Power-law properties of nocturnal arrhythmia avalanches: A novel marker for incident cardiovascular events.

BACKGROUND: Bursting nonsustained cardiac arrhythmia events are a common observation during sleep. OBJECTIVES: The purpose of this study was to investigate the hypothesis that nocturnal arrhythmia episode durations could follow a power law, whose exponent could predict long-term clinical outcomes. METHODS: We defined "nocturnal arrhythmia avalanche" (NAA) as any instance of a drop in electrocardiographic (ECG) template-matched R-R intervals ≥30% of R-R baseline, followed by a return to 90% of baseline. We studied NAA in ECG recordings obtained from the Sleep Heart Health Study (SHHS), Osteoporotic Fractures in Men Study (MrOS) Study, and Multi-Ethnic Study of Atherosclerosis (MESA). The association of nocturnal arrhythmia durations with a power-law distribution was evaluated and the association of derived power-law exponents (α) with major adverse cardiovascular (CV) events and mortality assessed with multivariable Cox regression. RESULTS: A total of 9176 participants were studied. NAA episodes distribution was consistent with power-law vs comparator distributions in all datasets studied (positive log likelihood ratio of power-law vs exponential in MESA: 83%; SHHS: 69%; MrOS: 81%; power-law vs log-normal in MESA: 95%; SHHS: 35%; MrOS: 64%). The NAA power-law exponent (α) showed a significant association of with adverse CV outcomes (association with CV mortality: SHHS hazard ratio 1.39 [1.07-1.79], P = .012; MrOS hazard ratio 1.42 [1.02-1.94], P = .039; association with CV events: MESA HR 3.46 [1.46-8.21], P = .005) in multivariable Cox regression, after adjusting for conventional CV risk factors and nocturnal ectopic rate. CONCLUSION: The NAA power-law exponent is a reproducible, predictive marker for incident CV events and mortality.

Evaluation of a Point-of-Use Kiosk for Improving the Fit of N95/P2 Respirators in Healthcare Settings: A Randomized Controlled Trial.

INTRODUCTION: Verifying the fit of disposable N95/P2 half-face respirators is critical. There are currently no objective ways to evaluate the implementation when used. Previously, we showed that only 26% of healthcare workers achieve appropriate fit at the point of use. METHODS: 657 quantitative fit tests were conducted on 166 subjects, using four different respirator styles. Randomization was performed; controls employing standard 'fit-check' and intervention using a custom built infra-red video kiosk. Primary outcome was passing rates of quantitative fit, with secondary outcomes of respirator type, gender, race, and previous experience. RESULTS: Intervention demonstrated significantly higher pass rate (50.6%) compared to controls (30.8%). The odds of passing with IR Kiosk compared to control was 2.3 (OR 2.3 95%CI 1.8 to 2.9, p<0.001). Duckbill style improved the greatest (OR 4.1 95%CI 2.1 to 7.9, p<0.001), and Tri-fold also showing substantial benefit (OR 2.66 95%CI 1.4 to 5.2, p<0.001). Gender and race did not influence the outcomes when using the kiosk, nor did previous experience. CONCLUSION: A custom point of use kiosk improved the odds of achieving a satisfactory fit of common respirator styles, independent of participant demographics. These findings open the door to addressing a critical gap in respiratory protection programs by providing individual assessment and interventions that improve worker safety at the time of highest risk. DATA AVAILABILITY STATEMENT: The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to their containing information that could compromise the privacy of research participants.

Effective and durable repigmentation for stable vitiligo: a randomized within-subject controlled trial assessing treatment with autologous skin cell suspension transplantation.

