Ventricular dyssynchrony imaging, echocardiographic and clinical outcomes of left bundle branch pacing and biventricular pacing.

BACKGROUND: Left bundle branch pacing (LBBP) is a novel physiological pacing technique which may serve as an alternative to cardiac resynchronization therapy (CRT) by biventricular pacing (BVP). This study assessed ventricular activation patterns and echocardiographic and clinical outcomes of LBBP and compared this to BVP. METHODS: Fifty consecutive patients underwent LBBP or BVP for CRT. Ventricular activation mapping was obtained by ultra-high-frequency ECG (UHF-ECG). Functional and echocardiographic outcomes and hospitalization for heart failure and all-cause mortality after one year from implantation were evaluated. RESULTS: LBBP resulted in greater resynchronization vs BVP (QRS width: 170 ± 16 ms to 128 ± 20 ms vs 174 ± 15 to 144 ± 17 ms, p = 0.002 (LBBP vs BVP); e-DYS 81 ± 17 ms to 0 ± 32 ms vs 77 ± 18 to 16 ± 29 ms, p = 0.016 (LBBP vs BVP)). Improvement in LVEF (from 28 ± 8 to 42 ± 10 percent vs 28 ± 9 to 36 ± 12 percent, LBBP vs BVP, p = 0.078) was similar. Improvement in NYHA function class (from 2.4 to 1.5 and from 2.3 to 1.5 (LBBP vs BVP)), hospitalization for heart failure and all-cause mortality were comparable in both groups. CONCLUSIONS: Ventricular dyssynchrony imaging is an appropriate way to gain a better insight into activation patterns of LBBP and BVP. LBBP resulted in greater resynchronization (e-DYS and QRS duration) with comparable improvement in LVEF, NYHA functional class, hospitalization for heart failure and all-cause mortality at one year of follow up.

Genome-wide Analysis Identifies Nuclear Factor 1C as a Novel Transcription Factor and Potential Therapeutic Target in Small Cell Lung Cancer.

BACKGROUND: Recent insights regarding mechanisms mediating stemness, heterogeneity, and metastatic potential of lung cancers have yet to be fully translated to effective regimens for the treatment of these malignancies. This study sought to identify novel targets for lung cancer therapy. METHODS: Transcriptomes and DNA methylomes of 14 SCLC and 10 NSCLC lines were compared to normal human small airway epithelial cells (SAEC) and induced pluripotent stem cell (iPSC) clones derived from SAEC. SCLC lines, lung iPSC (Lu-iPSC), and SAEC were further evaluated by DNase I hypersensitivity (DHS-seq). Changes in chromatin accessibility and depths of transcription factor (TF) footprints were quantified using Bivariate analysis of Genomic Footprint. Standard techniques were used to examine growth and tumorigenencity as well as changes in transcriptomes and glucose metabolism of SCLC cells following Nuclear Factor 1C (NFIC) knockdown, and to examine NFIC expression in SCLC cells following exposure to BET inhibitors. RESULTS: Significant commonality of transcriptomes and DNA methylomes was observed between Lu-iPSC and SCLC; however, this analysis was uninformative regarding pathways unique to lung cancer. Linking results of DNase-seq to RNA-seq enabled identification of networks not previously associated with SCLC. When combined with footprint depth, NFIC, a transcription factor not previously associated with SCLC, had the highest score of occupancy at open chromatin sites. Knockdown of NFIC impaired glucose metabolism, decreased stemness, and inhibited growth of SCLC cells in-vitro and in-vivo. ChIP-seq analysis identified numerous sites occupied by Bromodomain-containing protein 4 (BRD4) in the NFIC promoter region. Knock-down of BRD4 or treatment with Bromodomain and extra-terminal domain (BET) inhibitors (BETi) markedly reduced NFIC expression in SCLC cells and SCLC PDX models. Approximately 8% of genes downregulated by BETi treatment were repressed by NFIC knockdown in SCLC, while 34% of genes repressed following NFIC knockdown were also downregulated in SCLC cells following BETi treatment. CONCLUSIONS: NFIC is a key TF and possible mediator of transcriptional regulation by BET family proteins in SCLC. Our findings highlight the potential of genome-wide chromatin accessibility analysis for elucidating mechanisms of pulmonary carcinogenesis and identifying novel targets for lung cancer therapy.

Dietary Nitrate Metabolism in Porcine Ocular Tissues Determined Using 15N-Labeled Sodium Nitrate Supplementation.

