In silico investigation of the mechanisms underlying atrial fibrillation due to impaired Pitx2.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is a major cause of stroke and morbidity. Recent genome-wide association studies have shown that paired-like homeodomain transcription factor 2 (Pitx2) to be strongly associated with AF. However, the mechanisms underlying Pitx2 modulated arrhythmogenesis and variable effectiveness of antiarrhythmic drugs (AADs) in patients in the presence or absence of impaired Pitx2 expression remain unclear. We have developed multi-scale computer models, ranging from a single cell to tissue level, to mimic control and Pitx2-knockout atria by incorporating recent experimental data on Pitx2-induced electrical and structural remodeling in humans, as well as the effects of AADs. The key findings of this study are twofold. We have demonstrated that shortened action potential duration, slow conduction and triggered activity occur due to electrical and structural remodelling under Pitx2 deficiency conditions. Notably, the elevated function of calcium transport ATPase increases sarcoplasmic reticulum Ca2+ concentration, thereby enhancing susceptibility to triggered activity. Furthermore, heterogeneity is further elevated due to Pitx2 deficiency: 1) Electrical heterogeneity between left and right atria increases; and 2) Increased fibrosis and decreased cell-cell coupling due to structural remodelling slow electrical propagation and provide obstacles to attract re-entry, facilitating the initiation of re-entrant circuits. Secondly, our study suggests that flecainide has antiarrhythmic effects on AF due to impaired Pitx2 by preventing spontaneous calcium release and increasing wavelength. Furthermore, our study suggests that Na+ channel effects alone are insufficient to explain the efficacy of flecainide. Our study may provide the mechanisms underlying Pitx2-induced AF and possible explanation behind the AAD effects of flecainide in patients with Pitx2 deficiency.

In Silico Assessment of Class I Antiarrhythmic Drug Effects on Pitx2-Induced Atrial Fibrillation: Insights from Populations of Electrophysiological Models of Human Atrial Cells and Tissues.

Electrical remodelling as a result of homeodomain transcription factor 2 (Pitx2)-dependent gene regulation was linked to atrial fibrillation (AF) and AF patients with single nucleotide polymorphisms at chromosome 4q25 responded favorably to class I antiarrhythmic drugs (AADs). The possible reasons behind this remain elusive. The purpose of this study was to assess the efficacy of the AADs disopyramide, quinidine, and propafenone on human atrial arrhythmias mediated by Pitx2-induced remodelling, from a single cell to the tissue level, using drug binding models with multi-channel pharmacology. Experimentally calibrated populations of human atrial action po-tential (AP) models in both sinus rhythm (SR) and Pitx2-induced AF conditions were constructed by using two distinct models to represent morphological subtypes of AP. Multi-channel pharmaco-logical effects of disopyramide, quinidine, and propafenone on ionic currents were considered. Simulated results showed that Pitx2-induced remodelling increased maximum upstroke velocity (dVdtmax), and decreased AP duration (APD), conduction velocity (CV), and wavelength (WL). At the concentrations tested in this study, these AADs decreased dVdtmax and CV and prolonged APD in the setting of Pitx2-induced AF. Our findings of alterations in WL indicated that disopyramide may be more effective against Pitx2-induced AF than propafenone and quinidine by prolonging WL.

Afterdepolarizations and abnormal calcium handling in atrial myocytes with modulated SERCA uptake: a sensitivity analysis of calcium handling channels.

