A series of potent BODIPY photosensitisers featuring tellurophene motifs at boron.

This article describes the synthesis and photophysical properties of a series of BODIPY photosensitisers that feature tellurophene motifs appended at the boron centre. These compounds were obtained via nucleophilic substitution of various F-BODIPYs with lithiated tellurophene. The synthetic scope, photophysical characteristics and photosensitisation properties are discussed. Structural modifications around the BODIPY core resulted in an eight-fold improvement in light IC50 values compared to previous designs.

Catheter Ablation for Atrial Fibrillation-Influence of Modifiable Risk Factors and Ablation Modality on Procedural Efficacy and Safety.

BACKGROUND: Modifiable lifestyle risk factors, in particular obesity and related conditions, are important drivers of atrial fibrillation (AF), impacting the severity of symptoms and influence the efficacy and safety of treatment. OBJECTIVE: The study aimed to assess the impact of modifiable lifestyle factors on the effectiveness and safety of AF ablation, and examine the procedural characteristics, efficacy, safety and cost outcomes of cryoballoon vs radiofrequency ablation, in a real-world clinical setting. METHOD: Patients undergoing catheter ablation for AF (June 2017 to December 2020) were included in this retrospective analysis. Efficacy and safety outcomes were obtained from electronic medical records and state-wide databases. The primary outcome was successful isolation of the pulmonary veins and freedom from AF without repeat ablation or ongoing antiarrhythmic therapy at 12 months. RESULTS: The study included 141 patients (mean age 60±11 years, 57% male). The average body mass index (BMI) was 29.2±5.6 kg/m2. Ablation by cryoballoon was undertaken in 59% (radiofrequency 41%). Acutely successful pulmonary vein isolation was achieved in 92%, however, only 52% (n=74) met the primary outcome (successful isolation of the pulmonary veins and freedom from AF without repeat ablation or ongoing antiarrhythmic therapy) at 12 months. Successful management of AF was more likely in patients with lower BMI (p=0.006; particularly with BMI <27 kg/m2; p=0.004) and weight (p=0.003), and in those without obstructive sleep apnoea (p=0.032). The only independent predictor of the primary outcome was BMI (ß=0.25, p=0.004). Over 75% of complications occurred in those with BMI ≥27 kg/m2. CONCLUSIONS: Catheter ablation for AF is more likely to be unsuccessful in patients with uncontrolled risk factors, particularly obesity. Risk factor optimisation may improve procedural success and reduce the risk of procedural complications.

Molecular Signature Predictive of Long-Term Liver Fibrosis Progression to Inform Antifibrotic Drug Development.

BACKGROUND & AIMS: There is a major unmet need to assess the prognostic impact of antifibrotics in clinical trials because of the slow rate of liver fibrosis progression. We aimed to develop a surrogate biomarker to predict future fibrosis progression. METHODS: A fibrosis progression signature (FPS) was defined to predict fibrosis progression within 5 years in patients with hepatitis C virus and nonalcoholic fatty liver disease (NAFLD) with no to minimal fibrosis at baseline (n = 421) and was validated in an independent NAFLD cohort (n = 78). The FPS was used to assess response to 13 candidate antifibrotics in organotypic ex vivo cultures of clinical fibrotic liver tissues (n = 78) and cenicriviroc in patients with nonalcoholic steatohepatitis enrolled in a clinical trial (n = 19, NCT02217475). A serum protein-based surrogate FPS was developed and tested in a cohort of compensated cirrhosis patients (n = 122). RESULTS: A 20-gene FPS was defined and validated in an independent NAFLD cohort (adjusted odds ratio, 10.93; area under the receiver operating characteristic curve, 0.86). Among computationally inferred fibrosis-driving FPS genes, BCL2 was confirmed as a potential pharmacologic target using clinical liver tissues. Systematic ex vivo evaluation of 13 candidate antifibrotics identified rational combination therapies based on epigallocatechin gallate, which were validated for enhanced antifibrotic effect in ex vivo culture of clinical liver tissues. In patients with nonalcoholic steatohepatitis treated with cenicriviroc, FPS modulation was associated with 1-year fibrosis improvement accompanied by suppression of the E2F pathway. Induction of the PPARα pathway was absent in patients without fibrosis improvement, suggesting a benefit of combining PPARα agonism to improve the antifibrotic efficacy of cenicriviroc. A 7-protein serum protein-based surrogate FPS was associated with the development of decompensation in cirrhosis patients. CONCLUSION: The FPS predicts long-term fibrosis progression in an etiology-agnostic manner, which can inform antifibrotic drug development.