Nitrate (NO3-) obtained from the diet is converted to nitrite (NO2-) and subsequently to nitric oxide (NO) within the body. Previously, we showed that porcine eye components contain substantial amounts of nitrate and nitrite that are similar to those in blood. Notably, cornea and sclera exhibited the capability to reduce nitrate to nitrite. To gain deeper insights into nitrate metabolism in porcine eyes, our current study involved feeding pigs either NaCl or Na15NO3 and assessing the levels of total and 15N-labeled NO3-/NO2- in various ocular tissues. Three hours after Na15NO3 ingestion, a marked increase in 15NO3- and 15NO2- was observed in all parts of the eye; in particular, the aqueous and vitreous humor showed a high 15NO3- enrichment (77.5 and 74.5%, respectively), similar to that of plasma (77.1%) and showed an even higher 15NO2- enrichment (39.9 and 35.3%, respectively) than that of plasma (19.8%). The total amounts of NO3- and NO2- exhibited patterns consistent with those observed in 15N analysis. Next, to investigate whether nitrate or nitrite accumulate proportionally after multiple nitrate treatments, we measured nitrate and nitrite contents after supplementing pigs with Na15NO3 for five consecutive days. In both 15N-labeled and total nitrate and nitrite analysis, we did not observe further accumulation of these ions after multiple treatments, compared to a single treatment. These findings suggest that dietary nitrate supplementation exerts a significant influence on nitrate and nitrite levels and potentially NO levels in the eye and opens up the possibility for the therapeutic use of dietary nitrate/nitrite to enhance or restore NO levels in ocular tissues.

Neuromodulatory effects on synchrony and network reorganization in networks of coupled Kuramoto oscillators.

Neuromodulatory processes in the brain can critically change signal processing on a cellular level leading to dramatic changes in network level reorganization. Here, we use coupled non-identical Kuramoto oscillators to investigate how changes in the shape of phase response curves from Type 1 to Type 2, mediated by varying ACh levels, coupled with activity dependent plasticity may alter network reorganization. We first show that when plasticity is absent, the Type 1 networks, as expected, exhibit asynchronous dynamics with oscillators of the highest natural frequency robustly evolving faster in terms of their phase dynamics. At the same time, the Type 2 networks synchronize, with oscillators locked so that the ones with higher natural frequency have a constant phase lead as compared to the ones with lower natural frequency. This relationship establishes a robust mapping between the frequency and oscillators' phases in the network, leading to structure/frequency mapping when plasticity is present. Further we show that while connection plasticity can produce stable synchrony (so called splay states) in Type 1 networks, the structure/frequency reorganization observed in Type 2 networks is not present.

Public Reason, Bioethics, and Public Policy: A Seductive Delusion or Ambitious Aspiration?

Can Rawlsian public reason sufficiently justify public policies that regulate or restrain controversial medical and technological interventions in bioethics (and the broader social world), such as abortion, physician aid-in-dying, CRISPER-cas9 gene editing of embryos, surrogate mothers, pre-implantation genetic diagnosis of eight-cell embryos, and so on? The first part of this essay briefly explicates the central concepts that define Rawlsian political liberalism. The latter half of this essay then demonstrates how a commitment to Rawlsian public reason can ameliorate (not completely resolve) many of the policy disagreements related to bioethically controversial medical interventions today. The goal of public reason is to reduce the size of the disagreement by eliminating features of the disagreement that violate the norms of public reason. The norms of public reason are those norms that are politically necessary to preserve the liberal, pluralistic, democratic character of this society. What remains is reasonable disagreement to be addressed through normal democratic deliberative processes. Specific issues addressed from a public reason perspective include personal responsibility for excessive health costs, the utility of a metaphysical definition of death for organ transplantation, and the moral status of excess embryos generated through IVF and/or their use in medical research.

Ultra-High-Frequency ECG in Cardiac Pacing and Cardiac Resynchronization Therapy: From Technical Concept to Clinical Application.

Identifying electrical dyssynchrony is crucial for cardiac pacing and cardiac resynchronization therapy (CRT). The ultra-high-frequency electrocardiography (UHF-ECG) technique allows instantaneous dyssynchrony analyses with real-time visualization. This review explores the physiological background of higher frequencies in ventricular conduction and the translational evolution of UHF-ECG in cardiac pacing and CRT. Although high-frequency components were studied half a century ago, their exploration in the dyssynchrony context is rare. UHF-ECG records ECG signals from eight precordial leads over multiple beats in time. After initial conceptual studies, the implementation of an instant visualization of ventricular activation led to clinical implementation with minimal patient burden. UHF-ECG aids patient selection in biventricular CRT and evaluates ventricular activation during various forms of conduction system pacing (CSP). UHF-ECG ventricular electrical dyssynchrony has been associated with clinical outcomes in a large retrospective CRT cohort and has been used to study the electrophysiological differences between CSP methods, including His bundle pacing, left bundle branch (area) pacing, left ventricular septal pacing and conventional biventricular pacing. UHF-ECG can potentially be used to determine a tailored resynchronization approach (CRT through biventricular pacing or CSP) based on the electrical substrate (true LBBB vs. non-specified intraventricular conduction delay with more distal left ventricular conduction disease), for the optimization of CRT and holds promise beyond CRT for the risk stratification of ventricular arrhythmias.

