Clinical Characteristics To Guide The Extent Of Ablation In Paroxysmal AF Patients: Discovering An Old Science

Anthony G. Brooks, Narayanan Namboodiri, and Prashanthan Sander

Reverse Remodeling of the Atria After Treatment of Chronic Stretch in Humans Implications for the Atrial Fibrillation Substrate

ObjectivesThe aim of this report was to study the effect of chronic stretch reversal on the electrophysiological characteristics of the atria in humans.BackgroundAtrial stretch is an important determinant for atrial fibrillation. Whether relief of stretch reverses the substrate predisposed to atrial fibrillation is unknown.MethodsTwenty-one patients with mitral stenosis undergoing mitral commissurotomy (MC) were studied before and after intervention. Catheters were placed at multiple sites in the right atrium (RA) and sequentially within the left atrium (LA) to determine: effective refractory period (ERP) at 10 sites (600 and 450 ms) and P-wave duration (PWD). Bi-atrial electroanatomic maps determined conduction velocity (CV) and voltage. In 14 patients, RA studies were repeated ≥6 months after MC.ResultsImmediately after MC, there was significant increase in mitral valve area (2.1 ± 0.2 cm2, p < 0.0001) with decrease in LA (23 ± 7 mm Hg to 10 ± 4 mm Hg, p < 0.0001) and pulmonary arterial pressures (38 ± 16 mm Hg to 27 ± 12 mm Hg, p < 0.0001) and LA volume (75 ± 20 ml to 52 ± 18 ml, p < 0.0001). This was associated with reduction in PWD (139 ± 19 ms to 135 ± 20 ms, p = 0.047), increase in CV (LA: 1.3 ± 0.3 mm/ms to 1.7 ± 0.2 mm/ms, p = 0.006; and RA: 1.0 ± 0.1 mm/ms to 1.3 ± 0.3 mm/ms, p = 0.002) and voltage (LA: 1.7 ± 0.6 mV to 2.5 ± 1.0 mV, p = 0.005; and RA: 1.8 ± 0.6 mV to 2.2 ± 0.7 mV, p = 0.09), and no change in ERP. Late after MC, mitral valve area remained at 2.1 ± 0.3 cm2 (p = 0.7) but with further decrease in PWD (113 ± 19 ms, p = 0.04) and RA ERP (at 600 ms, p < 0.0001), with increase in CV (1.0 ± 0.1 mm/ms to 1.3 ± 0.2 mm/ms, p = 0.006) and voltage (1.8 ± 0.7 mV to 2.8 ± 0.6 mV, p = 0.002).ConclusionsThe atrial electrophysiologic and electroanatomic abnormalities that result from chronic stretch due to MS reverses after MC. These observations suggest that the substrate predisposing to atrial arrhythmias might be reversed

Injury Rates in Major League Baseball during the 2020 COVID-19 Season

Background: The 2020 Major League Baseball (MLB) season was drastically altered because of the COVID-19 pandemic. The changes included an extended layoff between March and July as well as a shortened preseason. Purpose/Hypothesis: To determine the incidence and epidemiology of MLB injuries in the abbreviated 2020 season compared with prior seasons. We hypothesized that there was an increase in the overall injury rate in the 2020 season compared with the 2018-2019 seasons and that it equally affected all body regions. Study Design: Descriptive epidemiology study. Methods: The MLB transactions database was queried to find players who had been placed on the injury list between 2018 and 2020. Injuries were categorized into upper extremity, lower extremity, spine/core, and other injuries. Incidence per 1000 athlete-exposures was calculated for the prior 2 seasons (2018-2019) and for the 2020 season separately. Incidence for each category was also calculated separately for pitchers and fielders. Incidence rate ratios (IRRs) and confidence intervals were used to compare injury rates in 2018-2019 versus 2020. The z test for proportions was used to determine significant differences between injury incidences. Results: In 2020, the overall incidence rate per 1000 athlete-exposures was almost twice the rate compared with the 2 seasons before COVID-19 (8.66 vs 5.13; IRR, 1.69 [95% CI, 1.53-1.87]; P \u3c .001). Injury incidence increased similarly in 2020 for both pitchers (IRR, 1.68 [95% CI, 1.47-1.91]; P \u3c .001) and fielders (IRR, 1.68 [95% CI, 1.45-1.96]; P \u3c .001). Increases in injury incidence were seen in the upper extremity, spine/core, and other injury categories; however, the incidence of the lower extremity did not change significantly. Conclusion: There was a significant increase in injury incidence for both pitchers and fielders in 2020. Injury rates increased in anatomic zones of the upper extremity and spine/core but were not significantly changed in the lower extremity. The overall increase in injury rate suggests that irregular or insufficient sport-specific preparation prior to the start of the season placed athletes at a greater risk of injury when play resumed

Defining childhood severe falciparum malaria for intervention studies.

