14.8 vs. 7.7, p < 0.001). After seven days, Self-vid outperformed Vid-Self (mean score 15.9 vs. 12.5, p < 0.001). Study 2: The Vid-Self (n = 30) and Self-Vid (n = 30) scores did not significantly differ (mean 16.5 vs. mean 16.5, p = 0.97). CONCLUSION: An instructional video as a stand-alone tool effectively promotes the acquisition of practical skills. The best results are yielded by a combination of an instructional video and self-study right after each other, irrespective of sequence. TRIAL REGISTRATIONS: ClinicalTrials.gov: NCT05066204 (13/04/2021) (Study 1) and NCT04842357 (04/10/2021) (Study 2).

Influence of rosuvastatin treatment on cerebral inflammation and nitro-oxidative stress in experimental lung injury in pigs.

BACKGROUND: Many patients with acute respiratory distress syndrome (ARDS) suffer from cognitive impairment after hospital discharge. Different mechanisms have been implicated as potential causes for this impairment, inter alia cerebral inflammation. A class of drugs with antioxidant and anti-inflammatory properties are ß-HMG-CoA-reductase inhibitors ("statins"). We hypothesized that treatment with rosuvastatin attenuates cerebral cytokine mRNA expression and nitro-oxidative stress in an animal model of acute lung injury. METHODS: After approval of the institutional and state animal care committee, we performed this prospective randomized controlled animal study in accordance with the international guidelines for the care and use of laboratory animals. Thirty-two healthy male pigs were randomized to one of four groups: lung injury by central venous injection of oleic acid (n = 8), statin treatment before and directly after lung injury (n = 8), statin treatment after lung injury (n = 8), or ventilation-only controls (n = 8). About 18 h after lung injury and standardized treatment, the animals were euthanised, and the brains and lungs were collected for further examinations. We determined histologic lung injury and cerebral and pulmonal cytokine and 3-nitrotyrosine production. RESULTS: We found a significant increase in hippocampal IL-6 mRNA after lung injury (p < 0.05). Treatment with rosuvastatin before and after induction of lung injury led to a significant reduction of hippocampal IL-6 mRNA (p < 0.05). Cerebral 3-nitrotyrosine was significantly higher in lung-injured animals compared with all other groups (p < 0.05 vs. animals treated with rosuvastatin after lung injury induction; p < 0.001 vs. all other groups). 3-Nitrotyrosine was also increased in the lungs of the lung-injured pigs compared to all other groups (p < 0.05 each). CONCLUSIONS: Our findings highlight cerebral cytokine production and nitro-oxidative stress within the first day after induction of lung injury. The treatment with rosuvastatin reduced IL-6 mRNA and 3-nitrotyrosine concentration in the brains of the animals. In earlier trials, statin treatment did not reduce mortality in ARDS patients but seemed to improve quality of life in ARDS survivors. Whether this is attributable to better cognitive function because of reduced nitro-oxidative stress and inflammation remains to be elucidated.

Risk factors for atrioventricular block after transcatheter aortic valve implantation: a single-centre analysis including assessment of aortic calcifications and follow-up.

AIMS: To assess the contribution of aortic valve calcification to the occurrence of transient or permanent atrioventricular block (AVB) and the need for permanent pacemaker implantation (PPI) after transcatheter aortic valve implantation (TAVI) in a large single-centre cohort. METHODS AND RESULTS: We retrospectively analysed pre-operative contrast-enhanced multidetector computed tomography scans of patients who underwent TAVI in our centre between 2012 and 2016. Calcium volume was calculated for each aortic cusp above (aortic valve), and below [left ventricular outflow tract (LVOT)] the basal plane. Clinical and procedural data as well as pre-operative electrocardiograms were evaluated. Multivariate analysis was performed to evaluate risk factors for transient and permanent AVB. A total of 342 patients receiving a balloon-expandable prosthesis were included in the study. Overall incidence of transient and permanent AVB was 4% (n = 14) and 7.6% (n = 26), respectively. On logistic regression analysis, baseline right bundle branch block [odds ratio (OR) 7.36, 95% confidence interval (CI) 2.6-20.6; P < 0.01], degree of oversizing (OR 1.04, 95% CI 1.01-1.07 P = 0.02), prior percutaneous coronary intervention (OR 2.8, 95% CI 1.1-7.3), and LVOT calcification beneath the non-coronary cusp (OR for an increase of 10 mm3 = 1.06, 95% CI 1-1.1; P = 0.03) were found to be independently associated with permanent AVB and PPI, whereas calcification of LVOT beneath the right coronary cusp (OR for an increase of 10 mm3 = 1.16, 95% CI 1.02-1.3; P = 0.02) and balloon post-dilation (OR 3.8, 95% CI 1.2-11.8; P = 0.02) were associated with reversible AVB. CONCLUSION: Left ventricular outflow tract calcifications are associated with transient and non-reversible AVB after TAVI, and its evaluation could help in predicting onset and reversibility of AVB.

