Lymphocyte Expression of Intracellular Cytokines and Heat Shock Proteins in Peripheral Blood of Patients with Atopic Dermatitis.

INTRODUCTION: The present study evaluates expression by activated CD4+ T helper1 (Th1) and T helper 2 (Th2) T lymphocytes of pro-inflammatory cytokines and cytoprotective heat shock proteins (HSPs) in peripheral blood of atopic dermatitis (AD) patients. METHODS: This research represents preliminary work by the authors to identify correlates between critical immune parameters with the potential to serve as guidelines for the development of pharmacological strategies for altering these factors to promote the restoration of healthy immune profiles in persons afflicted with major atopic diseases. The major experimental strategy used in this research assessed immune activation by peripheral blood mononuclear cells (PBMC) from 21 AD patients and 12 age- and gender-matched healthy control subjects cultured with phorbol myristate acetate (PMA) and ionomycin (PMA/I), which are mutagenic immune activators, to induce expression of pro-inflammatory biomarkers in CD4+ T cells differentiated to express Th1 or Th2 cytokines and heme oxygenase-1 (HO-1) intracellularly (i). Evaluations were performed using an FC500 Beckman-Coulter flow cytometer. Elevated CD4+ T cell expression of cytokines, interleukin-4 (iIL-4), interleukin- 5 (iIL-5), interleukin-10 (iIL-10), interferon-gamma (iIFN-g), tumor necrosis factor-alpha (iTNF-α), were observed. RESULTS: Additionally, the heat shock proteins (HSP) iHO-1 and iHSP-70 were evaluated in cells from the blood of AD patients versus the control subjects. The present study demonstrated an elevated expression of both Th1 and Th2-associated cytokines in CD4+ T cells of AD patients, with a significant direct correlation between Th1 and Th2 cell populations, thus yielding insight into the immune features of the AD-associated systemic inflammatory profile. CONCLUSION: Finally, the observed increased iHO-1 and iHSP-70 expressions likely represent adaptive physiologic countermeasures to AD-associated inflammatory tissue damage, suggesting that HSP inducers are promising candidates for the management of atopic disorders.

Mortality Outcomes in Patients With Cardiac Implantable Electronic Devices Before and After Transcatheter Aortic Valve Replacement.

Transcatheter aortic valve replacement (TAVR) carries a risk of high-grade AV block requiring cardiac implantable electronic device (CIED) implantation, which has been associated with a higher mortality rate. However, the outcomes of TAVR in patients with preexisting CIEDs are not well understood. We conducted a retrospective analysis of consecutive patients who underwent TAVR from December 2014 to December 2019 at our institution. Patients were categorized into 3 groups: preexisting CIED pre-TAVR (group 1), CIED implanted within 30 days after TAVR (group 2), and no CIED implanted (group 3). Cox proportional hazard was conducted to determine the primary end point of all-cause mortality. A total of 366 patients were included, of whom 93 (25.4%), 51 (13.9%), and 222 (60.7%) comprised group 1, 2, and 3, respectively. The median follow-up time was 2.3 years. The all-cause mortality rate was higher in group 1 than group 2 (hazard ratio [HR] 2.60, 95% confidence interval [CI] 1.09 to 6.18, p = 0.03) and group 3 (HR 1.96, 95% CI 1.24 to 3.08, p = 0.004). On the multivariate analysis, there was no statistically significant difference in mortality among the groups (group 1 vs group 2: HR 1.95, 95% CI 0.70 to 5.44, p = 0.20 and group 1 vs group 3: HR 1.27, 95% CI 0.66 to 2.43, p = 0.47). Preoperative hemoglobin ≤12 g/100 ml was an independent predictor of all-cause mortality (HR 1.75, 95% CI 1.10 to 2.80, p = 0.02). Group 1 had a higher 1 year congestive heart failure readmission rate (29%) than group 2 (17.6%) and group 3 (8.1%; p <0.0001). In conclusion, there was no difference in the adjusted long-term survival based on the CIED grouping. However, patients with preexisting CIEDs had higher all-cause mortality and 1-year congestive heart failure readmission rates owing to their higher co-morbidity burden, irrespective of their Society of Thoracic Surgeons score. This can be taken into account for preoperative risk stratification.