Delayed afterdepolarizations (DADs) and spontaneous depolarizations (SDs) are typically triggered by spontaneous diastolic Ca2+ release from the sarcoplasmic reticulum (SR) which is caused by an elevated SR Ca2+-ATPase (SERCA) uptake and dysfunctional ryanodine receptors. However, recent studies on the T-box transcription factor gene (TBX5) demonstrated that abnormal depolarizations could occur despite a reduced SERCA uptake. Similar findings have also been reported in experimental or clinical studies of diabetes and heart failure. To investigate the sensitivity of SERCA in the genesis of DADs/SDs as well as its dependence on other Ca2+ handling channels, we performed systematic analyses using the Maleckar et al. model. Results showed that the modulation of SERCA alone cannot trigger abnormal depolarizations, but can instead affect the interdependency of other Ca2+ handling channels in triggering DADs/SDs. Furthermore, we discovered the existence of a threshold value for the intracellular concentration of Ca2+ ([Ca2+]i) for abnormal depolarizations, which is modulated by the maximum SERCA uptake and the concentration of Ca2+ in the uptake and release compartments in the SR ([Ca2+]up and [Ca2+]rel). For the first time, our modelling study reconciles different mechanisms of abnormal depolarizations in the setting of 'lone' AF, reduced TBX5, diabetes and heart failure, and may lead to more targeted treatment for these patients. This article is part of the theme issue 'Uncertainty quantification in cardiac and cardiovascular modelling and simulation'.

A biradical-tagged phospholipid as a polarizing agent for solid-state MAS Dynamic Nuclear Polarization NMR of membrane proteins.

A novel Dynamic Nuclear Polarization (DNP) NMR polarizing agent ToSMTSL-PTE representing a phospholipid with a biradical TOTAPOL tethered to the polar head group has been synthesized, characterized, and employed to enhance solid-state Nuclear Magnetic Resonance (SSNMR) signal of a lipid-reconstituted integral membrane protein proteorhodopsin (PR). A matrix-free PR formulation for DNP improved the absolute sensitivity of NMR signal by a factor of ca. 4 compared to a conventional preparation with TOTAPOL dispersed in a glassy glycerol/water matrix. DNP enhancements measured at 400 MHz/263 GHz and 600 MHz/395 GHz showed a strong field dependence but remained moderate at both fields, and comparable to those obtained for PR covalently modified with ToSMTSL. Additional continuous wave (CW) X-band electron paramagnetic resonance (EPR) experiments with ToSMTSL-PTE in solutions and in lipid bilayers revealed that an unfavorable conformational change of the linker connecting mononitroxides could be one of the reasons for moderate DNP enhancements. Further, differential scanning calorimetry (DSC) and CW EPR experiments indicated an inhomogeneous distribution and/or a possibility of a partial aggregation of ToSMTSL-PTE in DMPC:DMPA bilayers when the concentration of the polarizing agent was increased to 20 mol% to maximize the DNP enhancement. Thus, conformational changes and an inhomogeneous distribution of the lipid-based biradicals in lipid bilayers emerged as important factors to consider for further development of this matrix-free approach for DNP of membrane proteins.

Anterior Segment Biometry Changes with Cycloplegia in Myopic Adults.

PURPOSE: To determine the effect of cycloplegia on corneal thickness, corneal curvature, anterior chamber depth (ACD), angle-to-angle (ATA) and white-to-white (WTW) distances, and axial length (AL). METHODS: Changes in corneal thickness, corneal curvature, ACD, ATA and WTW distances, and AL with and without cycloplegia were analyzed in 31 eyes of 31 young myopic adults, aged 26.4 ± 3.0 years. Pentacam was used to measure the corneal thickness, corneal volume, and corneal curvatures. Visante optical coherent tomography (OCT) measured corneal thickness, ATA distance, ACD, and pupil size. The AL and WTW distance were measured using IOLMaster. RESULTS: Cycloplegia induced significant flattening of corneal curvatures (p = 0.019, 0.001, and 0.003 for anterior sagittal, posterior tangential, and posterior sagittal curvatures, respectively). The difference in the posterior corneal curvature was greater in corneas with steeper posterior curvatures. Cycloplegia also induced significant deepening of ACD (0.08 ± 0.06, p < 0.001) and widening of both WTW (0.42 ± 0.43, p < 0.001) and ATA (0.08 ± 0.17, p = 0.015) distances. The cycloplegia-related increase in the ATA distance correlated negatively with AL (r = -0.361, p = 0.046), whereas the cycloplegia-related increase in WTW distance correlated weakly with the increase in ACD (r = 0.347, p = 0.056) but not with AL. The AL did not change with cycloplegia. Pentacam measured a slightly thicker cornea than OCT (p = 0.002). Both Pentacam and OCT detected a significant increase in corneal thickness of 4 µm, which could be attributed to reflex tearing, after cycloplegia. CONCLUSIONS: Cycloplegia resulted in deeper ACD, greater ATA distance, and flatter corneal curvatures. Surgeons should be aware of these cycloplegia-related alterations for more accurate phakic/functional intraocular lens selection and better refraction results.