Oesophageal injury following magnetically guided single-catheter ablation for atrial fibrillation: insights from the MAGNA-AF registry.

Aims: Oesophagogastroduodenoscopy (OGD) after catheter ablation (CA) of atrial fibrillation (AF) revealed a high rate of procedure related oesophageal lesions. We hypothesized that magnetically guided CA with careful radiofrequency energy titration at the posterior left atrial (LA) wall limits the incidence of oesophageal tissue damage. Methods and results: As a part of the prospective "Remote MAGNetic catheter Ablation for Atrial Fibrillation" (MAGNA-AF) registry, 251 out of 266 consecutive patients underwent OGD after magnetically guided single-CA for AF. All detected pathologies were analysed. Simultaneous pacing and ablation from the tip of the magnetically guided catheter was found to be a safe and feasible method for energy titration. Post-interventional OGD documented midoesophageal tissue damage in four (1.6%) patients. Although a thermal origin of these injuries must be discussed, none of them was located at the anterior oesophageal wall. Risk factors for midoesophageal lesions were female gender and concomitant acetylsalicylic acid (ASA) treatment. Mechanical lesions in 16 patients were attributed to periprocedural transoesophageal echocardiography (TOE). There was no atrio-oesophageal fistula (AOF). Five hundred and one incidental pathologies were found endoscopically, most frequent axial oesophageal herniation (71%), oesophagitis (22%), and gastritis (57%). Conclusion: Magnetically guided CA for AF with careful energy titration at the posterior LA wall and no oesophageal temperature monitoring is not associated with an increased incidence of oesophageal thermal injury. The routine use of periprocedural TOE may cause a low rate of mechanical oesophageal lesions but reliably prevents major complications like transient ischaemic attack, stroke, or cardiac tamponade. An observed high prevalence of upper digestive system inflammation (63%) may further support the recommendation for a routine post-interventional treatment with a proton-pump-inhibitor.

Bromocriptine for the treatment of peripartum cardiomyopathy: a multicentre randomized study.

AIMS: An anti-angiogenic cleaved prolactin fragment is considered causal for peripartum cardiomyopathy (PPCM). Experimental and first clinical observations suggested beneficial effects of the prolactin release inhibitor bromocriptine in PPCM. METHODS AND RESULTS: In this multicentre trial, 63 PPCM patients with left ventricular ejection fraction (LVEF) ≤35% were randomly assigned to short-term (1W: bromocriptine, 2.5 mg, 7 days) or long-term bromocriptine treatment (8W: 5 mg for 2 weeks followed by 2.5 mg for 6 weeks) in addition to standard heart failure therapy. Primary end point was LVEF change (delta) from baseline to 6 months assessed by magnetic resonance imaging. Bromocriptine was well tolerated. Left ventricular ejection fraction increased from 28 ± 10% to 49 ± 12% with a delta-LVEF of + 21 ± 11% in the 1W-group, and from 27 ± 10% to 51 ± 10% with a delta-LVEF of + 24 ± 11% in the 8W-group (delta-LVEF: P = 0.381). Full-recovery (LVEF ≥ 50%) was present in 52% of the 1W- and in 68% of the 8W-group with no differences in secondary end points between both groups (hospitalizations for heart failure: 1W: 9.7% vs. 8W: 6.5%, P = 0.651). The risk within the 8W-group to fail full-recovery after 6 months tended to be lower. No patient in the study needed heart transplantation, LV assist device or died. CONCLUSION: Bromocriptine treatment was associated with high rate of full LV-recovery and low morbidity and mortality in PPCM patients compared with other PPCM cohorts not treated with bromocriptine. No significant differences were observed between 1W and 8W treatment suggesting that 1-week addition of bromocriptine to standard heart failure treatment is already beneficial with a trend for better full-recovery in the 8W group. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, study number: NCT00998556.

