What did the transcatheter aortic valve replacement-surgical aortic valve replacement (TAVR-SAVR) trials tell us?

Two families of randomized trials comparing transcatheter aortic valve replacement (TAVR) to surgery for both the Balloon Expandable Valve and the Supra Annular Self-Expanding Valve have been completed to include all surgical risk levels. The result of these trials has led to the approval of TAVR for symptomatic severe aortic stenosis without using risk level as the sole criterion. We have seen an explosion of TAVR in the US to over 98,000 commercial cases in 2022. We have also seen a rapid increase in the use of TAVR in patients less than 65 years of age. With these increases, it is important to ask if they are being driven largely by the data or just the desire for TAVR by both patients and their physicians. Heart team input is a class I indication when deciding between TAVR and surgery. For surgical members of the heart team to appropriately counsel patients, a full understanding of what the TAVR surgery trials tell us as well as what they do not is essential. In this article we will explore those questions.

Surface-based morphometry of the corpus callosum in young children of ages 1-5.

The corpus callosum (CC) is a large white matter fiber bundle in the brain and is involved in various cognitive, sensory, and motor processes. While implicated in various developmental and psychiatric disorders, much is yet to be uncovered about the normal development of this structure, especially in young children. Additionally, while sexual dimorphism has been reported in prior literature, observations have not necessarily been consistent. In this study, we use morphometric measures including surface tensor-based morphometry (TBM) to investigate local changes in the shape of the CC in children between the ages of 12 and 60 months, in intervals of 12 months. We also analyze sex differences in each of these age groups. We observed larger significant clusters in the earlier ages between 12 v 24 m and between 48 v 60 m and localized differences in the anterior region of the body of the CC. Sex differences were most pronounced in the 12 m group. This study adds to the growing literature of work aiming to understand the developing brain and emphasizes the utility of surface TBM as a useful tool for analyzing regional differences in neuroanatomical morphometry.

Impact of Left Atrial Pressure on Outcomes After Mitral Transcatheter Edge-to-Edge Repair.

Background: Increased left atrial pressure (LAP) has been associated with adverse outcomes after mitral transcatheter edge-to-edge repair (M-TEER). We sought to evaluate outcomes based on differences in post-procedural LAP measured after final clip deployment. Methods: We included consecutive patients who underwent M-TEER at our institution between 2014-2022 with LAP monitoring. Patients were stratified into 3 groups according to tertiles of post-TEER mean LAP. Outcomes were assessed using Kaplan-Meier analysis and Cox proportional hazard models. Results: We included 273 patients (mean age 76.8±10.8 years, 42.5% women, 78.4% Caucasian). The mean post-TEER LAP was 8.7±1.7 mmHg in tertile 1 (N=85), 14.4±1.6 mmHg in tertile 2 (N=95), and 21.9±3.8 mmHg in tertile 3 (N=93). In comparison with tertile 1, both tertiles 2 and 3 were associated with increased risk of all-cause mortality or heart failure hospitalization at 2 years (adjHR 2.27, 95% CI 1.25-4.12; and adjHR 3.00, 95% CI 1.59-5.64 respectively). Among patients with primary MR, higher LAP was associated with increased risk of 2-year all-cause mortality or heart failure hospitalization [tertile 2 vs. 1: adjHR 3.00, 95% CI 1.37-6.56; and tertile 3 vs. 1: adjHR 5.52, 95% CI 2.04-14.95). However, in patients with secondary MR, neither being in tertile 2 (adjHR 1.53; 95% CI 0.55-4.24), nor tertile 3 (adjHR 2.18; 95% CI 0.82-5.77) were associated with the composite outcome compared with tertile 1. Any degree of LAP reduction following M-TEER was associated with lower mortality or heart failure hospitalization compared with no LAP reduction (adjHR 0.59; 95% CI 0.39-0.88). Conclusions: Elevated LAP after M-TEER was associated with increased 2-year risk of mortality or heart failure hospitalization. Exploration of reasons for elevated LAP after M-TEER, and ways to lower it warrant further investigation.

Synergy between the clavanins as a weapon against multidrug-resistant Enterobacter cloacae.