Outcomes With Single-Site Dual-Lumen Versus Multisite Cannulation for Adults With COVID-19 Respiratory Failure Receiving Venovenous Extracorporeal Membrane Oxygenation.

OBJECTIVES: To determine whether multisite versus single-site dual-lumen (SSDL) cannulation is associated with outcomes for COVID-19 patients requiring venovenous extracorporeal membrane oxygenation (VV-ECMO). DESIGN: Retrospective analysis of the Extracorporeal Life Support Organization Registry. Propensity score matching (2:1 multisite vs SSDL) was used to control for confounders. PATIENTS: The matched cohort included 2,628 patients (1,752 multisite, 876 SSDL) from 170 centers. The mean ( sd ) age in the entire cohort was 48 (11) years, and 3,909 (71%) were male. Patients were supported with mechanical ventilation for a median (interquartile range) of 79 (113) hours before VV-ECMO support. INTERVENTIONS: None. MEASUREMENTS: The primary outcome was 90-day survival. Secondary outcomes included survival to hospital discharge, duration of ECMO support, days free of ECMO support at 90 days, and complication rates. MAIN RESULTS: There was no difference in 90-day survival (49.4 vs 48.9%, p = 0.66), survival to hospital discharge (49.8 vs 48.2%, p = 0.44), duration of ECMO support (17.9 vs 17.1 d, p = 0.82), or hospital length of stay after cannulation (28 vs 27.4 d, p = 0.37) between multisite and SSDL groups. More SSDL patients were extubated within 24 hours (4% vs 1.9%, p = 0.001). Multisite patients had higher ECMO flows at 24 hours (4.5 vs 4.1 L/min, p < 0.001) and more ECMO-free days at 90 days (3.1 vs 2.0 d, p = 0.02). SSDL patients had higher rates of pneumothorax (13.9% vs 11%, p = 0.03). Cannula site bleeding (6.4% vs 4.7%, p = 0.03), oxygenator failure (16.7 vs 13.4%, p = 0.03), and circuit clots (5.5% vs 3.4%, p = 0.02) were more frequent in multisite patients. CONCLUSIONS: In this retrospective study of COVID-19 patients requiring VV-ECMO, 90-day survival did not differ between patients treated with a multisite versus SSDL cannulation strategy and there were only modest differences in major complication rates. These findings do not support the superiority of either cannulation strategy in this setting.

BODIPYs with Chalcogenophenes at Boron: Synthesis and Properties.

Reported herein are the synthesis and characterization of BODIPYs bearing heterocycles at boron. To synthesize this series, various chalcogenophenes (furan, thiophene, selenophene, and tellurophene) were lithiated and then used as nucleophiles to attack the boron center of a parent F-BODIPY. Compounds in the series were compared with respect to their photophysical and structural properties, and trends were discussed. By virtue of the "heavy atom effect", as the mass of the heterocycle appended to the BODIPY core increases, compounds exhibit a higher singlet oxygen quantum yield. The BODIPY with tellurophene at boron exhibits the highest quantum yield (ΦΔ = 0.68) in the series and reduced emission (Φf = 0.01).

Evaluating the magnet response in deep subcutaneous implanted cardioverter defibrillator implants.