Influence of monitoring and atrial arrhythmia burden on quality of life and health care utilization in patients undergoing pulsed field ablation: A secondary analysis of the PULSED AF trial.

BACKGROUND: Freedom from atrial arrhythmia (AA) recurrence ≥30 seconds after pulsed field ablation (PFA) in patients with atrial fibrillation (AF) was reported in PULSED AF (Pulsed Field Ablation to Irreversibly Electroporate Tissue and Treat AF; ClinialTrials.gov Identifier: NCT04198701). AA burden may be a more clinically meaningful endpoint. OBJECTIVE: The purpose of this study was to determine the influence of monitoring strategies on AA detection and AA burden association with quality of life (QoL) and health care utilization (HCU) after PFA. METHODS: Patients underwent 24-hour Holter monitoring at 6 and 12 months and weekly, and symptomatic transtelephonic monitoring (TTM). AA burden post-blanking was calculated as the greater of (1) percentage of AA on total Holter time; or (2) percentage of weeks with ≥1 TTM with AA out of all weeks with ≥1 TTM. RESULTS: Freedom from all AAs varied by >20% when differing monitoring strategies were used. PFA resulted in zero burden in 69.4% of paroxysmal atrial fibrillation (PAF) and 62.2% of persistent atrial fibrillation (PsAF) patients. Median burden was low (<9%). Most PAF and PsAF patients had ≤1 week of AA detection on TTM (82.6% and 75.4%) and <30 minutes of AA per day of Holter monitoring (96.5% and 89.6%), respectively. Only PAF patients with <10% AA burden averaged a clinically meaningful (>19 point) QoL improvement. PsAF patients experienced clinically meaningful QoL improvements irrespective of burden. Repeat ablations and cardioversions significantly increased with higher AA burden (P <.01). CONCLUSION: The ≥30-second AA endpoint is dependent on the monitoring protocol used. PFA resulted in low AA burden for most patients, which was associated with clinically relevant improvement in QoL and reduced AA-related HCU.

Pulsed Field Ablation for the Treatment of Atrial Fibrillation: PULSED AF Pivotal Trial.

BACKGROUND: Pulsed field ablation uses electrical pulses to cause nonthermal irreversible electroporation and induce cardiac cell death. Pulsed field ablation may have effectiveness comparable to traditional catheter ablation while preventing thermally mediated complications. METHODS: The PULSED AF pivotal study (Pulsed Field Ablation to Irreversibly Electroporate Tissue and Treat AF) was a prospective, global, multicenter, nonrandomized, paired single-arm study in which patients with paroxysmal (n=150) or persistent (n=150) symptomatic atrial fibrillation (AF) refractory to class I or III antiarrhythmic drugs were treated with pulsed field ablation. All patients were monitored for 1 year using weekly and symptomatic transtelephonic monitoring; 3-, 6-, and 12-month ECGs; and 6- and 12-month 24-hour Holter monitoring. The primary effectiveness end point was freedom from a composite of acute procedural failure, arrhythmia recurrence, or antiarrhythmic escalation through 12 months, excluding a 3-month blanking period to allow recovery from the procedure. The primary safety end point was freedom from a composite of serious procedure- and device-related adverse events. Kaplan-Meier methods were used to evaluate the primary end points. RESULTS: Pulsed field ablation was shown to be effective at 1 year in 66.2% (95% CI, 57.9 to 73.2) of patients with paroxysmal AF and 55.1% (95% CI, 46.7 to 62.7) of patients with persistent AF. The primary safety end point occurred in 1 patient (0.7%; 95% CI, 0.1 to 4.6) in both the paroxysmal and persistent AF cohorts. CONCLUSIONS: PULSED AF demonstrated a low rate of primary safety adverse events (0.7%) and provided effectiveness consistent with established ablation technologies using a novel irreversible electroporation energy to treat patients with AF. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04198701.