Glycoprotein biomarker panel for pancreatic cancer discovered by quantitative proteomics analysis.

Pancreatic cancer is a lethal disease where specific early detection biomarkers would be very valuable to improve outcomes in patients. Many previous studies have compared biosamples from pancreatic cancer patients with healthy controls to find potential biomarkers. However, a range of related disease conditions can influence the performance of these putative biomarkers, including pancreatitis and diabetes. In this study, quantitative proteomics methods were applied to discover potential serum glycoprotein biomarkers that distinguish pancreatic cancer from other pancreas related conditions (diabetes, cyst, chronic pancreatitis, obstructive jaundice) and healthy controls. Aleuria aurantia lectin (AAL) was used to extract fucosylated glycoproteins and then both TMT protein-level labeling and label-free quantitative analysis were performed to analyze glycoprotein differences from 179 serum samples across the six different conditions. A total of 243 and 354 serum proteins were identified and quantified by label-free and TMT protein-level quantitative strategies, respectively. Nineteen and 25 proteins were found to show significant differences in samples between the pancreatic cancer and other conditions using the label-free and TMT strategies, respectively, with 7 proteins considered significant in both methods. Significantly different glycoproteins were further validated by lectin-ELISA and ELISA assays. Four candidates were identified as potential markers with profiles found to be highly complementary with CA 19-9 (p < 0.001). Obstructive jaundice (OJ) was found to have a significant impact on the performance of every marker protein, including CA 19-9. The combination of α-1-antichymotrypsin (AACT), thrombospondin-1 (THBS1), and haptoglobin (HPT) outperformed CA 19-9 in distinguishing pancreatic cancer from normal controls (AUC = 0.95), diabetes (AUC = 0.89), cyst (AUC = 0.82), and chronic pancreatitis (AUC = 0.90). A marker panel of AACT, THBS1, HPT, and CA 19-9 showed a high diagnostic potential in distinguishing pancreatic cancer from other conditions with OJ (AUC = 0.92) or without OJ (AUC = 0.95).

Label-free relative quantification of alpha-2-macroglobulin site-specific core-fucosylation in pancreatic cancer by LC-MS/MS.

We describe a label-free relative quantification LC-MS/MS method for core-fucosylation in alpha-2-macroglobulin (A2MG) immunoprecipitated from human sera. The method utilizes endoglycosidase F partial deglycosylation to reduce glycosylation microheterogeneity, while retaining the innermost N-acetylglucosamine (GlcNAc) and core fucose. Precursor ion peak areas of partially deglycosylated peptides were obtained and site-specific core-fucosylation ratios based on the peak areas of core-fucosylated and nonfucosylated counterparts were calculated and evaluated for assay development. This assay was applied in a preliminary study of sera samples from normal controls and patients with pancreatic diseases, including pancreatic cancer and chronic pancreatitis. A2MG fucosylation levels at sites N396 and N1424 were found to decrease in both chronic pancreatitis and pancreatic cancer compared to normal controls. The two sites were identified by two peptides and their core-fucosylation ratios were found to be internally consistent. This method provides a platform to quantify fucosylation levels and can be used to study site-specific core-fucosylation aberrations in other glycoproteins for other diseases.

Isobaric protein-level labeling strategy for serum glycoprotein quantification analysis by liquid chromatography-tandem mass spectrometry.