INTRODUCTION: The manufacturer of subcutaneous implantable cardioverter defibrillators (S-ICDs) acknowledges that 'deep implants' may fail to elicit a magnet response, however, does not define 'deep implant' or recommend a maximum implant depth. This study aims to systematically evaluate the effect of subcutaneous tissue depth and magnet types on evoked magnet response. METHODS: Sunshine Coast University Hospital's S-ICD cohort underwent magnet response evaluation; where bar and donut magnets were compared and the evoked magnet response was recorded in three separate zones, guided by a template. Ordinal regression (OR) models assessed the relationship between the evoked magnet response and tissue depth (TD), measured via post-implant X-Ray. The patient's ability to hear the magnet response audible tone was recorded. RESULTS: Patients (n = 39) with measurable TD (n = 30) were analyzed. The bar magnet evoked a magnet response in all zones in 53% of patients, compared with 73% of patients with the donut magnet (p = 0.18). The relationship between bar magnet response and TD showed the odds of an evoked magnet response decreased by 11% every 1 mm increase in TD (OR of 0.89, p < 0.01), whereas the donut magnet decreased by 16% per 1 mm (OR of 0.84, p < 0.01). Directly over the S-ICD was the most effective in evoking magnet response with the bar (85% of patients), and off-centre was most effective for the donut magnet (100%). BMI and Praetorian score were not significantly associated with magnet response. We found 23% of patients were unable to detect the audible tone. CONCLUSION: We observed a statistically significant association between TD and ability to evoke magnet response. The bar magnet was less reliable than the donut magnet for therapy inhibition in deep implants.

Pseudo loss of capture on 12 lead electrocardiogram in patient with an implantable cardiac defibrillator.

This case report presents a 70-year-old-male, brought in by ambulance for assessment of chest pain and presyncope, with a paced ECG showing possible non-capture following ventricular pacing spikes. This was demonstrated to be pseudo non-capture with a 12-lead electrocardiogram performed in emergency and a device interrogation demonstrating ventricular capture.

Electrogram analysis to detect cathodal and anodal capture in left ventricular cardiac resynchronization pacing leads.

AIMS: Our study analyzed cardiac electrograms (EGMs) to identify characteristics for detecting cathodal, anodal, or cathodal-anodal (simultaneous) capture in left ventricular (LV) quadripolar pacing leads of cardiac resynchronization therapy (CRT) patients. The relationship between these EGM characteristics and the electrocardiogram (ECG) was also examined. METHODS: We performed a retrospective analysis of 54 bipolar pacing configurations across nine patients with implanted CRT devices and quadripolar leads who had undergone a 12 lead ECG optimization. Three pacing tests (cathode unipolar, anode unipolar, and bipolar) per bipolar pair were performed, examining ECG and EGM morphology changes accompanying each test and any transitions of morphology or amplitude during voltage stepdown. RESULTS: During the cathode and anode unipolar pacing tests, the EGM was biphasic (negative/positive) or monophasic (positive) in 52/53 (98%), and biphasic (positive/negative) or monophasic (negative) in 50/51 (98%), respectively. During bipolar LV capture threshold testing, 30 bipolar pairs displayed a sudden increase in EGM amplitude (median 9.4 mV, interquartile range [7-14 mV]) when transitioning from cathodal-anodal capture to cathodal or anodal capture. Ninety percent of these EGM transitions had a corresponding simultaneous change in ECG, while 10% had no ECG changes. Two patients demonstrated "quad-site" capture on their quadripolar lead with multipoint pacing enabled and cathodal-anodal capture from each stimulus. CONCLUSION: EGM characteristics during LV pacing tests can reliably detect cathodal, anodal, or cathodal-anodal capture, with greater sensitivity than 12 lead ECG changes. Integration of EGM analysis into routine CRT device follow up can be performed easily and may have implications for CRT efficacy.

On the feasibility of quantifying sodium channel Nav 1.6 protein in mouse brain using targeted ultra-high-performance/electrospray ionization multiple reaction monitoring mass spectrometry.

