Pulsed-field ablation does not induce esophageal and periesophageal injury-A new esophageal safety paradigm in catheter ablation of atrial fibrillation.

INTRODUCTION: Esophageal injury is one of the most serious complications of pulmonary vein isolation (PVI) with thermic energy sources. Better tissue selectivity of primarily non-thermic pulsed field ablation (PFA) may eliminate collateral injury, particularly the risk of atrio-esophageal fistula (AEF). OBJECTIVE: To compare the incidence of any (peri)-esophageal injury following PVI using PFA to thermic energy sources. METHODS: Using endoscopy, endoscopic ultrasound, and electrogastrography before and after PVI, esophageal and periesophageal injury (mucosal lesions, food retention, periesophageal edema, or vagal nerve injury) were assessed following PFA and radiofrequency (RF)- or cryoballoon (CB)-PVI. RESULTS: Between December 2022 and February 2023, 20 patients (67 ± 10 years, 53% male) undergoing PFA (Farapulse, Boston Scientific) for atrial fibrillation (AF) were studied and compared with a previous cohort of 57 patients who underwent thermic PVI (CB: n = 33; RF: n = 24). Following PFA-PVI, none of the patients had mucosal lesions, food retention, or ablation-induced vagal nerve injury; four patients showed periesophageal edema. Following thermic ablation, 33/57 patients (58%) showed esophageal and/or periesophageal injury (CB: 21/33 [64%], RF: 12/24 [50%]), in detail 4/57 mucosal lesions, 18/57 food retention, 17/57 vagal nerve injury, and 20/52 edema. Midterm success rates were similar for all energy sources. CONCLUSION: In contrast to thermic ablation tools, PFA is not associated with relevant esophageal and periesophageal injury, and might, therefore, reduce or eliminate the risk of potentially lethal AEF in interventional treatment of AF. The etiology of ablation-induced periesophageal edema is unknown but has not been shown to be related to lesion progression.

Pulmonary vein isolation-induced vagal nerve injury and gastric motility disorders detected by electrogastrography: The side effects of pulmonary vein isolation in atrial fibrillation (SEPIA) study.

INTRODUCTION: Safety of pulmonary vein isolation (PVI) has been established in clinical studies. However, despite prevention efforts the incidence of damage to (peri)-esophageal tissue has not decreased, and the pathophysiology is incompletely understood. Damage to vagal nerve branches may be involved in lesion progression to atrio-esophageal fistula. Using electrogastrography, we assessed the incidence of periesophageal vagal nerve injury (VNI) following atrial fibrillation ablation and its association with procedural parameters and endoscopic results. METHODS: Patients were studied using electrogastrography, endoscopy, and endoscopic ultrasound before and after cryoballoon (CB) or radiofrequency (RF) PVI. The incidence of ablation-induced neuropathic pattern (indicating VNI) in pre- and postprocedural electrogastrography was assessed and correlated with endoscopic results and ablation data. RESULTS: Between February 2021 und January 2022, 85 patients (67 ± 10 years, 53% male) were included, 33 were treated with CB and 52 with RF (38 with moderate power moderate duration [25-30 W] and 14 with high power short duration [50 W]). Ablation-induced VNI was detected in 27/85 patients independent of the energy form. Patients with VNI more frequently had postprocedural endoscopically detected pathology (8% mucosal esophageal lesions, 36% periesophageal edema, 33% food retention) but there was incomplete overlap. Pre-existing esophagitis increased the likelihood of VNI. Ablation data and esophageal temperature data did not predict VNI. CONCLUSION: PVI-induced VNI is quite common and independent of ablation energy source. VNI is part of (peri)-esophageal damage and only partially overlaps with endoscopic findings. VNI-associated acidic reflux may be involved in the complex pathophysiology of esophageal lesion progression to fistula.

Calculated parameters of luminal esophageal temperatures predict esophageal injury following conventional and high-power short-duration radiofrequency pulmonary vein isolation.