While peptide-level labeling using isobaric tag reagents has been widely applied for quantitative proteomics experiments, there are comparatively few reports of protein-level labeling. Intact protein labeling could be broadly applied to quantification experiments utilizing protein-level separations or enrichment schemes. Here, protein-level isobaric labeling was explored as an alternative strategy to peptide-level labeling for serum glycoprotein quantification. Labeling and digestion conditions were optimized by comparing different organic solvents and enzymes. Digestions with Asp-N and trypsin were found highly complementary; combining the results enabled quantification of 30% more proteins than either enzyme alone. Three commercial reagents were compared for protein-level labeling. Protein identification rates were highest with iTRAQ 4-plex when compared to TMT 6-plex and iTRAQ 8-plex using higher-energy collisional dissociation on an Orbitrap Elite mass spectrometer. The compatibility of isobaric protein-level labeling with lectin-based glycoprotein enrichment was also investigated. More than 74% of lectin-bound labeled proteins were known glycoproteins, which was similar to results from unlabeled and peptide-level labeled serum samples. Finally, protein-level and peptide-level labeling strategies were compared for serum glycoprotein quantification. Isobaric protein-level labeling gave comparable identification levels and quantitative precision to peptide-level labeling.

Prognostic implications of the magnetic resonance imaging appearance in papillary renal cell carcinoma.

OBJECTIVE: To evaluate the prognostic implications of the MRI appearance and pathological features of papillary renal cell carcinoma (pRCC). METHODS: A total of 128 pRCC in 115 patients who underwent preoperative MRI were characterised in terms of pathological type (type 1 vs. type 2), MRI appearance (focal vs. infiltrative) and additional MRI features. Patients were classified on the basis of the presence or absence of metastatic disease. RESULTS: There were 65 focal type 1, 54 focal type 2 and 9 infiltrative pRCC. All infiltrative pRCC were of histopathological type 2. Renal vein thrombus was present in 89 % of infiltrative pRCC and no cases of focal pRCC. Metastatic disease was observed in 3.7 % of focal type 1, 7.5 % of focal type 2 and 75.0 % of infiltrative type 2 pRCC. Infiltrative MRI appearance was a significant predictor of metastatic disease, independent of pathological type, size and T stage (P ≤ 0.020). Among focal pRCC on MRI, pathological type 2 was not a significant predictor of metastatic disease (P = 0.648). No combination of features achieved significantly greater accuracy for predicting metastatic disease than renal vein thrombus alone (P > 0.5). CONCLUSION: Infiltrative MRI appearance and renal vein thrombus identify a subset of pathological type 2 pRCC at a significantly increased risk of metastatic disease.

Evidence for the formation of fused aromatic ring structures in an organic soil profile in the early diagenesis.

The presence of fused aromatic ring (FAR) structures in soil define the stability of the recalcitrant soil organic matter (RSOM). FAR are important skeletal features in RSOM that contribute to its extended residence time. During the early diagenesis, FAR structures are formed through condensation and polymerization of biomolecules produced during plant residue and microbial product decay. Molecular level characterization of the RSOM extracted from an organic soil profile gives important insights into the formation of FAR. Advanced solid-state 13C nuclear magnetic resonance (NMR) spectroscopy, including recoupled long-range C-H dipolar dephasing experiments on extracted humic acids (HA) showed that they contain diagenetically formed FAR different from charcoal and lignin. Peaks characteristic of FAR are observed at all depths in the soil profile, with a greater prevalence observed in the HA extracts from the clay soil layer at the bottom. In the clay soil layer, 78% of the aromatic carbon was non-protonated, and this was 2.2-fold higher than the topsoil. These data further strengthen our understanding of the humification process that could occur in early diagenesis and help explain the importance of incorporating diagenesis as an important phenomenon for long-term carbon sequestration in soil.

Mechanisms of pulmonary arterial hypertension-induced atrial fibrillation: insights from multi-scale models of the human atria.