Finding new antibiotics that can act synergistically with each other offers many benefits such as lower dosages used for each drug, improved pathogen clearance, and ability to act against multi-drug resistant strains. In this study, six peptides isolated from the tunicate Styela clava were evaluated for their synergistic interaction using the checkerboard assay and the time kill kinetics assay. Using two different tests, we report synergy between clavanin D and clavaspirin in both tests and synergy between clavanin A and B only in the checkerboard test when used against the multidrug resistant E. cloacae 0136. This work demonstrates the possible cooperativity between homologous AMPs from a single organism and the advantage of using two susceptibility tests instead of one when testing synergistic combinations.

Prognostic Value of Right Ventricular Afterload in Patients Undergoing Mitral Transcatheter Edge-to-Edge Repair.

BACKGROUND: Pulmonary hypertension (PH) and secondary mitral regurgitation (MR) are associated with adverse outcomes after mitral transcatheter edge-to-edge repair. We aim to study the prognostic value of invasively measured right ventricular afterload in patients undergoing mitral transcatheter edge-to-edge repair. METHODS AND RESULTS: We identified patients who underwent right heart catheterization ≤1 month before transcatheter edge-to-edge repair. The end points were all-cause mortality and a composite of mortality and heart failure hospitalization at 2 years. Using the receiver operating characteristic curve-derived threshold of 0.6 for pulmonary effective arterial elastance ([Ea], pulmonary artery systolic pressure/stroke volume), patients were stratified into 3 profiles based on PH severity (low elastance [HE]: Ea <0.6/mean pulmonary artery pressure (mPAP)) <35; High Elastance with No/Mild PH (HE-): Ea ≥0.6/mPAP <35; and HE with Moderate/Severe PH (HE+): Ea ≥0.6/mPAP ≥35) and MR pathogenesis (Primary MR [PMR])/low elastance, PMR/HE, and secondary MR). The association between this classification and clinical outcomes was examined using Cox regression. Among 114 patients included, 50.9% had PMR. Mean±SD age was 74.7±10.6 years. Patients with Ea ≥0.6 were more likely to have diabetes, atrial fibrillation, New York Heart Association III/IV status, and secondary MR (all P<0.05). Overall, 2-year cumulative survival was 71.1% and was lower in patients with secondary MR and mPAP ≥35. Compared with patients with low elastance, cumulative 2-year event-free survival was significantly lower in HE- and HE+ patients (85.5% versus 50.4% versus 41.0%, respectively, P=0.001). Also, cumulative 2-year event-free survival was significantly higher in patients with PMR/low elastance when compared with PMR/HE and patients with secondary mitral regurgitation (85.5% versus 55.5% versus 46.1%, respectively, P=0.005). CONCLUSIONS: Assessment of the preprocedural cardiopulmonary profile based on mPAP, MR pathogenesis, and Ea guides patient selection by identifying hemodynamic features that indicate likely benefit from mitral-transcatheter edge-to-edge repair in PH or lack thereof.

Vorinostat, temozolomide or bevacizumab with irradiation and maintenance BEV/TMZ in pediatric high-grade glioma: A Children's Oncology Group Study.

Background: Outcomes for children with high-grade gliomas (HGG) remain poor. This multicenter phase II trial evaluated whether concurrent use of vorinostat or bevacizumab with focal radiotherapy (RT) improved 1-year event-free survival (EFS) compared to temozolomide in children with newly diagnosed HGG who received maintenance temozolomide and bevacizumab. Methods: Patients ≥ 3 and < 22 years with localized, non-brainstem HGG were randomized to receive RT (dose 54-59.4Gy) with vorinostat, temozolomide, or bevacizumab followed by 12 cycles of bevacizumab and temozolomide maintenance therapy. Results: Among 90 patients randomized, the 1-year EFS for concurrent bevacizumab, vorinostat, or temozolomide with RT was 43.8% (±8.8%), 41.4% (±9.2%), and 59.3% (±9.5%), respectively, with no significant difference among treatment arms. Three- and five-year EFS for the entire cohort was 14.8% and 13.4%, respectively, with no significant EFS difference among the chemoradiotherapy arms. IDH mutations were associated with more favorable EFS (P = .03), whereas H3.3 K27M mutations (P = .0045) and alterations in PIK3CA or PTEN (P = .025) were associated with worse outcomes. Patients with telomerase- and alternative lengthening of telomeres (ALT)-negative tumors (n = 4) had an EFS of 100%, significantly greater than those with ALT or telomerase, or both (P = .002). While there was no difference in outcomes based on TERT expression, high TERC expression was associated with inferior survival independent of the telomere maintenance mechanism (P = .0012). Conclusions: Chemoradiotherapy with vorinostat or bevacizumab is not superior to temozolomide in children with newly diagnosed HGG. Patients with telomerase- and ALT-negative tumors had higher EFS suggesting that, if reproduced, mechanism of telomere maintenance should be considered in molecular-risk stratification in future studies.