Ternary complexes of isopentenyl phosphate kinase from Thermococcus paralvinellae reveal molecular determinants of non-natural substrate specificity.

Isopentenyl phosphate kinases (IPKs) have recently garnered attention for their central role in biocatalytic "isoprenol pathways," which seek to reduce the synthesis of the isoprenoid precursors to two enzymatic steps. Furthermore, the natural promiscuity of IPKs toward non-natural alkyl-monophosphates (alkyl-Ps) as substrates has hinted at the isoprenol pathways' potential to access novel isoprenoids with potentially useful activities. However, only a handful of IPK crystal structures have been solved to date, and even fewer of these contain non-natural substrates bound in the active site. The current study sought to elucidate additional ternary complexes bound to non-natural substrates using the IPK homolog from Thermococcus paralvinellae (TcpIPK). Four such structures were solved, each bound to a different non-natural alkyl-P and the phosphoryl donor substrate/product adenosine triphosphate (ATP)/adenosine diphosphate (ADP). As expected, the quaternary, tertiary, and secondary structures of TcpIPK closely resembled those of IPKs published previously, and kinetic analysis of a novel alkyl-P substrate highlighted the potentially dramatic effects of altering the core scaffold of the natural substrate. Even more interesting, though, was the discovery of a trend correlating the position of two α helices in the active site with the magnitude of an IPK homolog's reaction rate for the natural reaction. Overall, the current structures of TcpIPK highlight the importance of continued structural analysis of the IPKs to better understand and optimize their activity with both natural and non-natural substrates.

A Systematic Prospective Comparison of Fluid Volume Evaluation across OCT Devices Used in Clinical Practice.

Objective: Treatment decisions in neovascular age-related macular degeneration (nAMD) are mainly based on subjective evaluation of OCT. The purpose of this cross-sectional study was to provide a comparison of qualitative and quantitative differences between OCT devices in a systematic manner. Design: Prospective, cross-sectional study. Subjects: One hundred sixty OCT volumes, 40 eyes of 40 patients with nAMD. Methods: Patients from clinical practice were imaged with 4 different OCT devices during one visit: (1) Spectralis Heidelberg; (2) Cirrus; (3) Topcon Maestro2; and (4) Topcon Triton. Intraretinal fluid (IRF), subretinal fluid (SRF), and pigment epithelial detachment (PED) were manually annotated in all cubes by trained human experts to establish fluid measurements based on expert-reader annotations. Intraretinal fluid, SRF, and PED volume were quantified in nanoliters (nL). Bland-Altman plots were created to analyze the agreement of measurements in the central 1 and 6 mm. The Friedman test was performed to test for significant differences in the central 1, 3, and 6 mm. Main Outcome Measures: Intraretinal fluid, SRF, and PED volume. Results: In the central 6 mm, there was a trend toward higher IRF and PED volumes in Spectralis images compared with the other devices and no differences in SRF volume. In the central 1 mm, the standard deviation of the differences ranged from ± 3 nL to ± 6 nL for IRF, from ± 3 nL to ± 4 nL for SRF, and from ± 7 nL to ± 10 nL for PED in all pairwise comparisons. Manually annotated IRF and SRF volumes showed no significant differences in the central 1 mm. Conclusions: Fluid volume quantification achieved excellent reliability in all 3 retinal compartments on images obtained from 4 OCT devices, particularly for clinically relevant IRF and SRF values. Although fluid volume quantification is reliable in all 4 OCT devices, switching OCT devices might lead to deviating fluid volume measurements with higher agreement in the central 1 mm compared with the central 6 mm, with highest agreement for SRF volume in the central 1 mm. Understanding device-dependent differences is essential for expanding the interpretation and implementation of pixel-wise fluid volume measurements in clinical practice and in clinical trials. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Influence of Grazing on Canola Grain, Canola Forage Yield, and Beef Cattle Performance.