Sutureless versus Transfemoral Transcatheter Aortic Valve Implant: A Propensity Score Matching Study.

BACKGROUND AND AIM OF THE STUDY: Transcatheter aortic valve implantation (TAVI), especially via the transfemoral (TF) route, is increasingly performed in patients considered in the 'gray zone' between TAVI and surgery. However, the best treatment option in this patient population remains to be established. METHODS: Since 2010, a total of 923 patients underwent either TAVI (n = 538) or sutureless aortic valve replacement (AVR) (n = 385) at the authors' institutions. Among these patients, 79 treated with TF-TAVI were compared with 79 propensity score-matched patients who had undergone elective isolated AVR with the sutureless Perceval bioprosthesis. RESULTS: In-hospital mortality did not differ significantly between patients who underwent sutureless AVR or TF-TAVI (none versus three; 3.8%; p = 0.123). Similarly, postoperative complications were comparable between groups. Atrioventricular block requiring postoperative pacemaker implantation occurred in seven patients (9.2%) of the sutureless group and in eight patients (11.1%) of the TF-TAVI group (p = 0.455). The use of blood products varied between groups in terms of red blood cell transfusions (1.7 ± 2 versus 0.3 ± 0.9 units for the sutureless group versus TF-TAVI group; p <0.001). Paravalvular leakage at discharge was present in three patients (3.8%) in the sutureless group and in 26 patients (32.9%) in the TF-TAVI group (p <0.001). The mean follow up was longer for sutureless AVR (36 ± 21 versus 27 ± 20 months; p = 0.003). Survival rates were 97.5% and 84.8% in the sutureless and TF-TAVI groups, respectively (p = 0.001). CONCLUSIONS: Both, TF-TAVI and sutureless AVR are well-standardized, safe and effective procedures. TF-TAVI seems to be a valuable alternative to surgical AVR for frail patients, reducing the need for perioperative blood transfusion. In contrast, in patients with a favorable long-term survival outcome, minimally invasive AVR remains the procedure of choice as it is associated with better long-term results.

Evidence of autoantibodies against cardiac troponin I and sarcomeric myosin in peripartum cardiomyopathy.

Peripartum cardiomyopathy (PPCM) is a major cause of pregnancy-related maternal heart failure that develops towards the end of pregnancy or in the months following delivery. In small retrospective case series, autoimmune responses in the pathogenesis of PPCM have been proposed upon identification of autoantibodies (AABs) to cardiac antigens. However, their clinical and prognostic relevance still remain unclear. In this study, we evaluated the presence of circulating AABs against cardiac sarcomeric myosin (MHC) and troponin I (TnI) in the sera of PPCM patients and in relation to clinical presentation. In this case-control study, 70 patients diagnosed with PPCM and 50 pregnancy-matched healthy women with normal cardiac function were enrolled. Clinical assessment, echocardiography and blood tests were performed at baseline and at 6 ± 2 months follow-up. The presence of serum AABs against MHC (anti-MHC) and TnI (anti-TnI) was determined with a custom-made enzyme-linked immunosorbent assay (ELISA). The seropositivity for these AABs was correlated with the severity of LV dysfunction and the occurrence of pericardial effusion indicative of perimyocardial inflammation at baseline. Potential impact of these AABs on disease progression was evaluated with regard to functional (left ventricular ejection fraction) and clinical improvement at follow-up. Either anti-MHC or anti-TnI or both AABs were detected in the serum of 46 % of PPCM patients and in 8 % of healthy controls. In PPCM the presence of either one of these AABs was associated with significantly lower baseline LVEF and lower rate of full cardiac recovery at follow-up. Patients who were seropositive for anti-TnI AABs showed more frequently pericardial effusion indicative of a more pronounced immune response of the peri-/myocardium in these patients. Further studies are required to clarify cellular and molecular circuits leading to elevated levels of AABs and their pathophysiological relevance for disease initiation and progression in PPCM.

Confronting heterogeneity in cryogenic electron microscopy data: Innovative strategies and future perspectives with data-driven methods.