BACKGROUND: Vitiligo lesions are often challenging to repigment with conventional medical therapies. Surgical autologous melanocyte transfer methods can be utilized for stable vitiligo but demand specialized skills and equipment. A point-of-care autologous cell harvesting device was designed enabling simple preparation of autologous skin cell suspension (ASCS) containing melanocytes, keratinocytes, and fibroblasts providing a straightforward approach for cellular transplantation. OBJECTIVE: To evaluate the safety and effectiveness of ASCS for repigmentation of stable vitiligo lesions among adults. METHODS: A US multicenter, randomized, within-subject controlled trial compared ASCS to NB-UVB only (Control) in similar vitiligo lesions. ASCS was applied after laser skin resurfacing and followed by NB-UVB treatment. The primary effectiveness endpoint was the proportion of lesions achieving ≥80% repigmentation at week-24. Repigmentation durability was assessed at week-52. RESULTS: Among 25 subjects, 36% of ASCS-treated lesions achieved ≥80% repigmentation at week-24 compared to 0% for Control (p<0.025), with durability through week-52. The safety profile of ASCS was acceptable, with favorable patient- and investigator-reported outcomes. LIMITATIONS: Study sample size limited robust subgroup analyses. CONCLUSION: Application of ASCS is a safe and effective treatment for repigmentation of stable vitiligo lesions with the potential to improve health-related quality of life and reduce burden of disease.

Ritlecitinib, a JAK3/TEC family kinase inhibitor, stabilizes active lesions and repigments stable lesions in vitiligo.

The efficacy of ritlecitinib, an oral JAK3/TEC family kinase inhibitor, on active and stable lesions was evaluated in patients with active non-segmental vitiligo in a phase 2b trial (NCT03715829). Patients were randomized to placebo or daily ritlecitinib 50 mg (with or without 4-week 100-mg or 200-mg loading dose), 30 mg, or 10 mg for 24 weeks. Active lesions showed greater baseline expression of inflammatory/immune markers IFNG and CCL5, levels of CD103, and T-cell infiltrates than stable lesions. Patients with more active than stable vitiligo lesions showed higher baseline serum levels of CXCL9 and PD-L1, while patients with more stable than active lesions showed higher baseline serum levels of HO-1. At Week 24, ritlecitinib 50 mg significantly stabilized mean percent change from baseline in depigmentation extent in both active lesions and stable lesions vs. placebo-response, with stable lesions showing greater repigmentation. After 24 weeks of treatment, ritlecitinib 50 mg increased expression of melanocyte markers in stable lesions, while Th1/Th2-related and co-stimulatory molecules decreased significantly in both stable and active lesions. Serum from patients with more active than stable lesions showed decreased levels of ICOS and NK cell activation markers. These data, confirmed at transcription/protein levels, indicate that stable lesion repigmentation occurs early with ritlecitinib, while active lesions require stabilization of inflammation first. ClinicalTrials.gov: NCT03715829.

Parsing patterns: Emerging roles of tissue self-organization in health and disease.

Patterned morphologies, such as segments, spirals, stripes, and spots, frequently emerge during embryogenesis through self-organized coordination between cells. Yet, complex patterns also emerge in adults, suggesting that the capacity for spontaneous self-organization is a ubiquitous property of biological tissues. We review current knowledge on the principles and mechanisms of self-organized patterning in embryonic tissues and explore how these principles and mechanisms apply to adult tissues that exhibit features of patterning. We discuss how and why spontaneous pattern generation is integral to homeostasis and healing of tissues, illustrating it with examples from regenerative biology. We examine how aberrant self-organization underlies diverse pathological states, including inflammatory skin disorders and tumors. Lastly, we posit that based on such blueprints, targeted engineering of pattern-driving molecular circuits can be leveraged for synthetic biology and the generation of organoids with intricate patterns.

Interruption of the intratumor CD8+ T cell:Treg crosstalk improves the efficacy of PD-1 immunotherapy.

PD-1 blockade unleashes potent antitumor activity in CD8+ T cells but can also promote immunosuppressive T regulatory (Treg) cells, which may worsen the response to immunotherapy. Tumor-Treg inhibition is a promising strategy to improve the efficacy of checkpoint blockade immunotherapy; however, our understanding of the mechanisms supporting tumor-Tregs during PD-1 immunotherapy is incomplete. Here, we show that PD-1 blockade increases tumor-Tregs in mouse models of melanoma and metastatic melanoma patients. Mechanistically, Treg accumulation is not caused by Treg-intrinsic inhibition of PD-1 signaling but depends on an indirect effect of activated CD8+ T cells. CD8+ T cells produce IL-2 and colocalize with Tregs in mouse and human melanomas. IL-2 upregulates the anti-apoptotic protein ICOS on tumor-Tregs, promoting their accumulation. Inhibition of ICOS signaling before PD-1 immunotherapy improves control over immunogenic melanoma. Thus, interrupting the intratumor CD8+ T cell:Treg crosstalk represents a strategy to enhance the therapeutic efficacy of PD-1 immunotherapy.