BACKGROUND: Luminal esophageal temperature (LET) monitoring is not associated with reduced esophageal injury following pulmonary vein isolation (PVI). OBJECTIVE: Detailed analysis of (the temporal and spatial gradients of) LET measurements may better predict the risk for esophageal injury. METHODS: Between January 2020 and December 2021, LET maxima, duration of LET rise above baseline, and area under the LET curve (AUC) were calculated offline and correlated with (endoscopy and endoscopic ultrasound detected) esophageal injury (i.e., mucosal esophageal lesions [ELs], periesophageal edema, and gastric motility disorders) following PVI using moderate-power moderate-duration (MPMD [25-30 W/25-30s]) and high-power short-duration (HPSD [50 W/13s]) radiofrequency (RF) settings. RESULTS: 63 patients (69 ± 9 years old, 32 male, 51 MPMD and 12 HPSD) were studied. The esophageal injury was frequent (40% in both groups), mucosal ELs were more common with MPMD, and edema was frequently observed following HPSD. RF-duration, total RF-energy at the left atrial (LA) posterior wall, and distance between LA and esophagus were not different between patients with/without esophageal injury. In contrast, to LET and LET duration above baseline, AUC was the best predictor and significantly increased in patients with esophageal injury (3422 vs. 2444 K. s). CONCLUSION: For both ablation strategies, AUC of the LET curves best predicted esophageal injury. HPSD is associated with similar rates of esophageal injury when (mostly subclinical) periesophageal alterations (that are of unclear clinical relevance) are included. Whether integration of these calculated LET parameters is useful to prevent esophageal injury remains to be seen.

Using dynamical systems mathematical modeling to examine the impact emotional expression on the therapeutic relationship: A demonstration across three psychotherapeutic theoretical approaches.

Objective: The purpose of this paper is to describe an approach to dynamical systems (DS) using a set of differential equations, and how an application of these equations can be used to address a critical element of the therapeutic relationship. Using APA's Three Approaches to Psychotherapy with a Female Client: The Next Generation and Three Approaches to Psychotherapy with a Male Client: The Next Generation videos, DS models were created for each of the six sessions with expert clinicians (Judith Beck, Leslie Greenberg, and Nancy McWilliams) from the three theoretical approaches. Method: A second-by-second observational coding system of the emotional exchanges of the therapists and clients was used as the data for the equations. Results: DS modeling allowed for a side-by-side comparison between the three approaches as well as between the two clients. Examining the graphs created by plotting the results of the DS equations (in particular, phase-space portraits) revealed that there were similarities among the three theoretical approaches, and there were notable differences between the two clients. Conclusions: DS modelling can provide researchers and clinicians with a powerful tool to investigate the complex phenomenon that is psychotherapy.

Advances in chemistry and bioactivity of parthenolide.

Review covering up to 07/2019(-)-Parthenolide is a germacrane sesquiterpene lactone, available in ample amounts from the traditional medical plant feverfew (Tanacetum parthenium). Acting as a covalently reactive compound, it displays anti-inflammatory, redox-modulating, and epigenetic activities, as well as selective cytotoxicity towards cancer stem and progenitor cells. Furthermore, parthenolide was found to modulate microtubule dynamics by interfering with the detyrosination of α-tubulin, a specific posttranslational modification of the cytoskeleton. This review interfaces recently achieved parthenolide syntheses with strategies for bioactivity-based derivatization. Furthermore, chemical probe development from parthenolide is discussed, leading to a qualified summary of reported biological activities and implicated or identified targets. Special emphasis is given to parthenolide-induced microtubule modulation and the recently characterized tubulin carboxypeptidase enzymes involved in nerve (re)growth, cardiac muscle cell function, and metastasis development.

Cornforth-Evans Transition States in Stereocontrolled Allylborations of Epoxy Aldehydes.

Allylboration reactions rank among the most reliable tools in organic synthesis. Herein, we report a general synthesis of trifunctionalized allylboronates and systematic investigations of their stereocontrolled transformations with substituted aldehyde substrates, in order to efficiently access diverse, highly substituted target substrates. A peculiar transition in stereocontrol was observed from the polar Felkin-Anh (PFA) to the Cornforth-Evans (CE) model for alkoxy- and epoxy-substituted aldehydes. CE-type transition states were uniformly identified as minima in advanced, DFT-based computational studies of allylboration reactions of epoxy aldehydes, conforming well to the experimental data, and highlighting the underestimated relevance of this model. Furthermore, a mechanism-based rationale for the substitution pattern of the epoxide was delineated that ensures high levels of stereocontrol and renders α,ß-epoxy aldehydes generally applicable substrates for target synthesis.