Final report of the phase II NEXT/CNS-GCT-4 trial: GemPOx followed by marrow-ablative chemotherapy for recurrent intracranial germ cell tumors.

Background: Patients with relapsed intracranial germinoma can achieve durable remission with standard chemotherapy regimens and/or reirradiation; however, innovative therapies are required for patients with relapsed and/or refractory intracranial nongerminomatous germ cell tumors (NGGCTs) due to their poor prognosis. Improved outcomes have been reported using reinduction chemotherapy to achieve minimal residual disease, followed by marrow-ablative chemotherapy (HDCx) with autologous hematopoietic progenitor cell rescue (AuHPCR). We conducted a phase II trial evaluating the response and toxicity of a 3-drug combination developed for recurrent intracranial germ cell tumors consisting of gemcitabine, paclitaxel, and oxaliplatin (GemPOx). Methods: A total of 9 patients with confirmed relapsed or refractory intracranial GCT were enrolled after signing informed consent, and received at least 2 cycles of GemPOx, of which all but 1 had relapsed or refractory NGGCTs. One patient with progressive disease was found to have pathologically confirmed malignant transformation to pure embryonal rhabdomyosarcoma (without GCT elements), hence was ineligible and not included in the analysis. Patients who experienced sufficient responses proceeded to receive HDCx with AuHPCR. Treatment response was determined based on radiographic tumor assessments and tumor markers. Results: A total of 7 patients achieved sufficient response and proceeded with HDCx and AuHPCR, and 5 subsequently received additional radiotherapy. A total of 2 patients developed progressive disease while receiving GemPOx. Myelosuppression and transaminitis were the most common treatment-related adverse events. With a mean follow-up of 44 months, 4 patients (3 NGGCTs, 1 germinoma) are alive without evidence of disease. Conclusions: GemPOx demonstrates efficacy in facilitating stem cell mobilization, thus facilitating the feasibility of both HDCx and radiotherapy.

Echocardiographic Profiling Predicts Clinical Outcomes After Mitral Transcatheter Edge-to-Edge Repair.

BACKGROUND: Prior studies investigating the impact of residual mitral regurgitation (MR), tricuspid regurgitation (TR), and elevated predischarge transmitral mean pressure gradient (TMPG) on outcomes after mitral transcatheter edge-to-edge repair (TEER) have assessed each parameter in isolation. We sought to examine the prognostic value of combining predischarge MR, TR, and TMPG to study long-term outcomes after TEER. METHODS AND RESULTS: We reviewed the records of 291 patients who underwent successful mitral TEER at our institution between March 2014 and June 2022. Using well-established outcomes-related cutoffs for predischarge MR (≥moderate), TR (≥moderate), and TMPG (≥5 mm Hg), 3 echo profiles were developed based on the number of risk factors present (optimal: 0 risk factors, mixed: 1 risk factor, poor: ≥2 risk factors). Discrimination of the profiles for predicting the primary composite end point of all-cause mortality and heart failure hospitalization at 2 years was examined using Cox regression. Overall, mean age was 76.7±10.6 years, 43.3% were women, and 53% had primary MR. Two-year event-free survival was 61%. Predischarge TR≥moderate, MR≥moderate, and TMPG≥5 mm Hg were risk factors associated with the primary end point. Compared with the optimal profile, there was an incremental risk in 2-year event-rate with each worsening profile (optimal as reference; mixed profile: hazard ratio (HR), 2.87 [95% CI, 1.71-5.17], P<0.001; poor profile: HR, 3.76 [95% CI, 1.84-6.53], P<0.001). Echocardiographic profile was statistically associated with the 2-year mortality end point (optimal as reference; mixed profile: HR, 3.55 [95% CI, 1.81-5.96], P<0.001; poor profile: HR, 3.39 [95% CI, 2.56-7.33], P=0.02). CONCLUSIONS: The echocardiographic profile integrating predischarge TR, MR, and TMPG presents a novel prognostic stratification tool for patients undergoing mitral TEER.