Discovery of CDC42 Inhibitors with a Favorable Pharmacokinetic Profile and Anticancer In Vivo Efficacy.

We previously reported trisubstituted pyrimidine lead compounds, namely, ARN22089 and ARN25062, which block the interaction between CDC42 with its specific downstream effector, a PAK protein. This interaction is crucial for the progression of multiple tumor types. Such inhibitors showed anticancer efficacy in vivo. Here, we describe a second class of CDC42 inhibitors with favorable drug-like properties. Out of the 25 compounds here reported, compound 15 (ARN25499) stands out as the best lead compound with an improved pharmacokinetic profile, increased bioavailability, and efficacy in an in vivo PDX tumor mouse model. Our results indicate that these CDC42 inhibitors represent a promising chemical class toward the discovery of anticancer drugs, with ARN25499 as an additional lead candidate for preclinical development.

Observable Atrial and Ventricular Fibrillation Episode Durations Are Conformant With a Power Law Based on System Size and Spatial Synchronization.

BACKGROUND: Atrial fibrillation (AF) and ventricular fibrillation (VF) episodes exhibit varying durations, with some spontaneously ending quickly while others persist. A quantitative framework to explain episode durations remains elusive. We hypothesized that observable self-terminating AF and VF episode lengths, whereby durations are known, would conform with a power law based on the ratio of system size and correlation length ([Formula: see text]. METHODS: Using data from computer simulations (2-dimensional sheet and 3-dimensional left-atrial), human ischemic VF recordings (256-electrode sock, n=12 patients), and human AF recordings (64-electrode basket-catheter, n=9 patients; 16-electrode high definition-grid catheter, n=42 patients), conformance with a power law was assessed using the Akaike information criterion, Bayesian information criterion, coefficient of determination (R2, significance=P<0.05) and maximum likelihood estimation. We analyzed fibrillatory episode durations and [Formula: see text], computed by taking the ratio between system size ([Formula: see text], chamber/simulation size) and correlation length (xi, estimated from pairwise correlation coefficients over electrode/node distance). RESULTS: In all computer models, the relationship between episode durations and [Formula: see text] was conformant with a power law (Aliev-Panfilov R2: 0.90, P<0.001; Courtemanche R2: 0.91, P<0.001; Luo-Rudy R2: 0.61, P<0.001). Observable clinical AF/VF durations were also conformant with a power law relationship (VF R2: 0.86, P<0.001; AF basket R2: 0.91, P<0.001; AF grid R2: 0.92, P<0.001). [Formula: see text] also differentiated between self-terminating and sustained episodes of AF and VF (P<0.001; all systems), as well as paroxysmal versus persistent AF (P<0.001). In comparison, other electrogram metrics showed no statistically significant differences (dominant frequency, Shannon Entropy, mean voltage, peak-peak voltage; P>0.05). CONCLUSIONS: Observable fibrillation episode durations are conformant with a power law based on system size and correlation length.

A comparative study of point-of-care protection from N95 filtering face-piece respirators in a Residential Aged Care Facility and a Tertiary Hospital-Respiratory protection challenges remain amidst long-term impacts of COVID-19.

This study compared the effectiveness of N95 FFRs in providing respiratory protection for healthcare staff in a residential aged care facility (RACF) and tertiary teaching hospital (TTH) who had previously passed their occupational respiratory protection program fit test. A total of 126 healthcare workers who were regularly using N95 FFRs and who had previously passed a fit test participated in this comparative study. In this study, participants were again fit tested with the PortaCount machine, and their self-assessed tolerability of wearing an N95 FFR was assessed using a standardized questionnaire. The main outcome measures included the pass rate of the fit test and the assessment of tolerability and comfort of the N95 FFR. Across all participants, the fit test pass rate was low (27%), indicating persistent gaps in respiratory protection programs for healthcare workers during the ongoing COVID-19 pandemic. Hospital workers were 3.7 times more likely to pass the test compared to their counterparts in RACFs (p < 0.001). It was also found that workers in RACFs reported higher levels of discomfort and overall dissatisfaction with N95 FFRs compared to hospital staff. These findings highlight the need for targeted interventions and improvements in respiratory protection practices beyond annual fit testing, particularly in RACFs, to ensure the safety of healthcare workers and the vulnerable population they serve.