Synthesis and biological profiling of parthenolide ether analogs.

Parthenolide (PTL) strongly inhibits the detyrosination of microtubules and accelerates neuronal growth. In order to access cyclic ether derivatives of PTL, ring-closing metathesis (RCM) was investigated in comparison to intramolecular sulfone alkylation. Incompatibility of RCM with epoxides was found in this setting. Biological evaluation for tubulin carboxypeptidase inhibition indicated that the epoxide is crucial for parthenolide's activity.

Doxycycline Injection for Sclerotherapy of Lower Eyelid Festoons and Malar Edema: Preliminary Results.

PURPOSE: To investigate the safety and efficacy of direct, intralesional doxycycline hyclate injection for improving the appearance of cosmetically significant lower eyelid festoons and malar edema. METHODS: An Institutional Review Board approved, retrospective review was performed of 15 consecutive patients with malar edema and/or festoons injected with doxycycline hyclate at a concentration of 10 mg/ml. Pre- and postinjection photographs were reviewed and graded on a scale of 0 to 3 (0: no festoon; 1: small festoon; 2: medium festoon; 3: large festoon) by 2 masked physician observers. Patients were excluded from the final analysis if they received an alternate dose concentration, had incomplete photographic records, or did not follow up. Student t test was used for statistical analysis. RESULTS: Twenty consecutive treatment areas of 11 patients were included in the analysis. Final follow up ranged from 3 to 104 weeks, with a mean follow up of 22.5 weeks. The average (standard deviation) initial festoon grade of 2.5 (0.58) decreased to 0.9 (0.82) with a p value of <0.001. The average number of injections performed per side was 1.4 (range: 1-2). The mean volume per injection was 0.72 ml (range: 0.15-2.0 ml). Commonly documented subjective complaints were burning sensation with injection, pain, bruising, and erythema. There were no other dermatologic or visual complications following treatment. CONCLUSIONS: These preliminary results suggest that intralesional injections of doxycycline hyclate at a concentration of 10 mg/ml may be an effective treatment option for cosmetically significant lower eyelid festoons and malar edema. Future prospective studies with increased patient numbers, increasing concentrations, combination therapies with local anesthetic or regional nerve blocks, and longer follow up are needed to validate these results and determine optimal injection technique.

Synthesis of (±)-4,5-dia-Parthenolide, an Unnatural Parthenolide Stereoisomer.

A short total synthesis of the novel unnatural parthenolide diastereomer (±)-4,5-dia-parthenolide was accomplished in 13 steps and an overall yield of 1.75% starting from commercially available (E,E)-farnesol. The challenging isopropenyl side chain oxidation was regioselectively achieved via a newly developed stepwise dihydroxylation procedure, employing a Bartlett-Smith iodocarbonate cyclization followed by iodide substitution and catalytic transesterification.

π-Extension of a 4-ethoxy-1,3-thiazole via aryl alkyne cross coupling: synthesis and exploration of the electronic structure.

A series of four donor aryl alkynyl substituted thiazole derivatives 3a-d and three similar aryl donor-acceptor systems 6a-c have been synthesized. All compounds bear different electron-donating groups in the 5-position of the thiazole core. The influence of both electron donor strength and the additional phenylethynyl unit on photophysical properties, i.e. UV/Vis absorption, fluorescence emission and fluorescence lifetime, has been evaluated. Additionally, theoretical calculations have been performed at the CAM-B3LYP/6-31+G(d,p) level and good agreement with the experimental data has been achieved. The new derivatives synthesized via palladium catalyzed cross coupling are characterised by moderately strong emission between 474 and 538 nm (ΦF = 0.35-0.39) and Stokes' shifts ranging from 0.54 to 0.79 eV (4392-6351 cm(-1)). The smaller chromophores of type 6 exhibit modest to high fluorescence emission (ΦF = 0.45-0.76) between 470 and 529 nm and their Stokes' shifts range from 0.59 to 0.65 eV (4765-5251 cm(-1)).