Do anxiety symptoms and coping motives serially mediate the association between psychotic-like experiences and cannabis-related problems in undergraduate recent cannabis users?

Many Canadian emerging adults (ages 18-25 years) use cannabis, with 60 % of past-three-month users experiencing one or more cannabis-related problems (i.e., adverse consequences of use). While psychotic-like experiences (PLEs) and cannabis problems overlap, little is known about the mechanisms explaining this link. One hypothesis is that PLEs are distressing and give rise to anxiety, with which emerging adults attempt to cope through increased cannabis use, in turn increasing their risk for cannabis-related problems. We tested a chained-mediational model to determine if anxiety and coping-with-anxiety motives for cannabis use sequentially mediated the link between PLEs and cannabis problems in emerging adult undergraduates; a conditional process model tested for moderation by sex. Emerging adult cannabis users (N = 413; mean [SD] age = 19.1 [1.5] years; 71.9 % female) from five Canadian universities provided cross-sectional, self-report survey data in fall 2021. Validated measures of PLEs, anxiety, cannabis coping-with-anxiety motives, and cannabis-related problems were administered. Path analyses supported the hypothesized chained mediational indirect effect (b = 0.027, 95 % bootstrap CI [0.012, 0.050]). No direct effect was found (p =.698), suggesting that the PLEs-to-cannabis problems association is fully explained by anxiety and cannabis coping-with-anxiety motives. Inconsistent with hypotheses, mediation did not depend on sex (95 % CIs crossed zero); therefore, anxiety and cannabis coping-with-anxiety motives explain the link between PLEs and cannabis problems in emerging adults regardless of their sex. Results highlight anxiety and cannabis coping-with-anxiety motives as potentially important intervention targets in cannabis-using emerging adults with PLEs, possibly preventing the development/worsening of cannabis-related problems.

Open repair of a proximal left subclavian artery mycotic aneurysm with median claviculectomy.

Surgical repair of a subclavian artery mycotic aneurysm is dependent on aneurysm-specific characteristics and anatomic exposures could require sternotomy, thoracotomy, or supraclavicular incisions. Alternatively, a median claviculectomy can be used. We successfully performed a subclavian artery to axillary artery bypass with median claviculectomy in a 23-year-old man with multiple comorbidities. Postoperative Doppler ultrasound showed a patent left axillary artery with a palpable left radial artery, and the patient demonstrated full left shoulder range of motion without any significant deformities. This case suggests that a median claviculectomy can produce satisfactory outcomes in patients with subclavian artery mycotic aneurysms.

Emergency and Compassionate Use of a Novel Ascending Endograft for Ascending and Arch Aortic Pathology.