Background Clinical trials of interventions designed to prevent severe falciparum malaria in children require a clear endpoint. The internationally accepted definition of severe malaria is sensitive, and appropriate for clinical purposes. However, this definition includes individuals with severe nonmalarial disease and coincident parasitaemia, so may lack specificity in vaccine trials. Although there is no “gold standard” individual test for severe malaria, malaria-attributable fractions (MAFs) can be estimated among groups of children using a logistic model, which we use to test the suitability of various case definitions as trial endpoints. Methods and Findings A total of 4,583 blood samples were taken from well children in cross-sectional surveys and from 1,361 children admitted to a Kenyan District hospital with severe disease. Among children under 2 y old with severe disease and over 2,500 parasites per microliter of blood, the MAFs were above 85% in moderate- and low-transmission areas, but only 61% in a high-transmission area. HIV and malnutrition were not associated with reduced MAFs, but gastroenteritis with severe dehydration (defined by reduced skin turgor), lower respiratory tract infection (clinician's final diagnosis), meningitis (on cerebrospinal fluid [CSF] examination), and bacteraemia were associated with reduced MAFs. The overall MAF was 85% (95% confidence interval [CI] 83.8%–86.1%) without excluding these conditions, 89% (95% CI 88.4%–90.2%) after exclusions, and 95% (95% CI 94.0%–95.5%) when a threshold of 2,500 parasites/μl was also applied. Applying a threshold and exclusion criteria reduced sensitivity to 80% (95% CI 77%–83%). Conclusions The specificity of a case definition for severe malaria is improved by applying a parasite density threshold and by excluding children with meningitis, lower respiratory tract infection (clinician's diagnosis), bacteraemia, and gastroenteritis with severe dehydration, but not by excluding children with HIV or malnutrition

Self-interest And Public Interest: The Motivations Of Political Actors

Self-Interest and Public Interest in Western Politics showed that the public, politicians, and bureaucrats are often public spirited. But this does not invalidate public-choice theory. Public-choice theory is an ideal type, not a claim that self-interest explains all political behavior. Instead, public-choice theory is useful in creating rules and institutions that guard against the worst case, which would be universal self-interestedness in politics. In contrast, the public-interest hypothesis is neither a comprehensive explanation of political behavior nor a sound basis for institutional design

Spatiotemporal characteristics of atrial fibrillation electrograms: a novel marker for arrhythmia stability and termination

Background: Sequentially mapped complex fractionated atrial electrograms (CFAE) and dominant frequency (DF) sites have been targeted during catheter ablation for atrial fibrillation (AF). However, these strategies have yielded variable success and have not been shown to correlate consistently with AF dynamics. Here, we evaluated whether the spatiotemporal stability of CFAE and DF may be a better marker of AF sustenance and termination. Methods: Eighteen sheep with 12 weeks of "one-kidney, one-clip" hypertension underwent open-chest studies. A total of 42 self-terminating (28–100 s) and 6 sustained (>15 min) AF episodes were mapped using a custom epicardial plaque and analyzed in 4-s epochs for CFAE, using the NavX CFE-m algorithm, and DF, using a Fast Fourier Transform. The spatiotemporal stability index (STSI) was calculated using the intraclass correlation coefficient of consecutive AF epochs. Results: A total of 67,733 AF epochs were analyzed. During AF initiation, mean CFE-m and the STSI of CFE-m/DF were similar between sustained and self-terminating episodes, although median DF was higher in sustained AF (p=0.001). During sustained AF, the STSI of CFE-m increased significantly (p=0.02), whereas mean CFE-m (p=0.5), median DF (p=0.07), and the STSI of DF remained unchanged (p=0.5). Prior to AF termination, the STSI of CFE-m was significantly lower (p<0.001), with a physiologically non-significant decrease in median DF (−0.3 Hz, p=0.006) and no significant changes in mean CFE-m (p=0.14) or the STSI of DF (p=0.06). Conclusions: Spatiotemporal stabilization of CFAE favors AF sustenance and its destabilization heralds AF termination. The STSI of CFE-m is more representative of AF dynamics than are the STSI of DF, sequential mean CFE-m, or median DF