This study aimed to use multi-scale atrial models to investigate pulmonary arterial hypertension (PAH)-induced atrial fibrillation mechanisms. The results of our computer simulations revealed that, at the single-cell level, PAH-induced remodelling led to a prolonged action potential (AP) (ΔAPD: 49.6 ms in the right atria (RA) versus 41.6 ms in the left atria (LA)) and an increased calcium transient (CaT) (ΔCaT: 7.5 × 10-2 µM in the RA versus 0.9 × 10-3 µM in the LA). Moreover, heterogeneous remodelling increased susceptibility to afterdepolarizations, particularly in the RA. At the tissue level, we observed a significant reduction in conduction velocity (CV) (ΔCV: -0.5 m s-1 in the RA versus -0.05 m s-1 in the LA), leading to a shortened wavelength in the RA, but not in the LA. Additionally, afterdepolarizations in the RA contributed to enhanced repolarization dispersion and facilitated unidirectional conduction block. Furthermore, the increased fibrosis in the RA amplified the likelihood of excitation wave breakdown and the occurrence of sustained re-entries. Our results indicated that the RA is characterized by increased susceptibility to afterdepolarizations, slow conduction, reduced wavelength and upregulated fibrosis. These findings shed light on the underlying factors that may promote atrial fibrillation in patients with PAH.

Circulating Tumor Cell Enumeration for Serial Monitoring of Treatment Outcomes for Locally Advanced Esophageal Squamous Cell Carcinoma.

We aim to reveal the clinical significance and potential usefulness of dynamic monitoring of CTCs to track therapeutic responses and improve survival for advanced ESCC patients. Peripheral blood (PB) (n = 389) and azygos vein blood (AVB) (n = 13) samplings were recruited prospectively from 88 ESCC patients undergoing curative surgery from 2017 to 2022. Longitudinal CTC enumeration was performed with epithelial (EpCAM/pan-cytokeratins/MUC1) and mesenchymal (vimentin) markers at 12 serial timepoints at any of the pre-treatment, all of the post-treatments/pre-surgery, post-surgery follow-ups for 3-year, and relapse. Longitudinal real-time CTC analysis in PB and AVB suggests more CTCs are released early at pre-surgery and 3-month post-surgery into the circulation from the CTRT group compared to the up-front surgery group. High CTC levels at pre-treatments, 1-/3-month post-surgery, unfavorable changes of CTC levels between all post-treatment/pre-surgery and 1-month or 3-month post-surgery (Hazard Ratio (HR) = 6.662, p < 0.001), were independent prognosticators for curative treatment. The unfavorable pre-surgery CTC status was independent prognostic and predictive for neoadjuvant treatment efficacy (HR = 3.652, p = 0.035). The aggressive CTC clusters were more frequently observed in AVB compared to PB. Its role as an independent prognosticator with relapse was first reported in ESCC (HR = 2.539, p = 0.068). CTC clusters and longitudinal CTC monitoring provide useful prognostic information and potential predictive biomarkers to help guide clinicians in improving disease management.

Mechanisms underlying pro-arrhythmic abnormalities arising from Pitx2-induced electrical remodelling: an in silico intersubject variability study.

BACKGROUND: Electrical remodelling as a result of the homeodomain transcription factor 2 (Pitx2)-dependent gene regulation induces atrial fibrillation (AF) with different mechanisms. The purpose of this study was to identify Pitx2-induced changes in ionic currents that cause action potential (AP) shortening and lead to triggered activity. METHODS: Populations of computational atrial AP models were developed based on AP recordings from sinus rhythm (SR) and AF patients. Models in the AF population were divided into triggered and untriggered AP groups to evaluate the relationship between each ion current regulated by Pitx2 and triggered APs. Untriggered AP models were then divided into shortened and unshortened AP groups to determine which Pitx2-dependent ion currents contribute to AP shortening. RESULTS: According to the physiological range of AP biomarkers measured experimentally, populations of 2,885 SR and 4,781 AF models out of the initial pool of 30,000 models were selected. Models in the AF population predicted AP shortening and triggered activity observed in experiments in Pitx2-induced remodelling conditions. The AF models included 925 triggered AP models, 1,412 shortened AP models and 2,444 unshortened AP models. Intersubject variability in IKs and ICaL primarily modulated variability in AP duration (APD) in all shortened and unshortened AP models, whereas intersubject variability in IK1 and SERCA mainly contributed to the variability in AP morphology in all triggered and untriggered AP models. The incidence of shortened AP was positively correlated with IKs and IK1 and was negatively correlated with INa , ICaL and SERCA, whereas the incidence of triggered AP was negatively correlated with IKs and IK1 and was positively correlated with INa , ICaL and SERCA. CONCLUSIONS: Electrical remodelling due to Pitx2 upregulation may increase the incidence of shortened AP, whereas electrical remodelling arising from Pitx2 downregulation may favor to the genesis of triggered AP.