PURPOSE: Patients with complicated ascending aortic pathology, including patients with acute type A aortic dissection may be at extreme risk for open repair. Thoracic endovascular aortic repair (TEVAR), infrequently used for the ascending aorta, may be considered an alternative in this setting. We describe early results for emergency and compassionate (E&C) use of a novel endograft, specifically designed for use to treat pathology of the ascending aorta. MATERIALS AND METHODS: This case series evaluated 19 patients (mean age, 68.84±13.12 years; 57.9% female) treated with ascending TEVAR for acute and chronic acute (4), subacute (1), or chronic (1) aortic dissection or pseudoaneurysm (13). Six of the 19 patients (31.5%) were treated under compassionate use and 13 patients (68.4%) were treated under the emergency use exemption. Ten patients (52.6%) received additional devices to extend treatment into the arch and descending aorta. RESULTS: Device delivery was achieved in all patients (100%). Thirty-day mortality and stroke occurred in 3 patients (15.8%) and in 1 patient (5.3%), respectively. In 1 patient (5.3%), with an Unanticipated Adverse Device Event, the aorta ruptured when the endograft eroded into the adventitial portion of dissection site at the posterior aspect of the ascending wall. Devices were explanted in 2 patients (10.5%), 353 and 610 days after the index procedure, respectively. Six patients had endoleaks (31.6%), including type I (n=2, 10.5%), type II endoleaks (n=3, 15.8%), and indeterminate endoleak (n=1, 5.3%). CONCLUSIONS: Delivery and deployment of a novel ascending thoracic stent graft with or without an additional branched arch extension is feasible in patients with complex anatomy and pathology, including acute aortic dissection and pseudoaneurysm. Additional experience with this novel device will further refine the patient population most suitable for endovascular ascending aortic repair for these pathologies. CLINICAL IMPACT: This study describes a novel stent graft specifically designed for treatment of ascending aortic pathology, including acute type A dissection. The patients described in this series constituted a group outside the formal US FDA sponsored clinical trial, and were those accepted as part of an emergency and compassionate use basis.

TAV-in-TAV in Failed Homograft: Redo TAVI in a Patient With 3 Previous Sternotomies.

A 59-year-old male patient with history of rheumatic heart disease with 3 previous surgical aortic valve replacements with the last one being homograft followed by transcatheter aortic valve implantation in failed homograft presented with severe aortic regurgitation and cardiogenic shock requiring urgent TAV-in-TAV-in homograft. (Level of Difficulty: Advanced.).

Feasibility and Outcomes of Mitral Transcatheter Edge-To-Edge Repair in Patients With Variable Degrees of Mitral Annular Calcification.

Background The clinical significance of mitral annular calcification (MAC) in patients undergoing mitral transcatheter edge-to-edge repair is not well understood. There is limited evidence regarding the feasibility, durability of repair, and the prognostic value of MAC in this population. We sought to examine the prognostic value of MAC, its severity, and its impact on procedural success and durability of mitral transcatheter edge-to-edge repair. Methods and Results We reviewed the records of 280 patients with moderate-severe or severe mitral regurgitation who underwent mitral transcatheter edge-to-edge repair with MitraClip from March 2014 to March 2022. The primary end point was cumulative survival at 1 year. Independent factors associated with the primary end point were identified using multivariable Cox regression. Among 280 patients included in the final analysis, 249 had none/mild MAC, and 31 had moderate/severe MAC. Median follow-up was 23.1 months (interquartile range: 11.1-40.4). Procedural success was comparable in the MAC and non-MAC groups (92.6% versus 91.4%, P=0.79) with similar rates of residual mitral regurgitation ≤2 at 1 year (86.7% versus 93.2%, P=0.55). Moderate/severe MAC was associated with less improvement in New York Heart Association III/IV at 30 days when compared with none/mild MAC (45.8% versus 14.3%, P=0.001). The moderate/severe MAC group had lower cumulative 1-year survival (56.8% versus 80.0%, hazard ratio [HR], 1.98 [95% CI, 1.27-3.10], P=0.002). Moderate/severe MAC and Society of Thoracic Surgeons predicted risk of mortality for mitral valve repair were independently associated with the primary end point (HR, 2.20 [1.10-4.41], P=0.02; and HR, 1.014 [1.006-1.078], P=0.02, respectively). Conclusions Mitral TEER is a safe and feasible intervention in selected patients with significant MAC and associated with similar mitral regurgitation reduction at 1 year compared with patients with none/mild MAC. Patients with moderate/severe MAC had a high 1-year mortality and less improvement in their symptoms after TEER.

First-in-Human Multicenter Experience of the Newest Generation Supra-Annular Self-Expanding Evolut FX TAVR System.