RATIONALE: Nav 1.6 is a transmembrane voltage gated sodium channel implicated in various forms of epilepsy. Modulation of its activity in epilepsy animal models can be accomplished using inhibitors which may result in changes in its expression. There is a need to generate reliable quantitative measurements of Nav 1.6 expression in animal models. This research explores the feasibility of quantifying Nav 1.6 expression in mouse brains using targeted multiple reaction monitoring (MRM) mass spectrometry. METHODS: A combination of in silico tryptic Nav 1.6 peptides and MRM transitions were used to select target peptides. This was followed by a simple proteomic work-up including plasma membrane isolation, trypsin-based proteolysis and ultra-high-performance/electrospray ionization tandem mass spectrometry (UHPLC/ESI-MS/MS) to detect the presence of Nav 1.6 in induced HEK293 cells. The unique Nav 1.6 peptide, DSLFIPR, was selected as probe for quantifying Nav 1.6 levels in brains from C57BL/6J wild-type mice as well as two kinds of mutants including Scn8aN1768D/+ and heterozygous null Scn8a+/- mice using isotope dilution targeted mass spectrometry. RESULTS: The feasibility of using targeted MRM for quantifying Nav 1.6 expression in mice brains was demonstrated. Expression of Nav 1.6 in brains (hippocampi) from wild-type and mutant Scn8aN1768D/+ mice were found to be around 0.40 fmol/µg. Mutant null Scn8a+/- heterozygous mice, on the other hand, showed levels of 0.22 fmol/µg as expected based on this particular mutation which only generates 50% of the expression in wild-type mice. Nav 1.6-overexpressed HEK293 cells showed 3.7 fmol/µg of Nav 1.6 expression, suitable for screening new compounds for Nav 1.6 blocking activity. CONCLUSIONS: The results of the present feasibility study support the use of DSLFIPIR for quantification of Nav1.6 in brain tissues using UHPL/ESI-MS/MS.

The mechanism of tail-anchored protein insertion into the ER membrane.

Tail-anchored (TA) proteins access the secretory pathway via posttranslational insertion of their C-terminal transmembrane domain into the endoplasmic reticulum (ER). Get3 is an ATPase that delivers TA proteins to the ER by interacting with the Get1-Get2 transmembrane complex, but how Get3's nucleotide cycle drives TA protein insertion remains unclear. Here, we establish that nucleotide binding to Get3 promotes Get3-TA protein complex formation by recruiting Get3 to a chaperone that hands over TA proteins to Get3. Biochemical reconstitution and mutagenesis reveal that the Get1-Get2 complex comprises the minimal TA protein insertion machinery with functionally critical cytosolic regions. By engineering a soluble heterodimer of Get1-Get2 cytosolic domains, we uncover the mechanism of TA protein release from Get3: Get2 tethers Get3-TA protein complexes into proximity with the ATPase-dependent, substrate-releasing activity of Get1. Lastly, we show that ATP enhances Get3 dissociation from the membrane, thus freeing Get1-Get2 for new rounds of substrate insertion.

Daphnia magna microRNAs respond to nutritional stress and ageing but are not transgenerational.

Maternal effects, where the performance of offspring is determined by the condition of their mother, are widespread and may in some cases be adaptive. The crustacean Daphnia magna shows strong maternal effects: offspring size at birth and other proxies for fitness are altered when their mothers are older or when mothers have experienced dietary restriction. The mechanisms for this transgenerational transmission of maternal experience are unknown, but could include changes in epigenetic patterning. MicroRNAs (miRNAs) are regulators of gene expression that have been shown to play roles in intergenerational information transfer, and here, we test whether miRNAs are involved in D. magna maternal effects. We found that miRNAs were differentially expressed in mothers of different ages or nutritional state. We then examined miRNA expression in their eggs, their adult daughters and great granddaughters, which did not experience any treatments. The maternal (treatment) generation exhibited differential expression of miRNAs, as did their eggs, but this was reduced in adult daughters and lost by great granddaughters. Thus, miRNAs are a component of maternal provisioning, but do not appear to be the cause of transgenerational responses under these experimental conditions. MicroRNAs may act in tandem with egg provisioning (e.g., with carbohydrates or fats), and possibly other small RNAs or epigenetic modifications.

Retrospective Cohort Study Examining Reduced Intensity and Duration of Anticoagulant and Antiplatelet Therapy Following Left Atrial Appendage Occlusion with the WATCHMAN Device.