Event-horizon-scale structure in the supermassive black hole candidate at the Galactic Centre.

The cores of most galaxies are thought to harbour supermassive black holes, which power galactic nuclei by converting the gravitational energy of accreting matter into radiation. Sagittarius A* (Sgr A*), the compact source of radio, infrared and X-ray emission at the centre of the Milky Way, is the closest example of this phenomenon, with an estimated black hole mass that is 4,000,000 times that of the Sun. A long-standing astronomical goal is to resolve structures in the innermost accretion flow surrounding Sgr A*, where strong gravitational fields will distort the appearance of radiation emitted near the black hole. Radio observations at wavelengths of 3.5 mm and 7 mm have detected intrinsic structure in Sgr A*, but the spatial resolution of observations at these wavelengths is limited by interstellar scattering. Here we report observations at a wavelength of 1.3 mm that set a size of 37(+16)(-10) microarcseconds on the intrinsic diameter of Sgr A*. This is less than the expected apparent size of the event horizon of the presumed black hole, suggesting that the bulk of Sgr A* emission may not be centred on the black hole, but arises in the surrounding accretion flow.

Proof of Concept of Telemedicine-Assisted Abdominal Ultrasound Examinations to Improve the Quality of Patient Care in Rural Areas.

(1) Background: Unclear sonographic findings without adequate specialist expertise in abdominal ultrasound (AU) may harm patients in rural areas, due to overlooked diagnoses, unnecessary additional imaging (e.g., CT scan), and/or patient transport to referral expert centers. Appropriate telemedical sonography assistance could lead to corresponding savings. (2) Methods: The study was designed as a randomized trial. Selected study centers performed AU with the best local expertise. Patients were selected and monitored according to the indication that they required AU. The study depicted three basic scenarios. Group 1 corresponds to the telemedically assisted cohort, group 2 corresponds to the non-telemedically assisted cohort, and group 3 corresponds to a telemedically supported cohort for teaching purposes. The target case number of all three groups was 400 patients (20 calculated dropouts included). (3) Discussion: This study might help to clarify whether telemedicine-assisted ultrasound by a qualified expert is non-inferior to presence sonography concerning technical success and whether one of the interventions is superior in terms of efficacy and safety in one or more secondary endpoints. Randomization was provided, as every patient who needed an AU was included and then randomized to one of the groups. The third group consisted of a lower number of patients who were selected from group 1 or 2 for teaching purposes in case of rare diseases or findings. (4) Conclusions: The study investigates whether there are benefits of telemedical ultrasound for patients, medical staff, and the health care system.

Extracellular signal-regulated kinase 1/2-mediated phosphorylation of p300 enhances myosin heavy chain I/beta gene expression via acetylation of nuclear factor of activated T cells c1.

The nuclear factor of activated T-cells (NFAT) c1 has been shown to be essential for Ca(2+)-dependent upregulation of myosin heavy chain (MyHC) I/ß expression during skeletal muscle fiber type transformation. Here, we report activation of extracellular signal-regulated kinase (ERK) 1/2 in Ca(2+)-ionophore-treated C2C12 myotubes and electrostimulated soleus muscle. Activated ERK1/2 enhanced NFATc1-dependent upregulation of a -2.4 kb MyHCI/ß promoter construct without affecting subcellular localization of endogenous NFATc1. Instead, ERK1/2-augmented phosphorylation of transcriptional coactivator p300, promoted its recruitment to NFATc1 and increased NFATc1-DNA binding to a NFAT site of the MyHCI/ß promoter. In line, inhibition of ERK1/2 signaling abolished the effects of p300. Comparison between wild-type p300 and an acetyltransferase-deficient mutant (p300DY) indicated increased NFATc1-DNA binding as a consequence of p300-mediated acetylation of NFATc1. Activation of the MyHCI/ß promoter by p300 depends on two conserved acetylation sites in NFATc1, which affect DNA binding and transcriptional stimulation. NFATc1 acetylation occurred in Ca(2+)-ionophore treated C2C12 myotubes or electrostimulated soleus. Finally, endogenous MyHCI/ß gene expression in C2C12 myotubes was strongly inhibited by p300DY and a mutant deficient in ERK phosphorylation sites. In conclusion, ERK1/2-mediated phosphorylation of p300 is crucial for enhancing NFATc1 transactivation function by acetylation, which is essential for Ca(2+)-induced MyHCI/ß expression.