Carbapenem resistance via the blaKPC-2 gene in Enterobacter cloacae blood culture isolate.

An Enterobacter cloacae blood culture isolate expressing carbapenem resistance via the Klebsiella pneumoniae carbapenemase KPC-2 gene is reported. To our knowledge, this is the first report of a nosocomial isolate with carbapenemase-mediated resistance causing infection in a patient from Tennessee.

PITX2 upregulation increases the risk of chronic atrial fibrillation in a dose-dependent manner by modulating IKs and ICaL -insights from human atrial modelling.

BACKGROUND: Functional analysis has shown that the paired-like homeodomain transcription factor 2 (PITX2) overexpression associated with atrial fibrillation (AF) leads to the slow delayed rectifier K+ current (IKs ) increase and the L-type Ca2+ current (ICaL ) reduction observed in isolated right atrial myocytes from chronic AF (CAF) patients. Through multiscale computational models, this study aimed to investigate the functional impact of the PITX2 overexpression on atrial electrical activity. METHODS: The well-known Courtemanche-Ramirez-Nattel (CRN) model of human atrial action potentials (APs) was updated to incorporate experimental data on alterations in IKs and ICaL due to the PITX2 overexpression. These cell models for sinus rhythm (SR) and CAF were then incorporated into homogeneous multicellular one-dimensional (1D), two-dimensional (2D), and three-dimensional (3D) tissue models. The proarrhythmic effects of the PITX2 overexpression were quantified with ion current profiles, AP morphology, AP duration (APD) restitution, conduction velocity restitution (CVR), wavelength (WL), vulnerable window (VW) for unidirectional conduction block, and minimal substrate size required to induce re-entry. Dynamic behaviors of spiral waves were characterized by measuring lifespan (LS), tip patterns and dominant frequencies. RESULTS: The IKs increase and the ICaL decrease arising from the PITX2 overexpression abbreviated APD and flattened APD restitution (APDR) curves in single cells. It reduced WL and increased CV at high excitation rates at the 1D tissue level. Although it had no effects on VW for initiating spiral waves, it decreased the minimal substrate size necessary to sustain re-entry. It also stabilized and accelerated spiral waves in 2D and 3D tissue models. CONCLUSIONS: Electrical remodeling (IKs and ICaL ) due to the PITX2 overexpression increases susceptibility to AF due to increased tissue vulnerability, abbreviated APD, shortened WL and altered CV, which, in combination, facilitate initiation and maintenance of spiral waves.

In Silico Assessment of Genetic Variation in PITX2 Reveals the Molecular Mechanisms of Calcium-Mediated Cellular Triggered Activity in Atrial Fibrillation.

Genome-wide association studies have identified genetic variants including rs13143308T in the homeobox gene Pitx2 associated with atrial fibrillation (AF) populations. However, the molecular mechanisms leading to AF due to the rs13143308T variant are poorly understood. Therefore, this study aims to investigate the effects of this variant-induced alteration in calcium handling on properties of Ca2+-transients (CaT) and spontaneous calcium-release events (SCaEs). Based on recent experimental data on variants-induced alterations in ryanodine receptor channels (RyR) and sarcoplasmic reticulum (SR) calcium ATPase 2a (SERCA2a), we incorporated modifications to calcium handling into a previously published model of the human atrial cardiomyocyte with a spatial representation of calcium wave propagation. We identified that the rs13143308T variant has a higher incidence of spontaneous membrane depolarizations and amplitude of CaT than atrial myocytes without this variant. We showed a higher density of SCaEs and content of SR Ca2+ in atrial myocytes with the rs13143308T risk variant. Further computational analysis revealed that these calcium-mediated triggered activities were mainly linked to the gain of SERCA2a function but not the RyR2 dysfunction. Taken together, our model provides a powerful tool for assessing the impact of genetic variants in Pitx2, and these simulated results enhance our understanding of the molecular mechanisms underlying Pitx2-induced AF.