BACKGROUND: Anticoagulant and antiplatelet therapy are recommended following WATCHMAN implantation (45 days and 6 months) to reduce the risk of embolic events. These patients are often also at high risk of recurrent bleeding complications. We aimed to assess the safety of reduced duration of treatment with anticoagulant and antiplatelet therapy in the early post implant period. METHODS: This was a retrospective cohort study assessing the duration of antiplatelet and anticoagulant therapy in 47 consecutive patients following WATCHMAN implant. The primary outcome was rate of major bleeding, stroke and systemic embolic complications. The secondary endpoints were rate of device thrombus and peri-device leak >4mm as assessed by transoesophogeal echocardiography. RESULTS: Forty-seven patients were followed up for a mean of 2.4+/-1.7 years (111.4 total patient-years). The rate of stroke was 1.8/100 patient-years (two events) and the rate of major bleeding complication was 8.9/100 patient-years. Three patients had peri-device leak >4mm and no patients had device thrombus visualised. 70.2% of patients had discontinued anticoagulation at 45 days, 89.4% had discontinued dual antiplatelet therapy at 90 days. Seven patients were not on any form of anticoagulant or antiplatelet at five months. Comparison of probability of survival free from stroke by time of cessation of anticoagulant and antiplatelet therapy demonstrated no significant differences (p-value for log rank test 0.238 and 0.820). CONCLUSION: Following WATCHMAN implant shortened periods of anticoagulants and antiplatelets may be considered, particularly in the context of high bleeding risk.

The relationship between hair pulling style and quality of life.

BACKGROUND: Past research has found different associations between hair pulling (HP) variables and quality of life (QOL), especially after controlling for depression. This study examined HP styles (automatic vs focused) for their associations with QOL and whether depression accounted for these relationships. METHODS: Our sample consisted of 187 adults who met DSM-IV diagnostic criteria for trichotillomania (TTM) or chronic HP (TTM criteria except B and/or C). Clinician-administered interviews were used to diagnose TTM/HP. Participants completed self-report scales for HP style and severity, QOL, and severity of depression. RESULTS: Significant correlations were reported between QOL and the focused style of HP, as well as with interference and distress from HP. Exploratory analyses also revealed a correlation between number of HP sites and QOL. None of the correlations remained significant after controlling for severity of depression. CONCLUSIONS: These results indicate that future research on HP style also should consider the impact of co-occurring depressive symptoms. Interventions addressing both depression and HP should be considered in treatment planning to optimize outcomes.

A Virtual Multi-institution Pediatric Radiology Peer Teaching Conference Improves Knowledge of Educators.

RATIONALE AND OBJECTIVES: Medical education led by peers and near-peers has been shown to benefit both teachers and learners and can be successfully incorporated into radiology education. The authors created a virtual, multi-institution pediatric radiology conference employing peer and near-peer teaching with the goals of improving radiology knowledge and enhancing the educational experience of radiology trainees. MATERIALS AND METHODS: Two radiology residency programs implemented a common pediatric radiology curriculum and joint quarterly virtual peer teaching conference. Conferences featured short teaching sessions led by six to ten radiology trainees and were facilitated by attending pediatric radiologists. Knowledge assessments (KA) consisting of multiple-choice questions inspired by conference learning objectives were sent to peer educators before the conference (pre-conference), directly after the conference (immediate post-conference), and three months after the conference (delayed post-conference). Surveys were distributed to peer educators immediately after conferences to assess conference reception and solicit feedback. Quantitative data was analyzed using ANOVA, Kruskal-Wallis test, and post-hoc Tukey HSD test. RESULTS: Four conferences featured 33 peer educators consisting primarily of first-year (60.6 %), second-year (18.2 %), and third-year (15.2 %) radiology residents. Compared to pre-conference scores, immediate post-conference scores were significantly increased (HSD 13, p = 0.02) and delayed post-conference scores were increased without statistical significance (HSD 5.8, p = 0.29). Almost all survey respondents perceived the conferences as helpful, well-organized, and effective in teaching pediatric radiology. A majority of participants expressed interest in participating in future peer teaching radiology conferences. CONCLUSION: A virtual pediatric radiology peer and near-peer teaching conference held between two radiology residencies improved short-term radiology knowledge of educators and was highly received.

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.