Interest is increasing in grazing winter canola (Brassica napus) as an alternative crop in winter wheat (Triticum aestivum) rotations in the Southern High Plains (SHP) of the USA and similar environments. In this stidy, winter cereal rye (Secale cereale) and winter canola pastures (forage) were compared for two winter growing seasons at New Mexico State University's Rex E. Kirksey Agricultural Science Center at Tucumcari, NM, USA, to determine the relative effect of pasture type on late-gestation beef cows and growing yearling cattle, along with the effect of grazing on canola grain production. Canola grain yields were reduced by 25% when canola was grazed until removal approximately one month after grazing was initiated, but before the onset of rapid regrowth after winter (641 vs. 486 kg grain ha-1 for never grazed or grazed canola, respectively, p < 0.0256). No differences existed for forage mass, nutritive value, or animal performance, although forage mineral composition of canola could be a concern. Grazing winter canola as a dual-purpose crop in the SHP and similar environments is feasible when proper grazing management is applied; producers should anticipate a 20-25% reduction in grain yield, but expect animal gains to offset that loss.

Oil-water interface and emulsion stabilising properties of rapeseed proteins napin and cruciferin studied by nonlinear surface rheology.

HYPOTHESIS: Two major protein families are present in rapeseed, namely cruciferins and napins. The structural differences between the two protein families indicate that they might behave differently when their mixture stabilises oil-water interfaces. Therefore, this work focuses on elucidating the role of both proteins in interface and emulsion stabilisation. EXPERIMENTS: Protein molecular properties were evaluated, using SEC, DSC, CD, and hydrophobicity analysis. The oil-water interface mechanical properties were studied using LAOS and LAOD. General stress decomposition (GSD) was used as a novel method to characterise the nonlinear response. Additionally, to evaluate the emulsifying properties of the rapeseed proteins, emulsions were prepared using pure napins or cruciferin and also their mixtures at 1:3, 1:1 and 3:1 (w:w) ratios. FINDINGS: Cruciferins formed stiff viscoelastic solid-like interfacial layers (Gs' = 0.046 mN/m; Ed' = 30.1 mN/m), while napin formed weaker and more stretchable layers at the oil-water interface (Gs' = 0.010 mN/m; Ed' = 26.4 mN/m). As a result, cruciferin-formed oil droplets with much higher stability against coalescence (coalescence index, CI up to 10%) than napin-stabilised ones (CI up to 146%) during two months of storage. Both proteins have a different role in emulsions produced with napin-cruciferin mixtures, where cruciferin provides high coalescence stability, while napin induces flocculation. Our work showed the role of each rapeseed protein in liquid-liquid multiphase systems.

Performance of a combined electrotrophic and electrogenic biofilm operated under long-term, continuous cycling.

OBJECTIVES: Evaluate electrochemically active biofilms as high energy density rechargeable microbial batteries toward providing persistent power in applications where traditional battery technology is limiting (, remote monitoring applications). RESULTS: Here we demonstrated that an electrochemically active biofilm was able to store and release electrical charge for alternating charge/discharge cycles of up to 24 h periodicity (50% duty cycle) with no significant decrease in average current density (0.16 ± 0.04 A/m2) for over 600 days. However, operation at 24 h periodicity for > 50 days resulted in a sharp decrease in the current to nearly zero. This current crash was recoverable by decreasing the periodicity. Overall, the coulombic efficiency remained near unity within experimental error (102 ± 3%) for all of the tested cycling periods. Electrochemical characterization here suggests that electron transfer occurs through multiple routes, likely a mixture of direct and mediated mechanisms. CONCLUSIONS: These results indicate that bidirectional electrogenic/electrotrophic biofilms are capable of efficient charge storage/release over a wide range of cycling frequency and may eventually enable development of sustainable, high energy density rechargeable batteries.

Inter and intradevice assessment of microperimetry testing in aging eyes.

Microperimetry (MP) is a psychometric examination combining retinal imaging and functional sensitivity testing with an increasing importance due to its potential use as clinical study outcome. We investigated the repeatability of pointwise retinal sensitivity (PWS) on the most advanced commercially available MP devices under their standard setting in a healthy aging population. Two successive MP examinations on both MP-3 (NIDEK CO., Ltd., Gamagori, Japan) and MAIA (CenterVue S.p.A. (iCare), Padova, Italy) were performed on healthy aging subjects in a randomized order. PWS repeatability was analysed for different macular regions and age groups using Bland-Altmann coefficients of repeatability (CoR). A total of 3600 stimuli from 20 healthy individuals with a mean age of 70 (11) years were included. Mean CoR in dB were ±4.61 for MAIA and ±4.55 for MP-3 examinations. A lower repeatability (p=0.005) was detected in the central millimetre on MAIA examinations. Higher subject age was associated with a lower repeatability of PWS on both devices (both p=0.003). Intra-device correlation was good (MAIA: 0.79 [0.76-0.81]; MP-3: 0.72 [0.68-0.76]) whereas a moderate mean inter-device correlation (0.6 [0.55-0.65]) could be detected. In conclusion, older subjects and the foveal region are associated with a worse pointwise repeatability.