Introducing HL7 FHIR Genomics Operations: a developer-friendly approach to genomics-EHR integration.

OBJECTIVE: Enabling clinicians to formulate individualized clinical management strategies from the sea of molecular data remains a fundamentally important but daunting task. Here, we describe efforts towards a new paradigm in genomics-electronic health record (HER) integration, using a standardized suite of FHIR Genomics Operations that encapsulates the complexity of molecular data so that precision medicine solution developers can focus on building applications. MATERIALS AND METHODS: FHIR Genomics Operations essentially "wrap" a genomics data repository, presenting a uniform interface to applications. More importantly, operations encapsulate the complexity of data within a repository and normalize redundant data representations-particularly relevant in genomics, where a tremendous amount of raw data exists in often-complex non-FHIR formats. RESULTS: Fifteen FHIR Genomics Operations have been developed, designed to support a wide range of clinical scenarios, such as variant discovery; clinical trial matching; hereditary condition and pharmacogenomic screening; and variant reanalysis. Operations are being matured through the HL7 balloting process, connectathons, pilots, and the HL7 FHIR Accelerator program. DISCUSSION: Next-generation sequencing can identify thousands to millions of variants, whose clinical significance can change over time as our knowledge evolves. To manage such a large volume of dynamic and complex data, new models of genomics-EHR integration are needed. Qualitative observations to date suggest that freeing application developers from the need to understand the nuances of genomic data, and instead base applications on standardized APIs can not only accelerate integration but also dramatically expand the applications of Omic data in driving precision care at scale for all.

Thinking in Stories: Narrative Reasoning of an Occupational Therapist Supporting People with Profound Intellectual Disabilities' Engagement in Occupation.

This article illustrates narrative reasoning using the findings from research into an occupational therapy intervention promoting changes in the ways a staff team facilitated meaningful engagement in occupation. Qualitative critical ethnographic case study research explored a single case over one year of an occupational therapist working with five people with profound intellectual disabilities and their support network. Data were collected using participant observation, interviews and document analysis. Illustrated by an ethnodramatic vignette, the findings demonstrate how the occupational therapist reasoned narratively by eliciting, telling and creating stories and how this supported individualization of her intervention to the specific context. Creation of a prospective story that the support network were invited to share, guided and propelled the intervention toward its hoped-for ending. Narrative reasoning was particularly apparent in opportunities to reflect aloud, supporting occupational therapists' need of opportunities for reflection through story-sharing and story-making. Case study and ethnographic research methodologies may be useful in further clinical reasoning research to better understand narrative reasoning.

Electrographic flow mapping for atrial fibrillation: theoretical basis and preliminary observations.

Ablation strategies remain poorly defined for persistent atrial fibrillation (AF) patients with recurrence despite intact pulmonary vein isolation (PVI). As the ability to perform durable PVI improves, the need for advanced mapping to identify extra-PV sources of AF becomes increasingly evident. Multiple mapping technologies attempt to localize these self-sustained triggers and/or drivers responsible for initiating and/or maintaining AF; however, current approaches suffer from technical limitations. Electrographic flow (EGF) mapping is a novel mapping method based on well-established principles of optical flow and fluid dynamics. It enables the full spatiotemporal reconstruction of organized wavefront propagation within the otherwise chaotic and disorganized electrical conduction of AF. Given the novelty of EGF mapping and relative unfamiliarity of most clinical electrophysiologists with the mathematical principles powering the EGF algorithm, this paper provides an in-depth explanation of the technical/mathematical foundations of EGF mapping and demonstrates clinical applications of EGF mapping data and analyses. Starting with a 64-electrode basket catheter, unipolar EGMs are recorded and processed using an algorithm to visualize the electrographic flow and highlight the location of high prevalence AF "source" activity. The AF sources are agnostic to the specific mechanisms of source signal generation.

Characterization of Phrenic Nerve Response to Pulsed Field Ablation.