Infra-Red Imaging to Detect Respirator Leak in Healthcare Workers During Fit-Testing Clinic.

OBJECTIVE: This study addressed the problem of objectively detecting leaks in P2 respirators at point of use, an essential component for healthcare workers' protection. To achieve this, we explored the use of infra-red (IR) imaging combined with machine learning algorithms on the thermal gradient across the respirator during inhalation. RESULTS: The study achieved high accuracy in predicting pass or fail outcomes of quantitative fit tests for flat-fold P2 FFRs. The IR imaging methods surpassed the limitations of self fit-checking. CONCLUSIONS: The integration of machine learning and IR imaging on the respirator itself demonstrates promise as a more reliable alternative for ensuring the proper fit of P2 respirators. This innovative approach opens new avenues for technology application in occupational hygiene and emphasizes the need for further validation across diverse respirator styles. SIGNIFICANCE STATEMENT: Our novel approach leveraging infra-red imaging and machine learning to detect P2 respirator leaks represents a critical advancement in occupational safety and healthcare workers' protection.

A real-time signal processing software package for the electrophysiology laboratory.

BACKGROUND: Real-time signal processing has to date been difficult to implement in the clinical electrophysiology laboratory. To date, no open access software solutions are available in electrophysiology (EP) laboratories to facilitate real-time intraprocedural signal analysis. We aimed to develop an open access, scalable Python plug-in to allow real-time signal processing during human EP procedures. METHODS AND RESULTS: A Python-based plug in for the widely available EnsiteX mapping system was developed. This plug-in utilized the LiveSync feature of the system to allow real-time signal analysis. An open access library was developed to allow end-users to implement real-time signal analysis using this platform, implemented in the Python programming language https://github.com/anand9176/WaveWatch5000Public. CONCLUSION: We have developed and demonstrated the feasibility of a readily scalable and open-access Python-based plug in to an electroanatomic mapping system (EnSiteX) to allow real-time processing and display of electrogram (EGM) based information for the procedural electrophysiologist to view intraprocedurally in the electrophysiology laboratory. The availability, to the clinician, of traditional and novel EGM-based metrics at the time of intervention, such as atrial fibrillation ablation, allows for key mechanistic insights into critical unresolved questions regarding arrhythmia mechanism.

Assessing Torque Transfer in Conduction System Pacing: Development and Evaluation of an Ex Vivo Model.

BACKGROUND: Conduction system pacing (CSP) faces challenges in achieving reliable and safe deployments. Complex interactions between tissue and lead tip can result in endocardial entanglement, a drill effect that prevents penetration. No verified ex vivo model exists to quantitatively assess this relationship. OBJECTIVES: The purpose of this study was to quantitatively characterize CSP lead tip to tissue responses for 4 commonly used leads. METHODS: CSP leads (from Medtronic, Biotronik, Boston Scientific, and Abbott) were examined for helix rotation efficiency in ex vivo ovine right ventricular septa. A custom jig was utilized for rotation measurements. Fifteen turns were executed, documenting tissue-interface changes every 90° using high-resolution photography. Response curves (input rotation vs helix rotation) were evaluated using piecewise linear regression, with a focus on output vs input response slopes and torque breakpoint events. RESULTS: We analyzed 3,840 quarter-turn CSP insertions with 4 different lead types. Helix rotations were consistently less than input: Abbott Tendril = 0.21:1, Medtronic 3830 = 0.21:1, Biotronik Solia = 0.47:1, and Boston Scientific Ingevity = 0.56:1. Torque breakpoint events were observed on average 7.22 times per insertion (95% CI: 6.08-8.35; P = NS) across all leads. In 57.8% of insertions (37 of 64), uncontrolled torque breakpoint events occurred, signaling unexpected excess helix rotations. CONCLUSIONS: Using a robust ex vivo model, we revealed a muted helix rotation response compared with input turns on the lead, and frequent torque change events during insertion. This is critical for CSP implanters, emphasizing the potential for unexpected torque breakpoint events, and suggesting the need for novel lead designs or deployment methods to enhance CSP efficiency and safety.