The surge in the influx of data from cryogenic electron microscopy (cryo-EM) experiments has intensified the demand for robust algorithms capable of autonomously managing structurally heterogeneous datasets. This presents a wealth of exciting opportunities from a data science viewpoint, inspiring the development of numerous innovative, application-specific methods, many of which leverage contemporary data-driven techniques. However, addressing the challenges posed by heterogeneous datasets remains a paramount yet unresolved issue in the field. Here, we explore the subtleties of this challenge and the array of strategies devised to confront it. We pinpoint the shortcomings of existing methodologies and deliberate on prospective avenues for improvement. Specifically, our discussion focuses on strategies to mitigate model overfitting and manage data noise, as well as the effects of constraints, priors, and invariances on the optimization process.

Cryo-EM structure of the complete inner kinetochore of the budding yeast point centromere.

The point centromere of budding yeast specifies assembly of the large kinetochore complex to mediate chromatid segregation. Kinetochores comprise the centromere-associated inner kinetochore (CCAN) complex and the microtubule-binding outer kinetochore KNL1-MIS12-NDC80 (KMN) network. The budding yeast inner kinetochore also contains the DNA binding centromere-binding factor 1 (CBF1) and CBF3 complexes. We determined the cryo-electron microscopy structure of the yeast inner kinetochore assembled onto the centromere-specific centromere protein A nucleosomes (CENP-ANuc). This revealed a central CENP-ANuc with extensively unwrapped DNA ends. These free DNA duplexes bind two CCAN protomers, one of which entraps DNA topologically, positioned on the centromere DNA element I (CDEI) motif by CBF1. The two CCAN protomers are linked through CBF3 forming an arch-like configuration. With a structural mechanism for how CENP-ANuc can also be linked to KMN involving only CENP-QU, we present a model for inner kinetochore assembly onto a point centromere and how it organizes the outer kinetochore for chromosome attachment to the mitotic spindle.

Simple and safe digitoxin dosing in heart failure based on data from the DIGIT-HF trial.

BACKGROUND: The present study aimed to develop a simple dosing score when starting the cardiac glycoside digitoxin in heart failure with reduced ejection fraction (HFrEF) employing first data from the randomized, double-blinded DIGIT-HF trial. METHODS AND RESULTS: In DIGIT-HF, digitoxin was started with a dose of 0.07 mg once daily (o.d.) in all patients. For score derivation, 317 patients were analyzed who had been randomized to digitoxin. In these patients, after scheduled determination of serum levels at study week 6, the digitoxin dose had remained unchanged or had been reduced to 0.05 mg o.d. (97% of patients) to achieve serum concentrations within a predefined range (10.5-23.6 nmol/l). In logistic regression analyses, sex, age, body mass index (BMI), and estimated glomerular filtration rate (eGFR) were associated with need for dose reduction and, therefore, selected for further developing the dosing score. Optimal cut-points were derived from ROC curve analyses. Finally, female sex, age ≥ 75 years, eGFR < 50 ml/min/1.73 m2, and BMI < 27 kg/m2 each were assigned one point for the digitoxin dosing score. A score of ≥ 1 indicated the need for dose reduction with sensitivity/specificity of 81.6%/49.7%, respectively. Accuracy was confirmed in a validation data set including 64 patients randomized to digitoxin yielding sensitivity/specificity of 87.5%/37.5%, respectively. CONCLUSION: In patients with HFrEF, treatment with digitoxin should be started at 0.05 mg o.d. in subjects with either female sex, eGFR < 50 ml/min/1.73m2, BMI < 27 kg/m2, or age ≥ 75 years. In any other patient, digitoxin may be safely started at 0.07 mg o.d.

Case report: Flattening of the tectal plate in obstructive hydrocephalus with auto-ventriculostomy.

BACKGROUND: Obstructive hydrocephalus in adulthood can be caused by stenosis in the aqueductal area. Chronic changes lead to a dilatation of the lateral ventricles and ballooning of infratentorial recesses. In rare cases a rupture of the floor of the third ventricle (so-called spontaneous ventriculostomy) has been described in the literature.Case presentation: We present two cases of chronic obstructive hydrocephalus due to aqueductal stenosis in adult patients. Magnetic resonance imaging included phase-contrast-imaging and revealed significant flow through the floor of the third ventricle in keeping with spontaneous ventriculostomy. In addition to other typical changes associated with chronic hydrocephalus, a distinct flattening of the tectal plate could be identified in one case. CONCLUSION: We present two cases of spontaneous ventriculostomy in patients with chronic hydrocephalus. To our knowledge, flattening of the tectal plate has not yet been described in the literature and may be caused by continuous cerebrospinal fluid-pulsation.