BACKGROUND: Phrenic nerve palsy is a well-known complication of cardiac ablation, resulting from the application of direct thermal energy. Emerging pulsed field ablation (PFA) may reduce the risk of phrenic nerve injury but has not been well characterized. METHODS: Accelerometers and continuous pacing were used during PFA deliveries in a porcine model. Acute dose response was established in a first experimental phase with ascending PFA intensity delivered to the phrenic nerve (n=12). In a second phase, nerves were targeted with a single ablation level to observe the effect of repetitive ablations on nerve function (n=4). A third chronic phase characterized assessed histopathology of nerves adjacent to ablated cardiac tissue (n=6). RESULTS: Acutely, we observed a dose-dependent response in phrenic nerve function including reversible stunning (R2=0.965, P<0.001). Furthermore, acute results demonstrated that phrenic nerve function responded to varying levels of PFA and catheter proximity placements, resulting in either: no effect, effect, or stunning. In the chronic study phase, successful isolation of superior vena cava at a dose not predicted to cause phrenic nerve dysfunction was associated with normal phrenic nerve function and normal phrenic nerve histopathology at 4 weeks. CONCLUSIONS: Proximity of the catheter to the phrenic nerve and the PFA dose level were critical for phrenic nerve response. Gross and histopathologic evaluation of phrenic nerves and diaphragms at a chronic time point yielded no injury. These results provide a basis for understanding the susceptibility and recovery of phrenic nerves in response to PFA and a need for appropriate caution in moving beyond animal models.

Evaluation of a novel mechanical compression device for hematoma prevention and wound cosmesis after CIED implantation.

BACKGROUND: An important complication of cardiac implantable electronic devices (CIED) implantation is the development of hematoma and device infection. OBJECTIVE: We aimed to evaluate a novel mechanical compression device for hematoma prevention and cosmetic outcomes following CIED implantation. METHODS: An open, prospective, randomized, single-center clinical trial was performed in patients undergoing CIED implantation. Patients were randomized to receive a novel mechanical compression device (PressRite, PR) or to receive the standard of care post device implantation. Skin pliability was measured with a calibrated durometer; the surgical site was evaluated using the Manchester Scar Scale (MSS) by a blinded plastic surgeon and the Patient and Observer Scar Scale (POSAS). Performance of PR was assessed through pressure measurements, standardized scar scales and tolerability. RESULTS: From the total of 114 patients evaluated for enrollment, 105 patients were eligible for analysis. Fifty-one patients were randomized to management group (PR) and 54 to the control group. No patients required early removal or experienced adverse effects from PR application. There were 11 hematomas (14.8% vs. 5.9% in the control and PR group respectively, p = NS). The control group had higher post procedure durometer readings in the surgical site when compared with the PR group (7.50 ± 3.45 vs. 5.37 ± 2.78; p = < .01). There were lower MSS scores in the PR group after 2 weeks (p = .03). CONCLUSION: We have demonstrated the safety of PR application and removal. In addition, PR appears to improve postoperative skin pliability, which could facilitate wound healing.

Meta-Analysis of New-Onset Atrial Fibrillation Versus No History of Atrial Fibrillation in Patients With Noncardiac Critical Care Illness.

The incidence of new-onset secondary atrial fibrillation (NOSAF) is as high as 44% in noncardiac critical illness. A systematic review and meta-analysis were performed to evaluate the impact of NOSAF, compared with history of prior atrial fibrillation (AF) and no history of AF in noncardiac critically ill patients. Patients undergoing cardiothoracic surgery were excluded. NOSAF incidence, intensive care unit (ICU)/hospital length of stay (LOS), and mortality outcomes were analyzed. Of 2,360 studies reviewed, 19 studies met inclusion criteria (n = 306,805 patients). NOSAF compared with no history of AF was associated with increased in-hospital mortality (risk ratio [RR] 2.06, 95% confidence interval [CI] 1.76 to 2.41, p <0.001), longer ICU LOS (standardized difference in means [SMD] 0.66, 95% CI 0.41 to 0.91, p <0.001), longer hospital LOS (SMD 0.31, 95% CI 0.07 to 0.56, p = 0.001) and increased risk of long-term (>1 year) mortality (RR 1.76, 95% CI 1.29 to 2.40, p <0.001). NOSAF compared with previous AF was also associated with higher in-hospital mortality (RR 1.29, 95% CI 1.12 to 1.49, p <0.001), longer ICU LOS (SMD 0.37, 95% CI 0.03 to 0.70, p = 0.03) but no difference in-hospital LOS (SMD -0.18, 95% CI -0.66 to 0.31, p = 0.47). In conclusion, NOSAF, in the setting of noncardiac critical illness is associated with increased in-hospital mortality compared with no history of AF and previous AF. NOSAF (vs no history of AF) is also associated with increased long-term mortality.