Proarrhythmia in the p.Met207Val PITX2c-Linked Familial Atrial Fibrillation-Insights From Modeling.

Functional analysis has shown that the p.Met207Val mutation was linked to atrial fibrillation and caused an increase in transactivation activity of PITX2c, which caused changes in mRNA synthesis related to ionic channels and intercellular electrical coupling. We assumed that these changes were quantitatively translated to the functional level. This study aimed to investigate the potential impact of the PITX2c p.Met207Val mutation on atrial electrical activity through multiscale computational models. The well-known Courtemanche-Ramirez-Nattel (CRN) model of human atrial cell action potentials (APs) was modified to incorporate experimental data on the expected p.Met207Val mutation-induced changes in ionic channel currents (I NaL , I Ks , and I Kr ) and intercellular electrical coupling. The cell models for wild-type (WT), heterozygous (Mutant/Wild type, MT/WT), and homozygous (Mutant, MT) PITX2c cases were incorporated into homogeneous multicellular 1D and 2D tissue models. Effects of this mutation-induced remodeling were quantified as changes in AP profile, AP duration (APD) restitution, conduction velocity (CV) restitution and wavelength (WL). Temporal and spatial vulnerabilities of atrial tissue to the genesis of reentry were computed. Dynamic behaviors of re-entrant excitation waves (Life span, tip trajectory and dominant frequency) in a homogeneous 2D tissue model were characterized. Our results suggest that the PITX2c p.Met207Val mutation abbreviated atrial APD and flattened APD restitution curves. It reduced atrial CV and WL that facilitated the conduction of high rate atrial excitation waves. It increased the tissue's temporal vulnerability by increasing the vulnerable window for initiating reentry and increased the tissue spatial vulnerability by reducing the substrate size necessary to sustain reentry. In the 2D models, the mutation also stabilized and accelerated re-entrant excitation waves, leading to rapid and sustained reentry. In conclusion, electrical and structural remodeling arising from the PITX2c p.Met207Val mutation may increase atrial susceptibility to arrhythmia due to shortened APD, reduced CV and increased tissue vulnerability, which, in combination, facilitate initiation and maintenance of re-entrant excitation waves.

Investigation of silver-containing layered materials and their interactions with primary amines using solid-state 109Ag and 15N NMR spectroscopy and first principles calculations.

Silver-containing layered networks of the form [Ag(L)] (L = 4-pyridinesulfonate or p-toluenesulfonate) were treated with primary amines in different ratios. The structures of the parent supramolecular networks are well-known; however, their interactions with primary amines lead to the formation of new layered materials for which single-crystal X-ray structures cannot be obtained. Solid-state (109)Ag, (15)N, and (13)C cross-polarization magic-angle spinning (CP/MAS) NMR experiments, in combination with powder X-ray diffraction experiments and ab initio calculations, are utilized to investigate the interactions between the primary amines and the parent materials, and to propose structural models for the new materials. (109)Ag chemical shift (CS) tensor parameters are extremely sensitive to changes in silver environments; hence, (1)H-(109)Ag CP/MAS NMR experiments are used to distinguish and characterize silver sites. The combination of (109)Ag and (15)N NMR experiments on starting materials and samples prepared with both (15)N-labeled and unlabeled amines permits the accurate measurements of indirect (1)J((109)Ag,(15)N) and (1)J((109)Ag,(14)N) spin-spin coupling constants, providing further information on structure and bonding in these systems. First principles calculations of silver CS tensors and (1)J((109)Ag,(14)N) coupling constants in model complexes aid in formulating the proposed structural models for the new materials, which are largely comprised of layers of silver-diamine cations.