Risk of conduction disturbances following different transcatheter aortic valve prostheses: the role of aortic valve calcifications.

OBJECTIVES: To assess the impact of prosthesis choice and aortic valve calcifications on the occurrence of conduction disturbances after transcatheter aortic valve implantation (TAVI). METHODS: We retrospectively analyzed the preoperative clinical characteristics, electrocardiograms, contrast-enhanced multidetector computed tomography scans and procedural strategies of patients who underwent TAVI in our center between January 2012 and June 2017. Quantification of calcium volume was performed for each aortic cusp above (aortic valve) and below (left ventricular outflow tract, LVOT) the basal plane. Multivariate analysis was performed to evaluate risk factors for the onset of new bundle branch block (BBB), transient and permanent atrioventricular block (tAVB, pAVB). RESULTS: A total of 569 patients were included in the study. Six different prostheses were implanted (Edwards Sapien XT, n = 162; Edwards Sapien 3, n = 240; Medtronic CoreValve, n = 27; Medtronic CoreValve Evolut R, n = 21; Symetis Acurate, n = 56; Symetis Acurate neo, n = 63). The logistic regression analysis for BBB showed association with baseline left anterior hemiblock. The logistic regression for tAVB, found the prior valvuloplasty and the balloon post-dilatation associated with the outcome. Baseline left and right BBB, degree of oversizing, and LVOT calcification beneath the non-coronary cusp were associated with pAVB. Neither the prosthesis model, nor the use of a self-expandable prosthesis showed statistical significance with the above-mentioned outcomes on univariate analysis. CONCLUSIONS: LVOT calcification beneath the non-coronary cusp, baseline left anterior hemiblock, right BBB, balloon post-dilatation, prior valvuloplasty and oversizing are independently associated with postprocedural conduction disturbances after TAVI. Use of a self-expandable prosthesis may show a lower incidence of AVB, if applied in lower calcified aortic valves.

Comparison between Surgical Access and Percutaneous Closure Device in 787 Patients Undergoing Transcatheter Aortic Valve Replacement.

BACKGROUND: The vascular access in transcatheter aortic valve replacement (TAVR) was initially dominated by a surgical approach. Meanwhile, percutaneous closure systems became a well-established alternative. The aim of this study was to compare the clinical outcome between the two approaches. METHODS: In this retrospective study, we observed 787 patients undergoing a TAVR-Procedure between 2013 and 2019. Of those, 338 patients were treated with surgical access and 449 with the Perclose ProGlide™-System (Abbott, Chicago, IL, USA). According to the Bleeding Academic Research Consortium (BARC) and Valve Academic Research Consortium (VARC) criteria, the primary combined endpoints were defined. RESULTS: Overall hospital mortality was 2.8% with no significant difference between surgical (3.8%) and percutaneous (2.2%) access (p = 0.182). Major vascular complications or bleeding defined as the primary combined endpoint was not significantly different in either group (Surgical group 5.3%, ProGlide group 5.1%, p = 0.899). In the ProGlide group, women with pre-existing peripheral artery disease (PAD) were significantly more often affected by a vascular complication (p = 0.001 for female sex and p = 0.03 for PAD). CONCLUSIONS: We were able to show that the use of both accesses is safe. However, the surgical access route should also be considered in case of peripheral artery disease.

Big in Japan: Regularizing Networks for Solving Inverse Problems.

Deep learning and (deep) neural networks are emerging tools to address inverse problems and image reconstruction tasks. Despite outstanding performance, the mathematical analysis for solving inverse problems by neural networks is mostly missing. In this paper, we introduce and rigorously analyze families of deep regularizing neural networks (RegNets) of the form B α + N θ ( α ) B α , where B α is a classical regularization and the network N θ ( α ) B α is trained to recover the missing part Id X - B α not found by the classical regularization. We show that these regularizing networks yield a convergent regularization method for solving inverse problems. Additionally, we derive convergence rates (quantitative error estimates) assuming a sufficient decay of the associated distance function. We demonstrate that our results recover existing convergence and convergence rates results for filter-based regularization methods as well as the recently introduced null space network as special cases. Numerical results are presented for a tomographic sparse data problem, which clearly demonstrate that the proposed RegNets improve classical regularization as well as the null space network.