Paradoxical interventions: A meta-analysis.

This article outlines the evidence base for the use of paradoxical interventions (PIs) in individual psychotherapy. Often misunderstood, PIs have shown long-term (distal) impacts on clinical outcomes, yet a review of the existing literature on these interventions illustrates a trending decline in consideration and use within both research and applied settings. Definitions of PIs and their constituent elements are presented along with clinical examples. We conducted one meta-analysis comparing PIs with a placebo or control and another comparing PIs to other therapeutic methods. PIs demonstrated a large effect (d = 1.1, k = 17 studies) compared to controls and a medium effect size (d = .49, k = 17 studies) compared to other therapeutic methods. We included a review of several case studies using PIs as well. Among the salient findings, there is a lack of assessment measure to track the implementation of PIs in session or a method to track their in-session effects. Further, there is a dearth of contemporary quantitative experimental research and development of PIs. We further advocate for the development and integration of PI training and supervision into clinical education and posteducation programs, given the current data demonstrating clinical utility. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Understanding the role of emotion and expertise in psychotherapy: An application of dynamical systems mathematical modeling to an entire course of therapy.

Introduction: The therapeutic relationship continues to be one of the most important factors in therapeutic outcomes. Given the place of emotion in the definition of the therapeutic relationship, as well as the demonstrated positive impact that emotional expression has on therapeutic process and outcome, it stands to reason that studying the emotional exchange between the therapist and client further would be warranted. Methods: This study used a validated observational coding system--the Specific Affect Coding System (SPAFF) and a theoretical mathematical model to analyze behaviors which make up the therapeutic relationship. Specifically, the researchers used to codify relationship-building behaviors between an expert therapist and his client over the course of six sessions. Dynamical systems mathematical modeling was also employed to create "phase space portraits" depicting the relational dynamics between the master therapist and his client over six sessions. Results: Statistical analysis was used to compare SPAFF codes and model parameters between the expert therapist and his client. The expert therapist showed stability in affect codes over six sessions while the client's affect codes appeared to be more flexible over time, though model parameters remained stable across the six sessions. Finally, phase space portraits depicted the evolution of the affective dynamics between the master therapist and his client as the relationship matured. Discussion: The clinician's ability to stay emotionally positive and relatively stable across the six sessions (relative to the client) was noteworthy. It formed the basis for a stable base from which she could explore alternative methods to relate to others that she had allowed to dictate her actions, which is in keeping with previous research on the role of therapist facilitation of the therapeutic relationship, emotional expression within the therapeutic relationship, and influence of these on client outcomes. These results provide a valuable foundation for future research on emotional expression as a key component of the therapeutic relationship in psychotherapy.

Nickel-Catalyzed 1,1-Aminoborylation of Unactivated Terminal Alkenes.

Herein, we disclose a Ni-catalyzed 1,1-difunctionalization of unactivated terminal alkenes that enables the incorporation of two different heteroatom motifs across an olefin backbone, thus streamlining the access to α-aminoboronic acid derivatives from simple precursors. The method is characterized by its simplicity and generality across a wide number of coupling counterparts.

Incidence and clinical relevance of upper gastrointestinal pathology during preprocedural endoscopy in patients undergoing pulmonary vein isolation.