First-in-Human Experience and Acute Procedural Outcomes Using a Novel Pulsed Field Ablation System: The PULSED AF Pilot Trial.

BACKGROUND: Pulsed field ablation (PFA) is a novel form of ablation using electrical fields to ablate cardiac tissue. There are only limited data assessing the feasibility and safety of this type of ablation in humans. METHODS: PULSED AF (Pulsed Field Ablation to Irreversibly Electroporate Tissue and Treat AF; https://www.clinicaltrials.gov; unique identifier: NCT04198701) is a nonrandomized, prospective, multicenter, global, premarket clinical study. The first-in-human pilot phase evaluated the feasibility and efficacy of pulmonary vein isolation using a novel PFA system delivering bipolar, biphasic electrical fields through a circular multielectrode array catheter (PulseSelect; Medtronic, Inc). Thirty-eight patients with paroxysmal or persistent atrial fibrillation were treated in 6 centers in Australia, Canada, the United States, and the Netherlands. The primary outcomes were ability to achieve acute pulmonary vein isolation intraprocedurally and safety at 30 days. RESULTS: Acute electrical isolation was achieved in 100% of pulmonary veins (n=152) in the 38 patients. Skin-to-skin procedure time was 160±91 minutes, left atrial dwell time was 82±35 minutes, and fluoroscopy time was 28±9 minutes. No serious adverse events related to the PFA system occurred in the 30-day follow-up including phrenic nerve injury, esophageal injury, stroke, or death. CONCLUSIONS: In this first-in-human clinical study, 100% pulmonary vein isolation was achieved using only PFA with no PFA system-related serious adverse events. Graphic Abstract: A graphic abstract is available for this article.

Toward a Quasi-dynamic Pulsed Field Electroporation Numerical Model for Cardiac Ablation: Predicting Tissue Conductance Changes and Ablation Lesion Patterns.

Pulsed field ablation (PFA) has the potential to evolve into an efficient alternative to traditional RF ablation for atrial fibrillation treatment. However, achieving irreversible tissue electroporation is critical to suppressing arrhythmic pathways, raising the need for accurate lesion characterization. To understand the physics behind the tissue response PFA, we propose a quasi-dynamic model that quantifies tissue conductance at end-electroporation and identifies regions that have undergone fully irreversible electroporation (IRE). The model uses several parameters and numerically solves the electrical field diffusion into the tissue by iteratively updating the tissue conductance until equilibrium at end-electroporation. The model yields a steady-state tissue conductance map used to identify the irreversible lesion. We conducted numerical experiments mimicking a lasso catheter featuring nine 3-mm electrodes spaced circumferentially at 3.75 mm and fired sequentially using a 1500 V and 3000 V pulse amplitude. The IRE lesion region has a surface area and volume of 780 mm2 and 1411 mm3, respectively, at 1500 V, and 1178 mm2 and 2760 mm3, respectively, at 3000 V. Lesion discontinuity was observed at 5.0 mm depth with 1500 V, and 7.2 mm depth with 3000 V. This quasi-dynamic model yields tissue conductance maps, predicts irreversible lesion and lesion penumbra at end-electroporation, and confirms larger lesions with higher pulse amplitudes.