Experimental lung injury induces cerebral cytokine mRNA production in pigs.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is an important disease with a high incidence among patients admitted to intensive care units. Over the last decades, the survival of critically ill patients has improved; however, cognitive deficits are among the long-term sequelae. We hypothesize that acute lung injury leads to upregulation of cerebral cytokine synthesis. METHODS: After approval of the institutional and animal care committee, 20 male pigs were randomized to one of three groups: (1) Lung injury by oleic acid injection (OAI), (2) ventilation only (CTR) or (3) untreated. We compared neuronal numbers, proportion of neurons with markers for apoptosis, activation state of Iba-1 stained microglia cells and cerebral mRNA levels of different cytokines between the groups 18 hours after onset of lung injury. RESULTS: We found an increase in hippocampal TNFalpha (p < 0.05) and IL-6 (p < 0.05) messenger RNA (mRNA) in the OAI compared to untreated group as well as higher hippocampal IL-6 mRNA compared to control (p < 0.05). IL-8 and IL-1beta mRNA showed no differences between the groups. We found histologic markers for beginning apoptosis in OAI compared to untreated (p < 0.05) and more active microglia cells in OAI and CTR compared to untreated (p < 0.001 each). CONCLUSION: Hippocampal cytokine transcription increases within 18 hours after the induction of acute lung injury with histological evidence of neuronal damage. It remains to be elucidated if increased cytokine mRNA synthesis plays a role in the cognitive decline observed in survivors of ARDS.

Aortic valve calcification as a risk factor for major complications and reduced survival after transcatheter replacement.

BACKGROUND: Aortic valve calcification is supposed to be a possible cause of embolic stroke or subclinical valve thrombosis after transcatheter aortic valve replacement (TAVR). We aimed to assess the role of aortic valve calcification in the occurrence of in-hospital clinical complications and survival after TAVR. METHODS: We retrospectively analyzed preoperative contrast-enhanced multidetector computed tomography scans of patients who underwent TAVR on the native aortic valve in our center. Calcium volume was calculated for each aortic cusp, above and below the aortic annulus. Outcomes were recorded according to VARC-2 criteria. RESULTS: Overall, 581 patients were included in the study (SapienXT = 192; Sapien3 = 228; CoreValve/EvolutR = 45; Engager = 5; Acurate = 111). Median survival was 4.98 years (interquartile range 4.41-5.54). Logistic regression identified calcium load beneath the right coronary cusp in left ventricular outflow tract (LVOT) as significantly associated with stroke (odds ratio [OR] 1.2; 95% confidence interval [CI] 1.03-1.3; p = 0.0019) and in-hospital mortality (OR 1.1; 95% CI 1.004-1.2; p = 0.04), whereas total calcium volume of the LVOT was associated with both in-hospital and 30 day-mortality (OR 1.2; 95% CI 1.01-1.4; p = 0.03, and OR 1.2; 95% CI 1.02-1.43; p = 0.029, respectively). Cox regression identified total calcium of LVOT (hazard ratio [HR] 1.18; 95% CI 1.02-1.38; p = 0.026), male sex (HR 1.88; 95% CI 1.06-3.32; p = 0.031), baseline creatinine clearance (HR 0.96; 95% CI 0.93-0.98; p < 0.001), and baseline severe aortic regurgitation (HR 7.48; 95% CI 2.76-20.26; p < 0.001) as risk factors associated with lower survival. CONCLUSION: LVOT calcification is associated with increased risk of peri-procedural stroke and mortality as well as shorter long-term survival.

Deep learning for photoacoustic tomography from sparse data.

The development of fast and accurate image reconstruction algorithms is a central aspect of computed tomography. In this paper, we investigate this issue for the sparse data problem in photoacoustic tomography (PAT). We develop a direct and highly efficient reconstruction algorithm based on deep learning. In our approach, image reconstruction is performed with a deep convolutional neural network (CNN), whose weights are adjusted prior to the actual image reconstruction based on a set of training data. The proposed reconstruction approach can be interpreted as a network that uses the PAT filtered backprojection algorithm for the first layer, followed by the U-net architecture for the remaining layers. Actual image reconstruction with deep learning consists in one evaluation of the trained CNN, which does not require time-consuming solution of the forward and adjoint problems. At the same time, our numerical results demonstrate that the proposed deep learning approach reconstructs images with a quality comparable to state of the art iterative approaches for PAT from sparse data.