BACKGROUND: Reflux-induced esophagitis might facilitate ablation-induced esophageal lesions (ELs) following pulmonary vein isolation (PVI), and these may progress to atrio-esophageal fistula (AEF). In contrast, preexisting ELs are not prone to progression but may affect procedure planning. OBJECTIVE: To study the incidence of preexisting esophageal and upper gastrointestinal (UGI) pathology in patients undergoing PVI, and the relation to ablation-induced ELs. METHODS: From 08/2018 to 09/2021, consecutive patients undergoing (radiofrequency [RF] or cryoballoon [CB]) PVI were examined by esophagogastroscopy (EGD) before and following ablation. Postprocedural endoscopic ultrasound (EUS) was added in 2021. RESULTS: 412 patients (median age 67.5 [IQR 61.3-75.0] years, 56.1% male) were studied. Preprocedural EGD showed abnormalities in 226/399 patients, 15% in the lower third of the esophagus. Half (99/226) were relevant for PVI, 13 procedures were postponed, 6 due to pathological EGD results. A third of the patients with new esophageal injury following ablation had preexisting esophagitis which was associated with a trend for a higher incidence of ELs after RF ablation (12.5 vs. 6.9%, p = 0.232), and a six- and two-fold higher rate of food retention after CB-PVI (28.6 vs. 4.5%, p = 0.008) and RF ablation (8.3 vs. 4.4%, p = 0.279), respectively. CONCLUSION: (1) EGD before PVI showed UGI abnormalities in > 50% of patients, one-fourth of these relevant for PVI. (2) Esophageal inflammation was associated with a higher incidence of post-ablation (peri)-esophageal injury. Whether having this information before ablation is able to reduce ELs or AEF remains to be shown.

Cytogenetic and Molecular Characterization of IDH-Wildtype Glioblastomas and Grade 4 IDH-Mutant Astrocytomas with Unusual Histology.

Glioblastoma (GBM) is a highly heterogenous tumor. Though several well-defined histological patterns of GBMs are known, these are infrequent, and the molecular correlates of several of these histological patterns are not well understood. We identified 31 adult-type infiltrating grade 4 gliomas with unusual histology in our institutional archives from 2016 to 2020, including tumors with a preponderant component of giant cell (n = 15), gemistocytes (n = 6), spindle cells (n = 5), small cells (n = 3), and ependymoma-like features (n = 2). We performed molecular and cytogenetic profiles of IDH-wildtype GBMs with unusual histology and compared to 48 tumors with conventional histology. We found that the majority (85%) of giant cell GBM had increased numbers of whole chromosome loss and genomic haploidization compared to conventional GBMs and other variants. Furthermore, we identified a genetically confirmed GBM with prominent ependymal features, indicating that glial tumors with ependymal features should be considered in the differential diagnosis of GBM. We also identified 6 IDH-mutant grade 4 astrocytomas with unusual histology and similar molecular and cytogenetic profiles to conventional appearing grade 4 IDH-mutant astrocytomas. These findings emphasize the role of molecular/cytogenetic analyses in the diagnostic clarification of GBMs with unusual histological patterns, refine the classification of unusual GBMs, and potentially pave the way for personalized therapies.

A case of AL amyloidosis presenting with refractory ventricular fibrillation.

A 66-year-old male with recent diagnosis of heart failure with reduced ejection fraction was referred to our institution for management of cardiogenic/vasodilatory shock. During his evaluation, he suffered a sudden cardiac arrest from refractory ventricular tachycardia/fibrillation (VT/VF) despite normal electrolytes and no evidence of prior ventricular arrhythmias. He was placed on rescue peripheral veno-arterial extracorporeal membrane oxygenation support (VA-ECMO) for 4 days and was decannulated without end-organ damage. Continued workup revealed Mayo stage IV immunoglobulin light chain (AL) amyloidosis. Unfortunately, he developed acute cerebellar hemorrhage several days later. Autopsy findings were consistent with AL amyloidosis, with extensive cardiac fibrosis and amyloid deposition in the myocardium and vasculature. While the most common cause of cardiac death in patients with amyloidosis is severe bradycardia and pulseless electrical activity, sustained ventricular arrhythmias have been reported. The use of implantable cardioverter defibrillators (ICD) is highly debated in this population given the lack of survival benefit. Our patient also developed refractory VT/VF arrest, and ICD shocks would not have rescued him while causing significant distress. Emergent VA-ECMO cannulation allowed us to make a diagnosis, yet this intervention cannot be routinely recommended given the limited survival of patients with AL amyloidosis.

Prolonged Remission of Prostate Cancer Presenting as Endobronchial Metastases Following Total Androgen Blockade: A Case Report and Literature Review.

We present a rare case of prostatic endobronchial metastases that was successfully treated with total androgen blockade (TAB). This case demonstrates prolonged remission on continuous TAB and continued remission employing intermittent therapy.