Uncovering Minimal Pathways in Melanoma Initiation.

Cutaneous melanomas are clinically and histologically heterogeneous. Most display activating mutations in Braf or Nras and complete loss of function of one or more tumor suppressor genes. Mouse models that replicate such mutations produce fast-growing, pigmented tumors. However, mice that combine Braf activation with only heterozygous loss of Pten also produce tumors and, as we show here, in an Albino background this occurs even with Braf activation alone. Such tumors arise rarely, grow slowly, and express low levels of pigmentation genes. The timing of their appearance was consistent with a single step stochastic event, but no evidence could be found that it required de novo mutation, suggesting instead the involvement of an epigenetic transition. Single-cell transcriptomic analysis revealed such tumors to be heterogeneous, including a minor cell type we term LNM ( L ow-pigment, N eural- and extracellular M atrix-signature) that displays gene expression resembling "neural crest"-like cell subsets detected in the fast-growing tumors of more heavily-mutated mice, as well as in human biopsy and xenograft samples. We provide evidence that LNM cells pre-exist in normal skin, are expanded by Braf activation, can transition into malignant cells, and persist with malignant cells through multiple rounds of transplantation. We discuss the possibility that LNM cells not only serve as a pre-malignant state in the production of some melanomas, but also as an important intermediate in the development of drug resistance.

Percolation theory as a conceptual framework to explain spontaneous atrial fibrillation termination: a pilot study.

Atrial fibrillation (AF) strikingly possesses the ability to abruptly transition into more organized electrical activity and spontaneously terminate, even after persisting for long periods. Despite being central to the clinical behavior and treatment of AF, these phenomena remain incompletely understood. In this paper, we hypothesized that the spontaneous termination of AF may represent a type of percolation phase transition, which is more likely to occur when a domain spanning cluster of refractory sites in the atrium are connected (called a 'percolation cluster'). This was assessed in n=50 computational simulations of AF developed using the Aliev-Panfilov (APV) 2-dimensional cell model. In self-terminating simulations of AF, it was found that the average refractory cluster size, χ(p) (median: 647.7), and the largest refractory cluster size, M1 (median: 1702.3), abruptly increased just prior to AF spontaneously terminating, indicating the onset of the formation of a domain spanning percolation cluster. In contrast, simulations of sustained AF did not demonstrate an increase in χ(p) (median: 463.0) and M1 (median: 1448.2). Self-terminating AF simulations also demonstrated hallmark properties characteristic of a percolation phase transition, such as an abrupt increase in χ(p) at the critical occupation probability pc. The cluster size distribution was also shown to obey a power law for various occupation probabilities p, also indicative of a percolation phase transition. Collectively, these properties suggests that the spontaneous termination of AF could be a form of percolation phase transition, which could provide new insights for AF treatment.

Excess Bed Days and Hospitalization Costs Associated With 30-Day Complications Following Catheter Ablation of Atrial Fibrillation.

BACKGROUND: The incidence and type of complications following catheter ablation of atrial fibrillation have been extensively examined, but the impact associated with these complications on the length of stay and hospitalization costs is unknown. METHODS AND RESULTS: This cohort study included 20 117 adult patients (mean age 62.6±11.4 years, 30.3% women, median length of stay 1 day [interquartile range 1-2 days]) undergoing atrial fibrillation ablation in financial years 2011 to 2017 in Australia with available cost data from the National Hospital Cost Data Collection, which determines government reimbursement of health services provided. The primary outcome was the costs associated with complications occurring up to 30 days postdischarge adjusted for inflation to 2021 Australian dollars. We used generalized linear models to estimate the increase in length of stay and cost associated with complications, adjusting for patient characteristics. Within 30 days of hospital discharge, 1151 (5.72%) patients experienced a complication with bleeding (3.35%) and pericardial effusion (0.75%) being the most common. On average, the occurrence of a complication was associated with an adjusted 3.3 (95% CI, 3.1-3.6) excess bed days of hospital care (totaling 3851 days), and a $7812 (95% CI, $6754-$8870) increase in hospitalization cost (totaling $9.0 million). Most of the total excess cost was attributable to bleeding ($3.8 million, 41.9% of total excess cost) and pericardial effusion ($1.6 million, 18.2%). CONCLUSIONS: Complications following atrial fibrillation ablation were associated with significant increase in length of stay and hospitalization costs, most of which were attributable to bleeding and pericardial effusion. Strategies to improve procedural safety and reduce health care costs should focus on these complications.