BACKGROUND: The latest-generation Evolut FX TAVR system (Medtronic) offers several potential design improvements over its predecessors, but early reported experience has been limited. OBJECTIVES: This study sought to report our multicenter, limited market release, first-in-human experience of transcatheter aortic valve replacement (TAVR) with the Evolut FX system and compare it with a single-center PRO+ (Medtronic) experience. METHODS: From June 27 to September 16, 2022, 226 consecutive patients from 9 US centers underwent transfemoral TAVR with the Evolut FX system for native aortic stenosis (89.4%) or prosthetic valve degeneration (10.6%). Commissural alignment was defined as 0° to 30° between native and FX commissures. Patient, anatomical, and procedural characteristics were retrospectively reviewed, and 30-day clinical and echocardiographic outcomes per Valve Academic Research Consortium-3 definitions were reported. RESULTS: Of 226 patients, 34.1% were low risk, 4% had a bicuspid valve, and 11.5% had a horizontal root (≥60°). Direct Inline sheath (Medtronic) was used in 67.6% and Lunderquist stiff wire (Cook Medical) in 35.4% of cases. Optimal hat marker orientation during deployment was achieved in 98.4%, with commissural alignment in 96.5%. At 30 days, 14.3% mild, 0.9% moderate, and no severe paravalvular leak were observed. Compared with the Evolut PRO+ experience from 1 center, FX had a more symmetrical implantation with shallower depth at the left coronary cusp (P < 0.001), fewer device recaptures (26.1% vs 39.5%; P = 0.004), and improved commissural alignment (96.5% vs 80.2%; P < 0.001). CONCLUSIONS: The Evolut FX system demonstrated favorable 30-day outcomes with a significant improvement over PRO+ in achieving commissural alignment, fewer device recaptures, and more symmetrical implantation. These features may benefit younger patients undergoing TAVR with the supra-annular, self-expanding valve, where lifetime management would be important.

Survey Results on Online Teaching and Learning Environments in the European EMMA Project.

In the Erasmus+ project EMMA, a concept for a common digital teaching and learning platform is to be developed for an online joint master program. In the initial phase, a status quo survey was carried out among the consortium members, which shows which digital infrastructures are already in use and which functions are considered particularly important by the teachers. This paper shows the first results of the short survey via online questionnaire and discusses the challenges derived from it. Due to the non-homogeneous infrastructure and software use, there are neither the teaching-learning platform nor digital communication applications tools that are used equally by all six European higher education institutions. However, the consortium pursues the idea of specifying a limited tool pool order to strengthen the user experience and usability of teachers and students with different interdisciplinary backgrounds and digitalization expertise.

Neuroimaging of complications arising after CD19 chimeric antigen receptor T-cell therapy: A review.

Chimeric antigen receptor (CAR) T cells targeting the CD19 (cluster of differentiation 19) cell surface glycoprotein have emerged as a highly effective immunologic therapy in patients with relapsed or refractory B-cell malignancies. The engagement of CAR T cells with CD19 on the surface of neoplastic B cells causes a systemic cytokine release, which can compromise the blood-brain barrier and cause an immune effector cell-associated neurotoxicity syndrome (ICANS). In a small proportion of ICANS patients who demonstrate neuroimaging abnormalities, certain distinct patterns have been recognized, including signal changes in the thalami, external capsule, and brainstem, the subcortical and/or periventricular white matter, the splenium of the corpus callosum, and the cerebellum. On careful review of the underlying pathophysiology of ICANS, we noticed that these changes closely mirror the underlying blood-brain barrier disruption and neuroinflammatory and excitotoxic effects of the offending cytokines released during ICANS. Furthermore, other uncommon complications of CD19 CAR T-cell therapy such as posterior reversible encephalopathy syndrome, ocular complications, and opportunistic fungal infections can be catastrophic if not diagnosed in a timely manner, with neuroimaging playing a significant role in management. In this narrative review, we will summarize the current literature on the spectrum of neuroimaging findings in ICANS, list appropriate differential diagnoses, and explore the imaging features of other uncommon central nervous system complications of CD19 CAR T-cell therapy using illustrative cases from two tertiary care institutions.