The Dimerization and Oligomerization of Alkenes Catalyzed with Transition Metal Complexes: Catalytic Systems and Reaction Mechanisms.

Dimers and oligomers of alkenes represent a category of compounds that are in great demand in diverse industrial sectors. Among the developing synthetic methods, the catalysis of alkene dimerization and oligomerization using transition metal salts and complexes is of undoubted interest for practical applications. This approach demonstrates substantial potential, offering not only elevated reaction rates but also precise control over the chemo-, regio-, and stereoselectivity of the reactions. In this review, we discuss the data on catalytic systems for alkene dimerization and oligomerization. Our focus lies in the analysis of how the activity and chemoselectivity of these catalytic systems are influenced by various factors, such as the nature of the transition metal, the ligand environment, the activator, and the substrate structure. Notably, this review particularly discusses reaction mechanisms, encompassing metal complex activation, structural and dynamic features, and the reactivity of hydride intermediates, which serve as potential catalytically active centers in alkene dimerization and oligomerization.

Can perioperative pCO2 gaps predict complications in patients undergoing major elective abdominal surgery randomized to goal-directed therapy or standard care? A secondary analysis.

The difference between venous and arterial carbon dioxide pressure (pCO2 gap), has been used as a diagnostic and prognostic tool. We aimed to assess whether perioperative pCO2 gaps can predict postoperative complications. This was a secondary analysis of a multicenter RCT comparing goal-directed therapy (GDT) to standard care in which 464 patients undergoing high-risk elective abdominal surgery were included. Arterial and central venous blood samples were simultaneously obtained at four time points: after induction, at the end of surgery, at PACU/ICU admission, and PACU/ICU discharge. Complications within the first 30 days after surgery were recorded. Similar pCO2 gaps were found in patients with and without complications, except for the pCO2 gap at the end of surgery, which was higher in patients with complications (6.0 mmHg [5.0-8.0] vs. 6.0 mmHg [4.1-7.5], p = 0.005). The area under receiver operating characteristics curves for predicting complications from pCO2 gaps at all time points were between 0.5 and 0.6. A weak correlation between ScvO2 and pCO2 gaps was found for all timepoints (ρ was between - 0.40 and - 0.29 for all timepoints, p < 0.001). The pCO2 gap did not differ between GDT and standard care at any of the selected time points. In our study, pCO2 gap was a poor predictor of major postoperative complications at all selected time points. Our research does not support the use of pCO2 gap as a prognostic tool after high-risk abdominal surgery. pCO2 gaps were comparable between GDT and standard care. Clinical trial registration Netherlands Trial Registry NTR3380.

Multimodal prerehabilitation for elderly patients with sarcopenia in colorectal surgery.

Sarcopenia, which is characterized by progressive and generalized loss of skeletal muscle mass and strength, has been well described to be associated with numerous poor postoperative outcomes, such as increased perioperative mortality, postoperative sepsis, prolonged length of stay, increased cost of care, decreased functional outcome, and poorer oncological outcomes in cancer surgery. Multimodal prehabilitation, as a concept that involves boosting and optimizing the preoperative condition of a patient prior to the upcoming stressors of a surgical procedure, has the purported benefits of reversing the effects of sarcopenia, shortening hospitalization, improving the rate of return to bowel activity, reducing the costs of hospitalization, and improving quality of life. This review aims to present the current literature surrounding the concept of sarcopenia, its implications pertaining to colorectal cancer and surgery, a summary of studied multimodal prehabilitation interventions, and potential future advances in the management of sarcopenia.

Precision Medicine and Rough Justice: Wicked Problems.

What exactly is a "wicked problem"? It is a social or economic problem that is so complex and so interconnected with other issues that it is extraordinarily difficult or impossible to resolve. This is because all proposed resolutions generate equally complex, equally wicked problems. In this essay, I argue that precision medicine, especially in the context of the U.S. healthcare system, generates numerous wicked problems related to distributive justice. Further, I argue that there are no easy solutions to these wicked problems. The need for trade-offs is inescapable. Rough justice is the best outcome we can hope for, and that outcome requires a commitment to processes of public reason that are fair and inclusive.