Constructing bilayer and volumetric atrial models at scale.

To enable large in silico trials and personalized model predictions on clinical timescales, it is imperative that models can be constructed quickly and reproducibly. First, we aimed to overcome the challenges of constructing cardiac models at scale through developing a robust, open-source pipeline for bilayer and volumetric atrial models. Second, we aimed to investigate the effects of fibres, fibrosis and model representation on fibrillatory dynamics. To construct bilayer and volumetric models, we extended our previously developed coordinate system to incorporate transmurality, atrial regions and fibres (rule-based or data driven diffusion tensor magnetic resonance imaging (MRI)). We created a cohort of 1000 biatrial bilayer and volumetric models derived from computed tomography (CT) data, as well as models from MRI, and electroanatomical mapping. Fibrillatory dynamics diverged between bilayer and volumetric simulations across the CT cohort (correlation coefficient for phase singularity maps: left atrial (LA) 0.27 ± 0.19, right atrial (RA) 0.41 ± 0.14). Adding fibrotic remodelling stabilized re-entries and reduced the impact of model type (LA: 0.52 ± 0.20, RA: 0.36 ± 0.18). The choice of fibre field has a small effect on paced activation data (less than 12 ms), but a larger effect on fibrillatory dynamics. Overall, we developed an open-source user-friendly pipeline for generating atrial models from imaging or electroanatomical mapping data enabling in silico clinical trials at scale (https://github.com/pcmlab/atrialmtk).

Non-invasive Imaging Techniques for Monitoring Cellular Response to Treatment in Stable Vitiligo.

Punch grafting procedures, where small pieces of normal skin are transplanted into stable vitiligo patches, results in repigmentation in only half of patients treated, yet the factors that determine whether a patient responds to treatment or not are still unknown. Reflectance confocal microscopy (RCM) is adept at visualizing melanocyte migration and epidermal changes over large areas while multiphoton microscopy (MPM) can capture metabolic changes in keratinocytes. With the overall goal of identifying optical biomarkers for early treatment response, we followed 12 vitiligo lesions undergoing punch grafting. Dendritic melanocytes adjacent to the graft site were observed before clinical evidence of repigmentation in treatment responsive patients but not in treatment non-responsive patients, suggesting that the early visualization of melanocytes is indicative of a therapeutic response. Keratinocyte metabolic changes in vitiligo skin adjacent to the graft site also correlated with treatment response, indicating that a keratinocyte microenvironment that more closely resembles normal skin is more hospitable for migrating melanocytes. Taken together, these studies suggest that successful melanocyte transplantation requires both the introduction of new melanocytes and modulation of the local tissue microenvironment.

Markov modeling of phase singularity interaction effects in human atrial and ventricular fibrillation.

Atrial and ventricular fibrillation (AF/VF) are characterized by the repetitive regeneration of topological defects known as phase singularities (PSs). The effect of PS interactions has not been previously studied in human AF and VF. We hypothesized that PS population size would influence the rate of PS formation and destruction in human AF and VF, due to increased inter-defect interaction. PS population statistics were studied in computational simulations (Aliev-Panfilov), human AF and human VF. The influence of inter-PS interactions was evaluated by comparison between directly modeled discrete-time Markov chain (DTMC) transition matrices of the PS population changes, and M/M/∞ birth-death transition matrices of PS dynamics, which assumes that PS formations and destructions are effectively statistically independent events. Across all systems examined, PS population changes differed from those expected with M/M/∞. In human AF and VF, the formation rates decreased slightly with PS population when modeled with the DTMC, compared with the static formation rate expected through M/M/∞, suggesting new formations were being inhibited. In human AF and VF, the destruction rates increased with PS population for both models, with the DTMC rate increase exceeding the M/M/∞ estimates, indicating that PS were being destroyed faster as the PS population grew. In human AF and VF, the change in PS formation and destruction rates as the population increased differed between the two models. This indicates that the presence of additional PS influenced the likelihood of new PS formation and destruction, consistent with the notion of self-inhibitory inter-PS interactions.