Anterior chamber depth measurement in phakic and pseudophakic eyes.

PURPOSE: To compare anterior chamber depth (ACD) measurements using two non-contact optical devices, Pentacam and IOLMaster, and a contact device, ultrasonic A-scan in phakic and pseudophakic eyes. METHODS: Ninety phakic and 94 pseudophakic eyes were enrolled in this prospective study. The difference between ACD measurements by the three devices was analyzed using the repeated-measures analysis of variance, and agreement among the three measurements was investigated. The accuracy of detecting the anterior lens surface of the intraocular lens (IOL) with or without blue-blocker was also assessed. RESULTS: In phakic eyes, the Pentacam measured the deepest ACD with the smallest standard deviation (3.26 +/- 0.41, 3.20 +/- 0.45, and 3.12 +/- 0.44 mm measured by Pentacam, IOLMaster, and A-scan, respectively, p < 0.001). In contrast, the Pentacam measurement of ACD had the largest standard deviation in pseudophakic eyes (4.05 +/- 0.58, 4.06 +/- 0.46, and 3.81 +/- 0.41 mm by Pentacam, IOLMaster, and A-scan, respectively, p < 0.001). The Pentacam instrument failed to correctly identify the anterior lens surface in 26.4% of IOLs without blue-blocker and in 58.5% of blue light-filtering IOLs (p = 0.016). Manual correction of the Pentacam image and subsequent ACD measurement improved the agreement between Pentacam and the other two devices. After manual adjustment, the average ACD value increased, and the standard deviation decreased significantly (4.34 +/- 0.28 mm). CONCLUSIONS: ACD measurements by Pentacam, IOLMaster, and A-scan were in better agreement in phakic eyes when compared with pseudophakic eyes. In pseudophakic eyes, the 95% limits of agreements between Pentacam and IOLMaster as well as Pentacam and A-scan were unsatisfactory. IOLs with blue-blocker might interfere with ACD measurements. However, this error can be corrected manually in the Pentacam examination.

Intraoperative ketorolac dose of 15mg versus the standard 30mg on early postoperative pain after spine surgery: A randomized, blinded, non-inferiority trial.

STUDY OBJECTIVE: The primary aim of this study is to show the non-inferiority of 15mg intraoperative dose of ketorolac as compared to the standard 30mg ketorolac by looking at the visual analog scale pain (VAS) scores 4h after an adult spine surgery. DESIGN: The study design is a prospective randomized non-inferiority clinical trial looking at non-inferiority of intraoperative 15mg ketorolac from the standard 30mg dose. SETTING: Quaternary care center. PATIENTS: 50 adult (18-65years of age) undergoing lumbar decompression spine surgery. INTERVENTIONS: Group A received a single intraoperative dose of 15mg ketorolac at the end of surgery and group B received single intraoperative dose of 30mg ketorolac. MEASUREMENTS: The primary outcome was the visual analog scale (VAS) pain scores 4h after an adult spine surgery. Secondary measures were morphine usage in the first 8 and 24h postoperatively, numeric rating scores (NRS) up to 24h, sedation, nausea, vomiting, respiratory depression, pruritus and bleeding complications. MAIN RESULTS: Intention to treat analysis showed a mean increase in 4h VAS pain score of 7.9mm (95% CI: -4.5mm to 20.4mm) in patients administered 15mg ketorolac. This difference was neither statistically (P=0.207) nor clinically significant (<18mm on VAS scale). A similar increase in the 15mg group was noted through a per protocol analysis, 6.9mm (95% CI: -6.6mm to 20.5mm, P=0.307) greater in the 15mg group. Non-inferiority of 15mg was not confirmed. No significant difference was found in secondary endpoints. CONCLUSIONS: Ketorolac 30mg intravenous was not superior to 15mg intravenous for post-operative pain management after spine surgery. However, 15mg failed to meet the pre-specified criteria for non-inferiority to the 30mg dose.