Risk factors for paravalvular leak after transcatheter aortic valve replacement.

OBJECTIVE: To assess risk factors for paravalvular leak (PVL) after transcatheter aortic valve implantation in a large single-center cohort, including measurement of aortic valve calcification using a reproducible method. METHODS: We retrospectively analyzed preoperative contrast-enhanced multidetector computed tomography scans of patients who underwent transcatheter aortic valve implantation in our center between 2009 and 2016. Calcium volume was calculated for each aortic cusp in the aortic valve, left ventricular outflow tract, and device landing zone. RESULTS: Overall, 539 patients were included in the study who had experience with 4 prothesis types (SapienXT [Edwards Lifesciences, Irvine, Calif] [n = 192], Sapien3 [Edwards Lifesciences] [n = 206], CoreValve EvolutR [Medtronic, Minneapolis, Minn] [n = 44], and Acurate [Symetis, Ecublens, Switzerland] [n = 97]). Median calcium volume in the device landing zone was 757 mm3, with no significant differences among the 4 prosthesis groups. None of the patients had severe PVL. The overall incidence of mild-to-moderate PVL was 15.8% (95% confidence interval [CI], 12.8%-19.1%). On multivariate logistic regression, device landing zone calcification (P = .00006; odds ratio for an increase of 100 mm3, 1.08; 95% CI, 1.04-1.13) and use of the CoreValve (P = .0028; odds ratio, 4.1; 95% CI, 1.6-10 with SapienXT as reference) prosthesis were found to be associated with mild or greater PVL. In contrast, degree of oversizing (P = .002; odds ratio, 0.97; 95% CI, 0.95-0.99), and use of Sapien3 (P = .00005; odds ratio, 0.23; 95% CI, 0.11-0.47 with SapienXT as reference) were associated with a lower incidence of mild or greater PVL. CONCLUSIONS: Aortic calcification volume in the device landing zone is associated with residual PVL after transcatheter aortic valve implantation. When taking calcification into account, the balloon-expandable prosthesis Sapien3 seems to be associated with a lower incidence of PVL.

Long-term follow-up in peripartum cardiomyopathy patients with contemporary treatment: low mortality, high cardiac recovery, but significant cardiovascular co-morbidities.

AIMS: Peripartum cardiomyopathy (PPCM) establishes late in pregnancy or in the first postpartum months. Many patients recover well within the first year, but long-term outcome studies on morbidity and mortality are rare. Here, we present 5-year follow-up data of a German PPCM cohort. METHODS AND RESULTS: Five-year follow-up data were available for 66 PPCM patients (mean age 34 ± 5 years) with a mean left ventricular ejection fraction (LVEF) of 26 ± 9% at diagnosis. Ninety-eight percent initially received standard heart failure therapy (beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and/or mineralocorticoid receptor antagonists), and 86% were additionally treated with dopamine D2 receptor agonists (mainly bromocriptine) and anticoagulation. After 1 year, mean LVEF had improved to 50 ± 11% (n = 48) and further increased to 54 ± 7% at 5-year follow-up with 72% of patients having achieved full cardiac recovery (LVEF >50%). At 5-year follow-up, only three patients (5%) displayed no recovery, of whom one had died. However, 20% had arterial hypertension and 17% arrhythmias, including paroxysmal supraventricular tachycardia, ventricular tachycardia, or ventricular fibrillation. Moreover, 70% were still on at least one heart failure drug. Subsequent pregnancy occurred in 16 patients with two abortions and 14 uneventful pregnancies. Mean LVEF was 55 ± 7% at 5-year follow-up in these patients. CONCLUSION: Our PPCM collective treated with standard therapy for heart failure, dopamine D2 receptor agonists, and anticoagulation displays a high and stable long-term recovery rate with low mortality at 5-year follow-up. However, long-term use of cardiovascular medication, persisting or de novo hypertension and arrhythmias were frequent.