The Shaping of T Cell Receptor Recognition by Self-Tolerance

SummaryDuring selection of the T cell repertoire, the immune system navigates the subtle distinction between self-restriction and self-tolerance, yet how this is achieved is unclear. Here we describe how self-tolerance toward a trans-HLA (human leukocyte antigen) allotype shapes T cell receptor (TCR) recognition of an Epstein-Barr virus (EBV) determinant (FLRGRAYGL). The recognition of HLA-B8-FLRGRAYGL by two archetypal TCRs was compared. One was a publicly selected TCR, LC13, that is alloreactive with HLA-B44; the other, CF34, lacks HLA-B44 reactivity because it arises when HLA-B44 is coinherited in trans with HLA-B8. Whereas the alloreactive LC13 TCR docked at the C terminus of HLA-B8-FLRGRAYGL, the CF34 TCR docked at the N terminus of HLA-B8-FLRGRAYGL, which coincided with a polymorphic region between HLA-B8 and HLA-B44. The markedly contrasting footprints of the LC13 and CF34 TCRs provided a portrait of how self-tolerance shapes the specificity of TCRs selected into the immune repertoire

Single transcriptional and translational preQ1 riboswitches adopt similar pre-folded ensembles that follow distinct folding pathways into the same ligand-bound structure

Riboswitches are structural elements in the 50 untranslated regions of many bacterial messenger RNAs that regulate gene expression in response to changing metabolite concentrations by inhibition of either transcription or translation initiation. The preQ1 (7-aminomethyl-7-deazaguanine) riboswitch family comprises some of the smallest metabolite sensing RNAs found in nature. Once ligand-bound, the transcriptional Bacillus subtilis and translational Thermoanaerobacter tengcongensis preQ1 riboswitch aptamers are structurally similar RNA pseudoknots; yet, prior structural studies have characterized their ligand-free conformations as largely unfolded and folded, respectively. In contrast, through single molecule observation, we now show that, at nearphysiological Mg2+ concentration and pH, both ligand-free aptamers adopt similar pre-folded state ensembles that differ in their ligand-mediated folding. Structure-based Go¯ -model simulations of the two aptamers suggest that the ligand binds late (Bacillus subtilis) and early (Thermoanaerobacter tengcongensis) relative to pseudoknot folding, leading to the proposal that the principal distinction between the two riboswitches lies in their relative tendencies to fold via mechanisms of conformational selection and induced fit, respectively. These mechanistic insights are put to the test by rationally designing a single nucleotide swap distal from the ligand binding pocket that we find to predictably control the aptamers0 pre-folded states and their ligand binding affinities

CHERI Concentrate: Practical Compressed Capabilities

We present CHERI Concentrate, a new fat-pointer compression scheme applied to CHERI, the most developed capability-pointer system at present. Capability fat-pointers are a primary candidate for enforcing fine-grained and non-bypassable security properties in future computer systems, although increased pointer size can severely affect performance. Thus, several proposals for capability compression have been suggested but these did not support legacy instruction sets, ignored features critical to the existing software base, and also introduced design inefficiencies to RISC-style processor pipelines. CHERI Concentrate improves on the state-of-the-art region-encoding efficiency, solves important pipeline problems, and eases semantic restrictions of compressed encoding, allowing it to protect a full legacy software stack. We analyze and extend logic from the open-source CHERI prototype processor design on FPGA to demonstrate encoding efficiency, minimize delay of pointer arithmetic, and eliminate additional load-to-use delay. To verify correctness of our proposed high-performance logic, we present a HOL4 machine-checked proof of the decode and pointer-modify operations. Finally, we measure a 50%-75% reduction in L2 misses for many compiled C-language benchmarks running under a commodity operating system using compressed 128-bit and 64-bit formats, demonstrating both compatibility with and increased performance over the uncompressed, 256-bit format